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72-Gene Classifier for Predicting Prognosis of ER-positive and Node-negative Breast
Cancer Patients Using Formalin-Fixed Paraffin-Embedded Tumor Tissues
01 Dec 2013 07:00 am
Publication date: Available online 22 November 2013
Source:Clinical Breast Cancer
Author(s): Minako Nishio , Yasuto Naoi , Ryo Tsunashima , Chiaki Nakauchi , Naofumi Kagara , Masafumi
Shimoda , Atsushi Shimomura , Naomi Maruyama , Kenzo Shimazu , Seung Jin Kim , Shinzaburo Noguchi
Background The 95-gene classifier (95-GC) can classify estrogen receptor(ER)-positive and node-negative
breast cancer patients into those with low and high risk of relapse with an accuracy similar to that of 21-GC
(Oncotype DX). Since 95-GC uses RNA from fresh-frozen (FF) tumor tissues, we herein attempted to
develop the gene classifier which is applicable to RNA from formalin-fixed paraffin-embedded (FFPE) tumor
tissues. Patients and Methods Twenty-five paired FF and FFPE tumor tissues were subjected to DNA
microarray for gene expression analysis. From the 95 probes included in the 95-GC, 72 were selected for
construction of the gene classifier for FFPE tumor tissues because the gene expression detected by these
72 probes was well preserved in the FFPE tumor tissues. Results 72-GC was constructed with these 72
probes for the training set comprising 549 FF tumor tissues and validated with 434 FF tumor tissues
(relapse-free survival at 10 years was 91% for the low-risk and 74% for the high-risk group (P = 3.74e-7).
Predictive capability of 72-GC for prognosis was found to be comparable to that of 95-GC. The 25 paired FF
and FFPE tumor tissues from each of 25 patients were classified into the same risk group by 72-GC for 23
patients (92% concordance). 72-GC using the FFPE tumor tissues showed that the prognosis for the lowrisk group was significantly (P = 0.007) better than for the high-risk group. Conclusions 72-GC is
comparable to 95-GC in terms of accuracy of prognosis prediction, and may be effective for FFPE tumor
tissues.
Teaser
Seventy two-gene classifier (72-GC) was developed for recurrence risk prediction for estrogen receptorpositive and node-negative breast cancer patients. 72-GC could differentiate the high-risk from the low-risk
patients with a high statistical significance, and is considered to be applicable to formalin-fixed paraffinembedded (FFPE) tumor tissues since the results of 72-GC on fresh frozen tissues and FFPE tissues
showed a high concordance.
A Comparison of Epidemiology, Biology, and Prognosis of Inflammatory Breast Cancer in
Japanese and US Populations
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Akina Natori , Naoki Hayashi , Kumiko Soejima , Gautam A. Deshpande , Osamu Takahashi ,
Massimo Cristofanilli , Naoto T. Ueno , Hideko Yamauchi
Background The epidemiology of inflammatory breast cancer (IBC) in East Asia has not been fully
investigated. We hypothesized the epidemiologic factors associated with IBC in Japanese populations are
different from other populations. To determine this, we conducted a comparison study assessing multiple
clinically relevant risk factors. Patients and Methods Patients diagnosed with IBC at St. Luke's International
Hospital (SLIH) in Tokyo, Japan, and at the University of Texas MD Anderson Cancer Center (MDA) in
Houston, Texas, from 2003 to 2009 were identified via the electronic medical records. Stage IV patients
were excluded. Epidemiological, biological, and overall survival (OS) data were collected and compared.
After all patient populations were combined, Cox proportional hazard regression analysis was performed.
Results Twenty-two patients at SLIH and 384 patients at MDA were identified. No differences were found
for IBC between SLIH and MDA regarding age at diagnosis ( P = .898), hormone receptor status ( P
= .144), overexpression of HER2 ( P = .136), or OS ( P = .323), however, BMI ( P < .01) and nuclear
grade (NG) ( P < .01) in Japanese patients were lower than those of US patients. Cox proportional
hazard regression analysis revealed ER status and race were associated with OS. Conclusion Despite the
small number of patients enrolled, IBC in a Japanese population demonstrated lower BMI and lower NG
than IBC in a US population with no difference in survival. ER status and race were prognostic factors when
the 2 populations were combined. To more robustly define IBC among East Asian individuals, we have
started to register Japanese patients with an International IBC Registry.
This is a comparative study of inflammatory breast cancer in a Japanese population (n = 22) vs. a
population in the United States (US) (n = 384) to determine whether there are differences in epidemiologic
factors and clinical features. Body mass index (BMI) and nuclear grade were significantly different between
the 2 populations. Estrogen receptor (ER) status and race were prognostic factors when populations in
Japan and US were combined.
A Randomized Phase II Trial Investigating the Effect of Platelet Function Inhibition on
Circulating Tumor Cells in Patients With Metastatic Breast Cancer
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Ryan P. Roop , Michael J. Naughton , Catherine Van Poznak , Jochen G. Schneider , Philip E.
Lammers , Timothy J. Pluard , Farley Johnson , Charles S. Eby , Katherine N. Weilbaecher
Background Blockade of platelet activation and aggregation can inhibit metastasis in preclinical models and
is associated with cancer prevention. To test whether disruption of platelet function with clopidogrel and
aspirin would decrease the number of circulating tumor cells (CTCs) in patients with metastatic breast
cancer, a randomized phase II study was performed. Methods Patients with metastatic breast cancer who
were not currently receiving cytotoxic chemotherapy were eligible. Patients were randomized to receive
either clopidogrel and aspirin or to a control group receiving no treatment. Phlebotomy was performed at
baseline, at 2 and 4 weeks, and monthly thereafter to obtain specimens to assess CTC, platelet
aggregation, and thrombin activity. The primary end point was the proportion of patients with detectable
CTCs at 1 month. Results Forty-eight patients were enrolled and 42 were evaluable at 1 month. Baseline
CTC numbers were ≥ 5 in 13% and ≥ 1 in 65% of patients. Despite adequate platelet function inhibition in
the treatment group, the proportion of patients with detectable CTCs was similar between the
clopidogrel/aspirin and control groups at baseline ( P = .21) and 4 weeks ( P = .75), showing no treatment
effect. Measured endogenous thrombin potential did not correlate with CTC number. No bleeding-related
serious adverse events (SAEs) occurred. Conclusion The baseline CTC numbers were lower than
expected, decreasing the ability to detect an impact of platelet inhibition on CTCs. Clopidogrel and aspirin
were well tolerated. Future studies evaluating the potential therapeutic role of antiplatelet therapy in breast
cancer remain of interest, and they may be informed by these results.
A randomized phase II clinical trial that investigated the effect of platelet inhibition on circulating tumor cells
(CTCs) in patients with metastatic breast cancer was performed. The negative results from this translational
study highlight the challenges of biomarker-driven trials and provide data pertinent to designing future
related studies.
A mammosphere formation RNAi screen reveals that ATG4A promotes a breast cancer
stem-like phenotype
14 Nov 2013 12:00 am
IntroductionBreast cancer stem cells are suspected to be responsible for tumour recurrence, metastasis
formation as well as chemoresistance. Consequently, great efforts have been made to understand the
molecular mechanisms underlying cancer stem cell maintenance. In order to study these rare cells in-vitro,
they are typically enriched via mammosphere culture. Here we developed a mammosphere-based negative
selection shRNAi screening system suitable to analyse the involvement of thousands of genes in the
survival of cells with cancer stem cell properties. Methods: We describe a sub-population expressing the
stem-like marker CD44+/CD24-/low in SUM149 that were enriched in mammospheres. To identify genes
functionally involved in the maintenance of the sub-population with cancer stem cell properties, we targeted
over 5000 genes by RNAi and tested their ability to grow as mammospheres. The identified candidate
ATG4A was validated in mammosphere and soft agar colony formation assays. Further, we evaluated the
influence of ATG4A expression on the sub-population expressing the stem-like marker CD44+/CD24low.
Next, the tumorigenic potential of SUM149 after up- or down-regulation of ATG4A was examined by
xenograft experiments. Results: Using this method, Jak-STAT as well as cytokine signalling were identified
to be involved in mammosphere formation. Furthermore, the autophagy regulator ATG4A was found to be
essential for the maintenance of a sub-population with cancer stem cell properties and to regulate breast
cancer cell tumourigenicity in vivo. Conclusion: In summary, we present a high-throughput screening
system to identify genes involved in cancer stem cell maintenance and demonstrate its utility by means of
ATG4A.
A multicenter phase I–II study of docetaxel plus epirubicin plus bevacizumab as first-line
treatment in women with HER2-negative metastatic breast cancer
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): K. Tryfonidis , I. Boukovinas , N. Xenidis , C. Christophyllakis , P. Papakotoulas , E. Politaki , N.
Malamos , A. Polyzos , S. Kakolyris , V. Georgoulias , D. Mavroudis
Purpose To assess the efficacy and toxicity of docetaxel (D) plus epirubicin (E) in combination with
bevacizumab (B) [DEB regimen] as front-line treatment in patients with metastatic breast cancer (MBC).
Patients and methods Women with previously untreated HER2-negative MBC received B (15 mg/kg), E
(75 mg/m2) and D (75 mg/m2) with prophylactic G-CSF support every 3 weeks (q3w) for up to 9 cycles
followed by B (15 mg/kg q3w) until disease progression. Primary endpoint was the overall response rate
(ORR). Circulating tumor cells (CTCs) were evaluated using the CellSearch system at different time points
during therapy. Results Eighty-three women were enrolled with median age 62 years, performance status
0–1 in 93%, triple negative disease in 12% and liver metastases in 47%. In an intention to treat analysis,
complete response was achieved in 13 (15.7%) and partial response in 42 (50.6%) (overall response rate
66.3%; 95% CI 56.09–76.44%). The median time to progression was 20.1 months and the 1-year overall
survival rate 82.3%. Grade 3–4 neutropenia occurred in 37%, febrile neutropenia in 10%, anemia in 4%,
thrombocytopenia in 2% and diarrhea in 2% of patients. There were two deaths possibly related to study
treatment (sigmoid perforation n = 1; sudden death n = 1). Moreover, one patient developed pulmonary
embolism and another one myocardial infarction while on treatment. Although DEB administration
significantly reduced the proportion of patients presenting CTCs, the detection of ≥5 or ≥1 CTCs before
treatment initiation was significantly associated with worse progression-free survival ( p = 0.001 and p
= 0.004) and overall survival ( p = 0.001 and p = 0.027), respectively. Conclusions The DEB regimen is a
very active but also potentially toxic combination in MBC. Detection of CTCs before treatment is associated
with worse outcome. Clinicaltrials.gov NCT00705315
A new scarless oncoplastic breast-conserving surgery: Modified round block technique
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Hisamitsu Zaha , Mai Onomura , Mikiko Unesoko
Round block technique (RBT) is often utilized in breast-conserving surgery, but has problems of late-onset
scar widening and changes in the shape or the position of the areola. We have modified RBT (MRBT) to
resolve those problems. A circumferential incision was made without excision of the periareolar skin, and
subcutaneous dissection was extended to the entire breast. The wound could be widened and moved onto
the distant tumor by application of a wound retractor. Partial mastectomy was then performed under direct
vision. The wound was easily closed without tension. Forty breast cancer patients were treated with MRBT.
The median distance between the nipple and the tumor was 5.2 cm, and the median areolar size was
2.8 cm. Cosmetic results were satisfactory with minimal scar formation. There were neither subsequent
changes in the shape nor the position of the areola. MRBT is a useful oncoplastic technique in patients with
small areolae, and/or when the tumor location is distant from the nipple.
A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and
trastuzumab in patients with HER2-positive solid tumors
19 Nov 2013 12:00 am
IntroductionTrastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing
breast and gastric cancers. However, patients may develop resistance through downstream signaling via
the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the
safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to
determine whether the combination with trastuzumab could inhibit compensatory signaling. Methods:
Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment
consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using
either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule.
Results: A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum
tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and
135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial.
The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash,
consistent with prior experience; one death unrelated to treatment was reported. There was one complete
response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients
had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinibbased therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206.
Conclusions: Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is
associated with clinical activity, supporting further investigation.Trial registration: ClinicalTrials.gov;
identifier: NCT00963547.
A review of the management of ductal carcinoma in situ following breast conserving surgery
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): M.M. Boxer , G.P. Delaney , B.H. Chua
Ductal carcinoma in situ (DCIS) is a heterogeneous, pre-malignant disease accounting for 10–20% of all
new breast tumours. Evidence shows a statistically significant local control benefit for adjuvant radiotherapy
(RT) following breast conserving surgery (BCS) for all patients. The baseline recurrence risk of individual
patients varies according to clinical-pathological criteria and in selected patients, omission of RT may be
considered, following a discussion with the patient. The role of adjuvant endocrine therapy remains
uncertain. Ongoing studies are attempting to define subgroups of patients who are at sufficiently low risk of
recurrence that RT may be safely omitted; investigating RT techniques and dose fractionation schedules;
and defining the role of endocrine therapy. Future directions in the management of patients with DCIS will
include investigation of prognostic and predictive biomarkers to inform individualised therapy tailored to the
risk of recurrence.
Accelerated partial breast irradiation using 3D conformal radiotherapy: Toxicity and
cosmetic outcome
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): M. Gatti , R. Ponzone , S. Bresciani , R. Panaia , F. Kubatzki , F. Maggiorotto , M.R. Di Virgilio ,
A. Salatino , B. Baiotto , F. Montemurro , M. Stasi , P. Gabriele
Purpose The aim of this paper is to analyze the incidence of acute and late toxicity and cosmetic outcome
in breast cancer patients submitted to breast conserving surgery and three-dimensional conformal
radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI). Methods and materials 84
patients were treated with 3D-CRT for APBI. This technique was assessed in patients with low risk stage I
breast cancer enrolled from September 2005 to July 2011. The prescribed dose was 34/38.5 Gy delivered
in 10 fractions twice daily over 5 consecutive days. Four to five no-coplanar 6 MV beams were used. In all
CT scans Gross Tumor Volume (GTV) was defined around the surgical clips. A 1.5 cm margin was added
by defining a Clinical Target Volume (CTV). A margin of 1 cm was added to CTV to define the planning
target volume (PTV). The dose–volume constraints were followed in accordance with the NSABP/RTOG
protocol. Late toxicity was evaluated according to the RTOG grading schema. The cosmetic assessment
was performed using the Harvard scale. Results Median patient age was 66 years (range 51–87). Median
follow-up was 36.5 months (range 13–83). The overall incidence of acute skin toxicities was 46.4% for
grade 1 and 1% for grade 2. The incidence of late toxicity was 16.7% for grade 1, 2.4% for grade 2 and
3.6% for grade 3. No grade 4 toxicity was observed. The most pronounced grade 2 late toxicity was
telangiectasia, developed in three patients. Cosmetics results were excellent for 52%, good for 42%, fair for
5% and poor for 1% of the patients. There was no statistical correlation between toxicity rates and
prescribed doses ( p = 0.33) or irradiated volume ( p = 0.45). Conclusions APBI using 3D-CRT is
technically feasible with very low acute and late toxicity. Long-term results are needed to assess its efficacy
in reducing the incidence of breast relapse.
Acknowledgement of reviewers 2013
29 Nov 2013 12:00 am
Adeno-associated virus-mediated expression of recombinant CBD–HepII polypeptide of
human fibronectin inhibits metastasis of breast cancer
28 Nov 2013 12:00 am
Abstract
CH50, a recombinant CBD–HepII polypeptide of human fibronectin, was shown to suppress tumor
metastasis in murine hepatocarcinoma and melanoma models. However, the effect of CH50 on human
cancer cells is still not clear. Here we evaluated the efficiency of CH50 delivered by recombinant adenoassociated virus (rAAV) vector for breast cancer treatment. Infection of the two human breast cancer cell
line MDA-MB-231 and MDA-MB-468 with a rAAV2 vector encoding CH50 resulted in secretion of soluble
CH50. In vitro rAAV-CH50 transduction inhibited adhesion to ECM molecules, and transwell migration and
invasion of breast cancer cells induced by fibronectin. In both breast cancer cells, rAAV-CH50 targeted
αVβ3 signaling, namely inhibited the expression of αVβ3, the activation of FAK, the upregulation of cdc2, and
the production and activation of MMP-9 by ECM molecules stimulation. rAAV-mediated tail vein transfusion
and stable expression of CH50 in the liver resulted in the long-term presence of CH50 in sera of nude mice.
Sustained CH50 expression mediated by rAAV vector suppressed the growth and spontaneous metastasis
of orthotopic breast cancer xenograft, experimental metastasis of circulating breast cancer cells, and
improved the long-term survival of breast tumor-bearing mice. These findings suggest for the first time that
rAAV-CH50 gene therapy may present a novel and promising strategy for treatment against metastatic
breast cancer.
Adjuvant treatment of premenopausal women with endocrine-responsive early breast
cancer: Design of the TEXT and SOFT trials
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Meredith M. Regan , Olivia Pagani , Gini F. Fleming , Barbara A. Walley , Karen N. Price ,
Manuela Rabaglio , Rudolf Maibach , Barbara Ruepp , Alan S. Coates , Aron Goldhirsch , Marco Colleoni ,
Richard D. Gelber , Prudence A. Francis
Objectives In 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT
randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal
women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for
women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain
premenopausal and are treated with tamoxifen? Methods TEXT randomized patients to receive
exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS,
tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization. Results TEXT and
SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease
and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13
additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS
events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in
2011 specified analyses based on chronological time and median follow-up. To assess the AI question,
exemestane + OFS versus tamoxifen + OFS, a combined analysis of TEXT and SOFT became the primary
analysis ( n = 4717). The OFS question became the primary analysis from SOFT, assessing the unique
comparison of tamoxifen + OFS versus tamoxifen alone ( n = 2045). The first reports are anticipated in
mid- and late-2014. Conclusions We present the original designs of TEXT and SOFT and adaptations to
ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for
premenopausal women with endocrine-responsive breast cancer. Trial Registration TEXT: Clinicaltrials.gov
NCT00066703 SOFT: Clinicaltrials.gov NCT00066690
Age related risk of myelodysplastic syndrome and acute myeloid leukemia among breast
cancer survivors
22 Nov 2013 12:00 am
Abstract
Increased incidence of acute myeloid leukemia (AML) has been identified among breast cancer (BC)
survivors but measurement has not included myelodysplastic syndrome (MDS). Our aim is to identify age
and stage related MDS/AML incidence post BC diagnosis. We used the 2001–2009 Surveillance,
Epidemiology, and end results (SEER) database to identify first primary stage I–III BC patients. Subsequent
MDS or AML diagnosis was identified with observed rates compared to expected MDS/AML incidence in
the general population. Age adjusted observed/expected rate ratios and 95 % confidence intervals (CI)
were calculated. The unadjusted all age and stage MDS/AML incidence rate was .15 % (470/306,691) with
a progressively higher rate by age (age 20–49 = .11, age 50–64 = .14, age 65+ =.21, and age 75+ =.18)
and stage (stage I = .11, stage II = .18, and stage III = .22). Compared to the general population, BC
patients had a 2.75-fold [95 % CI 2.51–3.00] increased relative risk of being diagnosed with MDS/AML.
Young age survivors had highest relative risk [age 20–49: relative risk (RR) = 10.60 (95 % CI 8.57–12.93);
age 50–64: 5.96 (95 % CI 5.13, 6.88); age 65–74 year-olds: 2.94 (95 % CI 2.45, 3.50); and age ≥75 yearolds: 1.28 (95 % CI 1.03, 1.56)]. Separately MDS relative risk was highest among young women [30.44
(95 % CI = 19.63, 44.62)]. MDS/AML relative risk increased from 1.87 to 5.66 for stage I–III. Conclusions:
Myelodysplastic syndrome and acute myeloid leukemia relative risk is substantially elevated among breast
cancer survivors especially those aged 20-49. While the actual number is small, MDS/AML is a serious
disease. More research is needed to identify the treatments that put women at risk and find less
leukemogenic options, especially for young women.
Angiogenic factors in relation to clinical effect in a phase II trial of weekly paclitaxel
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): B.K. Linderholm , E. Lidbrink , E. Tallroth , Z. Einbeigi , H. Svensson , A. von Wachenfeldt , B.
Norberg , L. Carlsson , M.E. Olsson , J. Bergh , N. Wilking , T. Hatschek
Background Several anticancer agents including paclitaxel have an inhibitory effect on angiogenesis. Aims
To compare the overall response rate and time to progression with changes in circulating angiogenic factors
during palliative treatment with weekly paclitaxel. Material and methods Patients with metastatic BC, ECOG
0–2, received weekly paclitaxel, concomitant with trastuzumab if HER2+ BC ( n = 7). Circulating vascular
endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were determined at base-line
and before start of new course. Results Fifty-five of 63 included patients were evaluable. The overall
response rate including stable disease ≥24 weeks (CR + PD + SD) was obtained in 25 of the evaluable
patients (45%). The median time to progression (TTP) was 5.3 months and overall survival (OS) 16.7
months. Patients with triple negative breast cancer (TNBC) showed a trend towards higher base-line VEGF
compared with hormone receptor positive or HER2+ tumours and had shorter TTP. Significant differences
in VEGF and bFGF levels at 12 weeks were found between patients with longer versus shorter TTP (VEGF:
p = 0.046, bFGF: p = 0.005) and between patients gaining versus lacking clinical benefit (VEGF: p = 0.05,
bFGF: p = 0.02). Conclusions The clinical utility of circulating VEGF may be a useful tool for monitoring
treatment efficacy.
Another review on triple negative breast cancer. Are we on the right way towards the exit
from the labyrinth?
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Roxana Chiorean , Cornelia Braicu , Ioana Berindan-Neagoe
Triple negative breast cancer is a heterogeneous group of tumors, lacking the expression of estrogen,
progesterone and HER-2 receptors. As frequency, it accounts about 15–20% of all breast cancers.
Although in the last years there was a “boom” in publishing over this issue, multiple molecular classifications
being elaborated, “the triple negative breast cancer odyssey ” is still far away from ending, as the
complicated molecular pathways of pathogenesis and drug resistance mechanisms remain yet insufficiently
explored. The aim of this review is presentation of molecular signatures that could predict outcome and
drug resistance in triple negative breast cancer.
Antiangiogenic therapy in HER2 positive metastatic breast cancer patients : a case series
01 Dec 2013 07:00 am
Publication date: Available online 21 November 2013
Source:Clinical Breast Cancer
Author(s): Olivia Le Saux , Benoît You , Gilles Freyer
Are text message reminders an effective intervention to improve uptake of breast
screening? A randomised controlled trial
30 Nov 2013 12:02 pm
Publication date: 29 November 2013
Source:The Lancet, Volume 382, Supplement 3
Author(s): Robert Kerrison , Heema Shukla , Deborah Cunningham , Oyinlola Oyebode , Ellis Friedman
Background Breast cancer is a major public health concern in the UK, one accounting for 16% of all cancer
incidences and 7% of all cancer deaths. Fortunately, the natural history of this malignancy can be
beneficially changed through the early detection and treatment of benign and malignant breast disease,
which have been enabled by mammographic screening techniques. However, the success of screening
programmes depends on their ability to attract the at-risk population, as well as the analytical specificity and
sensitivity of the screening test itself. The NHS Breast Screening Programme attracts about three-quarters
of the invited population each year. In 2010, all but one region reported a triennial coverage of more than
75%; London was the exception, reporting a regional coverage of 69%. London consistently fails to meet
the national target. Missed appointments are a primary cause of inefficiency in health-care delivery, with
adverse clinical implications for the non-attending patient and substantial monetary costs to the health
service. To ensure the future success of the breast screening programme, development of strategies to
improve uptake of hard-to-reach patients is imperative. Research has shown that receiving an appointment
reminder by text message has been successful in reducing non-attendance in other areas of health care;
the same might be true for breast screening. Our primary aim was to establish whether text message
reminders can significantly improve the uptake of breast screening by women on an intention-to-treat basis
in the London Borough of Hillingdon. Our secondary aim was to assess whether text message reminders
are an effective intervention for improvement of uptake of breast screening by hard-to-reach patients such
as women living in deprived areas and women of black and minority ethnic groups. Methods We undertook
a single-blind, randomised controlled trial to assess the effectiveness of sending a text message
appointment reminder 48 h before a patient's first breast screening appointment to improve uptake of the
programme by prevalent women aged 47–53 years in the London Borough of Hillingdon. 1640 women
without a history of breast screening, implant, or bilateral mastectomy were included in the study and
randomly assigned (1:1) to either the control (n=833) or intervention (n=807) group. Women in the control
group were invited to screening but received no reminder for their appointment, whereas women in the
intervention group received a text message reminder 48 h in advance. All women received an information
letter about the study with their invitation from the West of London Breast Screening Service. Patients were
not told whether they would be receiving a text message reminder or not. iPlato Patient Care Messaging
was used to deliver text message reminders. This trial is registered with ClinicalTrials.gov , NCT01977599 .
Findings Women in the text message reminder group were significantly more likely (odds ratio 1·32, 95% CI
1·12–1·53; p=0·0092) to attend their first breast screening appointment (69% uptake) than women in the
control group (63% uptake). Of the 807 women assigned to the text message reminder group, only 316
(39%) had a valid mobile telephone number recorded on the GP Clinical System and were subsequently
able to receive a text message reminder. Of the 316 patients who did receive a text message reminder, 252
(80%) attended breast screening. No adverse events were reported. These are preliminary data of an
ongoing trial expected to be completed in September, 2013. Full results including deprivation and ethnic
origin data will be available for the conference. Interpretation Receipt of a text message reminder 48 h
before a scheduled breast screening appointment significantly improves uptake. To ensure that the benefits
of text message reminders are achieved, work is needed to improve patient mobile records. Funding
Research funded by Imperial College Healthcare Charity.
Assessing breast cancer risk models in Marin County, a population with high rates of
delayed childbirth
01 Dec 2013 07:00 am
Publication date: Available online 22 November 2013
Source:Clinical Breast Cancer
Author(s): Mark Powell , Farid Jamshidian , Kate Cheyne , Joanne Nititham , LeeAnn Prebil , Rochelle
Ereman
Introduction This study was designed to compare the BCRAT (Gail), IBIS (Tyrer-Cuzick), and BRCAPRO
breast cancer risk assessment models using data from the Marin Women's Study, a cohort of women within
Marin County, California, with high rates of breast cancer, nulliparity, and delayed childbirth. Existing
models have not been well-validated in these high risk populations. Methods Discrimination was assessed
by AUC and calibration by estimating the ratio of expected to observed (E/O) cases. Models were assessed
using data from 12,843 participants of whom 203 developed cancer in a 5-year period. All tests of statistical
significance were two-sided. Results The IBIS model achieved an AUC of 0.65 (0.61-0.68 95% CI)
compared to 0.62 (0.59-0.66 95% CI) for BCRAT and 0.60 (0.56-0.63 95% CI) for BRCAPRO. The
estimated E/O ratios for the models were 1.08 (0.95-1.25 95% CI), 0.81 (0.71-0.93 95% CI), and 0.59 (0.520.68 95% CI) respectively. In women with age of first birth over 30, the AUC for the IBIS, BCRAT, and
BRCAPRO models was 0.69 (0.62-0.75 95% CI), 0.63 (0.56-0.70 95% CI), and 0.62 (0.56-0.68 95% CI)
and E/O ratios 1.15 (0.89-1.47 95% CI), 0.81 (0.63-1.05 95% CI), and 0.53 (0.41-0.68 95% CI) respectively.
Conclusions The IBIS model was well calibrated for the high risk Marin mammography population and
demonstrated the best calibration of the three models in nulliparous women. IBIS also achieved the highest
overall discrimination and displayed superior discrimination in women with age of first birth over 30.
Teaser
Breast cancer risk models have been found to be of limited value for women at high risk. We looked at three
existing models in 12,843 women of the Marin Women’s Study where rates of nulliparity and delayed
childbirth are very high. The IBIS model performed best, while the most widely used Gail model significantly
underestimated risk in these women.
Assessing racial/ethnic disparities in chemotherapy treatment among breast cancer patients
in context of changing treatment guidelines
22 Nov 2013 12:00 am
Abstract
Conflicting study results with regards to racial/ethnic disparities in chemotherapy use among breast cancer
patients may be due to the different sample populations, treatment data sources, and treatment eligibility
definitions used. This study examined chemotherapy disparity in the context of changing treatment
guidelines and explored factors that may help explain treatment differences observed. The data come from
a population-based study that included interview and medical record data (including state cancer registry)
from non-Hispanic (nH) White, nH Black, and Hispanic breast cancer patients diagnosed in 2005–2008.
Logistic regression using model-based standardization was used to estimate age-adjusted risk differences
and multivariate analysis was conducted to identify explanatory factors of the differences. Per the
2005/2006 National Comprehensive Cancer Network (NCCN) guidelines, minority patients appeared more
likely than nH White patients to receive a chemotherapy recommendation (0.87 vs 0.75, p = 0.003). When
eligibility was determined per the 2007 guidelines, there was no disparity because under these guidelines,
nH White patients were more likely than minority patients to have tumors that no longer required
chemotherapy. There was evidence that chemotherapy advances for breast cancer patients are
implemented in the clinical setting well ahead of NCCN guidelines. Finally, among eligible patients,
chemotherapy recommendation was very high and virtually always accepted and received, with no
disparities found at these points of clinical care. The findings suggest that an evaluation of guidelineadherent chemotherapy treatment patterns must carefully consider the definition of treatment eligibility,
given ongoing changes in treatment guidelines and early uptake of new diagnostic tools and treatments.
Assessing the Impact of Neoadjuvant Chemotherapy on the Management of the Breast and
Axilla in Breast Cancer
01 Dec 2013 07:00 am
Publication date: Available online 21 October 2013
Source:Clinical Breast Cancer
Author(s): Terri Patricia McVeigh , Dhafir Al-Azawi , David E. Kearney , Carmel Malone , Karl J. Sweeney ,
Kevin Barry , Ray McLaughlin , Maccon Keane , Michael J. Kerin
Background Nodal status is a sensitive prognostic indicator in breast cancer. Axillary metastases may be an
indication for neoadjuvant systemic therapy. The aims of this study were to compare pathologic response
rates to neoadjuvant chemotherapy (NAC) in the breast and axilla across different molecular subtypes of
breast cancer and to compare the predictive value of axillary assessment before and after chemotherapy in
determining final nodal status in this cohort of patients. Patients and Methods The cohort comprised
patients undergoing NAC from 2003 to November 2012. Data regarding patient and tumor characteristics,
management, and outcomes were obtained from a prospectively maintained database and analyzed using
PASW Statistics, version 18 (SPSS Inc, Chicago, IL). Results Two hundred two cancers were identified in
196 patients. One hundred thirty-one (65%) diagnostic axillary procedures were performed, 105 (80%)
before NAC, of which 93 (89%) were positive. In 28 (30%), downstaging was noted before NAC. Human
epidermal growth factor receptor 2 (HER2) subtypes had the highest rate of complete pathologic response
(n = 11 [61%]) and negative axillary clearance (AXCn) (n = 11 [69%]). Of 177 AXCns, 68 (38%) were
negative before NAC. Conclusion AXCn in patients undergoing NAC remains controversial. HER2 subtypes
are less likely to have axillary involvement after NAC and may demand different management.
The surgical management of the axillae in patients with breast cancer in whom disease burden is modified
by neoadjuvant chemotherapy is controversial. This observational study examines patients undergoing
neoadjuvant chemotherapy and surgery for breast cancer over a ten-year period. Her2-overexpressing
subtypes were less likely to have residual axillary disease and more likely to have complete pathological
response in the tumour.
Assessing the level of breast cancer awareness among recently diagnosed patients in Ain
Shams University Hospital
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Mohamed El-Shinawi , AlMoatazBellah Youssef , Mohammad Alsara , Mohamed K. Aly ,
Mohamed Mostafa , Ahmed Yehia , Marc Hurlbert , Reda Abd El-Tawab , Mona M. Mohamed
Breast cancer is the leading female malignancy among Egyptian women. The majority of Egyptian breast
cancer patients present at late stages of the disease with a large tumor size compared to Western
countries. Low breast cancer awareness, social and cultural factors were suggested to play crucial role in
late presentation of breast cancer among Egyptians. The aim of our present study is to establish a
questionnaire-based survey that can assess levels of breast cancer awareness among Egyptians. Patients
enrolled were interviewed and answered 60 questions related to knowledge, symptoms, risk factors,
prevention and management options of breast cancer. We evaluated our interactions with breast cancer
patients and defined the level of awareness gained from education and culture of Egyptian women. Our
results described that Egyptian breast cancer patients lack knowledge about their illness and condition. The
lowest levels of awareness were related to age, education and culture. We concluded that breast cancer
public awareness and women education programs covering factors identified in our study is warranted
among Egyptian population. Overview Objective To assess breast cancer awareness among recently
diagnosed breast cancer Egyptian patients. Subjects and methods Among 289 interviewed breast cancer
patients we enrolled 45 patients who fulfilled the study inclusion criteria. Participants were asked to answer
a validated 60-item questionnaire that inquires about socio-demographic characteristics, knowledge of
breast cancer symptoms, risk factors, symptoms, prevention, general management and willingness to
participate in awareness campaigns. The average of interview time was about 45 min, depending on
patient's age and education level. Results The mean age of included patients was 48.2 ± 10.19 years.
Geographical distribution revealed that 66.7% patients were from Cairo and the rest were from other
governorates, including Aswan, Sharqia, Mansora, Qena, Kalyobia, Elminya and Sohag. Among
interviewed patients 85% were non-working housewives, 42.2% of them were illiterate. Questions about
knowledge of breast cancer revealed that 53.33% of patients knew an acquaintance with breast cancer;
however, they spent a median time of 3 months to seek medical advice after recognizing the first symptom
with a delay range between a month and 72 months. We found that 73% of the participants presented to a
physician with the same first recognized symptom and 75.6% didn't think of cancer then as a possible
diagnosis. Total breast cancer knowledge scores had an average of 13.3 (out of 35 knowledge points), with
93% of the patients recognizing “painless breast mass” as a breast cancer symptom and 44% only
recognized the concept of breast self examination. Interestingly, 61.4% identified breastfeeding as a risk
factor for breast cancer, 60% did not recognize mammography as an early detection method, and 57.7%
agreed that clinical breast examination (CBE) is important for early detection. Regarding management, 75%
said breast cancer was potentially curable and 60% said medical care could be helpful regardless the age
of presentation. Conclusion Egyptian breast cancer patients knew little about their condition. Less
awareness was related to age and education level. Low knowledge of risk factors, early detection and
management of breast cancer should be addressed by designing patient education programs, where less
educated patients are supported by health care professionals to participate in the management of breast
cancer. Moreover, we found that 67% and 97% of enrolled breast cancer patients were willing as well to
participate in spreading awareness among their community and among their own families, respectively.
Association of Positive EBAG9 Immunoreactivity With Unfavorable Prognosis in Breast
Cancer Patients Treated With Tamoxifen
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Nobuhiro Ijichi , Takashi Shigekawa , Kazuhiro Ikeda , Toshiaki Miyazaki , Kuniko Horie-Inoue ,
Chikako Shimizu , Shigehira Saji , Kenjiro Aogi , Hitoshi Tsuda , Akihiko Osaki , Toshiaki Saeki , Satoshi
Inoue
Introduction Breast cancer is primarily a hormone-dependent tumor that is regulated by the status of the
estrogen and progesterone receptors. We previously identified EBAG9 as an estrogen-responsive gene in
MCF-7 human breast carcinoma cells. Upregulation of EBAG9 expression has been observed in several
malignant tumors such as advanced breast cancers, indicating that EBAG9 might contribute to tumor
progression. Patients and Methods In the present study, we generated a monoclonal antibody against
EBAG9, and then performed immunohistochemical analysis of EBAG9 expression in specimens obtained
from breast cancer patients treated with tamoxifen as an adjuvant therapy. Results EBAG9
immunoreactivity was detected in the cytoplasm of breast cancer cells and was significantly elevated in
breast cancer samples from patients who relapsed during or after adjuvant tamoxifen treatment. Positive
EBAG9 immunoreactivity was significantly correlated with poor patient prognosis. Conclusion These results
suggest that EBAG9 expression in tumor regions is associated with an unfavorable prognosis in breast
cancer patients treated with tamoxifen.
Acquired tamoxifen resistance in breast cancer has not been fully understood. We examined
immunohistochemical staining of estrogen receptor-binding fragment associated antigen 9 (EBAG9) in 100
breast cancer specimens excised from patients at surgery before tamoxifen treatment. Positive EBAG9
immunoreactivity (> 50% of the total cells) was significantly associated with decreased disease-free
survival. EBAG9 expression will be a prognostic factor in breast cancer patients treated with adjuvant
tamoxifen therapy.
Attitudes of UK breast and plastic surgeons to lipomodelling in breast surgery
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Joanna Skillman , Joseph Hardwicke , Lisa Whisker , David England
Lipomodelling is increasingly popular in breast surgery. The aims of this study were to elucidate the
prevalence and practice of lipomodelling by surgeons in the UK and explore their attitudes and reservations
to the technique. Methodology A study specific questionnaire was circulated to Breast and Plastic Surgeons
with an interest in breast reconstruction. Results 228 surgeons responded. Lipomodelling in breast surgery
was performed by 48/70 (69%) plastic surgeons and 17/158 (11%) breast surgeons ( p < 0.0001). Most
attitudes were positive with over 60% surgeons agreeing that the benefits of lipomodelling outweighed the
risks. Critics cited the lack of prospective, long term follow up data (16%) in addition to oncological (4%),
radiological (8%) and efficacy (4%) concerns. Conclusions Lipomodelling is performed by the majority of
plastic surgeons who responded. Despite oncological, radiological and efficacy concerns, the majority of
surgeons feel that the benefits of lipomodelling in the breast outweigh the risks.
Axillary Lymph Node Status and Prognosis in Multifocal and Multicentric Breast Carcinoma
18 Nov 2013 05:54 am
According to tumor-node-metastasis classification, tumor size should be based only on the largest tumor for
multifocal and multicentric (MFMC) carcinomas. We estimated tumor size of MFMC carcinoma using either
largest dimension of the largest tumor (dominant tumor size) or sum of the largest dimension of all tumors
(aggregate tumor size), and compared the risk of axillary lymph node metastasis and prognosis between
MFMC and unifocal carcinoma. We retrospectively reviewed the file records of 3,616 patients with MFMC
(258 patients, 7.1%) and unifocal (3,358 patients) carcinoma. In T1 and T2 tumor subgroups, using
dominant (p = 0.001 and p < 0.001) and aggregate (p = 0.017 and p = 0.004) tumor size axilla-positivity
ratio was significantly higher in MFMC carcinoma compared with unifocal carcinoma. In stage I and II
disease classified according to either dominant or aggregate tumor size, there was no significant survival
difference between MFMC and unifocal carcinoma patients. In patients with stage III disease by dominant
and aggregate tumor size disease-free survival was significantly worse in MFMC carcinoma compared with
unifocal carcinoma (p = 0.036 and p = 0.041); multifocality and multicentricity had no independent
prognostic significance (p = 0.074 and p = 0.079). The risk of axillary metastasis in MFMC carcinoma was
higher than unifocal carcinoma, regardless of the method employed for tumor size estimation. MFMC
carcinoma staged according to either dominant or aggregate tumor size had similar survival with unifocal
carcinoma. We recommend using the largest dimension of the largest tumor in estimation of tumor size for
MFMC carcinoma.
Axillary ultrasound for preoperative nodal staging in breast cancer patients: Is it of added
value?
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): R.J. Schipper , L.M. van Roozendaal , B. de Vries , R.M. Pijnappel , R.G.H. Beets-Tan , M.B.I.
Lobbes , M.L. Smidt
Background New insights show that an axillary lymph node dissection (ALND) may not always be indicated
for metastases detected by ultrasound (pathologically proven). This study investigated whether axillary
ultrasound accurately predicts pN0, pN1 and pN2–pN3 status. Methods Data were retrospectively collected
from all consecutive patients with invasive breast cancer who underwent (primary) surgery between 2008
and 2012. False negative percentages and negative predictive values (NPVs) for sonographic nodal staging
were calculated for all patients and again for cT1–2 patients treated by breast conserving therapy (BCT).
Results A total of 577 axillary ultrasounds were included. After negative ultrasound findings (cN0),
pathology showed pN2–pN3 disease in 4.4% of these cases, with an NPV of 95.5% (93.4–97.1%). When
cN1 (1–3 suspicious nodes) was predicted, pathology showed pN2–pN3 disease in 41.2%, with an NPV of
58.5% (44.2–71.5%). In the subgroup of patients with cT1–2 breast cancer that were treated by BCT,
pathology showed pN2–pN3 disease in 2.3% after negative ultrasound findings (cN0), with an NPV of
97.7% (94.9–99.0%). When cN1 was predicted ( n = 12), pathology showed pN2–pN3 disease in 50.0%,
with an NPV of 50.0% (22.3–77.9%). A direct ALND was performed in these 12 cN1 cases; pathology
showed six patients with pN1 (three patients with one and three with two macrometastases) and six with
pN2–pN3 disease (4, 5, 11, 13, 16 or 22 macrometastases, respectively). Conclusion In conclusion, a
negative axillary ultrasound generally excludes the presence of pN2–pN3 disease. An axillary ultrasound
cannot accurately differentiate between pN1 and pN2–pN3. It could be argued that the standard
performance of an axillary ultrasound in breast cancer patients is questionable; multidisciplinary discussion
could guide decisions on the use of axillary ultrasound for the individual patient.
Benign Papillomas Without Atypia Diagnosed on Core Needle Biopsy: Experience From a
Single Institution and Proposed Criteria for Excision
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Anupma Nayak , Selin Carkaci , Michael Z. Gilcrease , Ping Liu , Lavinia P. Middleton , Roland L.
Bassett Jr. , Jinxia Zhang , Hong Zhang , Robin L. Coyne , Therese B. Bevers , Nour Sneige , Lei Huo
Background The management of benign papilloma (BP) without atypia identified on breast core needle
biopsy (CNB) is controversial. In this study, we determined the upgrade rate to malignancy for BPs without
atypia diagnosed on CNB and whether there are factors associated with upgrade. Methods Through our
pathology database search, we studied 80 BPs without atypia identified on CNB from 80 patients from 1997
to 2010, including 30 lesions that had undergone excision and 50 lesions that had undergone ≥ 2 years of
radiologic follow-up. Associations between surgery or upgrade to malignancy and clinical, radiologic, and
pathologic features were analyzed. Results Mass lesions, lesions sampled by ultrasound-guided CNB, and
palpable lesions were associated with surgical excision. All 3 upgraded cases were mass lesions sampled
by ultrasound-guided CNB. None of the lesions with radiologic follow-up only were upgraded to malignancy.
The overall upgrade rate was 3.8%. None of the clinical, radiologic, or histologic features were predictive of
upgrade. Conclusion Because the majority of patients can be safely managed with radiologic surveillance, a
selective approach for surgical excision is recommended. Our proposed criteria for excision include
pathologic/radiologic discordance or sampling by ultrasound-guided CNB without vacuum assistance when
the patient is symptomatic or lesion size is ≥ 1.5 cm.
The management of benign papilloma (BP) without atypia identified on breast core needle biopsy (CNB) is
controversial. We describe the clinicopathologic features of 80 patients with such lesions in our institution,
with an upgrade rate to malignancy of 3.8%. A multidisciplinary approach to select patients for surgical
excision is recommended.
Bias in breast cancer research in the screening era
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Brian Cox , Mary J. Sneyd
Screening aims to detect breast cancer at an earlier stage than would occur if symptoms developed. The
characteristics of breast cancer that are detectable at screening depend on both the physical properties of
the screening test and specific anatomical features of breast cancer. As a result, breast cancer detected by
screening is a select subset of all breast cancer existing in the population. Therefore, biomedical, clinical
and epidemiological research into breast cancer using populations with access to screening can result in
major bias. The biases, with examples, are explained.
Biological therapies in breast cancer: Common toxicities and management strategies
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Romualdo Barroso-Sousa , Iuri A. Santana , Laura Testa , Débora de Melo Gagliato , Max S.
Mano
In recent years, a number of new molecules – commonly known as biological therapies – have been
approved or are in late stages of regulatory evaluation for the treatment of advanced breast cancer. These
innovative compounds have improved treatment efficacy and have probably contributed to the increase in
survival length observed in some breast cancer subtypes. However, these agents are not deprived of
toxicity, which can impair quality of life and may occasionally be life-threatening. In this article, we reviewed
the most common toxicities associated with these drugs and provided a number of practical
recommendations on their optimal clinical management.
Breast Boost Using Noninvasive Image-Guided Breast Brachytherapy vs. External Beam: A
2:1 Matched-Pair Analysis
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Kara Lynne Leonard , Jaroslaw T. Hepel , John R. Styczynski , Jessica R. Hiatt , Thomas A.
DiPetrillo , David E. Wazer
Background To compare clinical outcomes and toxicity in patients treated with NIBB boost with those in
patients treated with external beam (EB) boost. Patients and Methods Women with early stage breast
cancer treated with WBI and NIBB boost were identified. Control subjects treated with EB boost identified
as the best possible match with respect to age, stage, chemotherapy use, and fractionation were chosen for
a 2:1 comparison. Acute toxicity, late toxicity, and oncologic outcomes were reviewed. The McNemar
nonparametric test was used to evaluate marginal homogeneity between matched pairs. Results One
hundred forty-one patients were included in the analysis: 47 patients treated with NIBB boost and 94
matched control subjects treated with EB boost (electron, n = 93) or 3-D conformal radiation (n = 1). Grade
2+ desquamation developed in 18 patients (39%) treated with NIBB boost and in 49 patients (52%) treated
with EB boost ( P = .07). Breast size, electron energy, and fractionation predicted for acute desquamation (
P &lt; .0001, P &lt; .001, and P = .006). Median follow-up was 13.6 months. One patient (2%) who
received NIBB had Grade 2+ skin/subcutaneous fibrosis 15 months after completion of treatment. Among
those treated with EB, 9 patients (9.5%) developed Grade 2+ subcutaneous fibrosis, and 1 patient had
recurrent cellulitis. There was statistically significantly less combined skin/subcutaneous toxicity in those
treated with NIBB than in those treated with EB ( P = .046). Conclusion NIBB boost is associated with
favorable short-term clinical outcomes compared with EB.
Outcomes were compared for 47 women with breast cancer undergoing breast-conserving therapy with
whole breast irradiation (WBI) and noninvasive breast brachytherapy (NIBB) boost and 94 matched control
subjects treated with WBI and electron beam (EB) boost. Acute desquamation occurred in 39% and 52% of
patients, respectively. There was less skin/subcutaneous toxicity in those treated with NIBB than in those
treated with EB ( P = .046). NIBB compares favorably with EB.
Breast Cancer Survivors' Self-Reported Needs and Preferences of Survivorship Care
22 Nov 2013 04:46 am
Breast Conserving Surgery versus Mastectomy for Early-Stage Breast Cancer: Could
Patient Choice Lead to an Inferior Outcome?
22 Nov 2013 04:46 am
Breast cancer arising at a young age: Do we need to define a cut-off?
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Hatem A. Azim Jr. , Hamdy Azim
Breast cancer risk factors and disease origins linked - Medical News Today
25 Nov 2013 09:55 am
Breast cancer susceptibility risk associations and heterogeneity by E-cadherin tumor tissue
expression
30 Nov 2013 12:00 am
Abstract
E-cadherin is involved in cell–cell adhesion and epithelial-to-mesenchymal transitions. In cancers, loss or
inactivation of E-cadherin is associated with epithelial cell proliferation and invasion. Here, we sought to
determine, if risk associations for 18 breast cancer susceptibility single nucleotide polymorphisms (SNPs)
differed by E-cadherin tumor tissue expression in the Polish Breast Cancer Study (PBCS), using data on
1,347 invasive breast cancer cases and 2,366 controls. E-cadherin expression (low/high) was assessed
using immunohistochemical staining of tumor tissue microarrays. Replication data on 2,006 cases and
6,714 controls from the Study of Epidemiology and Risk Factors in Cancer Heredity was used to follow-up
promising findings from PBCS. In PBCS, we found the rs11249433 SNP at the 1p11.2 locus to be more
strongly associated with risk of E-cadherin low tumors (OR = 1.30, 95 % CI = 1.08–1.56) than with Ecadherin high tumors [OR = 1.06, 95 % CI = 0.95–1.18; case-only p-heterogeneity (p-het) = 0.05]. Findings
in PBCS for rs11249433 were replicated in SEARCH. Combined analyses of the two datasets for SNP
rs11249433 revealed significant heterogeneity by E-cadherin expression (combined case-only phet = 0.004). Further, among carriers of rs11249433, the highest risk was seen for E-cadherin low tumors
that were ER-positive and of lobular histology. Our results in two independent data sets suggest that
rs11249433, which is located between the NOTCH2 andFCGR1B genes within the 1p11.2 locus, is more
strongly associated with risk of breast tumors with low or absent E-cadherin expression, and suggest that
evaluation of E-cadherin tumor tissue expression may be useful in clarifying breast cancer risk factor
associations.
CD24 polymorphisms can not predict pathologic complete response to anthracycline- and
taxane-based neoadjuvant chemotherapy in breast cancer
01 Dec 2013 07:00 am
Publication date: Available online 22 November 2013
Source:Clinical Breast Cancer
Author(s): Xin Zhou
In this study, single-nucleotide polymorphisms (SNPs) of CD24 polymorphisms were genotyped by
Sequenom MassArray®iPLEX GOLD System in 170 patients with breast cancer and a total of 120 patients
with histologically confirmed T2-4N0-2 M0 breast cancer were recruited to
docetaxel/doxorubicin/cyclophosphamide (TAC) as neoadjuvant chemotherapy. Data were analyzed via
Chi-square test, and logistic regression analysis. There were no significant correlation between CD24
polymorphisms and any of the clinicopathologic variables, and no significant associations were found
between either of the polymorphisms and CD24 protein expression. The RR and the pCR rate were 68.8%
and 27.1% in the patients with CD24 rs3838646 CA/CA genotype, and 87.5% and 20.8% in CD24 CA/Del
&amp; Del/Del genotype. There were no statistically significant differences between the CA/CA group and
the Del allele group. The RR was 85.4% in the patients with CD24 rs52812045 C/C genotype, and 63.9% in
CD24 C/T &amp; T/T genotype. There was statistically significant difference between the C/C group and the
T allele group (OR=0.28; 95% CI 0.11-0.73, P = 0.01). The pCR rate was 29.2% in the patients with CD24
rs52812045 C/C genotype and 23.6% in CD24 C/T &amp; T/T genotype. There was no statistically
significant differences between the C/C group and the T allele group. In a multivariate analysis, there was
no correlation between CD24 rs3838646 or rs52812045 genotype and pCR..In conclusion, CD24
rs3838646 and rs52812045 polymorphism could not predict the pathologic complete response to
anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer..Additional larger studies are
required to confirm this finding.
CD44 is prognostic for overall survival in the NCI randomized trial on breast conservation
with 25 year follow-up
26 Nov 2013 12:00 am
Abstract
CD44 is a transmembrane glycoprotein involved in numerous cellular functions, including cell adhesion and
extracellular matrix interactions. It is known to be functionally diverse, with alternative splice variants
increasingly implicated as a marker for tumor-initiating stem cells associated with poor prognosis. Here, we
evaluate CD44 as a potential marker of long-term breast cancer outcomes. Tissue specimens from patients
treated on the National Cancer Institute 79-C-0111 randomized trial of breast conservation versus
mastectomy between 1979 and 1987 were collected, and immunohistochemistry was performed using the
standard isoform of CD44. Specimens were correlated with patient characteristics and outcomes. Survival
analysis was performed using the log rank test. Fifty-one patients had evaluable tumor sections and
available long-term clinical follow up data at a median follow up of 25.7 years. Significant predictors of OS
were tumor size (median OFS 25.4 years for ≤2 cm vs. 7.5 years for >2 cm, p = 0.001), nodal status
(median OS 17.2 years for node-negative patients vs. 6.7 years for node positive patients, p = 0.017), and
CD44 expression (median OS 18.9 years for CD44 positive patients vs. 8.6 years for CD44 negative
patients, p = 0.049). There was a trend toward increased PFS for patients with CD44 positive tumors
(median PFS 17.9 vs. 4.3 years, p = 0.17), but this did not reach statistical significance. These findings
illustrate the potential utility of CD44 as a prognostic marker for early stage breast cancer. Subgroup
analysis in patients with lymph node involvement revealed CD44 positivity to be most strongly associated
with increased survival, suggesting a potential role of CD44 in decision making for axillary management. As
there is increasing interest in CD44 as a therapeutic target in ongoing clinical trials, the results of this study
suggest additional investigation regarding the role CD44 in breast cancer is warranted.
CYP2D6 genotype in relation to hot flashes as tamoxifen side effect in a Dutch cohort of the
tamoxifen exemestane adjuvant multinational (TEAM) trial
22 Nov 2013 12:00 am
Abstract
In tamoxifen-treated breast cancer patients the occurrence of hot flashes may be associated with effective
estrogen receptor antagonism dependent on genetic variations of metabolic enzymes and the estrogen
receptor. Early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane
within the tamoxifen exemestane adjuvant multinational trial were genotyped for five CYP2D6 alleles.
CYP2D6 genotypes and phenotypes were related to the occurrence of hot flashes as adverse event during
the first year of tamoxifen use (primary aim) and the time to the occurrence of hot flashes as AE during the
complete time on tamoxifen (secondary aim). In addition, exploratory analyses on 22 genetic variants of
other metabolic enzymes and two common polymorphisms in the estrogen receptor-1 were performed. No
association was found between the CYP2D6 genotype/phenotype or any other genetic variant and hot
flashes during the first year. Only higher age was related to a lower incidence of hot flashes in the first year
(adjusted odds ratio 0.94, 95 % CI 0.92–0.96; p < 0.001). The ESR1 PvuII XbaI CG haplotype was
associated with the time to the occurrence of hot flashes during the complete time on tamoxifen (CG/CG vs.
CG/other + other/other: adjusted hazard ratio 0.49, 95 % CI 0.25–0.97; p = 0.04). In conclusion, the
CYP2D6 genotypes and phenotypes were not associated with the occurrence of hot flashes. Common
polymorphisms in the estrogen receptor-1 might predict hot flashes as common tamoxifen side effect,
although this finding needs replication.
Challenging single- and multi-probesets gene expression signatures of pathological
complete response to neoadjuvant chemotherapy in breast cancer: Experience of the
REMAGUS 02 phase II trial
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): F. Valet , P. de Cremoux , F. Spyratos , N. Servant , M.E. Dujaric , D. Gentien , J. Lehmann-Che
, V. Scott , B. Sigal-Zafrani , M.C. Mathieu , P. Bertheau , J.M. Guinebretière , J.Y. Pierga , S. Delaloge , S.
Giacchetti , E. Brain , O. Tembo , M. Marty , B. Asselain
This study was designed to identify predictive signatures of pathological complete response (pCR) in breast
cancer treated by taxane-based regimen, using clinicopathological variables and transcriptomic data
(Affymetrix Hgu133 Plus 2.0 devices). The REMAGUS 02 trial ( n = 153,training set) and the publicly
available M.D. Anderson data set ( n = 133, validation set) were used. A re-sampling method was applied.
All predictive models were defined using logistic regression and their classification performances were
tested through Area Under the Curve (AUC) estimation. A stable set of 42 probesets (31 genes)
differentiate pCR or no pCR samples. Single-or 2-probesets signatures, mainly related to ER pathway, were
equally predictive of pCR with AUC greater then 0.80. Models including probesets associated with ESR1,
MAPT, CA12 or PIGH presented good classification performances. When clinical variables were entered
into the model, only CA12 and PIGH, remained informative ( p = 0.05 and p = 0.005) showing that a
combination of a few genes provided robust and reliable prediction of pCR.
Characterizing the heterogeneity of triple-negative breast cancers using microdissected
normal ductal epithelium and RNA-sequencing
29 Nov 2013 12:00 am
Abstract
Triple-negative breast cancers (TNBCs) are a heterogeneous set of tumors defined by an absence of
actionable therapeutic targets (ER, PR, and HER-2). Microdissected normal ductal epithelium from healthy
volunteers represents a novel comparator to reveal insights into TNBC heterogeneity and to inform drug
development. Using RNA-sequencing data from our institution and The Cancer Genome Atlas (TCGA) we
compared the transcriptomes of 94 TNBCs, 20 microdissected normal breast tissues from healthy
volunteers from the Susan G. Komen for the Cure Tissue Bank, and 10 histologically normal tissues
adjacent to tumor. Pathway analysis comparing TNBCs to optimized normal controls of microdissected
normal epithelium versus classic controls composed of adjacent normal tissue revealed distinct molecular
signatures. Differential gene expression of TNBC compared with normal comparators demonstrated
important findings for TNBC-specific clinical trials testing targeted agents; lack of over-expression for
negative studies and over-expression in studies with drug activity. Next, by comparing each individual
TNBC to the set of microdissected normals, we demonstrate that TNBC heterogeneity is attributable to
transcriptional chaos, is associated with non-silent DNA mutational load, and explains transcriptional
heterogeneity in addition to known molecular subtypes. Finally, chaos analysis identified 146 core genes
dysregulated in >90 % of TNBCs revealing an over-expressed central network. In conclusion, use of
microdissected normal ductal epithelium from healthy volunteers enables an optimized approach for
studying TNBC and uncovers biological heterogeneity mediated by transcriptional chaos.
Circulating tumor cells and response to neoadjuvant paclitaxel and HER2-targeted therapy:
A sub-study from the NeoALTTO phase III trial
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Hatem A. Azim Jr. , Francoise Rothé , Claudia Monica Aura , Malcolm Bavington , Marion
Maetens , Ghizlaine Rouas , Geraldine Gebhart , Cristina Gamez , Holger Eidtmann , José Baselga ,
Martine Piccart-Gebhart , Catherine Ellis , Peter Vuylsteke , Hervé Cure , Julien Domont , Antonella Ferro ,
Juan Carlos Toral-Peña , Evandro de Azambuja , Christos Sotiriou , Serena Di Cosimo , Michail Ignatiadis
Background The role of circulating tumor cells (CTCs) in HER2-positive breast cancer patients receiving
neoadjuvant therapy is unclear. Patients &amp; methods We describe the CTC detection rate, HER2
phenotyping and pathological complete response (pCR) in patients enrolled in the NeoALTTO phase III trial.
Participation in the CTC sub-study was optional. CTC evaluation was performed centrally using
CellSearch® at baseline, week 2 and week 18 (prior to surgery) of neoadjuvant therapy. Results Samples
for CTC analysis were available for 51/455 patients randomized. At baseline, week 2 and week 18, we
detected ≥1 CTC/22.5 ml in 5/46 (11%), 4/41 (10%), and 5/31 (16%) patients and ≥1 HER2-positive
CTC/22.5 ml in 2/46 (4%), 2/41 (5%), and 3/31 (10%) patients with evaluable samples, respectively. 11/51
patients (21%) had ≥1 CTC/22.5 ml in at least one time point. pCR was observed in 3/11 (27.3%) versus
17/40 (42.5%) patients with detectable and no detectable CTCs, respectively ( p = 0.36). No pCR was
observed in the three patients with detectable HER2-positive CTCs prior to surgery. Conclusion Numerically
lower pCR rates were observed in patients with detectable CTCs, yet the study remains underpowered. A
meta-analysis of CTC studies in this setting is warranted.
Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer
receiving trastuzumab-based therapy
01 Dec 2013 07:00 am
Publication date: Available online 7 November 2013
Source:The Breast
Author(s): Valentina Rossi , Franco Nolè , Stefania Redana , Laura Adamoli , Rossella Martinello , Gaetano
Aurilio , Elena Verri , Anna Sapino , Giuseppe Viale , Massimo Aglietta , Filippo Montemurro
Background Five to 10% of women with newly diagnosed breast cancer have synchronous metastases ( de
novo stage IV). A further 20% will develop metastases during follow-up (recurring stage IV). We compared
the clinical outcomes of women with HER2-positive metastatic breast cancer (MBC) receiving first-line
trastuzumab-based therapy according to type of metastatic presentation. Patients and methods
Retrospective analysis of 331 MBC patients receiving first-line trastuzumab-based treatment. Response
rates (RR) were compared by the chi-square test. Time-to progression (TTP) and overall survival (OS)
curves were compared by the log-rank test. Cox-proportional hazards models were used to study predictors
of PFS and OS, including the type of metastatic presentation. Results Seventy-seven patients (23%) had de
novo stage IV disease. Forty-six of these patients underwent surgery of the primary (“ de novo /surgery”).
Response rates to first-line trastuzumab-based therapy and median progression-free survival did not differ
in patients with “recurring”, “ de novo /surgery” and “ de novo ” without surgery (“ de novo /no surgery) stage
IV breast cancer. However, women with “ de novo /surgery” stage IV breast cancer had the longest median
OS (60 months), and those with “ de novo /no surgery” stage IV breast cancer the shortest (26 months). For
women with recurring metastatic breast cancer median OS was 40 months (overall log-rank test, p
&lt; 0.01). Multivariate analysis confirmed these findings. Conclusion Our analysis shows that response
rates and PFS to first-line trastuzumab-based therapy do not differ significantly between de novo and
recurring stage IV, HER2 positive breast cancer. The observed difference in OS favoring women with de
novo stage IV disease submitted to surgery of the primary tumor could be the result of a selection bias.
Teaser
Microabstract: We compared the clinical outcomes of patients with HER2-positive breast cancer according
to type of metastatic presentation (“ de novo ” vs recurring stage IV). Response to treatment and clinical
outcomes were similar in the two groups of patients. However, receipt of surgery of the primary tumor
identified a subset patients with de novo stage IV disease with a particularly favorable outcome.
Combo of plant nutrients kills breast cancer cells - Medical News Today
26 Nov 2013 09:53 am
Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormonereceptor-positive advanced breast cancer following progression/recurrence after endocrine
therapy: a network meta-analysis
24 Nov 2013 12:00 am
Abstract
Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or
first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial
targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head
comparisons of these treatment options, an indirect comparison can inform treatment choice. This network
meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and
500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The
reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that
formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed
by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the
local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus
exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible
interval [CrI] 0.38–0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45–0.77). Similar results were obtained in an
alternate comparison based on central review of disease progression from BOLERO-2 with the data from
the other studies (HR = 0.40; 95 % CrI 0.31–0.51 and HR = 0.50; 95 % CrI 0.37–0.67, respectively), and in
a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI
0.38–0.58 and HR = 0.55; 95 % CrI 0.40–0.76, respectively). These results suggest that everolimus plus
exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who
progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor.
Comparing the outcome between multicentric and multifocal breast cancer: what is the
impact on survival, and is there a role for guideline-adherent adjuvant therapy? A
retrospective multicenter cohort study of 8,935 patients
21 Nov 2013 12:00 am
Abstract
Multifocal (MF) and multicentric (MC) breast cancers have been comprehensively studied, and their
outcomes have been compared with unifocal (UF) tumors. We attempted to answer the following questions:
(1) Does MF/MC presentation influence the outcome concerning BC mortality?, (2) Is there an impact of
guideline-adherent adjuvant treatment in these BC subtypes?, and (3)What is the influence of guideline
violations concerning surgery (breast-conserving surgery versus mastectomy) on the survival of MF/MC BC
patients? Between 1992 and 2008, we retrospectively analyzed 8,935 breast cancer patients from 17
participating breast cancer centers within the BRENDA study group. Of 8,935 breast cancer patients, 7,073
(79.2 %) had UF tumors, 1,398 (15.6 %) had MF tumors, and 464 (5.2 %) had MC tumors. RFS was
significantly worse for MF/MC BC patients compared to patients with UF tumors (MF p = 0.007;
MCp = 0.019). OAS was significantly worse for MC patients but not for MF patients compared to patients
with UF tumors (MF p = 0.321; MC p = 0.001). Guideline adherence was significantly lower in patients with
MF (n = 580; 41.5 %) and MC (n = 204; 44.0 %) compared to patients with UF (n = 3,871; 54.7 %)
(p < 0.001) tumors. Guideline violations were associated with a highly significant deterioration in survival
throughout all subgroups except for MC, with respect to RFS and OAS. For 100 %-guideline-adherent
patients, we could not find any significant differences in RFS and OAS after adjusting by nodal status,
grade, and tumor size. Furthermore, we could not find any significant differences in RFS and OAS in
patients with MF or MC stratified by breast-conserving therapy (BCT lumpectomy and radiation therapy)
and mastectomy. There is a strong association between improved RFS and OAS in patients with MF/MZ
BC. There are no significant differences in RFS and OAS for patients with breast-conserving therapy or
mastectomy.
Comparison of molecular subtype distribution in triple-negative inflammatory and noninflammatory breast cancers
25 Nov 2013 12:00 am
IntroductionBecause of its high rate of metastasis, inflammatory breast cancer (IBC) has a poor prognosis
compared with non-inflammatory types of breast cancer (non-IBC). In a recent study, Lehmann and
colleagues identified seven subtypes of triple-negative breast cancer (TNBC). We hypothesized that the
distribution of TNBC subtypes differs between TN-IBC and TN-non-IBC. We determined the subtypes and
compared clinical outcomes by subtype in TN-IBC and TN-non-IBC patients. Methods: We determined
TNBC subtypes in a TNBC cohort from the World IBC Consortium for which IBC status was known (39
cases of TN-IBC; 49 cases of TN-non-IBC). We then determined the associations between TNBC subtypes
and IBC status and compared clinical outcomes between TNBC subtypes. Results: We found the seven
subtypes exist in both TN-IBC and TN-non-IBC. We found no association between TNBC subtype and IBC
status (P = 0.47). TNBC subtype did not predict recurrence-free survival. IBC status was not a significant
predictor of recurrence-free or overall survival in the TNBC cohort. Conclusions: Our data show that, like
TN-non-IBC, TN-IBC is a heterogeneous disease. Although clinical characteristics differ significantly
between IBC and non-IBC, no unique IBC-specific TNBC subtypes were identified by mRNA gene
expression profiles of the tumor. Studies are needed to identify the subtle molecular or microenvironmental
differences that contribute to the differing clinical behaviors between TN-IBC and TN-non-IBC.
Contralateral prophylactic mastectomy in an Asian population: A single institution review
01 Dec 2013 07:00 am
Publication date: Available online 23 November 2013
Source:The Breast
Author(s): Yirong Sim , Veronique Kiak Mien Tan , Gay Hui Ho , Chow Yin Wong , Preetha Madhukumar ,
Benita Kiat Tee Tan , Wei Sean Yong , Yvonne Ying Ru Ng , Kong Wee Ong
Background Contralateral prophylactic mastectomy (CPM) removes the non-diseased breast in women who
have unilateral breast cancer. This reduces the incidence of contralateral breast cancer, and potentially
improves survival in high risk patients. Such surgical risk-reduction strategy is increasingly being adopted in
the United States, despite a decreasing incidence of contralateral breast cancer. The use of CPM in an
Asian population is yet unknown. We present the first Asian report on CPM rates and trends in Singapore,
the country with the highest incidence of breast cancer in Asia. Methods A retrospective review of all
patients who had breast cancer surgery from 2001 to 2010 at the largest healthcare system in Singapore
was performed. Patient demographics and tumour characteristics were analysed with regards to type of
surgery performed. Factors associated with CPM were identified. Results From 2001 to 2010, a total of
5130 patients underwent oncological breast surgery. A decreasing trend of mastectomies (82.7%–70.8%),
an upward trend of breast conserving surgery (BCS) (17.3%–29.2%) and an increasing trend in CPM
(0.46%–1.25%) is observed. Patients who opted for CPM are likely to be younger (48.4 ± 9.4 years),
married (60%), parous (56.7%), with no family history of breast/ovarian cancer (66.7%), and diagnosed at
an earlier stage. The rate of synchronous occult breast malignancy was found to be 10% ( n = 30), and
these were in patients who were of a low cancer-risk profile. Conclusions This retrospective study reflects
an increasing incidence of breast cancer in Singapore, with a decrease in mastectomies, and an increase in
BCS and CPM rates, similar to Western data. Similar to Western populations, the Asian woman who opts
for CPM is likely to be young and have an earlier stage of breast cancer. In contrast, the Asian woman is
likely to have no family history of breast or ovarian cancers. Commonly cited reasons for increased CPM
rates such as the increased availability of genetic counselling and pre-operative MRI evaluation, along with
wide use of reconstruction, do not feature as dominant factors in our population, suggesting that the Asian
patients may have different considerations when electing for CPM.
Cytochrome P450 E1 (CYP2E1) regulates the response to oxidative stress and migration of
breast cancer cells
08 Nov 2013 12:00 am
IntroductionThe cytochrome P450 (CYP) enzymes are a class of heme-containing enzymes involved in
phase I metabolism of a large number of xenobiotics. The CYP family member CYP2E1 metabolises many
xenobiotics and procarcinogens, it is not just expressed in the liver but also in many other tissues such as
the kidney, the lung, the brain, the gastrointestinal tract and the breast tissue. It is induced in several
pathological conditions including cancer, obesity, and type II diabetes implying that this enzyme is
implicated in other biological processes beyond its role in phase I metabolism. Despite the detailed
description of the role of CYP2E1 in the liver, its functions in other tissues have not been extensively
studied. In this study we investigated the functional significance of CYP2E1 in breast carcinogenesis.
Methods: Cellular levels of reactive oxygen species (ROS) were measured by H2DCFDA (2 2.9.2
2[prime],7[prime]-dichlorodihydrofluorescein diacetate ) staining and autophagy was assessed by tracing
the cellular levels of autophagy markers using western blot assays. The endoplasmic reticulum stress and
the unfolded protein response (UPR) were detected by luciferase assays reflecting the splicing of mRNA
encoding the X-box binding protein 1 (XBP1) transcription factor and cell migration was evaluated using the
scratch wound assay. Gene expression was recorded with standard transcription assays including
luciferase reporter and chromatin immunoprecipitation. Results: Ectopic expression of CYP2E1 induced
ROS generation, affected autophagy, stimulated endoplasmic reticulum stress and inhibited migration in
breast cancer cells with different metastatic potential and p53 status. Furthermore, evidence is presented
indicating that CYP2E1 gene expression is under the transcriptional control of the p53 tumor suppressor.
Conclusions: These results support the notion that CYP2E1 exerts an important role in mammary
carcinogenesis, provide a potential link between ethanol metabolism and breast cancer and suggest that
progression, and metastasis of advanced stages of breast cancer can be modulated by induction of
CYP2E1 activity.
DNA regulator stops cancer cells in their tracks
20 Nov 2013 09:42 am
DNA-PK inhibition by NU7441 sensitizes breast cancer cells to ionizing radiation and
doxorubicin
29 Nov 2013 12:00 am
Abstract
DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double-strand breaks
(DSBs) that are probably the most deleterious form of DNA damage. Inhibition of DNA-PK has been
considered as an attractive approach to decrease resistance to therapeutically induced DNA DSBs. Ionizing
radiation (IR) and doxorubicin, which induce DSBs, are used in the treatment of breast cancer. We
determined the cellular concentration of DNA-PK and other DSB-activated kinases: ATM and ATR and the
effect of DNA-PK inhibition by NU7441 on DNA repair, cell cycle, and survival after IR or doxorubicin
treatment in three human breast cancer cell lines (MCF-7, MDA-MB-231, and T47D) representing different
breast cancer subtypes. T47D cells had the highest expression of DNA-PKcs, ATM, and ATR and the most
rapid rate of DNA DSB repair. IR caused a 10- to 16-fold increase in DNA-PK activity and two to threefold
induction of ATM in all 3 cell lines. NU7441 inhibited IR-induced DNA-PK activity in all cell lines with IC50s in
the range 0.17–0.25 μM. NU7441 retarded the repair of DSB and significantly increased the sensitivity of all
cell lines to IR (4- to 12-fold) and doxorubicin (3- to 13-fold). The greatest sensitiziation by NU7441 was
observed in MDA-MB-231 cells. NU7441 affected the cell cycle distribution in all studied cell lines;
increasing accumulation of cells in G2/M phase after DNA damage. Our data indicate that DNA-PK might
be an effective target for chemo- and radio-potentiation in breast cancer and suggest that further
development of DNA-PK inhibitors for clinical use is warranted.
Diagnosis by blood test of early stages of breast cancer a hope for the near future - Medical
News Today
18 Nov 2013 09:42 am
Direct repression of MYB by ZEB1 suppresses proliferation and epithelial gene expression
during epithelial-to-mesenchymal transition of breast cancer cells
27 Nov 2013 12:00 am
IntroductionEpithelial-to-mesenchymal transition (EMT) promotes cell migration and is important in
metastasis. Cellular proliferation is often downregulated during EMT and the reverse transition (MET) in
metastases appears to be required for restoration of proliferation in secondary tumors. We studied the
interplay between EMT and proliferation control by MYB in breast cancer cells. Methods: MYB, ZEB1 and
CDH1 expression levels were manipulated by lentiviral small hairpin RNA (shRNA)-mediated
knockdown/overexpression, and verified by Western blotting, immunocytochemistry and qRT-PCR.
Proliferation was assessed by bromodeoxyuridine pulse labeling and flow cytometry, and sulforhodamine B
assays. EMT was induced with epidermal growth factor for 9 days or by exposure to hypoxia (1% oxygen)
for up to 5 days, and assessed by qRT-PCR, cell morphology and colony morphology. Protein expression in
human breast cancers was assessed by immunohistochemistry. ZEB1-MYB promoter binding and
repression were determined by Chromatin Immunoprecipitation Assay and a luciferase reporter assay,
respectively. Student's paired T tests, Mann--Whitney and repeated measures 2-way ANOVA tests
determined statistical significance (P < 0.05). Results: Parental PMC42-ET cells displayed higher
expression of ZEB1 and lower expression of MYB than the PMC42-LA epithelial variant. Knockdown of
ZEB1 in PMC42-ET and MDA-MB-231 cells caused increased expression of MYB and a transition to a
more epithelial phenotype, which in PMC42-ET cells was coupled with increased proliferation. Indeed, we
observed an inverse relationship between MYB and ZEB1 expression in two in vitro EMT cell models, in
matched human breast tumors and lymph node metastases, and in human breast cancer cell lines.
Knockdown of MYB in PMC42-LA cells (MYBsh-LA) led to morphological changes and protein expression
consistent with an EMT. ZEB1 expression was raised in MYBsh-LA cells and significantly repressed in MYB
over-expressing MDA-MB-231 cells, which also showed reduced random migration and a shift from
mesenchymal to epithelial colony morphology in two dimensional monolayer cultures. Finally, we detected
binding of ZEB1 to MYB promoter in PMC42-ET cells, and ZEB1 over-expression repressed MYB promoter
activity. Conclusions: This work identifies ZEB1 as a transcriptional repressor of MYB and suggests a
reciprocal MYB-ZEB1 repressive relationship, providing a mechanism through which proliferation and the
epithelial phenotype may be coordinately modulated in breast cancer cells.
Dual-colour CISH is a reliable alternative to FISH for assessment of topoisomerase 2-alpha
amplification in breast carcinomas
30 Nov 2013 12:00 am
Abstract
Anthracyclines are among the most powerful antineoplastic drugs available for breast cancer treatment.
Although HER2 amplification has been postulated to predict anthracycline benefit, numerous reports have
demonstrated that HER2/TOP2A co-amplification is the clinically useful predictive marker of response to
anthracyclines. The standard technique to evaluate gene status for target therapy selection is fluorescence
in situ hybridization (FISH), but this technique has some disadvantages. Dual-colour chromogenic in situ
hybridization (CISH) is an extension of the FISH protocol that allows bright-field microscopy and thus
represents a user-friendly alternative to FISH. In order to evaluate whether dual-colour CISH is a reliable
alternative to FISH in determining TOP2A gene amplification and to determine the frequency with
which TOP2A and HER2 were co-amplified, we analysed 100 invasive breast cancer specimens (70
consecutive and 30 HER2-amplified samples) using tissue microarrays. Thus, a 99 % agreement was found
between TOP2A status determined by dual-colour CISH and FISH, as well as a high degree of correlation
inTOP2A ratios using both techniques. TOP2A gene amplification was present in 8.6 % of the 70
consecutive samples studied, all of which were HER2-amplified. Co-amplification of TOP2A was observed
in 46.5 % of the additional 30 HER2-amplified samples (no TOP2A amplification was seen in nonamplified HER2 samples). We conclude that dual-colour CISH represents an excellent alternative to FISH
for determination of TOP2A gene status in invasive breast cancer. Our results showingTOP2A amplification
only in HER2-amplified cases also add to the evidence thatTOP2A determination should be restricted to
those cases.
ER and PR Immunohistochemistry and HER2 FISH versus Oncotype DX: Implications for
Breast Cancer Treatment
22 Nov 2013 05:05 am
Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor (HER2)
concordance between immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and
Oncotype DX, a commercially available RT-PCR-based assay which recently began reporting biomarker
results was assessed. ER concordance was 98.9% (262/265), Pearson correlation coefficient (r) = 0.42,
and Spearman's rank correlation (ρ) = 0.25. Positive percent agreement for ER was 98.9% (262/265). One
patient with discordant ER results was not offered hormone therapy based on the preferential use of
Oncotype DX. PR was concordant in 91.3% (242/265), r = 0.80, ρ = 0.75, and Cohen's kappa (κ) = 0.63.
Positive percent agreement for PR was 90.5% (218/241) and negative percent agreement was 100%
(24/24). HER2 concordance was 99.2% (245/247), r = 0.35, ρ = 0.28, and κ = 0.12. Positive percent
agreement for HER2 was 0% (0/2) and negative percent agreement was 100% (245/245). Of the three
FISH HER2-amplified cases, two were negative and one was equivocal, and all FISH HER2-equivocal
cases (n = 3) were negative by Oncotype DX. Patients that were FISH HER2-amplified, Oncotype DX
HER2-negative did not receive trastuzumab. Although our results demonstrated high concordance between
IHC and Oncotype DX for ER and PR, our data showed poor positive percent agreement for HER2.
Compared to FISH, Oncotype DX does not identify HER2-positive breast carcinomas. The preferential use
of Oncotype DX biomarker results over IHC and FISH is discouraged.
Ectopic Mammary Tissue as a Vulvar Mass in a Lactating Woman
22 Nov 2013 04:53 am
Editorial Board
01 Dec 2013 07:00 am
Publication date: October 2013
Source:Clinical Breast Cancer, Volume 13, Issue 5
Editorial Board/Masthead
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Effect of Age and Race Upon Quality of Life of Young Breast Cancer Survivors
01 Dec 2013 07:00 am
Publication date: Available online 25 October 2013
Source:Clinical Breast Cancer
Author(s): P.K. Morrow , A.C. Broxson , M.F. Munsell , K. Basen-Enquist , C.K. Rosenblum , L.R. Schover ,
L.H. Nguyen , L. Hsu , L. Castillo , K.M.E. Hahn , J.K. Litton , D.M. Mattair , G.N. Hortobagyi
Background Given their early age of diagnosis, young breast cancer (BC) survivors face issues that differ
widely from their older counterparts. Patients and Methods We mailed a survey to 2209 patients who were
≤45 years at time of BC diagnosis. Each survey was comprised of: the Quality of Life in Adult Cancer
Survivors instrument, Menopause Symptom Scale, and questions aimed at obtaining pertinent background
information. Results 1090 patients completed the survey. Mean age at time of diagnosis was 39.5 years;
median years from diagnosis was 6.6 years. Distress related to vaginal dryness (p=0.0002) and pain from
intercourse (p=0.0014) was significantly higher in patients who were &lt;5 years from diagnosis, compared
to those &gt;10 years from diagnosis. In the area of financial problems, black women had greater distress
than white women (p=0.0010). Compared to white women, Hispanic women had worse family distress
scores (p=0.0028) and summary cancer specific scores (p=0.0076). Patients &gt;10 years from diagnosis
had poorer sexual interest (p=0.003) than women who were closer to diagnosis. Women ≥40 years at
diagnosis had significantly lower sexual interest (p=0.0016) than women &lt;40 years. Stage and
neoadjuvant chemotherapy did not have a significant effect on QOL. Conclusion Even in comparison to
stage and neoadjuvant chemotherapy, race, age at diagnosis, and time from diagnosis have significant long
term effects on QOL following BC treatment.
Efficacy and Safety of Balugrastim Compared with Pegfilgrastim in Patients with Breast
Cancer Who Are Receiving Chemotherapy
01 Dec 2013 07:00 am
Publication date: Available online 25 October 2013
Source:Clinical Breast Cancer
Author(s): Constantin Volovat , Oleg A. Gladkov , Igor M. Bondarenko , Steve Barash , Anton Buchner ,
Peter Bias , Liat Adar , Noa Avisar
Background Recombinant-granulocyte colony stimulating factors (rG-CSFs) reduce incidence and duration
of chemotherapy-induced neutropenia and febrile neutropenia when given as adjunct therapy to patients
receiving myelosuppressive chemotherapy. Balugrastim is a long-acting G-CSF composed of a genetic
fusion between recombinant human serum albumin and G-CSF. We compared the efficacy and safety of
balugrastim and pegfilgrastim, a long-acting pegylated rG-CSF, in patients with breast cancer who were
scheduled to receive chemotherapy. Patients and Methods In this double-blind, randomized, phase III trial,
patients with ≥1.5×109 neutrophils/L were randomly assigned to subcutaneous injections of balugrastim 40
mg (n=153) or pegfilgrastim 6 mg (n=151). The primary efficacy endpoint was the duration of severe
neutropenia (DSN; days with an absolute neutrophil count &lt;0.5×109 cells/L) during cycle 1. Efficacy
analyses were performed in the per-protocol population. In a separate open-label, single-arm study, newly
recruited patients (n=77) received balugrastim 40 mg and were included in the safety analysis. Results The
mean DSN in cycle 1 was 1.1 days in the balugrastim group and 1.0 days in the pegfilgrastim group (95%
CI: -0.13 to 0.37). Two and 4 patients, respectively, had febrile neutropenia during cycle 1. Eighteen percent
of patients in the balugrastim group and 19% in the pegfilgrastim group had adverse events considered to
be related to study medication; 4.7% and 5.2% of patients, respectively, experienced serious adverse
events. Conclusions This study demonstrates the comparable safety and efficacy profile of balugrastim and
pegfilgrastim and the non-inferiority of balugrastim for reduction in DSN. There were no unexpected safety
events.
Teaser
Balugrastim is a once-per-cycle fixed-dose recombinant fusion protein composed of human serum albumin
and granulocyte colony-stimulating factor being developed to prevent chemotherapy-induced neutropenia.
This double-blind, randomized phase III trial assessed the efficacy and safety of balugrastim versus
pegfilgrastim in patients with breast cancer. Balugrastim demonstrated noninferiority to pegfilgrastim in
reducting the duration of severe neutropenia and had a favorable safety profile. Balugrastim is an effective
and safe alternative to pegfilgrastim for providing neutrophil support.
Emerging nanotherapeutic strategies in breast cancer
01 Dec 2013 07:00 am
Publication date: Available online 8 November 2013
Source:The Breast
Author(s): Elvin Blanco , Mauro Ferrari
Nanoparticle-based drug delivery platforms are emerging as powerful chemotherapeutic modalities in
breast cancer. Doxorubicin and paclitaxel nanoparticle formulations are currently used clinically, yielding
distinct pharmacokinetic parameters that prolong blood circulation times, enhance drug accumulation in
tumors, and limit adverse side effects to patients. And while these nanoconstructs have shown substantial
improvements in patient tolerability and survival, several emerging trends stand to make a significant impact
on future generations of nanoparticle platforms for breast cancer therapy. Firstly, there is a heightened
understanding of several processes involved in tumor growth, potentiation, and invasion, resulting in the
identification of several attractive molecular targets. This in turn has given rise to antibody-based
therapeutics, drug repositioning, and the burgeoning field of RNA interference (RNAi). Secondly, an
enhanced understanding of transport phenomena involved in delivery of chemotherapeutics has led to a
rethinking and retooling of nanoscale drug carrier designs. Nanoparticle platforms are now incorporating
features meant to overcome biological barriers and enhance drug accumulation within tumors, all the while
incorporating unique chemistries that enable for controlled release of therapeutic payloads. This review
aims to detail the current clinical state of nanoparticle-based therapeutics in breast cancer, as well as
highlight several platforms that exemplify the future generation of innovative approaches to chemotherapy
in breast cancer.
Endorsement and Auspices
01 Dec 2013 07:00 am
Publication date: 1 November 2013
Source:The Breast, Volume 22, Supplement 3
Eniluracil Plus 5-Fluorouracil and Leucovorin: Treatment for Metastatic Breast Cancer
Patients in Whom Capecitabine Treatment Rapidly Failed
01 Dec 2013 07:00 am
Publication date: Available online 1 November 2013
Source:Clinical Breast Cancer
Author(s): Edgardo Rivera , Jenny C. Chang , Vladimir Semiglazov , Olga Burdaeva , M. Gray Kirby ,
Thomas Spector
Background As part of a comparative phase II study of eniluracil/5-FU/Lv vs. capecitabine (Xeloda), an oral
5-FU prodrug for MBC, patients with rapid PD during capecitabine therapy crossed over to take eniluracil/5FU/Lv. Patients and Methods Ten evaluable patients with radiologically documented PD within 70 days of
capecitabine treatment were treated with a modified oral weekly eniluracil/5-FU/Lv regimen. Results After
switching to eniluracil/5-FU/Lv, 3 (30%) patients had PR. Six (60%) had SD, producing a total of 90% with
PR or SD. The median PFS was 140 days (vs. 42.5 days for capecitabine). Four (40%) patients had &gt;
7months PFS. Eniluracil/5-FU/Lv was well tolerated with mild to moderate diarrhea and nausea as the most
common side effects. Conclusion These positive efficacy and safety results encourage a larger study in
patients with rapid PD during capecitabine treatment. Eniluracil/5-FU/Lv might enable these patients to
continue with oral 5-FU rather than switching to the generally less well tolerated intravenous microtubuleinterfering agents. In addition, the eniluracil/5-FU/Lv regimen might also provide any overall survival
contribution of 5-FU that, for pharmacokinetic reasons, was not provided by capecitabine and would not be
provided if these patients progressed directly to the other approved treatments.
As part of a comparative phase II study of eniluracil plus 5-fluorouracil (5-FU) and leucovorin (Lv) vs.
capecitabine, an oral 5-FU prodrug for metastatic breast cancer (MBC), 10 evaluable patients with rapid
disease progression (PD) during capecitabine treatment crossed over to take eniluracil/5-FU/Lv. Of these
patients, 3 had partial tumor response (PR), 6 had stable disease (SD), and 4 had &gt; 7 months
progression-free survival (PFS) with eniluracil/5-FU/Lv treatment.
Evaluating Radiotherapy Options in Breast Cancer: Does Intraoperative Radiotherapy
Represent the Most Cost-Efficacious Option?
01 Dec 2013 07:00 am
Publication date: Available online 25 October 2013
Source:Clinical Breast Cancer
Author(s): Chirag Shah , Shahed Badiyan , Shariq Khwaja , Hardeepak Shah , Ami Chitalia , Anish
Nanavati , Neilendu Kundu , Vikram Vaka , Thomas B. Lanni , Frank A. Vicini
Introduction This study analyzed the cost-efficacy of intraoperative radiation therapy (IORT) compared with
whole-breast irradiation (WBI) and accelerated partial-breast irradiation (APBI) for early-stage breast
cancer. Materials and Methods Data for this analysis came from 2 phase III trials: the TARGIT (Targeted
Intraoperative Radiotherapy) trial and the ELIOT (Electron Intraoperative Radiotherapy) trial. Cost analyses
included a cost-minimization analysis and an incremental cost-effectiveness ratio analysis including a
quality-adjusted life-year (QALY) analysis. Cost analyses were performed comparing IORT with WBI
delivered using 3-dimensional conformal radiotherapy (3D-CRT), APBI 3D-CRT, APBI delivered with
intensity-modulated radiotherapy (IMRT), APBI single-lumen (SL), APBI multilumen (ML), and APBI
interstitial (I). Results Per 1000 patients treated, the cost savings with IORT were $3.6-$4.3 million, $1.6$2.4 million, $3.6-$4.4 million, $7.5-$8.2 million, and $2.8-$3.6 million compared with WBI 3D-CRT, APBI
IMRT, APBI SL, APBI ML, and APBI I, respectively, with a cost decrement of $1.6-$2.4 million compared
with APBI 3D-CRT based on data from the TARGIT trial. The costs per QALY for WBI 3D-CRT, APBI IMRT,
APBI SL, APBI ML, and APBI I compared with IORT were $47,990-$60,002; $17,335-$29,347; $49,019$61,031; $108,162-$120,173; and $36,129-$48,141, respectively, based on data from the ELIOT trial.
These results are consistent with APBI and WBI being cost-effective compared with IORT. Conclusion
Based on cost-minimization analyses, IORT represents a potential cost savings in the management of
early-stage breast cancer. However, absolute reimbursement is misleading, because when additional
medical and nonmedical costs associated with IORT are factored in, WBI and APBI represent cost-effective
modalities based on cost-per-QALY analyses. They remain the standard of care.
Increasingly intraoperative radiation therapy is being utilized in the management of early stage breast
cancer despite a lack of data supporting its efficacy based in part on potential cost savings with the
technique. While cost minimization demonstrates a reduction in cost with intraoperative therapy, this is
misleading. When factoring additional medical and non-medical costs whole breast irradiation and
accelerated partial breast irradiation represent cost effective modalities with more quality data supporting
their safety and efficacy.
Extending the Clinical Benefit of Endocrine Therapy for Women With Hormone ReceptorPositive Metastatic Breast Cancer: Differentiating Mechanisms of Action
01 Dec 2013 07:00 am
Publication date: Available online 25 October 2013
Source:Clinical Breast Cancer
Author(s): Stefan Glück
A goal of treatment for women with hormone receptor (HR)-positive metastatic breast cancer (MBC) is to
maintain a good quality of life and prolong survival; another important goal is to delay initiation of
chemotherapy. Most women with tumors that are estrogen receptor (ER)-positive and/or progesterone
receptor (PR)-positive are treated initially with endocrine therapy because of its effectiveness and relatively
low toxicity. Several classes of single-agent endocrine therapies are available for postmenopausal women,
including the nonsteroidal aromatase inhibitors (AIs), steroidal AIs, selective ER modulators, selective ER
down-regulators, progestin, androgens, and high-dose estrogen. In addition, combination therapy with
either 2 different endocrine agents or endocrine therapy in combination with newer targeted therapies,
represent relatively new strategies for the treatment of these patients. Nevertheless, disease resistance
ultimately develops with each endocrine regimen, and many questions remain regarding the optimal timing
and sequencing of these treatments. This article reviews the efficacy and safety of endocrine therapy
regimens in women with HR-positive MBC, and addresses the impact of prior endocrine therapies and the
mechanisms of action of the different endocrine regimens within the context of overall treatment goals.
Factors Associated with the Development of Chronic Pain after Surgery for Breast Cancer:
A Prospective Cohort from a Tertiary Center in the United States
13 Nov 2013 10:04 pm
Chronic pain has been shown to affect up to 60% of patients undergoing surgery for breast cancer. Besides
younger age, other risk factors for the development of chronic pain have not been consistent in previous
studies. The objective of the current investigation was to detect the prevalence and risk factors for the
development of chronic pain after breast cancer surgery by examining a patient population from a tertiary
cancer center in the United States. The study was a prospective observational cohort study. Subjects were
evaluated at least 6 months after the surgical procedure. Subjects responded to the modified short form
Brief pain inventory and the short form McGill pain questionnaire to identify and characterize pain.
Demographic, surgery, cancer treatment, and perioperative characteristics were recorded. Propensity
matching regression analysis were used to examine risk factors associated with the development of chronic
pain. 300 patients were included in the study. 110 reported the presence of chronic pain. Subjects with
chronic pain reported median (interquartile range [IQR]) rating of worst pain in the last 24 hours of 4 (2–5)
and a median (IQR) rating on average pain in the last 24 hours of 3 (1–4) on a 0–10 numeric rating scale.
Independent risk factors associated with the development of chronic pain were age, OR (95% CI) of 0.95
(0.93–0.98) and axillary lymph node dissection, 7.7 (4.3–13.9) but not radiation therapy, 1.05(0.56–1.95).
After propensity matching for confounding covariates, radiation was still not associated with the
development of chronic pain. Chronic pain after mastectomy continues to have a high prevalence in breast
cancer patients. Younger age and axillary lymph node dissection but not radiation therapy are risk factors
for the development of chronic pain. Preventive strategies to minimize the development of chronic pain are
highly desirable.
Factors predictive of immediate breast reconstruction following mastectomy for invasive
breast cancer in Australia
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): D. Roder , H. Zorbas , J. Kollias , C. Pyke , D. Walters , I. Campbell , C. Taylor , F. Webster
Purpose To investigate person, cancer and treatment determinants of immediate breast reconstruction
(IBR) in Australia. Methods Bi-variable and multi-variable analyses of the Quality Audit database. Results Of
12,707 invasive cancers treated by mastectomy circa 1998–2010, 8% had IBR. This proportion increased
over time and reduced from 29% in women below 30 years to approximately 1% in those aged 70 years or
more. Multiple regression indicated that other IBR predictors included: high socio-economic status; private
health insurance; being asymptomatic; a metropolitan rather than inner regional treatment centre; higher
surgeon case load; small tumour size; negative nodal status, positive progesterone receptor status; more
cancer foci; multiple affected breast quadrants; synchronous bilateral cancer; not having neo-adjuvant
chemotherapy, adjuvant radiotherapy or adjuvant hormone therapy; and receiving ovarian ablation.
Conclusions Variations in access to specialty services and other possible causes of variations in IBR rates
need further investigation.
Feasibility of four cycles of docetaxel and cyclophosphamide every 14 days as an adjuvant
regimen for breast cancer: A Wisconsin Oncology Network Study
01 Dec 2013 07:00 am
Publication date: Available online 26 October 2013
Source:Clinical Breast Cancer
Author(s): Mark E. Burkard , Kari B. Wisinski , Uchenna O. Njiaju , SarahMaria Donohue , Robert Hegeman
, Amy Stella , Patrick Mansky , Varsha Shah , Timothy Goggins , Rubina Qamar , Leah Dietrich ,
KyungMann Kim , Anne M. Traynor , Amye J. Tevaarwerk
Introduction Dose-dense therapies have had a major impact on reducing toxicity and improving outcomes in
breast cancer. A combination of docetaxel plus cyclophosphamide (TC) every 3 weeks has emerged as a
common chemotherapy regimen used for treatment of node-negative or lower-risk node-positive breast
cancer. We tested whether it is feasible to deliver TC on a dose-dense schedule, with therapy completed
within 10 weeks. Methods We enrolled women with early stage breast cancer on a single-arm phase II
study of adjuvant dose-dense TC (ddTC) through a regional oncology network. All women completed
primary surgery prior to accrual and subsequent therapy with TC was deemed appropriate by the treating
physician. Planned treatment was docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks
for 4 cycles with subcutaneous pegfilgrastim 6 mg administered 24-48 hours after the administration of each
chemotherapy cycle. Results Of 42 women enrolled, 41 were evaluable by prespecified criteria. Of these,
37 (90.2%) completed therapy within 10 weeks and 34 (83%) completed therapy at 8 weeks without dose
modification. Rates of neuropathy were similar to that reported previously. The rate of neutropenic fever
was low (2.5%). Rash and plantar/palmar erythrodythesia were common and reached grade 3 in four
subjects (9.8%). Conclusion Dose-dense TC is feasible with tolerability profiles similar to standard TC and a
low likelihood of neutropenic fever. This study supports further clinical development of this 8-week adjuvant
chemotherapy regimen.
Teaser
Adjuvant therapy for breast cancer can be improved by increasing dose density. We tested the feasibility of
delivering dose-dense docetaxel-cyclophosphamide (TC) in a single-arm phase II trial of 42 patients via the
Wisconsin Oncology Network. Treatment was safe, tolerable, and most patients completed therapy as
planned. Thus, this commonly used regimen can be delivered in 8 weeks.
Flat Epithelial Atypia: Comparison Between 9-Gauge and 11-Gauge Devices
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Alessandro Villa , Fabio Chiesa , Tiberio Massa , Daniele Friedman , Giuseppe Canavese , Paola
Baccini , Massimo Calabrese , Alberto Tagliafico
Background This study aimed to establish if women with a diagnosis of flat epithelial atypia (FEA) without
residual microcalcifications at stereotactic vacuum-assisted breast biopsy (VABB) could be managed with
mammographic follow-up (FU) instead of surgery and to compare 9-gauge and 11-gauge devices. Patients
and Methods From October 2003 to January 2011, 2382 VABB procedures were performed (1373 with 11gauge and 1009 with 9-gauge). We found 121 cases of pure FEA that were surgically treated: 57 with a 9gauge device (group 1) and 64 with an 11-gauge device (group 2). The underestimation rate (UR) of
malignancy for patients without and those with residual microcalcifications for each VABB device was
calculated. Differences between groups were analyzed with the Fischer exact test. Results The overall UR
of FEA was 4% (2 of 57) with the 9-gauge device and 8% (5 of 64) with the 11-gauge device. With a 9gauge device, the UR for patients without residual microcalcifications was 0% (0 of 46), and the UR for
patients with residual microcalcifications was 18% (2 of 11). With an 11-gauge device, the UR for patients
without residual microcalcifications was 0% (0 of 39), the UR for patients with residual microcalcifications at
post-biopsy mammograms was 16% (5 of 25). With a 9-gauge device, 80% (46 of 57) of patients did not
have residual microcalcifications after VABB. With an 11-gauge device, 60% (39 of 64) of patients had no
residual microcalcifications after VABB. Differences between the 9-gauge and 11-gauge devices were
statistically significant ( P &lt; .05). Conclusion Women with FEA without residual microcalcifications after
VABB can be managed conservatively. Nine-gauge VABB is associated with a lower percentage of residual
microcalcifications compared with an 11-gauge device, but it is safe to follow patients with FEA if all
calcifications are removed with the core biopsy.
One hundred twenty-one cases of pure flat epithelial atypia (FEA) diagnosed after 9-gauge and 11-gauge
vacuum-assisted breast biopsy (VABB) were evaluated. The underestimation rate (UR) for malignancy was
not significantly different in patients diagnosed with FEA using 11-gauge or 9-gauge devices. The UR after
complete removal of microcalcifications in patients diagnosed with FEA is &lt; 2%. VABB performed with a
9-gauge device worked better than a 11-gauge device to achieve a complete removal of microcalcifications.
When FEA is diagnosed with 11-gauge or 9-gauge VABB, surgical excisional biopsy may be avoided if all
the calcifications have been removed and the UR is lower than 2%.
GPR30 as an initiator of tamoxifen resistance in hormone-dependent breast cancer
29 Nov 2013 12:00 am
IntroductionTamoxifen is widely used to treat hormone-dependent breast cancer, but its therapeutic benefit
is limited by the development of drug resistance. Here, we investigated the role of estrogen G-protein
coupled receptor 30 (GPR30) on Tamoxifen resistance in breast cancer. Methods: Primary tumors (PTs) of
breast cancer and corresponding metastases (MTs) were used to evaluate the expression of GPR30 and
epidermal growth factor receptor (EGFR) immunohistochemically. Tamoxifen-resistant (TAM-R) subclones
derived from parent MCF-7 cells were used to investigate the role of GPR30 in the development of
tamoxifen resistance, using MTT assay, western blot, RT-PCR, immunofluorescence, ELISA and flow
cytometry. TAM-R xenografts were established to assess anti-tumor effects of combination therapy with
GPR30 antagonist G15 plus 4-hydroxytamoxifen (Tam), using tumor volume measurement and Terminal
deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Results: In 53 human breast cancer
specimens, GPR30 expression in MTs increased compared to matched PTs; in MTs, the expression
patterns of GPR30 and EGFR were closely related. Compared to parent MCF-7 cells, TAM-R cells had
greater growth responses to 17beta-estradiol (E2), GPR30 agonist G1 and Tam, and significantly higher
activation of Mitogen-activated protein (MAP) kinases; but this increased activity was abolished by G15 or
AG1478. In TAM-R cells, GPR30 cell-surface translocation facilitated crosstalk with EGFR, and reduced
cAMP generation, attenuating inhibition of EGFR signaling. Combination therapy both promoted apoptosis
in TAM-R cells and decreased drug-resistant tumor progression. Conclusions: Long-term endocrine
treatment facilitates the translocation of GPR30 to cell surfaces, which interferes with the EGFR signaling
pathway; GPR30 also attenuates the inhibition of MAP kinases. These factors contribute to tamoxifen
resistance development in breast cancer. Combination therapy with GPR30 inhibitors and tamoxifen may
provide a new therapeutic option for drug-resistant breast cancer.
General Information
01 Dec 2013 07:00 am
Publication date: 1 November 2013
Source:The Breast, Volume 22, Supplement 3
Hibernoma Mimicking Metastasis on Positron Emission Tomography–Computed
Tomography Imaging: A Misleading Finding in Oncologic Patient Follow-up
18 Nov 2013 05:52 am
How to Manage Idiopathic Granulomatous Mastitis: Suggestion of an Algorithm
22 Nov 2013 04:44 am
Immunohistochemical prediction of brain metastases in patients with advanced breast
cancer: The role of Rad51
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Katarzyna Sosińska-Mielcarek , Renata Duchnowska , Piotr Winczura , Andrzej Badzio , Hanna
Majewska , Joanna Lakomy , Rafał Pęksa , Beata Pieczyńska , Barbara Radecka , Sylwia Dębska ,
Wojciech Biernat , Jacek Jassem
Background There are no clinically useful biomarkers predictive of brain metastases (BM) in breast cancer.
In this study, we investigated the correlation between expression of selected proteins in the primary tumor
and the risk of BM in patients with metastatic breast cancer (MBC). Methods The study included 198 MBC
patients (96 with and 102 without BM). Using tissue microarrays derived from the primary tumor, we
assessed by immunohistochemical expression of ER, PR, HER2, Ki-67, CK5/6, EGFR, HER3, CXCR4,
Rad51, E-cadherin, and claudin 3 and 4. Results Ki-67 ≥14% (hazard ratio [HR] 2.76; P &lt; 0.001),
cytoplasmic expression of Rad51 (HR 1.87; P = 0.014) and ER-negativity (HR 1.72; P = 0.029) were
associated with increased risk of BM in the multivariate analysis. A three-biomarker profile including ER, Ki67 and Rad51 vs. other subtypes combined yielded an HR of 4.43 ( P &lt; 0.001). Conclusions ERnegativity, cytoplasmic expression of Rad51 and high Ki-67 are associated with increased risk of BM.
Implant-Associated Primary Anaplastic Large-Cell Lymphoma With Simultaneous
Involvement of Bilateral Breast Capsules
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Marnelli A. Bautista-Quach , Auayporn Nademanee , Dennis D. Weisenburger , Wengang Chen ,
Young S. Kim
Incidental radiation to axilla in early breast cancer treated with intensity modulated tangents
and comparison with conventional and 3D conformal tangents
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Tejinder Kataria , Shyam Singh Bisht , Deepak Gupta , Shikha Goyal , Kannan Jassal , Ashu
Abhishek , Kuldeep Sharma , Puneet Pareek , Vikash Kumar , Sandeep Jain , Manoj Tayal , N. Karthikeyan
Purpose To analyze incidental radiation doses to minimally dissected axilla with Intensity modulated
radiotherapy (IMRT), 3D conformal radiotherapy (3DCRT) and standard tangents (ST). Methods &amp;
materials We prospectively evaluated incidental radiation to axilla in fifty cases of early breast cancer
treated with breast conservation surgery with sentinel node biopsy alone followed by whole breast
irradiation with IMRT. Three plans were devised for each CT dataset, comprising ST, 3DCRT and IMRT
tangents. Doses to axillary nodal levels I, II and III were evaluated for mean dose, V95, V90, V80 and V50.
Comparisons were made using ANOVA. Results The mean doses delivered to axilla by the three
techniques (IMRT, 3DCRT, ST) were: 78% (range 67–90, SD ± 5.2%), 80% (63–95, ±7.5%) and 87% (73–
98, ±4.8%) for level I (IMRT vs ST; p = 0.037); 70% (46–89, ±12.4%), 72% (34–93, ±15.5%) and 65% (29–
87, ±11.8%) for level II; and 51% (28–76, ±11.1%), 53% (19–86, ±13.7%) and 41% (6–72, ±10.6%) for level
III, respectively. V90 values (volume receiving 90% of dose) for the three techniques were 49% (43–53,
±2.7%), 57% (51–65, ±3.1%) and 73% (65–80, ±3.4%) for level I (IMRT vs ST; p = 0.029); 35% (26–42,
±4.7%), 41% (33–50, ±4.2%) and 25% (17–36, ±4.5%) for level II (IMRT vs ST; p = 0.068); and 15% (9–22,
±3.4%), 16% (10–24, ±3.7%) and 8 (5–12, ±3.1%) for level III (IMRT vs ST; p = 0.039), respectively.
Conclusion Axillary levels I and II (lower axilla) receive substantial amount of incidental radiation doses with
all the three techniques; however, conformal techniques (IMRT, 3DCRT) deliver significantly lesser
incidental radiation to lower axilla than ST technique.
Insulin and Leptin Levels in Obese Patients With and Without Breast Cancer
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Maria Del Socorro Romero-Figueroa , José de Jesús Garduño-García , Jesús Duarte-Mote ,
Guadalupe Matute-González , Angel Gómez-Villanueva , Jhony De la Cruz-Vargas
Background Leptin has been associated with progression and poor survival in BC. Moreover, it is still
controversial as to whether the effect of leptin depends only on its correlation with body mass index (BMI),
or could be a direct role of adipokine in the development of BC. The aim of this study was to identify if there
was a difference between serum leptin levels and insulin in obese patients with and without BC. Patients
and Methods A cross-sectional study was made in 156 women, a group of 78 with obesity and BC and 78
with obesity without BC. When subjects agreed to participate, written informed consent was obtained from
all subjects. Biochemical variables such as glucose, triglycerides, high-density and low-density lipoprotein,
cholesterol, insulin, and leptin were measured and homeostasis model assessment (HOMA-IR) was
calculated. Results The age, number of parities, glucose, HOMA-IR, and leptin were significantly different at
P &lt; .05. Conclusion Serum leptin levels and leptin/BMI ratio were statistically significantly increased in
patients with BC.
Obesity and breast cancer (BC) are considered serious health problems worldwide. A possible link between
both diseases have been postulated. Leptin could be implicated in this link. We performed a cross-sectional
study in obese women, and found higher levels of leptin in BC patients. This could open a new research
area in BC prevention and treatment.
Intermittent letrozole therapy for metastatic breast cancer: case reports and literature review
01 Dec 2013 07:00 am
Publication date: Available online 25 October 2013
Source:Clinical Breast Cancer
Author(s): Lei Fan , Pedro E.R. Liedke , Steven J. Isakoff , Jessica St Louis , Paula D. Ryan , Paul E. Goss
Is There a Tradeoff in Using Modified High Tangent Field Radiation for Treating an
Undissected Node-Positive Axilla?
01 Dec 2013 07:00 am
Publication date: Available online 27 October 2013
Source:Clinical Breast Cancer
Author(s): Himanshu Nagar , Lili Zhou , Bertrand Biritz , Cristina Sison , Jenghwa Chang , Michael Smith ,
Dattatreyudu Nori , K.S. Clifford Chao , Mary Katherine Hayes
Introduction Recent data are changing axillary management in patients with 1 to 2 positive sentinel nodes.
The proposed omission of completion axillary node dissection calls into question the need for axillary nodal
irradiation. This study evaluates the difference in dose to the lung and heart and risk of radiation
pneumonitis (RP) for patients treated with standard tangent fields (STF) compared with modified high
tangent fields (MHTF). Materials and Methods Plans of 30 patients treated with STF were evaluated. A
second plan (MHTF) was developed to include axillary levels I (Ax1) and II (Ax2). Ax1 and Ax2 volumes
were contoured based on the RTOG (Radiation Therapy Oncology Group) Atlas guidelines. Dose-volume
histograms of the 2 plans were used to compare doses received by Ax1, Ax2, lung, and heart volumes. The
risk of RP was calculated using normal tissue complication probability (NTCP) modeling. Results The D 95
(dose to 95% of volume) received by Ax1 and Ax2 volumes increased from 16.38 Gy and 5.71 Gy for STF
to 49.38 Gy and 48.08 Gy for MHTF, respectively. Mean lung dose increased from 5.40 Gy for STF to 9.47
Gy for MHTF. Mean ipsilateral lung V 5 , V 10 , and V 20 values increased from 19%, 14%, and 10%,
respectively, for STF, to 32%, 24%, and 18%, respectively, for MHTF. Mean heart dose increased from 1.98
Gy for STF to 3.93 Gy for MHTF. Mean heart V 25 and V 30 values increased from 2% and 1%,
respectively, for STF, to 4% and 3%, respectively, for MHTF. NTCP for RP increased from near 0% for STF
to 1% for MHTF. Conclusion Modified high tangent fields are necessary for definitive coverage of Ax1 and
Ax2. This technique increases mean ipsilateral lung and heart doses as well as the V 5 , V 10 , and V 20 of
ipsilateral lung and the V 25 and V 30 of the heart. Risk of RP remains low by use of MHTF.
Axillary management in breast cancer patients continues to evolve. This study demonstrates that radiation
may be a safe option with respect to cardiac and pulmonary side effects for a surgically undissected axilla.
LTBP1L is focally induced in embryonic mammary mesenchyme, demarcates the ductal
luminal lineage and is upregulated during involution
21 Nov 2013 12:00 am
IntroductionLatent TGFbeta binding proteins (LTBPs) govern TGFbeta presentation and activation and are
important for elastogenesis. Although TGFbeta is well-known as a tumor suppressor and metastasis
promoter, and LTBP1 is elevated in two distinct breast cancer metastasis signatures, LTBPs have not been
studied in the normal mammary gland. Methods: To address this we have examined Ltbp1 promoter activity
throughout mammary development using an LTBP1L-LacZ reporter as well as expression of both Ltbp1L
and 1S mRNA and protein by qRT-PCR, immunofluorescence and flow cytometry. Results: Our data show
that Ltbp1L is transcribed coincident with lumen formation, providing a rare marker distinguishing ductal
from alveolar luminal lineages. Ltbp1 L and 1S are silent during lactation but robustly induced during
involution, peaking at the stage when the remodeling process becomes irreversible. Ltbp1L is also induced
within the embryonic mammary mesenchyme and maintained within nipple smooth muscle cells and
myofibroblasts. LTBP1 protein exclusively ensheaths basal cells of ducts and side branches. Conclusions:
These data show Ltbp1 is transcriptionally regulated in a dynamic manner that is likely to impose significant
spatial restriction on TGFbeta bioavailability during mammary development. We hypothesize that LTBP1
functions in a mechanosensory capacity to establish and maintain ductal luminal cell fate, support and
detect ductal distension, trigger irreversible involution, and facilitate nipple sphincter function.
Lapatinib¿induced NF-kappaB activation sensitizes triple-negative breast cancer cells to
proteasome inhibitors
12 Nov 2013 12:00 am
IntroductionTriple-negative breast cancer (TNBC), a subtype of breast cancer with negative expressions of
estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is
frequently diagnosed in younger women and has poor prognosis for disease-free and overall survival. Due
to the lack of known oncogenic drivers for TNBC proliferation, clinical benefit from currently available
targeted therapies is limited, and new therapeutic strategies are urgently needed. Methods: Triple-negative
breast cancer cell lines were treated with proteasome inhibitors in combination with lapatinib (a dual
epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor). Their in vitro and in vivo viability
was examined by MTT assay, clonogenic analysis, and orthotopic xenograft mice model. Luciferase
reporter gene, immunoblot, and RT-qPCR, immunoprecipitation assays were used to investigate the
molecular mechanisms of action. Results: Our data showed that nuclear factor (NF)-κB activation was
elicited by lapatinib, independent of EGFR/HER2 inhibition, in TNBCs. Lapatinib-induced constitutive
activation of NF-κB involved Src family kinase (SFK)-dependent p65 and IκBα phosphorylations, and
rendered these cells more vulnerable to NF-κB inhibition by p65 small hairpin RNA. Lapatinib but not other
EGFR inhibitors synergized the anti-tumor activity of proteasome inhibitors both in vitro and in vivo. Our
results suggest that treatment of TNBCs with lapatinib may enhance their oncogene addiction to NF-κB,
and thus augment the anti-tumor activity of proteasome inhibitors. Conclusions: These findings suggest that
combination therapy of a proteasome inhibitor with lapatinib may benefit TNBC patients.
Level III axillary lymph nodes involvement in node positive breast cancer received
neoadjuvant chemotherapy
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Zhaoqing Fan , Jinfeng Li , Tianfeng Wang , Yuntao Xie , Tie Fan , Benyao Lin , Tao Ouyang
Objective To investigate the incidence, associated factors and prognosis of level III node involvement for
breast cancer with positive axillary lymph nodes after neoadjuvant chemotherapy. Methods A consecutive
series of 521 node positive T 0–2 invasive breast cancer cases were included in this retrospective study.
Axillary node metastases were proved by ultrasound guided needle biopsy (NB) if ultrasonographic
abnormal node was detected or by sentinel node biopsy (SNB) if no abnormal node was detected. After 4 to
8 cycles of neoadjuvant chemotherapy (NCT）, axillary lymph nodes dissection included level III lymph
nodes were completed for each case. Results The pathologic complete response rate of axillary nodes was
31.1% (90/289) in NB positive subgroup. The incidence of residual positive level III lymph nodes were 9.0%
(47/521). Multivariate analysis showed that node NB positivity (OR = 2.212, 95% CI: 1.022–4.787, P
= 0.044), clinical tumor size &gt;2 cm before NCT (OR = 2.672, 95% CI: 1.170–6.098, P = 0.020), and
primary tumor non-response to neoadjuvant chemotherapy (OR = 1.718, 95% CI: 1.232–2.396, P = 0.001)
were independent predictors of level III lymph nodes positivity. At median follow-up time of 30 months, the
distant disease-free survival (DDFS) rate of level III node positive group was much lower than that of level
III negative group ( p = 0.011). Conclusions About 9% of node positive T 0–2 breast cancer will have
residual positive node in level III region after neoadjuvant chemotherapy. Node positivity proved by NB,
large tumor size, and primary tumor non-response to neoadjuvant chemotherapy are independent
predictors of level III lymph nodes positivity.
Life beyond Z11
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): M. Ahmed , M. Douek
The ACOSOG Z0011 (Z11) trial demonstrated the presence of a group of breast cancer patients with some
residual axillary disease who did not benefit from axillary lymph node dissection (ALND) in the presence of
whole breast radiotherapy and systemic therapy at short term follow-up. It is important that further long-term
follow-up of this cohort continues. The outcomes of those patients fitting Z11 criteria who do not undergo
ALND should be recorded on a prospective register to ensure close observation should any late divergence
in overall survival develop. It is also essential that future studies are inclusive of groups excluded from Z11
rather than simply a re-hash of the trial.
Lobular breast cancer in a CDH1 splice-site mutation carrier: Case report and review of the
literature
01 Dec 2013 07:00 am
Publication date: Available online 25 October 2013
Source:Clinical Breast Cancer
Author(s): Terri P. McVeigh , Joon K. Choi , Nicola M. Miller , Andrew J. Green , Michael J. Kerin
Introduction We present the case of a 49 year old female treated for an invasive lobular carcinoma, on a
background of a proven CDH1 gene mutation for which she had previously undergone a prophylactic
gastrectomy. Aim CDH1 mutations are known to predispose affected individuals to diffuse gastric cancer
and other cancers. We aim to outline the role of CDH1 in breast cancer, and to investigate current
guidelines in management and screening of mutation carriers. Methods A Medline and Scopus search was
carried out to identify articles with respect to CDH1 and breast cancer. Manual scanning of articles arising
from this search was carried out and irrelevant articles exluded. Results CDH1 mutations act to alter the
function of E-cadherin. Loss of E-cadherin expression is characteristic of lobular breast cancers. The
penetrance of lobular breast cancers in female CDH1 mutation carriers is variable. CDH1 nonsense and
frameshift mutations have been identified in sporadic cases. Breast cancer associated mutations have been
found to cluster at the 3` end of CDH1. Screening in this cohort is difficult because of the radiolucent nature
of lobular subtype of breast cancer. Prophylactic surgery is controversial given variability in penetrance.
Conclusion Female patients with CDH1 mutations should be offered, at minimum, annual surveillance with
breast MRI. Consideration should be given towards surgical prophylaxis, or to pharmaceutical prophylaxis
with oestrogen-based therapies.
Long non-coding RNA HOTAIR is an independent prognostic marker of metastasis in
estrogen receptor-positive primary breast cancer
21 Nov 2013 12:00 am
Abstract
Expression of HOX transcript antisense intergenic RNA (HOTAIR)—a long non-coding RNA—has been
examined in a variety of human cancers, and overexpression ofHOTAIR is correlated with poor survival
among breast, colon, and liver cancer patients. In this retrospective study, we examine HOTAIR expression
in 164 primary breast tumors, from patients who do not receive adjuvant treatment, in a design that is paired
with respect to the traditional prognostic markers. We show that HOTAIR expression differs between
patients with or without a metastatic endpoint, respectively. Survival analysis shows that
high HOTAIR expression in primary tumors is significantly associated with worse prognosis independent of
prognostic markers (P = 0.012, hazard ratio (HR) 1.747). This association is even stronger when looking
only at estrogen receptor (ER)-positive tumor samples (P = 0.0086, HR 1.985). In ER-negative tumor
samples, we are not able to detect a prognostic value of HOTAIR expression, probably due to the limited
sample size. These results are successfully validated in an independent dataset with similar associations
(P = 0.018, HR 1.825). In conclusion, our findings suggest that HOTAIR expression may serve as an
independent biomarker for the prediction of the risk of metastasis in ER-positive breast cancer patients.
Lymphocytic infiltrate is associated with favorable biomarkers profile in HER2overexpressing breast cancers and adverse biomarker profile in ER-positive breast cancers
24 Nov 2013 12:00 am
Abstract
The value for lymphocytic infiltration (LI) has been increasingly recognized for tumor assessment. In breast
cancer, however, the overall significance of LI remains poorly defined, probably due to its heterogeneity. A
large cohort of breast cancer was evaluated for the degree of LI and its association with traditional
pathologic factors, biomarker expression, and cancer subtypes. The number of CD8 cytotoxic effector and
FoxP3 regulatory T cell (Treg) was evaluated in those cases with high LI. High LI was associated with
negative ER and PR but positive HER2 and EGFR expression (p < 0.001 for all). In ER-positive cancers,
high LI was associated with poor prognostic features including higher grade, the presence of necrosis, and
lymphovascular invasion (LVI) (p = 0.007 for LVI and <0.001 for the others). Conversely, LI correlated with
smaller tumor size, a good prognostic feature (p = 0.046) in HER2+ ER-cancers. These observations
suggested LI may show opposite prognostic values in different breast cancer subgroups. Interestingly,
when the phenotype of LI in these subgroups was evaluated, a strong positive association with intratumoral
accumulation of Treg was found in ER-positive cancers (p = 0.003, Rs = 0.319), while the opposite was
observed in HER2+ ER-cancers (p < 0.001, Rs = −0.427). Also, in ER-positive cancers, positive
associations between peri- and intra-tumoral distribution were found with both CD8 and Tregs
(CD8: p < 0.001, Rs = 0.547; Treg: p = 0.001, Rs = 0.460). Nonetheless, in HER2+ ER-cancers, such
strong association was found with CD8 (p < 0.001, Rs = 0.766) but not Tregs. The results may implicate a
differential intratumoral migration of LI in different subtypes of breast cancer. In summary, the clinical value
of LI in breast cancers could be subtype-dependent. In ER-positive cancers, high LI correlated with biologic
parameters associated with poor prognosis, whereas in HER2 positive cancers, LI correlated with biologic
parameters of favorable prognosis.
Malignant Adenomyoepithelioma: A Rare Entity
22 Nov 2013 04:47 am
Metformin Decreases Circulating Androgen and Estrogen Levels in Nondiabetic Women
With Breast Cancer
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Carlo Campagnoli , Franco Berrino , Elisabetta Venturelli , Chiara Abbà , Nicoletta Biglia , Tiziana
Brucato , Patrizia Cogliati , Saverio Danese , Michela Donadio , Gianna Zito , Patrizia Pasanisi
Introduction Diabetic patients treated with metformin have a lower risk of developing BC or a better BC
prognosis. Metformin might reduce cancer growth through direct antiproliferative effects or through indirect
mechanisms, particularly the reduction of insulin. In a randomized study on nondiabetic BC patients in
natural menopause with high testosterone levels, we observed a significant decrease in insulin and in
testosterone levels with metformin 1500 mg/d compared with 1000 mg/d. We present the results of a new
analysis of our study on the effect of metformin on the bioavailability of sex hormones. Patients and
Methods One hundred twenty-four eligible women were initially invited to take metformin 500 mg/d for 3
months. The 108 women who completed the first 3 months continued the study using 1000 mg/d for 1
month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group
increased the dose to 1500 mg/d, and the other group continued with 1000 mg/d. Results Ninety-six women
completed the study, 43 receiving metformin 1500 mg/day, and 53 receiving 1000 mg/day. The women
receiving 1500 mg/d showed a greater and significant reduction of free testosterone (−29%) and estradiol
(−38%), a borderline significant reduction of estrone and insulin-like growth factor-1, and a nonsignificant
reduction of androstenedione. They also showed a nonsignificant increase of dehydroepiandrosterone
sulfate. Conclusion Metformin does not interfere with the production of dehydroepiandrosterone sulfate.
Besides, it decreases estradiol levels, basically through the reduction of testosterone. These hormonal
changes might have clinical relevance.
These are further data from a randomized controlled trial designed to test the effect of different doses of
metformin in patients with breast cancer (BC) and without diabetes, with the aim of modifying the hormonal
parameters linked to BC prognosis. A dose of 1500 mg/d of metformin causes significant reductions of the
levels of free testosterone and estradiol.
Multicentre experience of non-pegylated liposomal doxorubicin (NPLD) use in the
management of metastatic breast cancer
01 Dec 2013 07:00 am
Publication date: Available online 27 October 2013
Source:Clinical Breast Cancer
Author(s): Carlo Palmieri , Vivek Misra , Adam Januszewski , Hosney Yosef , Richard Ashford , Ian Keary ,
Neville Davidson
Background This study aimed to investigate the use of non-pegylated liposomal doxorubicin (NPLD) in the
management of metastatic breast cancer (MBC) within routine UK clinical practice and assess its efficacy
and tolerability. Patients and methods All patients that received NPLD for MBC at five institutions were
identified. Clinico-pathological details, echocardiographic data, and toxicities were documented. Response
to treatment, outcome, cardiotoxicity and safety were assessed. Results 63 patients (median age at NPLD
therapy 53.5 years) were identified who had received NPLD; 18 (29%) were anthracycline-naïve and 42
(67%) were anthracycline pre-treated (median cumulative dose of epirubicin 450 mg/m 2). In 3 cases, prior
treatment history was not available. NPLD was most frequently (16/63 patients; 25%) administered as firstline chemotherapy (median third-line; range 1-9), although given later in anthracycline pre-treated patients
(median fourth-line, range 1-9). Overall, 14 of 49 (29%) evaluable patients achieved an objective response,
which increased to 10/14 (71%) when NPLD was given first-line (anthracycline-naïve: 8/8 [100%]; pretreated: 2/4 [50%]; 2 adjuvant treatment unknown). Median progression-free survival was 7 months (firstline: 18 months vs. ≥second-line: 6 months; P=0.0066) and median overall survival was 10 months (firstline: 18 months vs. ≥second-line: 10 months; P=0.0971). Toxicities tended to be grade 1-2. 3 patients had
cardiotoxicity (left ventricular ejection fraction &lt;50% or a fall of ≥10% from baseline), which resolved
during treatment. Conclusion NPLD was used in both anthracycline-naïve patients and those with prior
exposure. There is evidence of clinical activity in those with prior exposure to anthracyclines with a low
incidence of cardiotoxicity.
Teaser
The use of NPLD in metastatic breast cancer within UK clinical practice was assessed. NPLD was most
frequently (16/63 patients; 25%) administered first-line (median third-line); in anthracycline pre-treated
patients, median fourth-line. 29% of patients achieved an objective response (anthracycline-naïve: 75%;
pre-treated: 15%). Toxicities tended to be grade 1-2. NPLD had clinical activity in anthracycline-naïve and
pre-treated patients with low toxicity.
Nab-Paclitaxel/Bevacizumab/Carboplatin Chemotherapy in First-Line Triple Negative
Metastatic Breast Cancer
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Erika Hamilton , Gretchen Kimmick , Judith Hopkins , P. Kelly Marcom , Gloria Rocha , Renee
Welch , Gloria Broadwater , Kimberly Blackwell
Background Triple negative metastatic breast cancer can be difficult to treat with primarily cytotoxic options.
Nab-paclitaxel has demonstrated improved PFS and tolerability compared with standard cremophorsolubilized paclitaxel; based on this, we examined the efficacy and safety of combining weekly nabpaclitaxel with carboplatin and bevacizumab in TNMBC. Patients and Methods In this phase II, multicenter
trial, patients with first-line TNMBC received nab-paclitaxel (100 mg/m2) and carboplatin (area under the
curve = 2) on days 1, 8, 15, and bevacizumab (10 mg/kg) on days 1 and 15 of a 28-day cycle. The primary
end point was safety and tolerability and secondary end points included PFS, ORR, and CBR. PFS was
calculated using the Kaplan-Meier method. Results Between July 16, 2007, and October 3, 2011, 34
patients were enrolled at 4 centers. Median age was 50.0 (range, 30-76) years and 77% (n = 26) of patients
received previous adjuvant therapy. Median PFS was 9.2 months (95% confidence interval [CI], 7.8-25.1
months). The CBR was 94% (95% CI, 80%-99%), and ORR was 85% (95% CI, 69%-95%) for the
combination. The regimen was well tolerated with the most common grade 3/4 adverse events being
neutropenia (n = 18; 53%) and thrombocytopenia (n = 6; 18%), with other serous events including 1 grade 3
and 1 grade 4 thrombotic event and 1 febrile neutropenia. Conclusion The combination of nab-paclitaxel,
bevacizumab, and carboplatin as first-line treatment for TNMBC was efficacious and well tolerated. The
PFS, CBR, and ORR, and tolerability of the regimen, compares favorably with other standard first-line
therapies.
In this phase II multicenter trial, nab-paclitaxel and carboplatin was administered weekly with biweekly
bevacizumab to 34 patients with first-line triple negative metastatic breast cancer (TNMBC). Progressionfree survival (PFS) was 9.2 months (n = 35), clinical benefit rate (CBR) 94%, and objective response rate
(ORR) 85%. This regimen, compared with historical control regimens, such as paclitaxel and bevacizumab,
compares favorably in efficacy and tolerability.
New Approaches in the Management of Male Breast Cancer
01 Dec 2013 07:00 am
Publication date: October 2013
Source:Clinical Breast Cancer, Volume 13, Issue 5
Author(s): Darren K. Patten , Laurence K. Sharifi , Maisam Fazel
Male breast cancer (MBC) is a rare condition that accounts for 0.1% of all male cancers. Our current
evidence base for treatment is derived from female breast cancer (FBC) patients. Risk factors for MBC
include age, genetic predisposition, race, sex hormone exposure, and environmental factors. Most patients
present later and with more advanced disease than comparable FBC patients. Tumors are likely to be
estrogen receptor and progesterone receptor positive, with the most common histologic type being invasive
ductal carcinoma. Triple assessment remains the criterion standard for diagnosis. Primary MBC is mostly
managed initially by simple mastectomy, with the option of breast conserving surgery, which carries an
increased risk of recurrence. Sentinel node biopsy is recommended as the initial procedure for staging the
axilla. Reconstructive surgery focuses on achieving primary skin closure, and radiotherapy largely follows
treatment protocols validated in FBC. We recommend chemotherapy for men with more advanced disease,
in particular, those with estrogen receptor negative histology. MBC responds well to endocrine therapy,
although it is associated with significant adverse effects. Third-generation aromatase inhibitors are
promising but raise concerns due to their failure to prevent estrogen synthesis in the testes. Fulvestrant
remains unproven as a therapy, and data on trastuzumab is equivocal with HER2 receptor expression and
functionality unclear in MBC. In metastatic disease, drug-based hormonal manipulation remains a first-line
therapy, followed by systemic chemotherapy for hormone-refractory disease. Prognosis for MBC has
improved over the past 30 years, with survival affected by disease staging, histologic classification, and
comorbidity.
New driver of breast cancer discovered
11 Nov 2013 09:40 am
No increase of local recurrence rate in breast cancer patients treated with skin-sparing
mastectomy followed by immediate breast reconstruction
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): D.R.J. van Mierlo , T.R. Lopez Penha , R.J. Schipper , M.H. Martens , J. Serroyen , M.B.I.
Lobbes , E.M. Heuts , S. Tuinder , M.L. Smidt
Background The aim of this study was to evaluate the incidence of local recurrence after SSM with IBR and
to determine whether complications lead to postponement of adjuvant therapy. Method Patients that
underwent IBR after SSM between 2004 and 2011 were included. Results A total of 157 reconstruction
procedures were performed in 147 patients for invasive breast cancer ( n = 117) and ductal carcinoma in
situ ( n = 40). The median follow-up was 39 months [range 6–97]. Estimated 5-year local recurrence rate
was 2.9% (95%CI 0.1–5.7). The median time to start adjuvant therapy was 27.5 days [range 19–92] in 18
patients with complications, and 23.5 days [range 8–54] in 46 patients without complications ( p = 0.025).
Conclusion In our single-institution cohort, IBR after SSM carried an acceptable local recurrence rate.
Complications caused a delay of adjuvant treatment but this was within guidelines and therefore not
clinically relevant.
Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines
and taxanes according to pathological subtypes: a pooled analysis
06 Nov 2013 12:00 am
IntroductionObesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of
menopausal status and treatment received. However, the association between obesity and survival
outcome by pathological subtype requires further clarification. Methods: We performed a retrospective
analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906,
GEICAM/9805, GEICAM/2003--02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant
treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease
recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect
differences of such prognostic effects by subtype. Results: Multivariate survival analyses adjusting for age,
tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status,
human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment
showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI<25
(reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to
1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity
(BMI>=35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR =
1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference
group. The prognostic effect of severe obesity did not vary by subtype. Conclusions: Severely obese
patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM,
and OM than patients with BMI<25. The magnitude of the harmful effect of BMI on survival-related
outcomes was similar across subtypes.
Outcomes and Chemotherapy-related Toxicity in HIV-infected Patients with Breast Cancer
01 Dec 2013 07:00 am
Publication date: Available online 20 November 2013
Source:Clinical Breast Cancer
Author(s): Sukhwant N. Singh , Yue Zhu , Saranya Chumsri , Susan Kesmodel , Bruce L. Gilliam , David J.
Riedel
Palpable Ductal Carcinoma in Situ: Analysis of Radiological and Histological Features of a
Large Series With 5-Year Follow-Up
01 Dec 2013 07:00 am
Publication date: December 2013
Source:Clinical Breast Cancer, Volume 13, Issue 6
Author(s): Sreekumar Sundara Rajan , Rashmi Verma , Abeer M. Shaaban , Nisha Sharma , Barbara Dall ,
Mark Lansdown
Background Palpable pure DCIS is a rare entity that presents differently than screen-detected DCIS. The
aim of this study was to evaluate the clinical, radiological, and pathological characteristics and management
of pDCIS in a retrospective cohort of patients. Patients and Methods Patients diagnosed with pDCIS from
January 1999 to December 2011 were identified from an electronic patient database and were included in
this study. Results During this period, 669 cases of DCIS were diagnosed and 62 (9.3%) were pDCIS
(mean age, 56.9 ± 15.1 years). The most common finding on ultrasound was mass in 43 patients (75%) and
only 18 (33%) cases had calcification on mammography. The lesion was mammographically occult in 20
patients (37%). Ultrasound was more sensitive and delineated the pDCIS in 45 (80%) cases. Mean size of
the pDCIS was 36.9 ± 30.4 mm and most were high grade (n = 42; 68%) and associated with comedo
necrosis in 36 (59%). Most were oestrogen receptor (ER)-positive (n = 34; 62%), however 21 patients
(38%) were ER-negative. Breast conservation was attempted in 30 patients (48%), however, because of
involved margins further therapeutic surgery was needed in 10 patients (33%). Axillary surgery (sentinel
lymph node biopsy or axillary nodal sampling) was performed in 34 patients (55%) and no lymph node
metastasis was identified. During a medial follow-up of 60 months, 1 patient has developed a mastectomy
scar recurrence and the rest remain disease-free. Conclusion Palpable DCIS is often occult on conventional
radiological imaging and is generally associated with aggressive pathological features. Hence, careful
individualized surgical planning through a multidisciplinary meeting is necessary for their management.
Palpable (p) ductal carcinoma in situ (DCIS) is a rare entity that presents differently than screen-detected
DCIS. pDCIS is often occult on conventional radilogical imaging and is generally associated with aggressive
pathological features. Careful individualized surgical planning in a multi-disciplinary meeting is necessary
for the management of patients presenting with pDCIS.
Pathological features and survival outcomes of very young patients with early breast
cancer: How much is “very young”?
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): Giuseppe Cancello , Patrick Maisonneuve , Manuelita Mazza , Emilia Montagna , Nicole
Rotmensz , Giuseppe Viale , Giancarlo Pruneri , Paolo Veronesi , Alberto Luini , Oreste Gentilini , Aron
Goldhirsch , Marco Colleoni
We collected information on 497 consecutive breast cancer patients aged less than 35 years operated at
the European Institute of Oncology. The main aim of the study is to compare biological and clinical features
dividing the population by age: &lt;25 years, 25–29 and 30–34 years old. Pattern of recurrence and survival
were also analyzed. Patients aged &lt;25 years had 81.8% poorly differentiated tumors compared with
66.7% and 56.5% in the 25–29 and 30-34 groups, respectively; no other significant difference were found in
the distribution of clinical and immunohistochemical features The distribution of Luminal A and B, Triple
Negative and HER2 subtypes (immunohistochemically defined) was not statistically different among the
three age groups. No difference was found in the incidence of loco-regional relapses, distant metastases,
disease-free survival ( p = 0.79) and overall survival ( p = 0.99) between the three age groups. This latter
findings was confirmed using age as a continuous variable assuming a linear association between age and
the outcomes considered, too. In conclusion, our data indicate that the group of patients with breast cancer
below 35 years is essentially a homogenous group when classical clinical and immunohistochemical
features were considered.
Patient and Clinical Perspectives on Changes to Mammography Screening Guidelines
22 Nov 2013 04:52 am
Patient information on breast reconstruction in the era of the world wide web. A snapshot
analysis of information available on youtube.com
01 Dec 2013 07:00 am
Publication date: Available online 8 November 2013
Source:The Breast
Author(s): M.L.H. Tan , K. Kok , V. Ganesh , S.S. Thomas
Breast cancer patient's expectation and choice of reconstruction is increasing and patients often satisfy their
information needs outside clinic time by searching the world wide web. The aim of our study was to analyse
the quality of content and extent of information regarding breast reconstruction available on YouTube
videos and whether this is an appropriate additional source of information for patients. A snapshot
qualitative and quantitative analysis of the first 100 videos was performed after the term ‘breast
reconstruction’ was input into the search window of the video sharing website www.youtube.com on the 1st
of September 2011. Qualitative categorical analysis included patient, oncological and reconstruction factors.
It was concluded that although videos uploaded onto YouTube do not provide comprehensive information, it
is a useful resource that can be utilised in patient education provided comprehensive and validated videos
are made available.
Patient preferences regarding intraoperative versus external beam radiotherapy following
breast-conserving surgery
30 Nov 2013 12:00 am
Abstract
The TARGIT-A Trial is an international randomized, prospective trial comparing intraoperative radiotherapy
(IORT) for equivalence to external beam radiotherapy (EBRT) following lumpectomy for invasive breast
cancer in selected low-risk patients; early results suggest that outcomes are similar. In addition to
effectiveness data and cost considerations, the preferences of patients should help inform practice. This
study was undertaken to explore and quantify preference in choosing between IORT and the current
standard, EBRT. Eligible subjects were current or past candidates for breast-conserving surgery and
radiation being seen at the University of California, San Francisco Breast Care Center. A trade-off
technique varying the risk of local recurrence for IORT was used to quantify any additional accepted risk
that these patients would accept to receive either treatment. Patients were first presented with a slideshow
comparing EBRT with the experimental IORT option before being asked their preferences given
hypothetical 10-year local recurrence risks. Patients were then given a questionnaire on demographic,
social and clinical factors. Data from 81 patients were analyzed. The median additional accepted risk to
have IORT was 2.3 % (−9 to 39 %), mean 3.2 %. Only 7 patients chose to accept additional risk for EBRT;
22 accepted IORT at no additional risk; and the remaining 52 chose IORT with some additional risk.
Patients weigh trade-offs of risks and benefits when presented with medical treatment choices. Our results
show that the majority of breast cancer patients will accept a small increment of local risk for a simpler
delivery of radiation. Further studies that incorporate outcome and side effect data from the TARGIT-A trial
clarify the expected consequences of a local recurrence, and include an expanded range of radiation
options that could help guide clinical decision making in this area.
Performance of BOADICEA and BRCAPRO genetic models and of empirical criteria based
on cancer family history for predicting BRCA mutation carrier probabilities: A retrospective
study in a sample of Italian cancer genetics clinics
01 Dec 2013 07:00 am
Publication date: December 2013
Source:The Breast, Volume 22, Issue 6
Author(s): L. Varesco , V. Viassolo , A. Viel , V. Gismondi , P. Radice , M. Montagna , E. Alducci , L. Della
Puppa , C. Oliani , S. Tommasi , M.A. Caligo , C. Vivanet , M. Zuradelli , P. Mandich , M.G. Tibiletti , P.
Cavalli , E. Lucci Cordisco , D. Turchetti , D. Boggiani , R. Bracci , P. Bruzzi , L. Bonelli
Purpose To evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and
empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing.
Patients and methods The probability of BRCA mutation according to the three tools was retrospectively
estimated in 918 index cases consecutively undergone BRCA testing at 15 Italian cancer genetics clinics
between 2006 and 2008. Results 179 of 918 cases (19.5%) carried BRCA mutations. With the strict use of
the criteria based on cancer family history 173 BRCA (21.9%) mutations would have been detected in 789
individuals. At the commonly used 10% threshold of BRCA mutation carrier probability, the genetic models
showed a similar performance [PPV (38% and 37%), sensitivity (76% and 77%) and specificity (70% and
69%)]. Their strict use would have avoided around 60% of the tests but would have missed approximately 1
every 4 carriers. Conclusion Our data highlight the complexity of BRCA testing referral in routine practice
and question the strict use of genetic models for BRCA risk assessment.
Phase I/II Trial of Vinorelbine and Sorafenib in Metastatic Breast Cancer
01 Dec 2013 07:00 am
Publication date: Available online 26 October 2013
Source:Clinical Breast Cancer
Author(s): Thehang Luu , Paul Frankel , Cathie Chung , Warren Chow , Joanne Mortimer , Arti Hurria ,
George Somlo
Purpose We investigated the efficacy and toxicity of sorafenib, a multi-kinase inhibitor of vascular
endothelial growth factor (VEGF) receptor tyrosine kinase, in combination with vinorelbine in a phase I/II
trial in patients with metastatic breast cancer (MBC). Patients and Methods Eleven patients were enrolled in
the phase I portion to determine the maximum tolerated dose (MTD), followed by 35 patients treated at the
MTD. The median age was 54 years (range 31-72). Tumors were estrogen receptor/progesterone receptor
(ER/PR) positive in 54%, and triple negative in 41% of patients. Twenty two percent of patients received
therapy as first-line, 37% as second-line, and 41% as third-line. Results Forty-one patients were treated at
the MTD, (6 during the Phase I; 35 in Phase II). The observed 44% 4-month progression-free survival rate
was similar to the estimated historical rate of 43% with vinorelbine . The combination was tolerated with
expected toxicities. Patients treated at MTD with prior bevacizumab treatment received a median of 1.5
cycles (range 1-10) compared to a median of 5 cycles (2-12) for patients without prior bevacizumab
Conclusion Further evaluation of vinorelbine and sorafenib in bevacizumab-naive patients may be of
interest if specific biomarkers guiding patient selection can be identified.
Teaser
Our results from this phase I/II trial are consistent with other anti-VEGF tyrosine kinase inhibitor (TKI) trials
in MBC. The combination of vinorelbine and sorafenib has not shown improved benefit compared to
historical single agent vinorelbine in MBC patients who received up to two lines of chemotherapies for
metastatic disease. However, the combination arm has no significant extra toxicity. The negative impact on
time to treatment failure in patients with prior bevacizumab is intriguing. One could postulate that the
decrease is a carryover effect from previous bevacizumab treatment in these patients due either to changes
in the tumor related to rebound effects. Based on our results, further evaluation of the combination of
chemotherapy with anti-VEGF TKI in patients who have not recieved first-line anti-VEGF (bevacizumab)
treatment may be of interest, but only if specific biomarkers guiding patient selection can be indentifed.
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