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

622 General Poster Session (Board #12A), Sat, 8:00 AM-12:00 PM
ADAM17 as a novel therapeutic target for HER2-positive breast cancer.
Presenting Author: Sumainizah Sukor, St Vincent’s University Hospital,
Dublin, Ireland
Background: Although the HER2 gene is amplifiend/overexpressed in
15-20% of breast cancers, only a proportion of these patients benefit from
anti-HER2 therapy. Clearly additional biomarkers and/or therapeutic targets
are necessary to enhance efficacy and improve outcome in these
patients. Here, we tested the hypothesis that inhibition of ADAM17mediated
release of HER ligands may enhance response to trastuzumab
and lapatinib. Methods: The ADAM17-selective inhibitor, PF-5480090
(Pfizer) both alone and in combination with lapatinib, trastuzumab or 5FU
was tested for potential growth inhibitory effects on a panel of 4 HER2positive
breast cancer cell lines (BT474, MDA-MB-453, SKBR3 and
JIMT-1). Results: Using the MTT viability assay, treatment with 1 �M TMI-2
resulted in a significant reduction in cell proliferation compared to vehicle
control in BT474 (p�0.01), MDA-MB-453 (p � 0.005), JIMT-1 (p�0.002)
and SKBR3 cells (p � 0.005). Addition of PF-5480090 to lapatinib
resulted in a significant reduction in cell growth compared to lapatinib
alone (JIMT-1: p � 0.005; SKBR3: p � 0.005; MDA-MB-453: p �
0.005), while addition of PF-5480090 to trastuzumab resulted in significant
reduction in cell growth compared to trastuzumab alone (JIMT-1: p �
0.005; SKBR3: p � 0.005; MDA-MB-453: p�0.001). Addition of
PF-5480090 to 5FU resulted in significant reduction in growth compared
to 5FU alone (JIMT-1: p � 0.005; SKBR3: p � 0.005; MDA-MB-453:
p�0.001). Consistent with its ability to block proliferation, addition of
PF-5480090 significantly reduced release of TGFalpha (BT474: p�0.003;
JIMT1: p�0.023; SKBR3: p�0.036 and MDA-MB-453: p�0.014).
Conclusions: Inhibitionof ADAM17 resulted in growth inhibitory responses
in HER2-positive breast cancer cell lines. Furthermore, addition of PF-
5480090 to lapatinib, trastuzumab or 5FU resulted in significant growth
inhibition compared to these agents alone. We propose that inhibition of
ADAM17 may be used in combination with existing treatments for
HER2-positive breast cancer. Acknowledgement. The authors thank SFI
(SRC award, 08/SRC/B1410 to MTCI) for funding this work.
624 General Poster Session (Board #12C), Sat, 8:00 AM-12:00 PM
Phase I/II trial of primary chemotherapy with nonpegylated liposomal
doxorubicin, paclitaxel, and lapatinib in patients with HER2-positive,
early-stage breast cancer. Presenting Author: Sherko Kuemmel, Kliniken
Essen Mitte, Evang. Huyssens Stiftung/Knappschaft , Essen, Germany
Background: Combinations of trastuzumab and anthracyclines in HER2positive
breast cancer are highly active but associated with a high
incidence of cardiotoxicity. The risk of cardiac damage can be significantly
reduced through liposomal encapsulation of anthracyclines. This phase I/II
study was initiated to evaluate the combination of non-pegylated liposomal
doxorubicin (NPLD), paclitaxel and lapatinib as primary treatment for
patients with early stage, HER2-positive primary breast cancer. Methods:
Patients with newly diagnosed HER2-positive (IHC 3� or FISH�) early
stage (T1c N1-2 or T2 N0-2) breast cancer were treated with NPLD
(60mg/m2 ; day 1), paclitaxel (175mg/m2 , day 1) and lapatinib (750-1500
mg orally daily) in 3-week intervals for up to 6 cycles. The primary
endpoints were dose-limiting toxicities (DLT) and pathological complete
response (pCR). Secondary endpoints include safety, incidence of cardiac
events, and clinical response. Exploratory endpoints include molecular
markers for sensitivity or resistance to chemotherapy and/or lapatinib
evaluated. Results: A total of 84 patients have been included to date.No
DLTs were observed and the maximum tolerated doses were NPLD
60mg/m2 , paclitaxel 175mg/m2 and lapatinib 1500mg. Recommended
phase 2 doses (P2D) were NPLD 60mg/m2 , paclitaxel 175mg/m2 and
lapatinib 1250mg. The treatment was generally well tolerated and associated
with toxicities that were consistent with the known side-effects of the
individual agents. No cardiac event has been observed to date. Preliminary
efficacy data confirm a pCR breast rate of 41.7% and pCR rate in breast
and lymph nodes of 37.5%, in 24 evaluable patients treated at �P2D.
Conclusions: The combination of NPLD, paclitaxel and lapatinib is well
tolerated and has high antitumour activity in patients with HER2-positive
primary breast cancer. The phase II part of the study is ongoing and
updated results will be presented.
Breast Cancer—HER2/ER
37s
623 General Poster Session (Board #12B), Sat, 8:00 AM-12:00 PM
HER2 assessment and Ki-67 labeling index in a cohort of male breast
cases: The Ich Network on Cancer Research (INCaRe) experience. Presenting
Author: Giovanna Masci, Humanitas Cancer Center, IRCCS, Rozzano,
Italy
Background: The overall incidence of male breast cancers (MBC) is around
1% of all breast cancers and is on the rise.Most of our current knowledge
regarding its biology and treatment strategies has been extrapolated from
its female counterpart. However, from literature data, it is more and more
evident that MBC has biological differences compared with female breast
cancer (FBC). While hormone receptors are more frequently positive in
MBC than in FBC, HER-2 seems to be less expressed in MBC than in FBC,
with data ranging from 0 to 18%; no data on Ki-67 have been so far
reported. Methods: We retrospectively analyzed the immunohistochemical
expression of hormone receptors status, HER-2 protein expression, and
Ki-67 in 76 consecutive MBCs, treated within the Humanitas Institutes
Network on Cancer Research (INCaRe). HER-2 determinations were carried
out according to ASCO/ACP and NEQAS guidelines: cases with score 2� at
IHC were further examined by fluorescent in situ hybridation (FISH).
Results: From 2000 to 2011, we treated 76 male breast cases (age 25-87,
median 64): 72 patients (94%) had ductal carcinoma and 4 had rare
histotypes (2 papillary, 1 mucinous and 1 cribryform). Thirthy-two of 76
patients (42%) had positive axillary lymph-nodes, while 6 (8%) were
metastatic at diagnosis. Of these, estrogen receptor and progesterone
receptor were positive in 96% and 93% patients respectively; HER-2,
evaluable in 67 patients, was positive in 11 (16%). Ki-67 was evaluable in
75 patients and was � 20% in 24 cases (32%), with 20/24 (26%) with
Ki-67 � 30%. Grading was evaluable in 65 patients: G1 in 2 (3%), G2 in
41(63%) and G3 in 22 (34%), respectively. Conclusions: In these series,
MBC show different patterns from FBC, with some favorable aspects such
as higher hormone receptor status and much lower HER-2 expression and
some unfavorable features, such as higher Ki-67 values. Although further
studies are needed to confirm these data, different treatment strategies
would be suggested in MBC than its female counterpart.
625 General Poster Session (Board #12D), Sat, 8:00 AM-12:00 PM
An assessment of disease features and immune response in breast cancer
patients that did not recur after receiving HER2 peptide, AE37 vaccine in a
randomized phase II trial. Presenting Author: Diane F Hale, Brooke Army
Medical Center, San Antonio, TX
Background: In a phase I trial of AE37, the Ii-Key hybrid of HER2 derived
peptide AE36 (776-790), administered with immunoadjuvant GMCSF
demonstrated the vaccine to be safe and capable of stimulating CD4�helper T cells with HER2 specific anti-tumor activity. Here we present analysis of
immune markers and patient feature that may impact recurrence from an
ongoing prospective, randomized, single-blinded Phase IIb trial of
AE37�GMCSF v GMCSF alone in adjuvant high risk breast cancer (BC)
patients. Methods: After completion of standard therapy; disease-free, node
positive or high risk node negative BC patients (pts) were randomized to
receive either AE37�GMCSF or GMCSF in 6 monthly intradermal inoculations.
Immunologic responses were measured using [ 3H]-thymidine incorporation
assay (in vitro), delayed-type hypersensitivity (DTH) reactions (in
vivo) and T regulatory cells (Tregs). Among those vaccinated recurrent pts
(VR) are compared to non recurrent (VNR) pts. Results: We have vaccinated
109 pts with 8.3% recurrence rate at 2 year median follow up. VR v VNR
were younger (44 v 50 yo p�0.11), had higher grade (67% v 44%
p�0.32), more ER/PR- (44% v 38% p�0.75), larger tumors (89% v 50%
p�0.06), and node positive (89% v 70% p�0.37). No difference for HER2
status (IHC 3�, 44% v 49% p�0.64). Both VR and VNR responded to
vaccine though the mean DTH and proliferative stimulation index was
approximately 10% less in VR pts (18 v 20 p�0.73; 1.96 v 2.2 p�0.77
respectively). The most predictive measure was change in Tregs with VR pts
less likely to decrease their Tregs levels (50% v 76% p�0.17) after
vacination and more likely experience increased Tregs (17% v 8%
p�0.48). A decrease in Tregs had an inverse trend towards recurrence
(p�0.17). Conclusions: Preliminarily, it appears most pts immunologically
respond to vaccine though slightly less for VR in most assays. The changes
of Tregs appear to correlate best with disease recurrence. Whether this
reflects an association with disease status or a failure of the vaccine is yet to
be seen. These levels may become important in predicting risk for clinical
recurrence in future vaccine trials.
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