Download EARLY BREAST CANCER SYSTEMIC THERAPY

EARLY BREAST CANCER SYSTEMIC THERAPY
Comparison of the mutational landscape of breast cancer during pregnancy
and non-pregnant controls
S. Loibl1, N. Pfarr2, K. Weber1, S. Villegas-Angel3, A. Stenzinger4, J. Furlanetto1,
J. Budczies3, F. Marmé5, C. Denkert3, W. Weichert2
1
Medicine and Research, German Breast Group, Neu-Isenburg, Germany, 2Institute of
Pathology, Technical University Munich, Munich, Germany, 3Pathology, Charité
Hospital, Berlin, Germany, 4Institute of Pathology, University Hospital Heidelberg,
Heidelberg, Germany, 5National Center for Tumor Diseases, University Hospital
Heidelberg, Heidelberg, Germany
Background: Currently, breast cancer during pregnancy (BCP) is not believed to be
biologically different from breast cancer (BC) unrelated to pregnancy based on limited
datasets mainly obtained by immunohistochemistry. Therefore, the aim of the study is
to compare the pattern of somatic mutations between pregnant and non-pregnant patients (pts) with BC using a dataset of pregnant pts enrolled in the BCP study and nonpregnant controls obtained from the TCGA database.
Methods: The BCP study (GBG 29; BIG 03-02) is a multicentre observational study for
BC during pregnancy. FFPE core biopsies taken before therapy were retrospectively
analysed for somatic mutations by an Ion Torrent Proton/PGM sequencing platform.
The samples were assayed on a custom designed BC panel (BCPv2) including 236
amplicons split into two primer pools and covers hotspot regions of 138 exons of 25
genes. Only non-synonymous mutations without germline origin were processed.
Results: Comparison of the mutational patterns between BCP and TCGA cohorts
showed 1.03 mutations per pt in average in BCP vs. 1.27 in TCGA. The most frequent
somatic mutations for both cohorts were TP53 (65% vs. 37%), PIK3CA (11% vs. 29%)
and GATA3 (6% vs. 18%). Exact matching of BCP and TCGA cohorts was performed
based on age, HR, HER2 and grading and yielded 41 pts from both datasets. After
matching BCP pts had significantly less frequently Nþ tumors compared to TCGA pts
(p ¼ 0.046) with no significant difference for TP53 (p ¼ 0.502) and GATA3 (p ¼ 1.000)
mutational status; PIK3CA mutations were detected in only 2.4% of the pregnant vs.
22.0% of the non-pregnant pts (p ¼ 0.015). Within HR subgroups, overall TP53 was
the most frequently mutated gene with higher mutational rate in HR-negative pts
(52.4% vs. 75.0% for BCP; 23.8% vs. 85.0% for TCGA).
Conclusions: Overall the mutational landscape does not seem to differ between pregnant and non-pregnant pts. Imbalances in the PIK3CA mutational rate after matching
might be explained by a remaining bias caused by differences in sensitivity or specificity
of methods used to detect mutations or differences in variables not used for matching.
Further comparisons using other datasets and looking into gene expression patterns are
currently conducted.
Legal entity responsible for the study: N/A
Funding: This research is funded by the German Cancer Consortium-DKTK and the
BANSS Foundation.
Disclosure: All authors have declared no conflicts of interest.
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Impact of the sterol 27-hydroxylase (CYP27A1) and 27hydroxycholesterol on tumor-pathological features, prognosis and
response to statin treatment in breast cancer
S. Kimbung1, C.-Y. Chang2, P.-O. Bendahl1, L. Dubois2, W.J. Thompson2,
D.P. McDonnell2, S. Borgquist1
1
Division of Oncology and Pathology, Department of Clinical Sciences, Lund University,
Lund, Sweden, 2Department of Pharmacology and Cancer Biology, Duke University
School of Medicine, Durham, NC, USA
The impact of systemic 27-hydroxycholesterol (27HC) and intra-tumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase
CYP27A1 which regulates intracellular cholesterol homeostasis. 27HC also acts as an
endogenous selective estrogen receptor (ER) modulator capable of increasing breast
cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect
of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42
breast cancer patients treated with atorvastatin within a phase II clinical trial. Further,
the associations between CYP27A1 expression with other primary tumor pathological
features and clinical outcomes were studied in two additional independent cohorts.
Statin treatment effectively decreased serum 27HC and deregulated CYP27A1 expression in tumors. However, these changes were not associated with anti-proliferative responses to statin treatment. CYP27A1 was heterogeneously expressed among primary
tumors, with high expression significantly associated with high tumor grade, ER
negativity and the basal-like subtype. High CYP27A1 expression was independently
C 2017 IMPAKT Breast Cancer Conference organizers, ESMO and BIG
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Annals of Oncology 28 (Supplement 1): i4–i5, 2017
doi:10.1093/annonc/mdx142
prognostic for longer recurrence-free and overall survival. Importantly, the beneficial
effect of high CYP27A1 in ER positive breast cancer seemed limited to women 50
years. These results establish a link between CYP27A1 and breast cancer pathobiology
and prognosis and suggest that the efficacy of statins in reducing serum lipids does not
directly translate to anti-proliferative effects in tumors. It is implied from these studies
that other undetermined serum or tumor factors mediate the anti-proliferative effects
of statins in breast cancer.
Legal entity responsible for the study: Lund University
Funding: This work was supported by grants from the Governmental Funding of
Clinical Research from the National Health Services, the Swedish Breast Cancer
Organization (BRO), the Mrs. Berta Kamprad Foundation, the Swedish Research
Council, and the Swedish Cancer Foundation.
Disclosure: All authors have declared no conflicts of interest.
Evaluation of changes in the HR status and Her2 expression following
neoadjuvant chemotherapy
C.R. Ponce1, F.A. Colo1, M. Maino1, V.Y. Fabiano1, C.M. Loza1, M. Amat2, A. Nervo3,
V. Costanzo3, J.B. Loza1, R. Chacon3
1
Patologıa Mamaria, Instituto Alexander Fleming, Buenos Aires, Argentina, 2Patologıa,
Instituto Alexander Fleming, Buenos Aires, Argentina, 3Oncologıa, Instituto Alexander
Fleming, Buenos Aires, Argentina
Objective: The hormone receptor and HER2 expression of a primary breast carcinoma
plays a significant role in patient management, treatment and prognosis. The aim of
this study was to compare immunohistochemical (IHC) profiles of primary breast carcinomas before and after neoadjuvant chemotherapy (NAC) to assess the subsequent
effects on hormone receptor and Her2 status.
Methods: Retrospective analysis of 85 breast cancer patients surgically treated from
March 2010 to December 2016 at our institute, who underwent NAC. Results obtained
from core biopsy before treatment were compared with results obtained from surgical
specimen after treatment. All the specimens were subjected to histological study and
IHC for HR and HER2 status (FISH when IHC was 2þ).
Results: Mean age was 47 years (range: 27-69) and 58% were premenopausal. The
histologic type was invasive ductal carcinoma in 83,52% (n ¼ 71). 27,05% (n ¼ 23) had
Luminal A tumors; 9,4% (n ¼ 8) Luminal B; 14,1% (n ¼ 12) Luminal B Herþ; 18,8%
(n ¼ 16) Her2þ and 30,5% (n ¼ 26) triple-negative. Pathologic complete response
(pCR) rate was 30,5% (n ¼ 26). pCR was achieved in 30,7% (n ¼ 8) of triple-negative
tumors; 8,6% (n ¼ 2) of luminal A tumors; 37,5% (n ¼ 3) of luminal B; 25% (n ¼ 3) of
luminal B Her2þ and 56,25% (n ¼ 9) of Her2þ tumors. For the analysis of changes on
biological markers, all the 26 patients with pCR and other 6 patients without complete
data were excluded. Among 14 patients who were HER2positive before treatment, 7
had HER2negative tumors after NAC, whereas 4 of the 39 patients with HER2-negative
tumors before treatment had HER2-positive tumors afterward. Out of 32 patients with
ER-positive tumors before treatment, 1 had ER-negative tumors after NAC, whereas 9
of the 21 patients who were ER-negative before treatment had ER-positive tumors
afterward.
Conclusions: Changes, like those seen in our study, have been previously reported. We
consider HER2 status as well as hormone receptors should be reevaluated post NAC,
since changes can be observed in order to accurately determine appropriate use of targeted therapy. The clinical relevance of these changes and the implications for subsequent adjuvant systemic therapy requires further long-term follow-up.
Legal entity responsible for the study: Instituto Alexander Fleming
Funding: FUCA
Disclosure: All authors have declared no conflicts of interest.
A randomized, double-blind, placebo-controlled window of opportunity trial
evaluating clinical effects of high dose vitamin D in patients with breast cancer
A. Arnaout1, C. Addison2, S. Robertson3, G. Pond4, N. Chang3, M. Clemons5
Surgery, Ottawa Hospital Cancer Center, Ottawa, ON, Canada, 2Cancer Therapeutics,
Ottawa Hospital Research Institute, Ottawa, ON, Canada, 3Pathology, Ottawa Hospital,
Ottawa, ON, Canada, 4Ontario Clinical Trials Oncology Group, McMaster University,
Hamilton, ON, Canada, 5Medical Oncology, Ottawa Hospital Cancer Center, Ottawa,
ON, Canada
1
Background: Epidemiologic and preclinical laboratory data suggest that there is a role
for vitamin D in breast cancer therapy through its tumor suppressive effects. The