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SABCS 2007 Summary
30th Annual San Antonio Breast Cancer Symposium
December 13-16, 2007
Adjuvant Therapy
The Worldwide Overview: New Results for Systemic
Adjuvant Therapies
R. Peto – Plenary Lecture
Dr. Peto attributed dramatic improvements in breast cancer survival
since 1990 to many moderate advances in treatment
Moderate survival improvements need a meta-analysis spanning long
durations (>10 y) and large populations of patients (>10,000)
Meta-analyses by EBCTCG were presented:
RT after mastectomy, by nodal status (N=30,000)
RT benefit is greater in N1–3 and N4+ patients
5 years of tamoxifen, by ER/PgR status (N=15,000
ER+/PgR+ and ER+/PgR– show similar recurrence
ER status shows tamoxifen gains of 13%–14% (P<0.0001) at 15 years;
carryover increases to 10 years then levels off
10 years vs 5 years tamoxifen needs more data (ATLAS trial)
The Worldwide Overview: New Results for Systemic
Adjuvant Therapies
R. Peto – Plenary Lecture
AI vs tamoxifen in ER+ breast cancer (N=20,000)
The 2005–2006 update of AI vs tamoxifen as adjuvant therapy was
presented on >20,000 patients at 5–10 years after initiation of
endocrine therapy
AI superior to tamoxifen for breast cancer recurrence 3.5%, no
significant difference in survival
Superiority with AI seen in ER+ patients (Lancet, 2005)
CT vs no CT by age, ER status, and regimen (N=80,000)
Taxane vs no CT: morbidity (HR=0.46), ER status does not matter
Taxane vs no CT in women aged 50–69 years: morbidity (HR=0.66,
P=0.08), ER status does matter
SABCS Official Satellite Symposium for 2007
Controversies in Adjuvant Endocrine Therapy for Breast
Cancer
Recommendations
Adjuvant Endocrine Therapy in 2007: What Have We Accomplished and What
Uncertainties Remain?
Kathleen Pritchard
All Patients Should Receive Up-Front Therapy With an Aromatase Inhibitor
Alan Coates
Patients Should Start With Tamoxifen and Switch to an Aromatase Inhibitor
Harold Burstein
Patients With High-Risk Estrogen Receptor–Positive Early-Stage Breast Cancer Need >5
Years of Adjuvant Endocrine Therapy
James N. Ingle
An Additional Aromatase Inhibitor Is Not Needed if Significant Time Has Passed Since
Completing Tamoxifen
Matthew Ellis
Patients at Risk of Osteopenia or Osteoporosis Should Receive Preventative Therapy
With Bisphosphonates Regardless of Initial Bone Mineral Density
Adam Brufsky
Patients Should Receive Bisphosphonate Therapy Only if They Have Clinically
Diagnosed Osteopenia or Osteoporosis
Julie Gralow
ATAC: 100-Month Median Follow-Up (FU) Shows Continued Superior
Efficacy and No Excess Fracture Risk for Anastrozole (A) Compared
With Tamoxifen (T) After Treatment Completion
J. Forbes et al – Abstract #41
Objective
To provide a 100-month update of the efficacy of anastrozole compared
with tamoxifen monotherapy in the HR+ subpopulation of ATAC
Design
The ATAC trial is a randomized, phase III study of anastrozole alone,
tamoxifen alone, or tamoxifen + anastrozole combination in women with
early breast cancer
Results
All treatments completed before this analysis: 46,292 women-years
Time to recurrence
– Increased separation of curves was seen between 5–9 years
– Absolute difference in recurrence increased from 2.8% at 5 years to 4.8% at
9 years
– Significantly greater carryover effect for anastrozole vs tamoxifen in years 5–
9 (HR=0.75, P=0.01)
ATAC: 100-Month Median Follow-Up (FU) Shows Continued Superior
Efficacy and No Excess Fracture Risk for Anastrozole (A) Compared
With Tamoxifen (T) After Treatment Completion
J. Forbes et al – Abstract #41
Results (con’t)
Risk reduction for recurrence (years 5–9)
– 33% tamoxifen vs 50% anastrozole
Time to distant recurrence (years 5–9): curves widened to 15.6% tamoxifen
vs 13.2% anastrozole at 9 years (HR=0.84, P=0.022)
Contralateral breast cancer widened to 4.2% tamoxifen vs 2.5% anastrozole
at 9 years (HR=0.60, P=0.004)
Anastrozole treatment did not show a significant benefit for survival
– Death after recurrence (HR=0.90, P=0.2)
– Death due to all causes (HR=0.97, P=0.7)
Safety off treatment (5–9 y)
– Fewer endometrial cancers for anastrozole vs tamoxifen (1 vs 12) off treatment
– Fewer fractures off treatment (146 anastrozole vs. 143 tamoxifen) compared
with on treatment (375 anastrozole vs. 234 tamoxifen)
– No new morbidity/mortality concerns
Quality of Life in the Intergroup Exemestane Study (IES) 5
Years Postrandomisation
L. Fallowfield et al – Abstract #1091
Objective
To determine the QOL effects of 5 years tamoxifen and tamoxifenexemestane switch therapy in the adjuvant setting
Design
QOL from the IES at 5 years postrandomization, which is 2–3 years off
treatment
QOL was assessed by FACT-B questionnaire and for physical,
functional and breast cancer concerns using TOI. Severity and
prevalence of individual symptoms were reported
Results
All Good overall QOL persists following exemestane treatment
Loss of libido did not recover for either treatment group
Exemestane-containing arm had significant cases of vaginal discharge
compared with tamoxifen alone (8.8% vs 19.4%) at the 5-year time point
ATLAS (Adjuvant Tamoxifen, Longer Against Shorter): International
Randomized Trial of 10 Versus 5 Years of Adjuvant Tamoxifen Among
11,500 Women – Preliminary Results
R. Peto et al – Abstract #48
Objective
Preliminary results of ATLAS trial designed to determine efficacy benefit
of 5 vs 10 years of adjuvant tamoxifen
Design
ATLAS trial randomized patients completing 5 years adjuvant
tamoxifen to 5 additional years tamoxifen vs stopping tamoxifen
Results
~48,000 women-years; estimated 90% ER+ patients (several
unknown)
Recurrence rate significantly lower for 10 years tamoxifen
Recurrence rate was similar regardless of ER status, time from
initial start of therapy (5–9 and 10–14 y), and nodal status
Overall mortality and breast cancer mortality were lower for 10
years tamoxifen; however, neither were significant
Biomarkers
Biomarking the Oestrogen Dependence of Breast Cancer
M. Dowsett
William L. McGuire Memorial Lecture - Abstract #ML-1
Molecular heterogeneity is a source of potential biomarkers
Modulators of estrogen response: synthetic enzymes, catabolic
enzymes, coactivators/corepressors, signal transduction kinases,
methylators
ER molecular response: AP1, estrogen response elements,
nongenomic response
Estrogen synthesis: estradiol as a biomarker for aromatase
inhibitors
Helped reveal impact of combinations, drug vs drug comparisons,
dose comparisons, PD-PK interactions, and avoided long phase II
studies
PD biomarker reveals a more complete inhibition with letrozole vs
anastrozole (>99% vs ≥93%, P=0.0003)
Biomarking the Oestrogen Dependence of Breast Cancer
M. Dowsett
William L. McGuire Memorial Lecture - Abstract #ML-1
Intratumoral estrogen synthesis is modulated by several enzymes (ie,
AKR1C3, HSD17B7)
Prognostic/predictive biomarkers for endocrine therapy
PgR– associated with worse prognosis and benefit from tamoxifen
ATAC trial: PgR– status greatly improves benefit from anastrozole
(HR=0.43)
TransATAC: Confirms PgR– results of ATAC and reveals HER2+ staining
shortens TTR
Acquisition of resistance to endocrine therapy
ER and HER2 activation during tamoxifen resistance (MCF7 cells)
7/26 (27%) patients show changes in ER or HER2 status following
tamoxifen resistance
Biomarking the Oestrogen Dependence of Breast Cancer
M. Dowsett
William L. McGuire Memorial Lecture - Abstract #ML-1
Biomarkers as measures of endocrine response
IMPACT trial: Neoadjuvant Evaluation of Ki67 biomarker during
neoadjuvant anastrozole vs tamoxifen vs combination
– % decrease in Ki67 correlates with clinical response (P<0.02)
– % decrease in Ki67 (>2.7-fold) at 2weeks with anastrozole is
predictive of RFS (HR=2.01, P=0.002)
– HER2+ tumors correlate with a smaller % decrease in Ki67 at 12
weeks, suggesting mechanism of adaptability
– Apoptosis significantly correlates with Ki67 but is not a better
correlative of clinical response
GIDE: evaluated genes that change expression by 2-fold
mGIDE: mean change in 175 genes with the greatest change;
strong correlation to ER status (P=0.0004)
– POETIC: further categorization of genes by malignant feature
Prognostic and Predictive Value of the 21-Gene Recurrence Score
Assay in Postmenopausal, Node-Positive, ER–Positive Breast Cancer
K. Albain et al – Abstract #10
Previous study has shown that a high RS predicts prognosis for
women with node-negative breast cancer treated with tamoxifen and
predicts benefit with chemotherapy
Objective
To determine whether the 21-gene RS is prognostic for patients
receiving tamoxifen
To determine whether the RS predicts a group that does not benefit
from tamoxifen following chemotherapy
Design
The 21-gene RS was evaluated in postmenopausal, N+, ER+ patients
in 2 of 3 arms of SWOG 8814: 5 years tamoxifen (n=148) and CAF ×6
(n=219)
RS was determined by RT-PCR for 21 genes (Genomic Health, Inc)
Prognostic and Predictive Value of the 21-Gene Recurrence Score
Assay in Postmenopausal, Node-Positive, ER–Positive Breast Cancer
K. Albain et al – Abstract #10
Results
45% of patients had sufficient RNA for RT-PCR
DFS benefit of CAF-T compared with tamoxifen in high-risk patients
Greatest survival benefit for CAF-T in patients with higher RS; No
benefit in patients with low RS; benefit seen in 2 nodal subsets n>3
and n=1–3
10-Year DFS, %
RS Score, (% pts)
Tam Alone
n=148
CAF-Tam
n=219
Significant
Difference
Low <18 (40)
60 (40–76)
64 (50–75)
P=0.97
Intermediate 18–30 (28)
49 (32–63)
63 (48–74)
P=0.48
High ≥31 (32)
43 (28–57)
55 (40–67)
P=0.03
-6
-8
Tam, 4+ nodes n=54
CAF-T, 4+ nodes n=86
Tam, 1–3 nodes n=94
CAF-T, 1–3 nodes n=133
-4
Chemo benefit 4+ nodes
-2
Chemo benefit 1–3 nodes
0
5-Year Probability of Event
1
Prognostic and Predictive Value of the 21-Gene Recurrence Score
Assay in Postmenopausal, Node-Positive, ER–Positive Breast Cancer
K. Albain et al – Abstract #10
0
20
40
60
Recurrence Score
80
100
Automated Image Analysis for High-Throughput Quantitative
Detection of ER and PgR Expression Levels in Large-Scale Clinical
Studies: the TEAM Trial Experience
D. Faratian et al – Abstract #5028
Objective
To validate the use of automated image analysis for the detection of ER
and PgR expression levels
Design
This imaging study was conducted on a substudy of patients from the
TEAM trial
587 cases were arrayed on 3 tissue microarrays and compared with 197
full sections stained by IHC for ER and PgR
Results
Scoring for ER and PgR by automated imaging on tissue microarrays
showed excellent concordance
No improvement in scoring with analysis of >3 scores
Lower interclass correlation for ER, suggests automated TMA analysis is
superior to manual scoring
Cytochrome P450 2D6 Activity Predicts Adherence to Tamoxifen
Therapy
J. Rae et al – Abstract #77
CYP450 2D6 is a liver enzyme responsible for converting tamoxifen to
its more active metabolite endoxifen
Caucasians and Western Europeans
% population
CYP2D6 activity
1–2
Ultra metabolizer
70
Extensive metabolizer
20
Intermediate metabolizer
~8
Poor metabolizer
NCCTG trial 89-30-52 results: women with less active 2D6 alleles had a
shorter time to relapse, suggesting the hypothesis that 2D6 activity
decreases adherence to therapy by increasing adverse effects such
as hot flashes1
1. Goetz et al. J Cin Oncol 2005; 23:9312-9318
Cytochrome P450 2D6 Activity Predicts Adherence to Tamoxifen
Therapy
J. Rae et al – Abstract #77
Design
In the COBRA trial patients (N=297) were evaluated by AmpliChip®
CYP450 Test
Results
28 (10.5%) patients stopped taking tamoxifen because of adverse effects
within 1 year
No poor metabolizers discontinued
10.8% of the highest metabolizers stopped treatment
Linear correlation between CYP450 activity and adherence to therapy
Conclusions
Patients most likely to benefit from tamoxifen, high 2D6 metabolizers, are
most likely to be dropped from therapy
Impact of CYP2A6 Genotype on Pharmacokinetics, Safety, and
Efficacy of Letrozole Treatment in Japanese Postmenopausal
Women With Metastatic Breast Cancer
H. Minami et al – Abstract #2084
Objectives
To determine the effects of CYP2A6 genotype on letrozole treatment
outcomes of postmenopausal women with metastatic breast cancer in a
Japanese population
To determine the PK effects of CYP2A6 genotype on letrozole
Design
88 metastatic breast cancer patients treated with letrozole were grouped
by CYP2A6 alleles
Results
Patients with nonreference allele of CYP2A6 had higher plasma letrozole
No differences in safety by CYP2A6 genotype
No differences in efficacy by CYP2A6 genotype
Outcome Prediction for Clinical Stage II and III ER+ Breast Cancer Based on
Treatment Response, Pathological Stage, Tumor Grade, Ki67 Proliferation
Index, and Estrogen Receptor Status After Neoadjuvant Endocrine Therapy
M. Ellis et al – Abstract #62
Objectives
To determine predictors of relapse in letrozole- and tamoxifen-treated
neoadjuvant, stage II/III, ER+ breast cancer patients
Design
This study evaluated predictors of relapse in letrozole and tamoxifen
neoadjuvant-treated ER+ breast cancer patients with clinical stage II or III
disease
Results
Patients that were downstaged to stage 1 had 100% relapse-free survival
at 61.2 months median follow-up
Predictive model incorporating tumor stage, node status, Ki67 level,
tumor grade, ER status, and clinical response into 4 groups of patients
with RFS of 100%, 82%, 52%, and 0%
Changes in Cyclins’ and CDKs’ mRNA Expression During
Neoadjuvant Treatment With Letrozole
A. Larionov et al – Abstract #6099
Objectives
To identify the molecular signaling that is involved in the antiproliferative
response and clinical response to aromatase inhibitors
Design
Women with large ER+ tumors (N=80) were treated with neoadjuvant
letrozole for 3 months before surgery; core biopsies were taken at 10–
14 days following initiation of letrozole
Letrozole-treated tumors were assessed for proliferation by Ki67
immunohistochemistry and for gene expression by RT-PCR
Results
Letrozole decreased expression of cyclins B1, A2, and D1 and NUSAP1
but not CDKs 2 and 4
Changes in the S-G2-M cyclin kinases (cyclin A2, CDK2, cyclin B1, CDK1)
were more closely associated with response and proliferation than the
G0-G1-S cyclin kinases (CDK4 and cyclin D1)
Menopausal Hormone Therapy
and Breast Cancer Risk
A Review of HRT and Breast Cancer in Other Epidemiologic
Studies
J. Cuzick – Abstract #MS2-2
Dr. Cuzick reviewed epidemiologic evidence from several key
trials; here is a summary of key points:
Nurses health study (1976–1994)
Increased risk seen in estrogen (1.32) and estrogen + progestin
patients (1.41)
Oxford group (n=52,705; large
proportion of premenopausal women)
RR was higher with greater use of HRT
5 years post–HRT = no increased risk
Risk increased with duration of use (2.3% increase/y used)
Breast cancers were typically good prognosis (localized); no
increased risk in obese women
A Review of HRT and Breast Cancer in Other Epidemiologic
Studies
J. Cuzick – Abstract #MS2-2
Million Women Study (N=1,084,110) between 1996–2001
50–64 years; 2.6-year follow-up
Increased RR was restricted to current users (1.66): E + P (2.00), estrogen only
(1.3), tibolone (1.45; relatively small sample size)
Dose duration relationship
Increased histologies: lobular and tubular, both with dose response
relationships
RR of fatal cancer increased (1.22) for current users
Combined studies
12 years of use doubles risk
40% drop in HRT use in 2000–2003 has led to a 15% drop in ER+ breast cancer, no
drop in ER– tumors
LifT Study
Evaluated 1/2 dose of tibolone vs placebo; trial halted for increased risk of stroke
(HR=2.19, P=0.019); decreased breast cancer risk (HR=0.32, P=0.015)
The Women’s Health Initiative Randomized Trials of Menopausal
Hormone Therapy: Results and Impact on Clinical Practice
R. Chlebowski – Abstract #MS2-1
WHI objectives: to determine the balance of risks and
benefits of menopausal hormones on the overall health of
women aged 50–79 years
In 1992, 38% of postmenopausal women were on HRT
WHI estrogen + progestin (E + P) vs placebo: time to first
event was measured for a global assessment of risk
Notable HRs for E + P vs placebo:
– Invasive BC, 1.26
– CRC, 0.63
– Global index, 1.15
– 19 adverse events per 10,000 women-years
– Dementia doubled after 4 years for E + P (HR=2.05)
– Findings led to black box warnings for coronary heart disease, heart attack,
stroke, and breast cancer
– 40% drop in HRT use in 2002–2003
The Women’s Health Initiative Randomized Trials of Menopausal
Hormone Therapy: Results and Impact on Clinical Practice
R. Chlebowski – Abstract #MS2-1
WHI estrogen vs placebo
In Patient characteristics: greater BMI than normal, all had
hysterectomy, and 41% bilateral oophorectomy
HRs for several adverse effects were substantially different than the E +
P trial: CHD (0.91), breast cancer (0.77), CRC (1.08), global index (1.01)
Patients 50–59 years had greatly fewer CHD events
WHI secondary analysis
Stroke and BC risks increased irrespective of years from
menopause
Heart attacks Notable may decrease as women approach
menopause
Drugs that increase arterial vascular events have negative impact
on cognition
The Women’s Health Initiative Randomized Trials of Menopausal
Hormone Therapy: Results and Impact on Clinical Practice
R. Chlebowski – Abstract #MS2-1
Breast cancer in WHI E + P vs placebo trial
Curves for incidence of invasive breast cancer cross over at ~4 years;
1-year RR=0.48
More advanced stage at diagnosis with E + P, similar histology
Increased breast cancer with more years on study and prior therapy
Abnormal mammograms requiring short-interval follow-up increased
substantially, with an increase in events for 5 years
Conclusions
Strong trend toward fewer invasive BC on estrogen alone
Increased abnormal breast mammograph with E + P and E alone
E + P increases incidence of BC, increases delays in cancer
diagnosis; risk was independent of age
Advanced Breast Cancer Therapy
Randomised Phase III trial of Exemestane or Tamoxifen in First-Line
Hormonal Treatment of Postmenopausal Women With Metastatic
Breast Cancer
I. Chernozemsky et al – Abstract #2102 (no poster, abstract only)
Objectives
To evaluate the efficacy and safety of exemestane compared with
tamoxifen as up-front therapy in advanced breast cancer
Design
A randomized phase III study of exemestane (n=83) vs tamoxifen (n=84)
in postmenopausal women with HR+, locally recurrent, advanced breast
cancer
Patients continued therapy until disease progression
Results
ORR of 37.4% and 29.8% for patients treated with exemestane and
tamoxifen, respectively
Duration of response was longer with exemestane 59 weeks vs 39 weeks
TTP was longer with exemestane 52 weeks vs 36 weeks
Fulvestrant vs Exemestane Following Nonsteroidal Aromatase
Inhibitor Failure: First Overall Survival Data From the EFECT Trial
S. Chia et al – Abstract #2091
Objectives
To evaluate the efficacy of fulvestrant and exemestane in advanced
breast cancer following progression or recurrence on a nonsteroidal
aromatase inhibitor
Design
The phase III EFECT trial evaluated fulvestrant and exemestane
therapies in HR+, advanced breast cancer patients with progression or
recurrence following nonsteroidal aromatase inhibitors
This is the first report of overall survival from this study
Results
Median overall survival of 24.3 months vs 23.1 months in fulvestranttreated vs exemestane-treated patients
Randomized Phase II Study of Gefitinib (Iressa) or Placebo in
Combination With Tamoxifen in Patients with Hormone Receptor–
Positive Metastatic Breast Cancer
K. Osborne, et al – Abstract 2067
Objectives
To explore the efficacy of tamoxifen + gefitinib in ER+ or PR+ metastatic
breast cancer
Design
Phase II study tamoxifen + gefitinib (n=153) vs tamoxifen + placebo
(n=136) in ER+ and/or PR+, CT-naive, metastatic breast cancer
Patient stratification by (S1) no prior tamoxifen or tamoxifen >1 year
before study and (S2) prior AI
Premenopausal and postmenopausal women allowed
Results
Combination in S1 was superior for PFS (10.9 vs 8.8 mo) and clinical
benefit (50.5% vs 45.5%)
No objective responses were observed
No unexpected safety results
Survival Analysis of Sequential Use of Tamoxifen Versus Aromatase
Inhibitors for Estrogen-Positive Metastatic Breast Cancer in
Postmenopausal Women
V. Kyritsis et al – Abstract #2083
Objectives
To compare the survival effects of sequential tamoxifen and
aromatase inhibitor therapies in a community setting
Design
Retrospective analysis of patients treated in breast cancer
regional cancer centers
Metastatic breast cancer, ER+, M1 or distant relapse, >54 years
Results
Overall survival of 37 months for Tam → AI (n=221)
Overall survival of 21 months for AI → Tam (n=63)
Exemestane Resistance
The Role of Amphiregulin in Exemestane-Resistant Breast Cancer
Cells: Evidence of an Autocrine Loop
X. Wang et al – Abstract #4112
Prior screens of AI-resistant cell lines independently resistant to anastrozole
(AnaR), letrozole (LetR), and exemestane (ExeR) have identified amphiregulin
expression as a unique property of ExeR
Objective
To determine the role of amphiregulin in exemestane-resistant breast cancer
Design
This is a preclinical study evaluating exemestane resistance in the MCF7 ExeR
model system
Results
Amphiregulin expression is greatly elevated in ExeR by an ER-dependent
mechanism
Proliferation in ExeR can be blocked by inhibiting amphiregulin (siRNA),
estrogen (ICI 182,780), EGFR (AG1478), and MAPK (U0126)
Exe
ER
AREG
EGFR
(Proposed Model by Authors)
MAPK
Proliferation
IGF-1 / Insulin Signaling
Energy Balance, Insulin, and Breast Cancer
M. Pollak – Plenary Lecture 3
Obesity is epidemic: estimated 20% of US population >30 BMI, with an
increasing trend in prevalence
Evidence linking energy, insulin, and breast cancer is a culmination of
many small interdisciplinary correlations
Known Breast
Cancer Risks
BMI
Breast Cancer
Prognosis
Death and distant
recurrence
Link to IGF-1/Insulin
Obesity is linked to hyperinsulinemia
Caloric intake
Excess energy intake increases
insulin levels
Birth weight
Core blood IGF-1 levels correlate with
birthweight
Adolescent growth
spurt
Adolescent growth is stimulated by
IGF-1
Lack of exercise
Death
Exercise reduces insulin levels
Energy Balance, Insulin, and Breast Cancer
M. Pollak – Plenary Lecture 3
Insulin/IGF-1
Conserved function in nematode → suggests more than just a pancreatic β-cell–
secreted hormone
Stimulates cellular proliferation and metabolism
More energy intake = greater requirement for insulin to signal proliferation
IGF-1 signaling in breast cancer
IGF signaling overlaps with HER2 pathway; IGF-1R is involved in resistance to
HER2
IGF receptors in most breast cancers
Link between insulin and breast cancer proliferation rate
IGF-deficient mice are smaller, less likely to develop tumors, and tumors are
smaller
IGF:IGFBP-3 predicts mammographic density
Modest evidence of breast cancer risk associated with serum IGF-1 levels and
IGF polymorphisms
Energy Balance, Insulin, and Breast Cancer
M. Pollak – Plenary Lecture 3
Strategies for inhibiting IGF-1 signaling in cancer
Anti-IGF/IGFR therapies
– >$1 billion pharmaceutical investment
– Includes ligand and receptor mAbs and RTKIs
Rapamycin analogues by target mTOR downstream of IGF
Metformin
– Lowers hyperglycemia in type 2 diabetes by lowering hepatic glucose
uptake
– LKB1, upstream of AMPK, is a tumor suppressor involved in metformin
activity
– Inhibits MCF7 breast cancer translation and cell growth
– Long-term use leads to reduced cancer risk 0.62
Opportunities to consider personalizing treatment based on BMI?
Gene Expression Profiles of ER+/PgR– Breast Cancer Are Associated With
Genomic Instability and Akt/mTOR Signaling, and Predict Poor Patient
Outcome Better Than Clinically Assigned PgR Status
C Creighton et al. – Abstract #33
Objectives
To molecularly characterize the ER+/PgR– breast tumors with respect to
ER+/PgR+ and ER-/PgR- tumors
Design
Gene expression was evaluated in human breast tumors for which ER
and PgR status was determined by IHC
Gene signatures for ER+/PgR+ and ER–/PgR– were identified based on
published data sets (Wang et al Lancet, 2005; and Miller et al PNAS,
2005)
Results
ER+/PgR– tumors had a mixture of 3 different gene expression subtypes
(ER+/PgR+, ER– /PgR– , and unique ER+/PgR– signature)
Gene signature for ER+/PgR- predicts poorer prognosis (P=0.0006);
more prognostic than clinical assay
Significantly greater copy number alterations in ER+/PgR–
PI3K/mTOR-responsive genes are manifested in ER+/PgR– tumors
Insulin-Like Growth Factor I Activates Gene Transcription Programs
Strongly Associated With ER– Breast Cancer and Poor Patient
Prognosis
C. Creighton et al – Abstract #1113
Objectives
To identify correlations in IGF-1 signaling to breast cancer
subtypes and prognosis
Design
Compared IGF-1 gene signature to public data sets of human
breast tumors
Results
IGF-1 gene signature is present in majority of ER– and ~25% ER+
breast tumors
Patients with IGF-1 gene signature had significantly poorer
prognosis by metastasis-free survival, distant metastasis -free
survival, and disease-specific survival
Insulin Sensitivity Gene Expression and Efficacy of Systemic
Adjuvant Therapy in Women With Early Breast Cancer
A. Gennari et al – Abstract #3093
Objectives
To evaluate the prognostic value of an insulin sensitivity–gene
score (IS) in early breast cancer patients according to type of
adjuvant systemic therapy
Design
IS was evaluated on two merged databases (GSE3494 and
GSE2990)
Median value of the score was determined as the cut-off for lowand high-risk categories
Results
Relapse-free survival (RFS) for all 438 patients: HR=1.56 (P=0.01)
RFS for 130 patients on tamoxifen (HR=3.35, P<0.001)
RFS for 267 patients with no therapy (HR=1.12, P=0.60)
Phase II Double-Blind Randomized Trial of Daily Oral RAD001 (Everolimus)
Plus Letrozole (LET) or Placebo (P) Plus LET as Neoadjuvant Therapy for
ER+ Breast Cancer
J. Baselga et al – Abstract #2066
Objectives
To determine the benefit of adding RAD001 plus LET in
postmenopausal ER+ newly diagnosed preoperative breast
cancer
Design
Untreated, invasive, M0 breast cancer
Patients randomized to 16 weeks of either LET alone or LET +
RAD001
Tumor biopsies were taken at screen, 2 weeks, and surgery
Results
More responders in patients receiving combination assessed by
ultrasound (58% vs 47%; P=0.035) and by clinical response
(68.1% vs 59.1%; P=0.062)
Phase II Double-Blind Randomized Trial of Daily Oral RAD001 (Everolimus)
Plus Letrozole (LET) or Placebo (P) Plus LET as Neoadjuvant Therapy for
ER+ Breast Cancer
J. Baselga et al – Abstract #2066
Overall Clinical Response
RAD001 + LET, n=138
LET, n=132
CR
18 (13.0)
12 (9.1)
PR
76 (55.1)
66 (50.0)
No change, n (%)
34 (24.6)
39 (29.5)
PD, n (%)
6 (4.3)
13 (9.8)
NA/NE, n (%)
4 (2.9)
2 (1.5)
ORR (CR + PR), n (%)
94 (68.1)
78 (59.1)
95% CI
60.3–75.9
50.7–67.5
Safety of combination was generally acceptable; most frequent
(>2%) grade 3/4 AEs in RAD001 + LET: hyperglycemia (5.1%),
stomatitis (2.2%), infections (2.2%), interstitial lung
disease/pneumonitis (2.2%)
Biomarker Analysis of a Phase II Double-Blind Randomized Trial of Daily Oral
RAD001 (Everolimus) Plus Letrozole or Placebo Plus Letrozole as Neoadjuvant
Therapy for Patients With Estrogen Receptor Positive Breast Cancer
H. Gardner et al – Abstract #4006
Objectives
To identify potential pharmacodynamic indicators of response and predictive
biomarkers of response for RAD001 in breast cancer
Design
This is a biomarker analysis of the neoadjuvant study of letrozole vs
letrozole + RAD001 in ER+, newly diagnosed, localized breast cancer
Tumor biopsies were evaluated at screening, day 15, and at surgery
following neoadjuvant treatment
Results
Downregulation of cyclin D and PgR with letrozole alone
Downregulation of phospho-S6 with RAD001 + letrozole
Patients treated with RAD001 showed a near doubling of cell cycle response
by Ki67
No single predictive biomarker of RAD001 cell cycle response was identified
Pan-HER Strategies
HKI-272, an Irreversible Pan-erbB Receptor Tyrosine Kinase Inhibitor:
Preliminary Phase II Results in Patients With Advanced Breast Cancer
H. Burstein et al – Abstract #6061
Objectives
To explore the safety and efficacy of HKI-272, an oral RTKI that
irreversibly inhibits ErbB-2 receptors
Design
Phase II study of 240 mg daily HKI-272 in erbB-2 gene-amplified
advanced breast cancer patients until disease progression; patients
were stratified by prior trastuzumab treatment
Results
N=102
HKI-272 was generally well tolerated; the most common grade 3/4 AE
was diarrhea (26%)
Prior Trastuzumab
No Prior Trastuzumab
Independent assessment
ORR, %
22
53
Median PFS, wk
16
33
Systems Approach to Growth Factor Signaling and to Therapeutic
Intervention in Breast Cancer
Y. Yarden et al – Abstract #MS1-1
Pertuzumab (Omnitarg) is a humanized mAb that has pan-HER activity
by blocking HER2 dimerization to HER1, HER2, HER3, and HER4
650
600
550
500
450
400
350
300
250
200
150
100
50
0
Vehicle control
Omnitarg (30/15 mg/kg/w ip
Herceptin (30/15 mg/kg/w ip
Omnitarg + Herceptin
0
10
20
30
40
50
60
Treatment period (days)
70
80
Safety of Pertuzumab Plus Trastuzumab in a Phase II Trial of Patients With
HER2-Overexpressing Metastatic Breast Cancer Which Had Progressed
During Trastuzumab Therapy
P. Fumoleau et al – Abstract #73
Objectives
Determine safety of pertuzumab + trastuzumab
Design
Safety evaluation of trastuzumab (6 mg/kg Q3W with a 4 mg/kg loading
dose; or 6 mg/kg Q3W with 8 mg/kg loading dose) + pertuzumab (420
mg Q3W with 840 mg loading dose)
Up to 3 lines of prior cytotoxic therapy and/or prior trastuzumab with
disease progression
Results
Study fully enrolled (n=61)
Only 1 grade 3 treatment-related event (diarrhea)
2 patients had decreasing left ventricular ejection fractions that were
asymptomatic
ORR=18.2%, clinical benefit rate = 39.4% (n=33)
Patient Management
Comparison of Joint Problems as Reported by Patients in a
Randomized Adjuvant Trial of Anastrozole and Letrozole
L. Renshaw et al – Abstract #2072
Objectives
To compare the effects of anastrozole, letrozole, and tamoxifen on joint pain
and stiffness
Design
Patients were given either 12 weeks of letrozole followed by 12 weeks
anastrozole or 12 weeks anastrozole then 12 weeks letrozole
Following AI treatment all patients were prescribed tamoxifen to complete 5
years of hormonal therapy
Results
Significantly more joint symptoms on AIs than tamoxifen
No difference in joint symptoms with anastrozole or letrozole
55% of patients with symptoms on anastrozole had no symptoms on
letrozole, and 56% of patients with symptoms on letrozole had no symptoms
on anastrozole
Conclusion
Switching AI therapy is rational strategy for resolving joint problems
A Prospective Study Comparing Clinical Rheumatological Findings and
Tenosynovial and Synovial Changes on Magnetic Resonance Imaging of Breast
Cancer Patients Receiving Adjuvant Aromatase Inhibitors or Tamoxifen
L. Morales et al – Abstract #3053
Objectives
To investigate changes in rheumatologic features and magnetic
resonance imaging (MRI) of hands and wrists of patients receiving an AI
or tamoxifen
Design
A prospective study of rheumatologic features in postmenopausal
women with early breast cancer receiving either tamoxifen (n=5) or
an AI (n=12)
Patients were evaluated at baseline and 6 months by questionnaire,
rheumatologic examination, and MRI of hands and wrists
Results
More than half of all patients had preexisting musculoskeletal
disorders
AI users were significantly more likely to develop new symptoms,
experience worsening of symptoms, including decreased grip
strength, and tenosynovial changes
Risk Factors for Joint Symptoms in the ATAC Trial
I. Sestak et al – Abstract #2071
Objectives
Determine To investigate potential risk factors for joint symptoms in women
receiving endocrine therapy for early breast cancer
To evaluate the impact of anastrozole and tamoxifen therapies on risk factors for
joint symptoms
Design
The ATAC trial is a randomized, phase III study of anastrozole alone, tamoxifen
alone, or tamoxifen + anastrozole combination in women with early breast
cancer
Joint symptoms were defined as arthralgia, arthritis, arthrosis, or joint disorder
(COSTART)
Results
Increases in joint symptoms were observed in patients with prior HRT (12.3%),
hormone receptor positivity (8.2%), obesity (6.8%), prior chemotherapy (5.9%),
and treatment with anastrozole (5.7%)
Anastrozole treatment and prior HRT use had an additive effect for risk of joint
symptoms (P=0.02)
Endometrial Status in the Intergroup Exemestane Study
(IES) Up to Two Years Posttreatment
G. Bertelli et al – Abstract #2078
Objectives
To compare the effects on the uterus of tamoxifen-exemestane
switch to tamoxifen alone
Design
Patients in the IES subprotocol were evaluated for endometrial
thickness
Results
Majority of patients had uterine abnormalities at baseline
following 2–3 years of tamoxifen
51% of patient with abnormal endometrial thickness (≥5 mm)
resolved to normal levels following exemestane compared with
29% on tamoxifen alone
Abnormal endometrial thickness resolved following the end of
treatment in the tamoxifen arm
The Effects of Exemestane, Anastrozole, and Tamoxifen on Bone Mineral Density
and Bone Turnover Markers in Postmenopausal Early Breast Cancer Patient:
Preliminary Results of N-SAS National Surgical Adjuvant Study) BC04, the TEAM
Japan Substudy
T. Aihara et al – Abstract #2086
Objectives
To determine differences in exemestane, anastrozole, and
tamoxifen on bone mineral density and bone turnover markers in
postmenopausal women with breast cancer
Design
N-SAS BC 04 is a subprotocol of the TEAM trial comparing 5
years of anastrozole, exemestane, and tamoxifen-exemestane
switch
Results
At 24 months: BMD increased with tamoxifen and decreased with
exemestane and anastrozole
Bone turnover markers (BAP and NTX) decreased with tamoxifen
and increased with exemestane and anastrozole
A Phase III Study of the Effect of Denosumab Therapy on Bone Mineral
Density in Women Receiving Aromatase Inhibitors for Nonmetastatic
Breast Cancer
G. Ellis et al – Abstract #47
Objectives
To evaluate the effects of the RANKL inhibitor denosumab on
bone mineral density (BMD) in women receiving adjuvant
aromatase inhibitor (AI) therapy
Design
HR+, nonmetastatic breast cancer patients were randomized to
receive denosumab or placebo every 6 months for 4 doses
Patients were stratified by duration of AI therapy (6 vs >6 mo)
Results
N=252; significant increases in lumbar spine BMD were 5.5% (12
mo) and 7.6% (24 mo)
Significant improvements in total body and total hip BMD were
seen in denosumab-treated patients
AEs for patients receiving denosumab were comparable to AI
therapy alone
The ZHO-FAST Trial: Zoledronic Acid Effectively Inhibits Aromatase
Inhibitor Associated Bone Loss in Postmenopausal Women With Early
Breast Cancer Receiving Adjuvant Letrozole: 24-Month BMD Results
R. De Boer et al – Abstract #501
Objectives
To determine the effectiveness of zoledronic acid (ZA) in preventing
aromatase inhibitor–associated bone loss
Design
In the Z-FAST study postmenopausal early breast cancer patients were
randomized to receive the IV bisphosphonate ZA either as an up-front
regimen with letrozole or on a delayed regimen when a patient’s T-score
decreased to <–2 while on letrozole
Results
N=1066
At 24 months, up-front ZA patients showed higher BMD than delayed ZA
patients in lumbar spine (8.2%) and total hip (4.7%)
16% of delayed ZA patients initiated therapy
34.4% of patients receiving up-front ZA returned to normal T-score (>–1)
The Effect of Zoledronic Acid on Aromatase Inhibitor–Associated Bone
Loss in Postmenopausal Women With Early Breast Cancer Receiving
Adjuvant Letrozole: The Z-FAST Study 36-Month Follow-Up
A. Brufsky et al – Abstract #27
Objectives
To determine the effectiveness of ZA in prevention of aromatase inhibitor–
associated bone loss
Design
In the Z-FAST study postmenopausal early breast cancer patients (N=602) were
treated with letrozole and randomized to receive ZA (4 mg IV every 6 mo) either
as an up-front regimen or on a delayed regimen when a patient’s T-score
decreased to <–2
This is an update from the 36-month follow-up of the Z-FAST
Results
Increases in mean lumbar and total hip BMD of 3.72% and 1.66% in the ZA upfront arm compared with decreases of 2.95% and 3.51% in the delayed arm;
absolute differences in BMD between arms were significant (P<0.001)
ZA increased BMD to normal levels (T>–1) in 40.4% of up-front patients and 7.6%
of delayed patients
ZA-induced increases in BMD were progressive through 36 months
Health-Related Quality of Life and Psychological Distress in Japanese Patients
With Breast Cancer Treated With Tamoxifen, Exemestane or Anastrozole for
Adjuvant Therapy: A Phase III Randomized Study of National Surgical Adjuvant
Study of Breast Cancer (N-SAS BC) 04
M. Takehara et al – Abstract #2088
Objectives
To compare the HRQOL impact of adjuvant treatment with
exemestane, tamoxifen, and anastrozole in postmenopausal
women with early breast cancer
Design
N-SAS BC 04 is a subprotocol of the TEAM trial evaluating lipid
parameters and BMD in patients receiving 5 years adjuvant
exemestane, anastrozole, or tamoxifen-exemestane switch
Patients completed HRQOL scales at baseline and 3 and 12
months
Results
HRQOL scales benefited tamoxifen over anastrozole and
exemestane
Prevalence of Cognitive Complaints Is Not Higher In Postmenopausal
Breast Cancer Patients Before Adjuvant Hormonal Therapy Compared to
Heathy Controls
C. Schilder et al – Abstract #1099
Objectives
To determine the prevalence of cognitive problems in
postmenopausal breast cancer patients before adjuvant therapy
Design
Postmenopausal patients from TEAM study were compared with
a healthy group of friends or families
Assessments were made for memory, concentration, thinking,
and language problems by interview; anxiety/depression by
Hopkins Symptom Check List (HSCL); and fatigue by
Multidimensional Fatigue Scale (MFI)
Results
Cognitive complaints were not higher in breast cancer patients
Higher depression scores were associated with concentration
problems in both breast cancer patients and controls
NCIC CTG MAP.3: Enrollment and Study Drug Adherence of Ethnic
Minority Women in a Breast Cancer Prevention Trial
B. Moy et al –Abstract #3048
Objectives
To identify correlations between patient ethnicity and adherence
to study drug in the NCIC CTG MAP.3 trial
Design
The NCIC CTG MAP.3 trial enrolled 4560 postmenopausal women
at elevated risk for breast cancer to receive either placebo or
exemestane as oral daily regimens
Drug adherence was assessed by pill counts at 6 months
Results
Enrollment by race: white (86%), black (5%), Asian (1%), American
Indian (<1%), mixed race (<1%), and missing (7%)
Ethnic minorities were significantly less likely than whites to be
>90% adherent to study drug (P=0.03)