Annual Meeting Proceedings Part 1 - American Society of Clinical ...

524 Poster Discussion Session (Board #14), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Vasomotor (VM) and musculoskeletal (MSK) symptoms and association
with outcomes on extended adjuvant letrozole therapy: Analyses from NCIC
CTG MA.17. Presenting Author: Pedro Emanuel Rubini Liedke, Massachusetts
General Hospital, Avon International Breast Cancer Center, Boston,
MA
Background: Surrogate markers of clinical outcomes can potentially guide
cancer therapy. New onset MSK symptoms and VM symptoms on aromatase
inhibitors (AI) for hormone receptor positive (HR�) early breast cancer
(EBC) have been investigated as markers of clinical outcomes, but results
have been conflicting. MA.17 showed improved disease free survival (DFS)
with letrozole (L) as extended adjuvant therapy after 5 years of tamoxifen
(T). We performed this exploratory analysis of new onset symptoms and
their association with clinical outcomes in the MA.17 trial. Methods:
Patients (pts) with HR� EBC were randomized to receive L or placebo (P)
for 5 years after 5 years of T. Symptoms were collected according to CTC v.
2.0 at baseline, 1 month (mo), 6 mos, and every 12 mos thereafter.
Analyses included pts with new symptoms of any grade who received
therapy and excluded pts with baseline symptoms, EBC not HR�, and
deaths/ relapses prior to each time point. Symptoms were categorized as
VM - hot flashes/flushes, flushing, or sweating; and MSK - arthritis,
arthralgia, myalgia, bone pain, or MSK other. Multivariate Cox Models
adjusting for age, nodal status, duration of T and prior chemotherapy were
used for analysis of DFS, distant DFS (DDFS), and overall survival (OS)
assessed before unblinding. Hazard Ratios [HR] and 95% confidence
intervals (CI) for patients with either VM or MSK symptoms are presented
below for L using pts with no symptoms as controls. Results: Emergent VM
symptoms were associated with improved DFS and DDFS on L (Table). No
association was found for MSK symptoms at any time point. No association
between either MSK or VM and OS was found at any time point.
Conclusions: New VM symptoms initiating with extended letrozole were
associated with improved outcomes. Similar findings have been seen with
up-front AI therapy. Our results should be confirmed as they are of potential
significance in guiding therapy.
Month of assessment
VM
1
HR (95% CI)
6 12
DFS 0.22 (0.05-0.92) 0.25 (0.07-0.85) 0.42 (0.15-1.18)
DDFS
MSK
0.17 (0.02-1.26) 0.13 (0.02-0.99) 0.54 (0.16-1.81)
DFS 2.33 (0.54-10.04) 0.70 (0.24-2.07) 0.68 (0.24-1.91)
DDFS 1.91 (0.25-14.74) 0.57 (0.13-2.58) 0.45 (0.10-2.15)
526 Poster Discussion Session (Board #16), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Common polymorphisms in the estrogen receptor-1 may determine risk of
hot flashes in early breast cancer patients using tamoxifen. Presenting
Author: Vincent O. Dezentje, Department of Clinical Oncology, Leiden
University Medical Center, Leiden, Netherlands
Background: In breast cancer patients the occurrence of hot flashes as
common side effect of tamoxifen therapy may be associated with effective
estrogen receptor antagonism dependent on genetic variations of metabolic
enzymes and the estrogen receptor. Methods: 742 early breast cancer
patients who were randomized to receive tamoxifen, followed by exemestane
after 2.5 to 3 years within the Tamoxifen Exemestane Adjuvant
Multinational (TEAM) Trial were genotyped for 30 germ line genetic
variants of 11 enzymes that are involved in the tamoxifen metabolism and
the estrogen receptor 1 (ESR1). These genetic variants were related to the
occurrence of hot flashes during the first year of tamoxifen use (primary
aim) and during the complete tamoxifen treatment period (secondary aim).
A multivariable logistic regression was used to adjust for age and adjuvant
chemotherapy. Results: No genetic variant was associated with the occurrence
of hot flashes during the first year. 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 (CG/CG vs
CG/other � other/other: adjusted odds ratio 0.44, 95% CI 0.21-0.92;
p�0.03), ESR1 PvuII XbaI TA haplotype (TA/TA � TA/other vs other/other:
adjusted odds ratio 1.86, 95% CI 1.09-3.14; p�0.02) and age (adjusted
odds ratio 0.94, 95% CI 0.92-0.97; p�0.001) were associated with the
occurrence of hot flashes during the total tamoxifen treatment period. No
association was found between the CYP2D6 predicted phenotype and hot
flashes. Conclusions: Common polymorphisms in the estrogen receptor-1
might help to predict the occurrence of hot flashes in breast cancer patients
treated with adjuvant tamoxifen. If replicated, this may provide clinicians
with a tool to offer more personalized hormonal therapy.
Breast Cancer—HER2/ER
13s
525 Poster Discussion Session (Board #15), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Genetic variants associated with toxicity-related discontinuation of adjuvant
aromatase inhibitor (AI) therapy. Presenting Author: Norah Lynn
Henry, University of Michigan Medical Center, Ann Arbor, MI
Background: Discontinuation of adjuvant AI therapy due to intolerable
symptoms occurs in up to 30% of patients. Predictors of which patients will
be unable to tolerate these medications have not been defined. We
hypothesized that inherited variants in candidate genes are associated with
treatment discontinuation because of AI-associated toxicity. Methods: We
prospectively evaluated reasons for treatment discontinuation in women
with hormone receptor positive breast cancer initiating adjuvant AI through
a multicenter, prospective, randomized clinical trial of exemestane (exe)
versus letrozole (let). Using multiple genetic models, we evaluated potential
associations between 136 single nucleotide polymorphisms (SNP) in
24 candidate genes, selected a priori, primarily with roles in estrogen
metabolism and signaling, and discontinuation of AI therapy because of
toxicity. To account for multiple comparisons, statistical significance was
defined as p�0.0003. Results: Of the 467 enrolled patients who had
available germ line DNA, 152 (33%) discontinued AI therapy because of
toxicity. After adjusting for multiple covariates, multivariable analyses
revealed that two inherited genetic variants in ESR1, which encodes
estrogen receptor (ER) alpha, and one in CYP19A1 were associated with
increased risk of discontinuation of AI therapy because of toxicity (Table). A
variant in NCOR1 (ER co-repressor) was associated with decreased risk of
discontinuation of letrozole because of toxicity. Conclusions: Variants in
genes involved in estrogen metabolism and signaling may be associated
with toxicity of AI therapy.
Statistical model Gene SNP AI HR (95% CI) p value
Recessive CYP19A1 rs28566535 Either 8.2 (2.7-24.9) �0.0002
Exe 8.1 (1.6-41) 0.012
Let 7.5 (1.5-38.1) 0.016
ESR1 rs9322335 Either 4.2 (2-8.6) �0.0001
Exe 10.5 (2.9-38.7) �0.0004
Let 3.3 (1.2-9.1) 0.018
ESR1 rs9322336 Either 3.7 (1.8-7.4) �0.0004
Exe 7.2 (2.7-19.5) 0.0001
Let 3 (1-8.8) 0.050
Additive NCOR1 rs1065822 Either 0.7 (0.5-0.9) 0.015
Exe 1.1 (0.7-1.6) 0.77
Let 0.3 (0.2-0.6) �0.0002
527 Poster Discussion Session (Board #17), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Impact of adjuvant trastuzumab on outcomes of HER2-positive breast
cancer patients treated with HER2-targeted therapy in the metastatic
setting. Presenting Author: Rashmi Krishna Murthy, University of Texas
M. D. Anderson Cancer Center, Houston, TX
Background: Trastuzumab (T) was approved for the adjuvant treatment of
women with early-stage, HER-2 overexpressing (HER2�) breast cancer in
2006. There are limited data outlining the outcomes of patients with
HER2� breast cancer who receive adjuvant T-based therapy and then
receive T and/or lapatinib in the metastatic setting. Methods: We identified
540 patients with HER2� breast cancer treated with T or lapatinib as part
of their first-line treatment for metastatic disease from 01/1997 to
11/2011. HER-2 positivity was assessed by immunohistochemistry (score,
3�) or fluorescence in situ hybridization (HER2/CEP17 ratio � 2). We
excluded 17 patients from this analysis because they were either lost to
follow-up or received less than 2 cycles of therapy at the institution.
Statistical analyses were performed using the chi-square test to compare
proportions between groups and the Cox proportional hazards regression
analysis to compare survival times and estimate the corresponding hazard
ratio with 95% confidence interval. Results: Of the 523 patients eligible for
analysis, 76 patients had received T in the adjuvant setting and 447 had
not. In the group who did not receive adjuvant T, 48% (213/447) of
patients achieved a complete or partial response (CR/PR), whereas only
13% (14/76) achieved a CR/PR in the adjuvant T group (P�.0001). After
adjustment for age, disease-free interval, post-menopausal status, stage at
presentation, ER/PR status, and nuclear grade, the odds ratio was 0.27 (CI
0.13 - 0.56, p � 0.0004). Overall survival from first evidence of metastasis
was significantly longer in the group who did not receive adjuvant T (39
months vs. 24 months, HR � 1.8, 95% CI 1.3-2.4). For OS, the adjusted
hazard ratio was 1.5 (CI 1.04 - 2.1, p � 0.029). Age, DFI and stage were
also significant predictors of OS. Conclusions: Patients with HER2�
metastatic breast cancer who were T naive, had a higher response rate
(CR/PR) to front line HER2 targeted therapy and a longer OS compared to
patients with metastatic HER2� breast cancer who received T in the
adjuvant setting. These findings highlight the importance of recognizing a
pre-treated population and calls for further research in this area.
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