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

631 General Poster Session (Board #13B), Sat, 8:00 AM-12:00 PM
Prognostic role of HER2 loss after neoadjuvant therapy in patients with
HER2-positive operable breast cancer. Presenting Author: Valentina Guarneri,
Department of Oncology, Hematology and Respiratory Diseases,
Modena University Hospital, Modena, Italy
Background: Emerging literature data are consistently showing that a
change in HER2 status adversely affect the prognosis of breast cancer
patients. Aim of the present analysis is to evaluate the prognostic impact of
HER2 loss in breast cancer patients with HER2 positive disease treated
with neoadjuvant therapy with or without anti-HER2 agents. Methods: A
total of 94 HER2 positive patients were identified from a prospectively
maintained database. The first cohort (A) includes 40 patients treated with
chemotherapy alone (enrolled before 2005). The second cohort (B)
includes 54 patients treated with neoadjuvant chemotherapy in combination
with anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression
was evaluated by IHC or FISH on pre-treatment core biopsy and on
surgical specimen after neoadjuvant therapy. Patients were considered as
having HER2 positive disease in case of IHC 3� or FISH amplification.
Results: No imbalance in terms of age, stage at diagnosis, tumor grade and
expression of hormone receptor was observed in the two cohorts. In detail,
67% and 61% of the patients have a co-expression of HER2 and hormone
receptor in cohort A and B, respectively. The rate of breast conservation was
significantly higher in cohort B (chemotherapy�anti-HER2 agents) as
compared to cohort A (chemotherapy alone) (59% vs 38%, p�0.048).
Similarly, the rate of pathologic complete response (pCR) was significantly
higher in cohort B (42.6% vs 7.5% in cohort A, p�0.001). A change in
HER2 expression from biopsy to post-therapy samples was observed in
35% of the patients in cohort A vs 9% of the patients in cohort B (p�0.04).
No patients achieving a pCR have recurred so far vs 25% of the patients
with less than pCR (p�0.005). The rate of recurrence was significantly
higher for patients experiencing a change in HER2 expression (47% vs
15% in patients with no change, p�0.007). At 5 years, 53% of the
patients with Her2 change and 75% of the patients without Her2 change
were alive and free of recurrence (log rank test: p�0.03). Conclusions: The
rate of HER2 loss was significantly higher in patients not receiving
anti-HER2 agents as a part of the neoadjuvant therapy. In this series, the
change in HER2 status has a negative prognostic impact.
633 General Poster Session (Board #13D), Sat, 8:00 AM-12:00 PM
Effect of acquired resistance to lapatinib in HER2-positive breast cancer
cells on the Bcl-2 family members MCL-1 and BAX. Presenting Author:
Alex J. Eustace, National Institute for Cellular Biotechnology, Dublin City
University, Dublin, Ireland
Background: Lapatinib (L) is approved for the treatment of trastuzumab (T)
resistant HER2 positive metastatic breast cancer. Not all HER2 positive
tumors respond to L and patients who initially respond frequently relapse,
due to the development of resistance to L. Understanding the molecular
changes associated with L resistance may lead to the identification of
targets to overcome resistance. Methods: SKBR3 cells were treated with
either 250 nM L, or 125nM L and 5 �g/ml T twice weekly for 6 months to
establish the resistant cell lines SKBR3-L and -TL. We measured by TUNEL
assay the effect of L on apoptotic induction in SKBR3, -L and -TL cells.
Gene array analysis of the SKBR3, -L and -TL cells identified differences in
the expression of apoptosis-related genes, which were validated by immunoblotting.
Finally using combinations of obatoclax (O) and L were tested in L
resistant cells. Results: In SKBR3 cells, L (500 nM) induces apoptosis
(15.8 � 2.0%) compared to untreated controls (4.6�2.7%), whilst in
SKBR3-L and -TL cells L did not induce significant apoptosis compared to
controls. Gene array analysis showed that BAX mRNA is down regulated 3.2
fold in SKBR3-L cells compared to the parental cells. In SKBR3-TL cells,
MCL-1 mRNA expression is increased 2.1 fold, whilst BAX mRNA is down
regulated 2.1 fold compared to the parental cells. Immunoblotting confirmed
that BAX protein expression was reduced in the SKBR3-L (1.5 fold,
p�0.058) and significantly reduced in SKBR3-TL cells (2.0 fold, p�0.039)
compared to SKBR3. MCL-1 protein expression was significantly increased
in the SKBR3-L (1.6 fold, p�0.035) and -TL cells (2.3 fold, p�0.031)
compared to SKBR3. Combining O (200 nM) and L (500 nM) in both
SKBR3 and SKBR3-L cells produced greater growth inhibition than either
drug on its own (SKBR3: 86.9�1.0% vs 73.5�3.1% for L (p�0.01) and
44.7�7.7% for O, (p�0.01); SKBR3-L: 54.2� 8.6% vs 26.9�2.4% for L
(p�0.027) and 33.8�10.7% for O (p�0.04)). Conclusions: Extended
exposure to L in SKBR3-L and –TL cells alters the apoptotic response to L.
O alone and in combination with L results in growth inhibition in L resistant
cells.
Breast Cancer—HER2/ER
39s
632 General Poster Session (Board #13C), Sat, 8:00 AM-12:00 PM
Effect of neratinib (N) alone and in combination with trastuzumab (T) in
HER2-positive breast cancer (BC) cell lines. Presenting Author: Alexandra
Canonici, Molecular Therapeutics for Cancer Ireland, Dublin, Ireland
Background: HER-2, a member of the transmembrane receptor tyrosine
kinase ErbB family, is over-expressed in approximately 25% of BC. HER-2
targeted therapies, in particular, T, a monoclonal antibody targeting
HER-2, and lapatinib (L), a reversible HER-2 tyrosine kinase inhibitor, have
been shown to significantly improve the prognosis for HER-2 positive BC
patients. However, resistance to T and/or L is a significant clinical problem.
The aim of this study is to assess the activity of N (HKI-272), an irreversible
HER-2 tyrosine kinase inhibitor, in HER-2 overexpressing BC cell lines,
including T and/or L resistant cells. Methods: Using proliferation assays, the
effect of N was assessed alone and in combination with T in HER-2 positive
BC cell lines, including T and/or L resistant cell lines. The effect of N on
HER-2 and downstream signalling molecules, Erk and Akt, was determined
by immunoblotting. Results: HER-2 positive BC cell lines, including T
and/or L resistant cells, are sensitive to N alone with IC50 values
(concentration which inhibits 50% of growth) ranging from 1 to 280 nM.
The combination of N and T has additive effects in SkBR3 and BT474
which are sensitive to T and also in SKBR3-Lwhich are resistant to L. In the
cell lines HCC1954, HCC1954-L, MDA-MB-453, JIMT1 and SKBR3-HL
which are resistant to T, combined treatment with T and N showed no
enhancement compared to N alone. Finally, N decreased phosphorylation
of HER-2, Erk and Akt in all cell lines tested. Conclusions: Our results
suggest that N should be studied in patients with HER-2 positive BC,
including patients with T and/or L resistant BC. We also demonstrate that N
in combination with T may be more effective than either agent alone in T
sensitive cells.
634 General Poster Session (Board #13E), Sat, 8:00 AM-12:00 PM
Evaluation of Ile655Val HER2 polymorphism associated with cardiac
toxicity following the administration of trastuzumab in women with breast
cancer. Presenting Author: Caroline Diorio, URESP, Centre de Recherche
FRSQ du CHA Universitaire de Québec, Quebec City, QC, Canada
Background: Trastuzumab is well tolerated without major side effects
except for cardiac toxicity. Although a number of clinical parameters have
been associated with trastuzumab-associated cardiac toxicity (TACT), there
is some indication that genetic variation of the HER2 gene may play a toxic
role in a population of metastatic breast cancer patients. However, this
finding needs confirmation and we looked at a population of non-metastatic
breast cancer. This study aimed to evaluate the association between
cardiac toxicity and HER2 [Ile655Val] polymorphism in non-metastatic
breast cancer patients treated with trastuzumab. Methods: The Ile655Val
HER2 polymorphism was assessed in 73 women using TaqMan technology.
For this study, the genotyping was performed using DNA extracted from
normal breast tissue located at more than 1 cm of any other lesions. Charts
review was used to collect information on TACT which was defined as any
decline in LVEF � 10 % from the baseline to � 55 % or a decline in LVEF
� 5%to�50 % (lower limit of normal). The Fisher exact test was used to
evaluate the association between cardiac toxicity and HER2 polymorphism.
Results: No deviation from the Hardy-Weinberg equilibrium has been
observed for the allele and genotype frequencies. The distribution of HER2
polymorphism was 3 Val/Val (4%), 18 Ile/Val (25%) and 52 Ile/Ile (71%).
In this population, 19% (14/73) developed a cardiac toxicity. We found
that 29% (6/21) of Ile/Val or Val/Val carriers compared to 15% (8/52) of
Ile/Ile carriers showed TACT, but this association did not reach statistical
significance (P � 0.21). Conclusions: HER2 Ile655Val polymorphism may
be an efficient marker of TACT considering this tendency with this small
cohort of patients. Larger sample is needed to strengthen this conclusion,
since this result may influence on prescribing decision for adjuvant
chemotherapy and anti-HER2 therapy in HER2 positive patients.
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