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

52s Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy
1012 Poster Discussion Session (Board #4), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
DNA repair metagene signature as a prognostic and predictive factor in
molecular breast cancer subtypes. Presenting Author: Libero Santarpia,
Istituto Toscano Tumori Hospital of Prato, Prato, Italy
Background: We aimed to assess the prognostic and predictive role of DNA
repair genes in breast cancer (bc) molecular subtypes. Methods: We
evaluated Affymetrix gene expression profiling from untreated N- patients
(N � 684), neoadjuvant treated tumors with taxanes- (N � 320),
anthracyclines- (N � 211), and cisplatin- (N � 22) containing regimens.
We assessed within 3 BC molecular subgroups (ER�/HER2-, HER2�, and
ER-/HER2-) bimodality distribution, prognosis by association with distant
relapse (N � 454, N � 105, and N � 125) and predictive value for
likelihood of pathological complete response (pCR) (N � 208, N � 105,
and N � 240). Moreover, we explored the function of relevant genes in BC
cell lines. Results: Three genes (ERCC2, XRCC3, and RECQL4) showed
bimodality in each bc subtype. Eight genes were associated with poor
prognosis (including RECQL4) and 1 gene with good prognosis (ATM)[P�
.0001] only in ER�/HER2- tumors. Our results suggest a subtype and
treatment specific association with pCR although they did not satisfy
stringent criteria for false discovery correction. In ER-/HER2- mismatch
repair (MR) (MSH2 and MSH6) and MTMR15 genes were associated with
response and resistance to taxane-containing regimens, respectively.
TOP2A was the only gene associated with response to anthracycline but not
taxanes in HER2� tumors. RECQL4 had a positive trend with higher pCR in
both ER� and ER-/HER2- tumors. In in vitro studies we found that
RECQL4 interacts with PARP1 and that the expression of these genes was
correlated with sensitivity to chemotherapy and PARP inhibitors.
Conclusions: We identified MR genes as potential predictive markers of
response to taxanes-based regimens in ER-/HER2-. A novel gene RECQL4
showed bimodal distribution, prognostic value, and a trend for predictive
association with response to taxanes-based chemotherapy, which was also
confirmed by in vitro analysis. ATM deserves further evaluation as prognostic
marker in ER�/HER2-.
1014 Poster Discussion Session (Board #6), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Targeting XRCC1 (X-ray repair cross-complementing gene 1) deficiency in
tumors for personalized cancer therapy. Presenting Author: Srinivasan
Madhusudan, School of Molecular Medical Sciences, Nottingham University
Hospitals, Nottingham, United Kingdom
Background: XRCC1 is essential for DNA base excision repair, single strand
break repair and nucleotide excision repair. XRCC1 deficiency promotes
genomic instability and may increase cancer risk. Methods: We evaluated
XRCC1 immunohistochemically in early stage breast (n�2046), ovarian
(n�157), gastric (n�140), colorectal (n�250) and pancreaticobiliary
cancers (n�240). Pre-clinically, we evaluated a panel of XRCC1 deficient
and proficient Chinese hamster ovary and human cancer cell lines. Double
strand break repair (DSB) inhibitors targeting ATM (KU55933), DNA-PKcs
(NU7441) and ATR (NU6027) were evaluated for synthetic lethality and
cisplatin alone or in combination with DSB inhibitors for chemopotentiation.
Results: In breast cancer,XRCC1 loss (16%) was associated with
higher grade (p�0.0001), loss of hormone receptors (p�0.0001), presence
of triple negative (p�0.0001) and basal like phenotypes (p�0.001).
Loss of XRCC1 was associated with a 2-fold increase in risk of death and
metastasis (p�0.0001) and independently with poor outcome (p�0.0001).
In ovarian cancer, XRCC1 was positive in 44% of tumour and was
significantly associated with higher stage (p�0.001), clear/endometroid
type (p�0.015) and sub-optimal debulking (p�0.004). XRCC1 positive
tumours were more resistant to platinum chemotherapy (p�0.0001).
XRCC1 positivity conferred a 2 fold increase of risk of death (p�0.002) and
independently associated with poor survival (p�0.002). In gastric cancers,
XRCC1 was positive in 37% of tumours. This was significantly associated
with high stage disease (p�0.001) and poor survival (p�0.001). Preclinically,
KU55933, NU7441 and NU6027 were synthetically lethal in
XRCC1 deficient compared to proficient cells as evidenced by DSB
accumulation, G2/M cell cycle arrest and apoptosis. XRCC1 deficient cells
were hypersensitive to cisplatin which was enhanced by DSB repair
inhibitors compared to in proficient cells. Conclusions: This is the largest
study to confirm the clinical significance of XRCC1 expression in solid
tumours. XRCC1 deficiency in human tumours may be suitable for
synthetic lethality application and exploited for cisplatin chemotherapy
potentiation.
1013 Poster Discussion Session (Board #5), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
HAGE (DDX43) protein expression as an independent biomarker of poor
clinical outcome of breast cancer (BC) and potential as a therapeutic target
for ER-negative BC. Presenting Author: Stephen Chan, Nottingham University
Hospital, Nottingham, United Kingdom
Background: Recently, we have confirmed that HAGE is involved in
promoting proliferation as assessed by increased thymidine incorporation
and our preliminary results using shRNA to permanently knockdown HAGE
expression also suggests the involvement of HAGE in tumor motility and
metastasis. In this study we aimed to analyze the expression of HAGE in
large well-characterized BC cohorts to determine its relationship with other
clinico-pathological parameters and to investigate its prognostic value.
Methods: HAGE protein expression was assessed in: a) 40 normal breast
tissue (NBT), b) 60 invasive BCs and their matching NBT, c) BC cell lines,
d) A series of 1650 consecutive cases of primary BC who treated with
adjuvant CMF and/or endocrine therapies. Further validation was performed
in 2 independent series of high risk ER- BC: a) 300 ER –BC who did
not received any CT and b) 396 ER- BC treated with adjuvant anthracycline
(ATC) based CT. Results: The NBT showed negative HAGE expression
(HAGE-) throughout. HAGE overexpression (HAGE�) was observed in 10%
of BC and was significantly associated with aggressive clinico-pathological
features including: ER-, high grade and triple negative phenotypes.
Moreover, HAGE� expression showed an adverse outcome with a 2-4 fold
increase in the risk of death, recurrence and metastases (ps�0.00001)
compared to HAGE-; ps�0.0001. Using a multivariate Cox regression
model including ER status, grade, size and tumour stage, HAGE expression
was confirmed as a powerful independent prognostic factor (p�0.0001).
The poor clinical outcome of HAGE� was further confirmed in high risk
(NPI�3.4) ER- patients who did not received any CT (p�0.0001). While,
adjuvant CT either CMF or ATC had a positive impact on HAGE�/high risk
ER- BC as HAGE� had a similar risk of death, recurrence and distant
metastases to HAGE- expression. Conclusions: This is the first report which
shows HAGE to be a potential predictor for poor prognosis in BC patients,
and may be an attractive novel target for molecular and vaccine therapy for
those patients. A prospective trial of adjuvant chemotherapy/vaccine to
confirm this finding is warranted.
1015 Poster Discussion Session (Board #7), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Cancer gene profile of metastatic breast cancer. Presenting Author: Funda
Meric-Bernstam, University of Texas M. D. Anderson Cancer Center,
Houston, TX
Background: There is great interest in using genomic information to guide
therapy selection in cancer patients. The aim of this study was to determine
the spectrum of genomic alterations identified in MBC patients, and
evaluate the concordance of alterations between primary and recurrent
tumors. Methods: We performed comprehensive profiling on formalin-fixed
paraffin embedded samples from 42 patients with MBC using a targeted
next generation sequencing (NGS) assay in a CLIA laboratory (Foundation
Medicine). Genomic libraries were captured for 3,230 exons in 182 cancer
related genes plus 37 introns from 14 genes often rearranged in cancer and
sequenced to an average depth of 390X with 99% of bases covered
�100X. In total 30 primary and 37 recurrent tumors were profiled,
including 3 separate recurrences in 1 patient and matched primaryrecurrences
in 22 patients. Point mutations, indels, copy number alterations
and rearrangements were assessed. Alterations that are targetable
with established or investigational therapeutics were considered “actionable”.
Results: At least 1 genomic alteration was identified in all but 2
breast samples (both primary tumors). Point mutations were identified in
several cancer-related genes including PIK3CA, TP53, PTEN, CDH1,
ARID1A, AKT1, NF1, FBXW7 and FGFR3. Amplification was observed in
HER2; 11of12HER2 IHC positive samples were found to have HER2
gains by NGS; in addition, a HER2 gain was identified by NGS in a HER2-
(1� IHC) sample. Amplification of PIK3CA, IGF1R, FGFR2, AKT2, MDM2,
and MCL1 plus a CDKN2A homozygous deletion were also identified. While
the majority of known driver alterations (85%) were concordant in the
matched pairs of primary and recurrent tumors, in 11 of 22 sets there was
at least 1 discordant driver alteration, and these included both gains and
losses of potential therapeutic targets. Overall 32 of 42 patients (76%) had
an actionable genomic alteration. Conclusions: Genomic profiling of breast
cancer samples reveals genomic alterations in most metastatic breast
cancer patients. Over three quarters of patients have actionable findings,
suggesting that genomic profiling may assist in individualized pathwaydirected
therapy.
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