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

658s Tumor Biology
10508 Poster Discussion Session (Board #1), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Next-generation RNA sequencing reveals transcriptomic changes after
brief exposure to preoperative nab-paclitaxel, bevacizumab, and trastuzumab.
Presenting Author: Vinay Varadan, Philips Research North America,
Briarcliff Manor, NY
Background: Identification of differentially expressed transcripts after brief
exposure to preoperative therapy can help determine likely response
markers. We quantify and compare differential gene and isoform expression
using RNA-seq on patient samples with 10 day exposure to one dose of
trastuzumab, bevacizumab or nab-paclitaxel. Methods: We sequenced
transcriptomes of 23 pairs of core biopsy RNA from breast cancers pre/post
10 day exposure to therapy. Paired-end sequencing was done on the
Illumina GAII platform using amplified total RNA with 74bp read length,
yielding data on transcript abundance for a total of 22,160 genes and
34,449 transcripts. Differential expression of transcripts between pre/post
samples was estimated assuming Poisson-distributed read-counts, followed
by multiple testing correction and enrichment analysis of 185 KEGG
pathways. Results: PAM50-based clustering showed individual samples
cluster together, demonstrating that tumor subtypes do not change over the
10-day treatment (SABCS 2011). We identified genes that were significantly
differentially expressed (p�0.05; FDR�0.1) in at least 60% of
samples within each therapy arm: 780 genes in trastuzumab, 302 in
bevacizumab, and 176 in nab-paclitaxel. Surprisingly, only THAP11 and
TINF2 were common amongst them. THAP11 is involved in stem cell
maintenance and TINF2 is important for regulation of telomere length.
Immune system and metabolism-related pathways were commonly affected
(p�0.05) across all arms. The bevacizumab arm showed significant
down-regulation of angiogenesis-associated genes: ESM1 and VEGFR2 in
� 80% of samples. The nab-paclitaxel arm exhibited changes in TGF-beta
signaling, Nod-like receptor and Wnt signaling. The trastuzumab arm
exhibited consistent alteration of ErbB2 and mTOR pathways, with SOX11
and TOP2B downregulated in every sample. Conclusions: This is the first
study to compare gene expression with brief exposure across therapies
using RNA-seq technology. The unique aspects of transcriptional response
to each treatment underscore the need for specific markers of therapeutic
response to nab-paclitaxel, bevacizumab and trastuzumab.
10510 Poster Discussion Session (Board #3), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous
assessment of MAPK pathway aberrations. Presenting Author: Filip Janku,
Department of Investigational Cancer Therapeutics (Phase I Program),
University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Loss of PTEN function increases PI3K/mTOR signaling.
Preclinical data suggest that PTEN aberrations can predict sensitivity to
drugs targeting the PI3K/mTOR pathway. Methods: Tumors from 461
patients with diverse cancers referred to the Clinical Center for Targeted
Therapy were tested for cytoplasmic immunohistochemical expression of
PTEN using the following scoring system: negative (no staining); positive
(intact staining); reduced staining, with stroma serving as an internal
positive control. Whenever possible, tumors were also tested for mutations
in the MAPK pathway (KRAS, NRAS, and BRAF). We analyzed outcomes of
patients treated with PI3K /mTOR with respect to their PTEN status.
Results: Of 461 patients, 47 (10%) had negative PTEN expression, 168
(36.5%) had positive PTEN expression, and 246 (53.5%) had reduced
PTEN. In tumor types with �10 patients tested, negative PTEN was most
frequent in uterine (10/33, 33%), renal (3/11, 27%), salivary gland (2/10,
20%), colorectal (15/82, 18%), breast (2/15, 13%), pancreatobiliary
(3/24, 13%), and prostate cancers (2/19, 11%). Of 206 patients tested for
MAPK (KRAS, NRAS, and BRAF) pathway mutations, patients with either
negative or reduced PTEN had more MAPK mutations than patients with
positive PTEN expression (72/144, 50% vs. 20/62, 32%, p�0.02). A total
of 153 (33%) patients received therapies with PI3K /mTOR inhibitors and
17 (11%, 95% CI 0.07-0.17) achieved a partial response (PR). Proportions
of PRs were 2/13 (15%) for PTEN negative, 3/50 (6%) for PTEN
positive, and 12/90 (13%) for reduced PTEN. There was no significant
difference in PR rate amongst patients with positive PTEN expression
compared to patients with negative or reduced PTEN (3/50, 6% vs.
14/103, 14%; p�0.27). Conclusions: Complete loss of PTEN expression
was found in 10% of patients. Positive PTEN expression was found in
36.5% of patients. PTEN status did not predict response to PI3K/mTOR
inhibitors, perhaps because patients with negative and reduced PTEN
expression had a higher incidence of simultaneous MAPK (KRAS, NRAS,
BRAF) mutations.
10509 Poster Discussion Session (Board #2), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Early change in 18-fluorodeoxyglucose (FDG) uptake on positron emission
tomography (PET) to predict response to preoperative systemic therapy
(PST) in HER2-negative primary operable breast cancer: Translational
breast cancer research consortium (TBCRC008). Presenting Author: Roisin
M. Connolly, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins
School of Medicine, Baltimore, MD
Background: PST allows for improved surgical outcomes and response
assessment without compromising long term outcomes. PST is an attractive
model for assessing surrogate markers of response to therapy. We
hypothesized that changes in tumor standardized uptake values corrected
for lean body mass (SUL) max on FDG- PET by cycle 1 day 15 (C1D15) of
therapy would predict pathological complete response (pCR) to PST in
women with stage 2-3, grade 2-3, HER2-negative breast cancer. Methods:
TBCRC008 is a multicenter placebo-controlled trial that investigates pCR
following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel
with or without vorinostat. FDG-PET followed by tumor biopsies were
performed at baseline and C1D15. We correlated % reduction in SULmax
on FDG-PET (PERCIST 1.0; Wahl RL, J Nuc Med 2009) with pCR (no
invasive cancer in breast/axilla). We compared % reduction in SULmax
between responders (pCR) and non responders (no pCR) using nonparametric
Wilcoxon rank sum test. We explored association of % reduction in
SULmax at pre-specified cutoff with response using Fisher’s exact test and
logistic regression. We correlated baseline, C1D15, and % change in Ki67
at C1D15 with pCR. Results: Accrual is complete. Of 62 women enrolled
(10/2009-11/2011), 40 have completed study PST and surgery (median
age 47.5 [range 30-68], ER-positive 67%). Overall pCR was 26%. In an
intent to treat analysis (n�39), we observed a significant difference in
median % reduction in SULmax between responders vs not (66.6% vs
32.4%, p �0.001). We observed a higher proportion of reduction in
SULmax � 60% in responders vs not (80% vs 3.5%, p �0.001). The
differences in baseline, C1D15 and % change in Ki67 were not significant
between responders and non-responders. Conclusions: Change in SULmax
on FDG-PET 15 days after initiating PST was significantly greater in
patients with pCR versus no pCR. Future studies will determine whether
altering therapy based on early changes in SULmax will improve pCR.
Unblinded data from all participants will be presented at the meeting.
10511 Poster Discussion Session (Board #4), Tue, 8:00 AM-12:00 PM and
11:30 AM-12:30 PM
Analysis of the intratumoral heterogeneity of PIK3CA mutant alleles in
breast cancer (BC): Implications for the luminal (LUM) phenotype. Presenting
Author: Leticia De Mattos-Arruda, Medical Oncology Department, Vall
d’Hebron University Hospital, Barcelona, Spain
Background: The hyperactivation of the phosphatidylinositol 3-kinase
(PI3K) pathway may confer endocrine therapy resistance and is an
attractive target for LUM patients (pts). However, PI3KCA mutations could
be heterogeneously distributed within the tumor as different genetic clones
and this could have therapeutic implications. Our aim was to assess the
frequency of PIK3CA mutant alleles in different BC phenotypes. Methods:
DNA was obtained from 75 consecutive BC FFPE samples and was profiled
with the OncoCarta Panel v1.0 (Sequenom). Frequencies of mutant alleles
(% mutant allele, mA) of PIK3CA mutations were extracted from the
MassARRAY spectrum data. The viable tumor area (TA) was scored by H&E.
Pts were stratified by BC phenotypes: ER�/HER2- (LUM); HER2� (HER2);
triple negative (TN). Results: 25.3% of pts had PIK3CA mutations. The
mean PIK3CA mA (p�0.04) and mean TA (p�0.07) differed among
phenotypes. LUM tumors demonstrated greater frequencies of PIK3CA
mutation (38% vs.15%, p�0.05) and mean PIK3CA mA (31% vs.17%,
p�0.01) than non-LUM.There was a significant linear correlation between
mA and TAfor LUM tumors (r�0.91); when HER2 and TN tumors were also
considered this relation was less pronounced (r�0.66). Overall, LUM pts,
median age 55 (42-84), had significantly better clinical outcomes
(p�0.00024), whilst analyses of prognosis did not differ among LUM pts
(PIK3CA mutant vs. wild-type, p�0.68) nor mutant pts (LUM vs. non-
LUM, p�0.36). Outcomes will be presented. To assess the intratumoral
heterogeneity of PIK3CA mutations, we determined the mA/TA ratio. The
mA/TA ratio should be 0.5 for a homogeneous distribution of the heterozygous
PIK3CA mutation. The ratio of LUM patients was close to 0.5, while
for non-LUM it was lower, suggesting a non-homogeneous distribution of
PIK3CA mutant alleles in non-LUM tumors. Conclusions: Our analysis
indicates that LUM tumors tend to be homogeneous regarding PIK3CA
mutation as compared to HER2 and TN. This suggests that PIK3CA
oncogenic activation could be an early hit for tumor initiation in LUM
tumors, which could be more specifically targetable; thus, pts would derive
greater benefit from PI3K-inhibitors plus hormonal therapy.
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