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

656s Tumor Biology
10500 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Gene expression-based predictors of chemotherapy response in basal-like
breast cancer. Presenting Author: Aleix Prat, Lineberger Comprehensive
Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Background: The Basal-like subtype is generally associated with high
chemo-sensitivity, but not all tumors respond and/or benefit to the same
extend. In this study, we sought to identify gene expression predictors of
neoadjuvant chemotherapy sensitivity in Basal-like breast cancer. Methods:
Expression of 542 genes was measured using the Nanostring nCounter
platform from 69 FFPE pre-treated samples of the GEICAM/2006-03
phase II trial, which were treated with epirrubicin/cyclophosphamide
followed by docetaxel�/-carboplatin. Research-based PAM50 and Claudinlow
predictors were also evaluated. The association between response
(Miller-Payne criteria) and gene/signature expression was assessed by
multivariable ordinal logistic regression. Significant findings were evaluated
in 109 independent triple-negative and Basal-like tumors treated with
anthracycline/taxane-based chemotherapy (Hatzis et al.). Finally, interaction
tests were performed to identify genes/signatures associated with
carboplatin response. Results: In GEICAM/2006-03, 61/69 (88%) tumors
were identified as Basal-like by PAM50. High correlation to the Basal-like
centroid, or high expression of proliferation-related genes (i.e. FANCA),
were found to be significantly associated with high chemo-sensitivity,
whereas high expression of genes associated with mesenchymal/stem cell
biological processes (i.e. SNAI1 and IL6) and/or luminal differentiation
(i.e. MUC1 and FOXA1) were significantly associated with chemoresistance;
similar findings were observed in Hatzis et al. Finally, high
expression of genes associated with proliferation/DNA-repair (i.e. ATR) and
tight junctions (i.e. CLDN3/4/7) were found associated with carboplatin
response, whereas expression of the Claudin-low signature was found
associated with carboplatin resistance. Conclusions: High expression of
Basal-like and/or proliferation-related genes and low expression of luminal/
mesenchymal/stem cell-like biological processes were consistently identified
as predictive of chemotherapy response. Our data suggests that gene
expression profiling might help shed light into the biological and clinical
heterogeneity of Basal-like breast cancer.
10502 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
A heuristic platform for clinical interpretation of cancer genome sequencing
data. Presenting Author: Eliezer Mendel Van Allen, Dana-Farber Cancer
Institute, Boston, MA
Background: The ability to identify and effectively sort the full spectrum of
biologically and therapeutically relevant genetic alterations identified by
massively parallel sequencing may improve cancer care. A major challenge
involves rapid and rational categorization of data-intensive output, including
somatic mutations, insertions/deletions, copy number alterations, and
rearrangements into ranked categories for clinician review. Methods: A
database of clinically actionable alterations was created, consisting of over
100 annotated genes known to undergo somatic genomic alterations in
cancer that may impact clinical decision-making. A heuristic algorithm was
developed, which selectively identifies somatic alterations based on the
clinically actionable alterations database. Remaining variants are sorted
based on additional heuristics, including high priority alterations based on
presence in the Cancer Gene Census, biologically significant cancer genes
based on presence in COSMIC or MSigDB, and low priority alterations in the
same gene family as biologically significant cancer genes. The heuristic
algorithm was applied to whole exome sequencing data of clinical samples
and whole genome sequencing data from a cohort of prostate cancer
samples processed using established Broad Institute pipelines. Results:
Application of the heuristic algorithm to the prostate cancer whole genome
rearrangement data identified 172 (out of 5978) rearrangements involving
actionable genes (averaging 2-3 events per tumor). Furthermore, two
clinical samples processed prospectively were analyzed, yielding three
potentially actionable alterations for clinical review. Conclusions: The
heuristic model for clinical interpretation of next generation sequencing
data may facilitate rapid analysis of tumor genomic information for
clinician review by identifying and prioritizing alterations that can directly
impact care. Our platform can also be applied to research data to
prospectively explore clinically relevant findings from existing cohorts.
Future analytical approaches using heuristic or probabilistic algorithms
should underpin a robust prospective assessment of clinical cancer
genome data.
10501 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Estrogen receptor alpha (ESR1) gene amplification status and clinical
outcome in tamoxifen-treated postmenopausal patients with endocrineresponsive
early breast cancer: An analysis of the prospective ABCSG-6
trial. Presenting Author: Christian F. Singer, Medical University of Vienna,
Department of OB/GYN, Vienna, Austria
Background: Estrogen receptor alpha (ER�) expression is a prognostic
parameter in breast cancer and predicts response to endocrine therapy.
One of the factors important for protein expression is amplification of its
encoding gene ESR1. We have investigated the value of ESR1 amplification
in predicting the long-term clinical outcome in tamoxifen-treated
postmenopausal women with endocrine-responsive breast cancer. Methods:
394 patients who had been randomized into the tamoxifen-only arm of the
prospectively designed endocrine ABCSG-06 trial and in whom FFPE tumor
tissue was available were included in this analysis. Immunohistochemical
ER� expression was evaluated both locally and centrally using the Allred
score, while ESR1 gene amplification status was evaluated by FISH
analysis using the ESR1/CEN6 ratio. Results: ESR1 copy number gains
were detected in 187 of 394 (47%) tumor specimen and was associated
with favorable clinical outcome. At a median follow-up of 10 years, women
with intratumoral ESR1 copy number gains had a significantly longer
distant recurrence-free survival (adjusted HR for relapse 0.48; 95% CI
0.28-0.83; p�0.009) and breast cancer-specific survival (adjusted HR for
death 0.46; CI 0.46-0.71; p�0.006) when compared to women with
normal ESR1 copy numbers. Immunohistochemical ER� protein expression,
evaluated by Allred score, was significantly correlated with ESR1 copy
number alterations (p�0.0001; Chi-Square test), but did itself not allow to
discriminate between patients with poor and good prognosis. Conclusions:
ESR1 amplification status is an independent and powerful predictor for
long-term distant recurrence-free and breast cancer-specific survival in
postmenopausal women with endocrine-responsive early-stage breast cancer
who received 5 years of tamoxifen.
10503 Oral Abstract Session, Mon, 8:00 AM-11:00 AM
Circulating tumor cell counts (CTC) as prognostic of overall survival (OS) in
SWOG S0421-docetaxel with or without atrasentan for metastatic castration
resistant prostate cancer (mCRPC). Presenting Author: Nicholas J.
Vogelzang, Comprehensive Cancer Centers of Nevada and US Oncology
Research, Las Vegas, NV
Background: CTC are promising biomarkers in mCRPC but have not been
prospectively validated for docetaxel treatment (Rx). Using CellSearch
technology (J&J), we enumerated CTC in this Phase 3 trial & assessed
prognostic value for OS. The aim of this correlative study nested within
0421 was to compare CTC via CellSearch technology to newer microfilter
technologies (Cote & Goldkorn PIs RO1 CA141077). Comparative data
analysis is ongoing. Methods: CTC were drawn at baseline (d1) & pre-cycle 2
(d21) of Rx & shipped overnight to a central site for enumeration (CTC/7.5
ml). Cox regression evaluated the association between OS and (i) baseline
CTC counts & (ii) CTC dynamics (d1 to d21) in pts with good (�5) vs. poor
(��5) baseline CTC counts. Receiver operator characteristic (ROC) analysis
and Characteristics & Regression Trees (CART) were used to explore
further prognostic CTC cutpoints for 2-yr survival. Results: Of 263 patients
(pts) consented, 238 were evaluable at d1 & 232 at d21. At d1 median
CTC was 5 (range 0-5916) & d1 CTC � vs. �� 5 was associated with
baseline PSA (mean 99 vs. 320 ng/ml, p�0.004) and worse bone pain
(36% vs. 51%, p�0.03). There was a significant difference in OS for d1
CTC � vs. ��5, with a hazard ratio (HR) of 2.92 (95% CI 1.92-4.43,
p�0.001) after adjustment for PSA & other factors. In pts with low d1 CTC
(� 5), an increase in CTC was associated with shorter OS, HR 4.04 (95%CI
1.56-10.44, p�0.004); in pts with high d1 CTC (��5), a ��2-fold
decrease in CTC was associated with longer OS, HR 0.45 (95%CI
0.24-0.84, p�0.012); adjusting for risk factors. D1 CTC and 2-year
survival had ROC AUC of 0.781. CART analysis identified prognostic
subgroups based on CTC of 0, 1-5, 6-53, and �53: (HR 0.36, 0.77,1.3
and 2.8). Conclusions: In this phase 3 trial, d1 CTC was prognostic of OS
after risk factor adjustment. CTC dynamics from d1 to d21 were also
prognostic of OS. These data are an exploratory subset analysis of the
overall study. Yet, they comprise the largest docetaxel-based prospective
cohort to date, which validates a 5 CTC prognostic threshold for OS &
identifies new potential prognostic subgroups that may extend the clinical
utility of CTC enumeration in mCRPC.
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