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

12s Breast Cancer—HER2/ER
520 Poster Discussion Session (Board #10), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Reduction in Ki-67 in benign breast tissue of high-risk premenopausal
women with the SERM acolbifene. Presenting Author: Carol J. Fabian,
University of Kansas Medical Center, Kansas City, KS
Background: Selective Estrogen Receptor Modulators (SERMs) are approved
for reduction of risk for breast cancer; however, uptake and use is
limited. We conducted a pilot study of a 4th generation SERM to determine
tolerability and effect on tissue biomarkers in healthy women at high risk
for development of breast cancer. Methods: Premenopausal women at
elevated risk for breast cancer were screened by random periareolar fine
needle aspiration (RPFNA) performed during the follicular phase of the
menstrual cycle. Women were eligible if breast epithelial cells exhibited
evidence of cytologic hyperplasia with or without atypia, as well as Ki-67
�2% by immunocytochemistry. Following 6-8 months of open-label
acolbifene (20 mg/d), the RPFNA was repeated. The primary endpoint was
modulation of the proportion of cells that expressed Ki-67. Body composition
(DEXA), pelvic sonography, mammographic breast density, and serum
levels of IGF-1/IGFBP3 and several bioavailable hormones were assessed
pre and post intervention. Results: 76 women were screened by RPFNA,
with 25 eligible and enrolled in the intervention over a 9 month period. All
25 (7 on oral contraceptives) subjects completed the study, had a second
RPFNA, and were evaluable. Median Ki-67 at baseline was 4.6% (range
2.4 – 21.9%) and off study 1.4% (range 0 – 6.6%); median change was a
reduction of 3.0% (range -20.2% to �2.8%; decreased in 23, increased in
2) or a relative reduction of 77%. The end-of-study Ki-67 was significantly
less than baseline (p�0.001, 2-tailed Wilcoxon test). There were no
statistically significant changes in cytomorphology over this short intervention
period. There was a marginal effect on breast density (16 decreased; 8
increased; p�0.067). Adverse events were minimal with greatest grade of
3 reported by 2 subjects, grade 2 by 7 subjects, and grade 1 by 11
subjects. No serious adverse event was reported and no subject discontinued
the study due to an AE. Conclusions: Based on preliminary evaluation
showing favorable modulation of proliferation and minimal adverse events,
further investigation of acolbifene, a fourth generation SERM, as a breast
cancer chemoprevention agent for premenopausal women appears warranted.
Supported by NO1-CN-35135.
522 Poster Discussion Session (Board #12), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Mucin-1 protein and mRNA expression in breast cancer: Predictive value
for therapy response and survival after neoadjuvant chemotherapy. Presenting
Author: Bruno Valentin Sinn, Charité Universitätsmedizin Berlin,
Berlin, Germany
Background: Mucin-1 (MUC1) is expressed in normal epithelial cells and in
breast cancer. Immunotherapeutic agents targeting MUC1 are currently
tested in clinical trials. Methods: We evaluated the frequency of MUC1
expression by immunohistochemistry (IHC; n � 691) and quantitative
RT-PCR (qRT-PCR; n � 286) in formalin-fixed paraffin-embedded (FFPE)
pre-treatment biopsies from patients of the GeparTrio trial (NCT 00544765).
mRNA levels were analyzed as a continuous variable, a distribution-based
cut-off was chosen for IHC data. The predictive value for therapy response
and survival after neoadjuvant anthracycline/taxane-based chemotherapy
(CTX) was evaluated. Results: MUC1 was detectable by IHC in 95%.
qRT-PCR covered a dynamic range of 3 orders of magnitude. IHC and
mRNA data were correlated (p � 0.001). MUC1 was detected in higher
quantities in HR� tumors (p � 0.001), the lowest levels were found in
HR-/HER2- tumors (p � 0.001). High MUC1 protein and mRNA expression
were associated with lower probability of pathologic complete response
(pCR) in the overall population (p � 0.001) and in HR� (p � 0.004 and �
0.001), HER2- (p � 0.001) and HR�/HER2- tumors (p � 0.001). In
multivariable logistic regression, MUC1 was independently predictive (high
MUC1 protein: odds ratio (OR) 0.464, 95% CI 0.300 – 0.719, p � 0.001;
MUC1 mRNA (per 20-dCT unit): OR 0.673, CI 0.546 – 0.829, p � 0.001).
MUC1 protein and mRNA expression were associated with longer patient
survival in the overall population (p � 0.03 and � 0.001) and in HER2tumors
(p � 0.005 and � 0.001). MUC1 mRNA was also prognostic in
HR� (p � 0.001) and HR�/HER2- tumors (p � 0.001). In multivariable
analysis, protein and mRNA expression were independently prognostic
(high MUC1 protein: hazard ratio (HR) 0.388, CI 0.166 – 0.907, p �
0.029; MUC1 mRNA per 20-dCT unit: HR 0.763, CI 0.595 – 0.909, p �
0.005). Conclusions: MUC1 is frequently expressed in breast cancer and
detectable by IHC and qRT-PCR from FFPE tissue. Despite its association
with HR� status, it provides independent predictive information for
therapy response and survival after neoadjuvant CTX. In clinical immunotherapy
trials, MUC1 expression may serve as a predictive marker.
521 Poster Discussion Session (Board #11), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Aspirin use and mortality in women with stage I-III breast cancer: A
population-based study. Presenting Author: Thomas Ian Barron, Trinity
College Dublin, Dublin, Ireland
Background: Recent observational studies have associated aspirin (ASP)
use with large reductions in breast cancer (BC) mortality. However, these
studies have provided limited information on dose or duration of ASP use,
key issues relevant to translation of the results into clinical practice.
Methods: Linked National Cancer Registry Ireland and prescription refill
data (General Medical Services Ireland, GMS) were used to identify women
aged 50-80 with incident stage I-III BC (2001-2006). ASP use was defined
as high or low by the median number of ASP days’ supply (85 days) in the
90 days pre-diagnosis. Full capture of ASP use is expected as the GMS
provides all medications, including ASP, without charge. Hazard ratios
(HR) with 95% confidence intervals (CI) for ASP use and (i) all-cause and
(ii) BC-specific mortality were estimated using Cox proportional hazards
models adjusted for age, stage, grade, ER, PR, HER-2 status, comorbidity
and other drug exposures. Analyses were stratified by tumor stage and nodal
status. Results: 2714 women with stage I-III BC were identified (median
follow-up � 3.3 years), of whom 642 (23.7%) used ASP in the 90 days pre
diagnosis. High and low ASP exposure groups were strongly predictive of
post-diagnosis ASP exposure levels (High: mean post diagnosis exposure
duration – 83% of follow-up; dose – 75mg/day in 91% of women. Low:
mean post-diagnosis exposure duration – 58% of follow-up; dose –
75mg/day in 80% of women). Women with any ASP use had a nonsignificant
reduction in all-cause (HR 0.85 95%CI 0.68, 1.06) and
BC-specific (HR 0.86 95%CI 0.65, 1.15) mortality, compared to ASP
unexposed women. However, in the dose response analysis high ASP
exposure was associated with a significant reduction in all-cause (HR 0.70
95% CI 0.51, 0.95) and BC-specific (HR 0.63 95% CI 0.42, 0.96)
mortality. No reduction was observed for low ASP exposure. The benefits of
ASP exposure were greater in early stage, node negative disease. Conclusions:
Only high ASP exposure was associated with a significant reduction in all
cause and BC-specific mortality. These findings may explain inconsistent
results from previous studies. Our findings can inform future clinical trials.
523 Poster Discussion Session (Board #13), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Impact of expression levels of mRNA HER2 and ESR1 on the pathologic
complete remission (pCR) rate after neoadjuvant treatment with anthracycline-taxane
containing chemotherapy in combination with trastuzumab in
the GeparQuattro trial. Presenting Author: Jens Bodo Huober, University of
Tuebingen and Kantonsspital St. Gallen, St. Gallen, Switzerland
Background: Recent data suggest that benefit from (neo)adjuvant trastuzumab
might be related to expression of HER2 and estrogen receptor
(ESR1). We investigated mRNA levels of HER2 and ESR1 in core biopsies
in HER2 positive tumors of the GeparQuattro trial and compared it to
response to neoadjuvant treatment. Methods: In the GeparQuattro trial 445
HER2� pts were included based on local testing and received neoadjuvant
trastuzumab and chemotherapy (either4xEC¡4 x docetaxel (D) or4xEC
¡ 4 x D/capecitabine (C) or 4xEC¡4x D ¡4 X C). In 217 available
pretherapeutic core biopsies HER2 levels were analysed by IHC, SISH and
quantitative RT-PCR using predefined cutoffs; pCR was defined as ypT0is;
ypN0. Results: Only 73% of the tumors (158 of 217) were centrally HER2
positive (cHER2�) by IHC/SISH, while 59 tumors (27%) were centrally
HER2 negative (cHER2-). As all pts had received neoadjuvant trastuzumab,
this gave us the possibility to evaluate response of HER2- tumors to
trastuzumab. The pCR rate of cHER2� tumors was significantly increased
(46.8%, p�0.0005) compared to cHER2-, who had a pCR rate of only
20.3%. Similar results were obtained if HER2 positivity was determined by
RT-PCR (pCR rate 50% vs. 17.4%, p�0.0005). Assessment of HER2
status by RT-PCR showed a concordance of 86.2% with the IHC/SISH
status. In uni- and multivariate logistic regression analysis of cHER2�
cases including continuous HER2 and ESR1 mRNA levels the HER2
mRNA expression was significantly associated with prediction for a pCR in
(univ.: OR 1.43, 95% CI 1.11-1.83, p�0.005; multiv.: OR 1.42, 95% CI
1.11-1.83, p�0.006). In the cHER2� tumors, the pCR rate was similar
for ESR1 mRNA positive (47.4%) and ESR1 negative tumors (46.3%).
Conclusions: Only pts with cHER2� tumors independently of the method
used have an additional benefit in terms of a pCR from adding trastuzumab
to chemotherapy. In cHER2-negative patients the pCR rate is comparable
to the pCR rate in the non trastuzumab treated population. Increasing
HER2 mRNA levels were associated with a better response to trastuzumab
based treatment in cHER2 � tumors.
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