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

8s Breast Cancer—HER2/ER
504 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Intrinsic subtype and its clinical significance in early node-negative breast
cancer: Results from two randomized trials of adjuvant chemoendocrine
therapy. Presenting Author: Ewan K. A. Millar, The Kinghorn Cancer
Centre, Sydney, Australia
Background: Gene expression profiling has identified four main intrinsic
subtypes of breast cancer which have distinct clinical behaviours and
responses to therapy. A simplified immunohistochemical (IHC) panel can
provide meaningful discrimination and help guide patient management.
Methods: Using tissue microarrays (TMA) created from two randomized
trials of adjuvant chemoendocrine therapy in node negative early breast
cancer (IBCSG VIII and IX,n� 1220) we assessed intrinsic subtype as
follows: “luminal A” (LA): ER and/or PR present, Ki-67 low (�median:
19%), HER2-; “Luminal B” (LB): ER and/or PR present, Ki-67
high(��19% median) and/or HER2� (IHC 3� or FISH amplified); HER2
enriched: ER and PR negative, HER2 positive (IHC 3� or FISH amplified),
Triple Negative (TNP): ER, PR and HER2 negative. p53� and high cyclin
D1 expression were then assessed to determine if they provided any further
additive discriminatory value. Results: The standard definitions of intrinsic
subtype demonstrated a significant difference in disease-free survival
between the subtypes in both trials VIII and IX (p� 0.02), but this was not
significant in multivariate analysis. The discrimination between luminal A
and B tumors could not be improved upon by the addition of p53 or cyclin
D1 expression. The standard definitions demonstrated that TNP and
HER2-enriched tumors benefited from the addition of chemotherapy to
endocrine therapy, but LA and LB did not. p53� was associated with a
poorer prognosis in ER� luminal tumors but improved prognosis in ERnon-luminal
tumors (Interaction p � 0.002). Conclusions: Intrinsic subtyping
using a panel of ER, PR, HER2 and Ki67 provides meaningful
prognostic information to help guide patient management in early breast
cancer. Whilst it predicts benefit from the addition of chemotherapy in TNP
and HER2-enriched tumors it did not in this series do so for LB. Although
p53 status did not improve the definition of luminal tumors, p53�
appeared to have a divergent effect on outcome dependent on ER status.
LBA506 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
Evaluation of lapatinib as a component of neoadjuvant therapy for HER2�
operable breast cancer: NSABP protocol B-41. Presenting Author: Andre
Robidoux, National Surgical Adjuvant Breast and Bowel Project and Centre
Hospitalier de l’Universite de Montreal, Montreal, QC, Canada
The full, final text of this abstract will be available at
abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3,
2012, and in the Annual Meeting Proceedings online
supplement to the June 20, 2012, issue of Journal of
Clinical Oncology. Onsite at the Meeting, this abstract will
be printed in the Sunday edition of ASCO Daily News.
505 Oral Abstract Session, Sun, 8:00 AM-11:00 AM
13-gene signature to predict rapid development of brain metastases in
patients with HER2-positive advanced breast cancer. Presenting Author:
Renata Duchnowska, Military Institute of Medicine, Warsaw, Poland
Background: Brain metastases (BM) of breast cancer constitute an important
part of therapeutic failures and are associated with severe morbidity
and mortality. The risk of BM is particularly high in HER2� advanced
breast cancer pts. We earlier developed in this group a 13-gene signature
strongly predicting for rapid development of BM (J Clin Oncol 2008; 26:
45s). Now, we validated these results in an independent group of pts and
on culture model system. Methods: Discovery group included 87 samples
analyzed using cDNA synthesis, annealing, selection, extension, ligation
and array hybridization (DASL). Independent validation group included 75
samples analyzed using quantitative reverse-transcriptase PCR. 3D culture
validation model system used immortal, non-tumorigenic human MCF10A
breast epithelial cells with and without ectopic expression of HER-2 and
RAD51, a DNA double strand break repair gene (one of the three genes of
this group overexpressed in 13-gene signature). The number and morphology
of breast acini were scored using indirect immunoflourescence and
confocal microscopy. Results: Median brain metastasis-free survival (BMFS)
in the discovery group for ‘high’ vs. ‘low’ expression signature tumors was
36 months and 66 months, respectively (P�0.0068), and in the validation
group 54 and 86 months, respectively (P�0.032). Short BMFS was also
associated with ER-negativity; BMFS in the cohort of ‘high’ 13-gene
signature and ER- tumors vs. other 3 groups was 31 months and 66 months
in discovery group, and 41 and 77 months in validation group (P�0.0001
and P�0.02, respectively). Overexpression of RAD51 in MCF-10A breast
cells altered their three-dimensional acinar morphology and increased the
percentage of invasive structures by 6.5 fold, both in the presence and
absence of HER2 overexpression. Conclusions: 13-gene signature and
ER-negativity predict rapid development of BM in HER� advanced breast
cancer pts. RAD51 may promote aggressiveness in breast epithelial cells.
These data may be useful in the design of BM preventive trials and may
prompt new treatment strategies.
507 Clinical Science Symposium, Sat, 1:15 PM-2:45 PM
Tumor PIK3CA mutations, lymphocyte infiltration, and recurrence-free
survival (RFS) in early breast cancer (BC): Results from the FinHER trial.
Presenting Author: Sherene Loi, Jules Bordet Institute, Brussels, Belgium
Background: Tumor PIK3CA mutations (mts) and lymphocyte infiltration
(LI) are prognostic in BC, but their importance is unknown in HER2positive
(HER2�) BC treated with adjuvant trastuzumab (T). Methods: The
FinHER trial randomized 1010 patients (pts) with pN� or high-risk pN- BC
to 3 cycles of docetaxel (D) or vinorelbine, followed by 3 cycles of FEC. Pts
with HER2� BC were further randomized to 9 weeks of T or no T (n�232).
Pts treated with D and T had superior outcome in prior analyses. BC
samples were subjected to somatic hotspot mt profiling (Sequenom) and
quantification of percentage tumor LI using full-face H&E sections. RFS
and interactions with T were explored with Kaplan-Meier and Cox regression
analyses. Results: The median FU time was 62 months. 935 (92.6%) and
687 (68.1%) tumors underwent LI and mt analysis, respectively. Correlation
of LI assessment between 2 pathologists was 0.78 (p�0.001). 54 mts
detected in 13 genes were evaluated. PIK3CA mts (exons 1,2,9,13,18,20)
was present in 25.3% (n�174) and ERBB2 mt in 4.5% (n�31) BCs. Only
1 AKT mt was found and none in KRAS, BRAF, NRAS or PTEN. In
ER�/HER2-, HER2� and ER-/HER2- subtypes the prevalence of PIK3CA
mts was 30.2%, 19.5% and 9.2%; ERBB2 mt 6.3%, 1.9% and 2.6%,
respectively (both p�0.05). Neither PIK3CA nor ERBB2 mts were associated
with RFS overall or within BC subgroups. No interaction was found for
the benefit with T and presence of PIK3CA mt in HER2� BC (interaction
p�0.17 T vs no T). Increasing LI was associated with favorable RFS in
ER-/HER2- BC (continuous score adjusted p�0.032); 3-y RFS was 90%
with extensive LI (�30% infiltrated) vs 66% with non-extensive LI
(p�0.007). In HER2� BC, whilst there was no association with prognosis
overall, there was a significant interaction with the benefit from T vs. no T
and increasing LI (continuous score interaction p�0.042) with 3-yr RFS
96% vs 78% for extensive and non-extensive LI treated with T respectively
(p�0.014). Conclusions: We report 3 clinically relevant findings from this
large clinical trial dataset: 1) PIK3CA mts were not prognostic; 2) LI is a
strong prognostic factor in ER-/HER2- BC and 3) for the first time that
extensive LI predicts benefit from adjuvant T.
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