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

606 General Poster Session (Board #10A), Sat, 8:00 AM-12:00 PM
A neoadjuvant, randomized, open-label phase II trial of afatinib (A) versus
trastuzumab (T) versus lapatinib (L) in patients (pts) with locally advanced
HER2-positive breast cancer (BC). Presenting Author: Mothaffar F. Rimawi,
Baylor College of Medicine, Houston, TX
Background: A is an oral, irreversible, ErbB Family Blocker. This Phase II
study investigated A, L and T monotherapy in pts with locally advanced
HER2 (ErbB2)-positive BC in a 6-wk preoperative treatment window.
Methods: This international, multi-institutional, open-label, randomized,
Phase II study included pts with HER2-positive locally advanced disease
Stage IIIa–c and inflammatory BC with no evidence of distant metastatic
disease, at least one tumor lesion �5 cm in diameter, and an ECOG score
0–1. Pts agreed to fresh tumor biopsies for biomarker analyses at trial
entry, and at 3 and 6 wks of treatment. Pts received 50 mg A once daily,
1500 mg L once daily, or T 2 mg/kg weekly after a loading dose of 4 mg/kg
for 6 wks. Results: 73 pts were screened and 29 pts randomized and
treated* (10 pts A, 8 pts L, 11 pts T). All pts were female, median age 49
(range 25–88) yrs, 28/29 pts had Stage III disease, 3/29 pts had
inflammatory BC, median tumour size was 6.4 cm, and median time to
treatment was 1.4 months (range 0–3.4). After 6 wks of treatment, OR was
assessed using RECIST 1.0 (Table). Best objective response during
treatment was 80%, 75%, and 36.4% in the pts treated with A, L, and T,
respectively. Drug-related AEs assessed by CTCAE v.3.0 occurred in all pts
treated with A, 75% of pts treated with L, and 45.5% of patients treated
with T (largely GI and skin-related AEs for A and L, and GI and
musculoskeletal AEs for T). Three pts treated with A and one pt with L had
drug-related AEs of CTCAE Grade 3. Conclusions: Afatinib showed a high
OR rate in this Phase II trial of a 6-wk preoperative treatment window and
compared favorably to two approved agents in HER2-positive BC, albeit at a
slightly higher rate of AEs. Further trials will be needed to identify the
potential role of A as a single agent or in combination with other agents in
HER2-positive BC.
A L T
Partial response 7 (70.0)* 6 (75.0) 4 (36.4)
Stable disease 2 (20.0) 1 (12.5) 6 (54.5)
Progressive disease 0 (0.0) 1 (12.5) 1 (9.1)
*One pt not included in this table withdrew from the study on Day 11;
end-of-study tumor assessment showed partial response. Study closed early due
to slow accrual.
608 General Poster Session (Board #10C), Sat, 8:00 AM-12:00 PM
Correlation of quantitative p95HER2 and HER2 protein expression with
pathologic complete response (pCR) in HER2-positive breast cancer
patients (pts) treated with neoadjuvant (NEO) trastuzumab-containing
therapy. Presenting Author: Jose Caetano Villasboas, University of Miami
Sylvester Comprehensive Cancer Center, Miami, FL
Background: Elevated p95 [HER2-M611-CTF (carboxy-terminal-fragment)
also known as p110 or p95HER2] expression has been correlated with poor
outcomes in HER2� pts with metastatic breast cancer treated with
trastuzumab (T); however, limited data have been presented on the
correlation between p95 and pCR to T in the NEO setting, where p95 was
measured by immunohistochemistry. In the current study, we sought to
determine whether quantitative p95 and HER2 expression correlated with
pCR in pts treated with T � chemotherapy in the NEO setting. Methods:
HER2 expression (H2T) was quantified by HERmark in 47 breast tumors
using formalin-fixed, paraffin-embedded sections. Tissue remained in 40
cases to measure p95 by VeraTag and compare to a previously published
cutoff (Clin Cancer Res 16:4226, 2010). pCR data were available for 45
cases. pCR was defined as the absence of invasive disease in the breast.
Results: The overall pCR rate was 46.7% (ER�: 14.3% vs. ER-: 75%;
Wilcoxon rank p�0.0001) and was significantly associated with higher
H2T levels (p�0.02). In ER- subjects (N�24), no difference in H2T levels
was observed between pCR vs non-pCR groups [median H2T�111.5 (IQR
63.4-162.2) vs 150.5 (IQR 43 – 226.2), respectively; p�0.721]. However,
within the ER� group (N�21), H2T levels were significantly higher in
the pCR group vs non-pCR group [median H2T�254 (IQR 181.5-584.5) vs
37.3 (IQR 16.4-89); p�0.024]. Using multivariate logistic regression,
increasing log(H2T) (p � 0.011), ER-negativity (p � 0.027) and low p95
(p � 0.074) were found to correlate or trend with pCR. Conclusions: pCR
was significantly associated with high H2T expression in ER� HER2�
breast cancer pts who received NEO therapy with T � chemotherapy. A
trend towards pCR was seen in tumors that had low p95. These data
suggest that quantitative H2T and p95 may provide additional information
on response to T-based regimens in breast cancer, particularly ER� breast
cancer. Additional investigation into the possible relationship between
quantitative levels of HER2 and p95 expression and T response in the NEO
setting in larger cohorts is warranted.
Breast Cancer—HER2/ER
33s
607 General Poster Session (Board #10B), Sat, 8:00 AM-12:00 PM
Elevated pretreatment serum activin A and progression-free and overall
survival in trastuzumab-treated metastatic breast cancer. Presenting Author:
Allan Lipton, Penn State Hershey Medical Center, Hershey, PA
Background: About half of HER2-positive metastatic breast cancer patients
will respond tofirst-line trastuzumab-containing therapy, but most will
progress within a year. Trastuzumab resistance remains a vexing clinical
problem, and better predictive and prognostic biomarkers are needed.
Activin A is a TGF-B superfamily member and regulates cell proliferation,
apoptosis, differentiation, and immune response. Methods: Serum activin A
was measured using ELISA (R&D Systems, Minneapolis, MN) in 60
metastatic breast cancer patients before starting first-line trastuzumabcontaining
therapy. Progression-free survival (PFS) and overall survival
(OS) were analyzed using the Kaplan-Meier method and Cox modeling with
both continuous and dichotomous (median) serum activin A analyses.
Results: Pretreatment serum activin A levels averaged 2376 pg/ml, and had
a median of 629 pg/ml and 25th and 75th quartile values of 406 and 1791
pg/ml, respectively. Patients who were hormone receptor negative had
significantly higher activin A levels (median 1287 vs 450 pg/ml, p�0.002).
Higher serum activin A was significant on a continuous basis for predicting
reduced PFS to first-line trastuzumab-containing therapy (p�0.003), and
for predicting shorter OS (p�0.0001). When analyzed using a dichotomous
(median) cutpoint, the elevated serum activin A cohort had a significantly
reduced PFS (HR 2.79, p �0. 002) (median 6.6 mo vs. 31.1 mo) and OS
(HR 5.24, p �0.0001) (median 19.6 mo vs. median not reached). In
multivariate analysis for PFS with other covariates (age, line of therapy, CA
15-3, and hormone receptor status), activin A was the only significant
covariate (p�0.021). In multivariate analysis for OS, activin A (p�0.002)
and CA 15-3 (p�0.03) remained significant as prognostic factors.
Conclusions: Elevated pretreatment serum activin A predicts reduced PFS
and overall survival in metastatic breast cancer patients treated with
first-line trastuzumab-containing therapy. Activin A deserves further study
as an adverse biomarker, and to select patients most likely to respond to
activin A-targeted therapy.
609 General Poster Session (Board #10D), Sat, 8:00 AM-12:00 PM
Incidence and risk of central nervous system (CNS) metastases as a site of
first recurrence in patients (pts) with HER2-positive (HER2�) breast
cancer treated with adjuvant trastuzumab (T). Presenting Author: Erin
Macrae Olson, The Ohio State University Comprehensive Cancer Center,
Stefanie Spielman Comprehensive Breast Center, Columbus, OH
Background: T is the mainstay of adjuvant therapy in pts with HER2�
breast cancer. CNS disease as the site of first relapse after exposure to
adjuvant T has been reported, although the overall incidence and relative
risk (RR) of this remains unclear. We performed an up-to-date metaanalysis
to determine the risk of CNS metastases as the first site of
recurrence in pts with HER2� breast cancer who received adjuvant T.
Methods: Pubmed databases were searched for articles from 1966 to 2011.
Abstracts presented at the American Society of Clinical Oncology and the
San Antonio Breast Cancer Symposium were also searched for relevant
clinical trials. Eligible studies include randomized trials with adjuvant T
administered for 1 year in pts with HER2� breast cancer who reported CNS
metastases as first site of disease recurrence. Statistical analyses were
conducted to calculate the summary incidence, RR, and 95% CIs using
fixed effects inverse variance models. Results: A total of 9,020 pts were
included. The incidence of CNS metastases as first site of disease
recurrence in HER2� pts receiving adjuvant T was 2.56% (95% CI 2.07%
to 3.01%) compared to 1.94% (95% CI: 1.54% to 2.38%) in HER2� pts
who did not receive adjuvant T. The RR of CNS as first site of relapse in
T-treated pts was 1.35 (95% CI 1.02 to 1.78, p�0.038) compared with
control arms without T therapy. In subgroup analyses, there was no
significant difference in CNS incidence or risk between pts treated with
concurrent versus sequential T (p�0.29), weekly versus every 3 week T
(p�0.56), and no difference in the T groups between studies due to
median follow up time in years (p�0.68). No evidence of publication bias
was observed (Q�1.78; P�0.62; I2 � 0.0%). Conclusions: This is the
largest report to date demonstrating that adjuvant T is associated with an
increased risk of CNS metastases as a site of first recurrence in HER2�
breast cancer pts.
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