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

10544 General Poster Session (Board #43A), Mon, 1:15 PM-5:15 PM
DJ-1 as a predictor of pathologic complete remission of neoadjuvant
chemotherapy with breast cancer patients. Presenting Author: Takahiko
Kawate, Basic Pathology, National Defence Medical Colleage, Saitamaken,
Japan
Background: DJ-1 is a multifunctional protein which is encoded by the
causative gene of familial Parkinson disease (i.e., PARK7), and is associated
with carcinogenesis. DJ-1 is also a candidate marker for the presence
of breast cancer cells, in which it is secreted in nipple fluid and serum. We
previously reported that a DJ-1 expression pattern that is low at the protein
level and high at the mRNA level is associated with DJ-1 secretion. This
secretory expression pattern correlated with a negative hormone receptor
status and with unfavorable clinical outcome in breast cancer patients.
However, the association of the DJ-1 secretion pattern with therapeutic
effect has yet to be determined. Methods: A total of 299 patients received
neoadjuvant chemotherapy and surgery from 2002 to 2010 at our
institution. We performed immunohistochemistry and in-situ hybridization
of DJ-1 in both the needle biopsy and operative specimens of 147 cases
with a follow-up time of 3.1 years. The average degree of staining intensity
was evaluated semi-quantitatively using an image analyzer. Univariate and
multivariate analyses were used to evaluate the predictive value of the
therapeutic effect of neoadjuvant chemotherapy. Results: A low expression
of DJ-1 protein was detected in the needle biopsy and operative specimens
of 89 of the 147 cases, regardless of a high or maintained mRNA level. The
tumor response was evaluated as pathological complete remission (pCR) in
39 cases and as non-pCR in the remaining 108 cases. A low expression of
DJ-1 protein, which was detected in 34 (87.2%) pCR cases, was a
significant predictor on univariate analysis (P �0.001). On multivariate
analysis, a low expression of DJ-1 was shown to be a significant independent
predictor similar to established predictors such as estrogen receptor
status and human epidermal growth factor receptor 2 score. Conclusions: A
low expression of DJ-1 protein can serve as a novel and important predictor
of a neoadjuvant chemotherapeutic effect, as well as a promising indicator
for serologic diagnosis in breast cancer patients.
10546 General Poster Session (Board #43C), Mon, 1:15 PM-5:15 PM
Evaluation of CYP3A5, VEGF-a, and VEGFR2 polymorphisms as markers of
sunitinib toxicity. Presenting Author: Cristina Rodriguez de Antona, Spanish
National Cancer Research Center, Madrid, Spain
Background: Sunitinib (Sun) is a multitargeted tyrosine-kinase inhibitor
approved for the treatment of renal cell carcinoma (RCC), GIST and
pancreatic neuroendocrine tumors (pNETs). It is known that a polymorphism
in Sun metabolizing gene CYP3A5, was associated with an increased
risk of dose reductions due to toxicity (tox). Additionally, polymorphisms in
VEGF-A and VEGFR2 were suggested to increase the risk of hypertension
(HT) during treatment (García-Donas, et al. Lancet Oncol 2011). These
data have not been validated so far. We aim to assess the value of these
polymorphisms as markers of tox using a wide range of solid tumors treated
with Sun. Methods: In this non-interventional and retrospective study, DNA
was collected from 28 patients with different pathologies (16 pNETs, 5
medullary thyroid carcinomas, 2 NETs of the lung, 2 undifferentiated
follicular carcinomas, 1 undifferentiated papillar carcinoma, 1 GIST, and 1
carcinoid of the rectum) treated with Sun in a daily practice setting.
Genotyping for CYP3A5*1 allele (rs776746), VEGF-A -2578C�A
(rs699947) and VEGFR2 Q472H (rs1870377) was performed. Associations
between the genotypes and Sun dose reductions and HT were
performed using univariable analyses. Results: In agreement with previous
reports, we found that VEGF-A rs699947 conferred a statistically significant
increased risk of developing HT during treatment (HR�9.8,
95%CI�1.2-82.0, P�0.034). CYP3A5*1 high metabolizing allele showed
a trend towards the increase in the risk of Sun dose reductions due to tox
(HR�2.4, 95%CI�0.8-6.8, P�0.11) with a median time to dose reduction
of 7.0 months for wild type homozgygous patients and 4.6 months for
heterozygous patients. A trend was also found on the relation between
VEGF-A rs699947 A/A patients (HR�3.8, 95%CI�0.8-16.8, P�0.080)
and dose reduction risk. No significant associations were found for VEGFR2
rs1870377. Conclusions: The present study suggests that VEGF-A rs699947
is a risk factor for Sun HT and has a role in other tox leading to dose
reductions. Similarly, CYP3A5*1 shows a trend towards an increased risk
of Sun dose reductions. If confirmed, these markers could be used to
identify a subset of patients with an increased risk of Sun toxicity.
Tumor Biology
667s
10545 General Poster Session (Board #43B), Mon, 1:15 PM-5:15 PM
Correlation between miRNA (miR) and gene expression profiles (GEP) and
response to neoadjuvant chemotherapy (NT) in patients with locally
advanced and inflammatory breast cancer (BC). Presenting Author: Sierra
Mi Li, City of Hope, Duarte, CA
Background: GEP may predict for pathologic complete response (pCR).
Correlation between miRs, GEP, and pCR may reveal novel targets.
Methods: Patients (pts) with HER2- BC were randomized to receive
docetaxel, doxorubicin, cyclophosphamide (TAC, arm A) or A and C given
every 2 weeks x 4, followed by carboplatin and nab-paclitaxel (arm B). Pts
with HER2� BC received NT per arm B, with trastuzumab added (arm C).
Core biopsies were snap-frozen prior to NT, and RNA extracted for gene
array analysis (Agilent 44K microarray) and deep sequence miRNA analysis
(Solexa/Illumina platform). HER2 testing by IHC [3�] or FISH and/or gene
array was carried out (Blueprint). MiRs were measured in 72 of 119
enrolled pts. Of 882 miRNAs reported by Solexa sequencing, 487 were
assessed (observed at raw counts � 10 in at least 3 pts). TargetScan was
used to obtain miRNA targets and negative correlation between miR and
mRNA expression was applied. Results: In 44 HER2- cases, we found 17
miRs differentially expressed between pts who achieved pCR vs. pts who
did not (� pCR), 13 with predicted targets by TargetScan (TS). We found
28 canonical pathways (including Embryonic Cell, EGF signaling, Estrogendependent
signaling) affected by the identified miRs, and inclusive of 74
target mRNAs identified (Agilent) and correlating with pCR. The top
overexpressed miRs are 31 [gene targets: FZD4]; 18a [IGF1, ALDH5A1];
19a [PIK3R, IGF1]) and 3 lowest expressors are miR-190b [MMP1]; 29c
[FOS, WNT5B]; 342-3p [BMP7]. Among the 28 HER2� cases there were
14 miRNAs differentially expressed between BCs with pCR vs �pCR, and 8
had predicted targets from TS. We found 10 canonical pathways (including
p53, HER-2, PTEN) affected by miRs, which included 44 target mRNAs
(Agilent) correlating with pCR. The most overexpressed miRs are miR-708
[gene target: RRM2B; 193a-p5 [BMPR1B, RPRM] ; 92b [CCNE2, DKK2].
The lowest expressors are: miR-30a [FZD1, SMAD1, TP63]; miR-450-5p
[FOXO1, WINT5A, ERBB2]; miR-497 [PIK3R1, FGFR1, FOXO1].
Conclusions: Combined assessment of miRNA and gene expression patterns
is feasible, and may yield information leading to individualized and
improved NT.
10547 General Poster Session (Board #43D), Mon, 1:15 PM-5:15 PM
Pharmacogenetic predictors of adverse events in stage II-III colon cancer
(CC) patients treated with oxaliplatin and fluoropyrimidines-based adjuvant
chemotherapy (CT): A GEMCAD study. Presenting Author: Ana Custodio,
Department of Medical Oncology, La Paz University Hospital, Madrid,
Spain
Background: Although the benefit of oxaliplatin-based adjuvant CT has been
demonstrated in patients with resected stage II-III CC, the recommendation
to administer postoperative treatment must consider its potential
adverse events. Predicting individual patients´risk of severe toxicity could
potentially improve the quality of care by allowing individualization of
treatment. We investigate the utility of determining single nucleotide
polymorphisms (SNPs) in genes involved in oxaliplatin and fluoropyrimidines
metabolisms to predict the toxicity of adjuvant CT in stage II-III CC
patients. Methods: DNA was extracted from formalin-fixed paraffinembedded
samples from 379 surgically treated high-risk stage II (27.71%)
and stage III (72.29%) CC patients receiving adjuvant CT (54.35%
FOLFOX, 45.65% XELOX) from January 2004 to December 2008. Genotyping
was performed for 35 SNP in 18 genes using the MassARRAY
(SEQUENOM) technology. Results: A total of 89 (23.4%) patients experienced
at least one grade 3-4 adverse event. The most common grade 3-4
toxicities were neutropenia (15.3%), diarrhea (8.17%) and neurotoxicity
(7.65%). The MTHFR rs1801133 C�T C/C (30.1% C/C, 17.5% C/T,
21.7% T/T; p�0.043) and XRCC2 rs3218408 T�G T/T (28.3% T/T,
16.2% G/T and 10% G/G; p�0.007) genotypes were associated with
higher risk of any grade 3-4 toxicities, whereas the incidence of severe
toxicity was lower in patients with the UMPS rs3772807 G�C C/C (14%
C/C, 21% C/G, 28.9% G/G; p�0.021) and DPYD rs970337 G�A A/A
(16.7% A/A, 21.1% A/G, 30.1% G/G; p�0.028) genotypes. In addition,
the DPYD rs970337 G�A A/A genotype was associated with a lower rate of
grade 3-4 diarrhea (5% A/A, 9.4% A/G, 8.1% G/G; p�0.030), the ABCG2
rs3114018 A�C C/C genotype with an increased rate of grade 3-4
neutropenia (15.2% C/C, 6.3% A/C, 4.5% A/A; p�0.034) and the ERCC1
rs11615 T�C T/T genotype with a lower rate of grade 3-4 neurotoxicity
(5.4% T/T, 9.1% C/T, 10.2% C/C; p�0.032). Conclusions: Our data
suggest that SNPs in genes involved in oxaliplatin and fluoropyrimidines
metabolisms can potentially predict severe toxicity in stage II-III CC
patients treated with adjuvant CT.
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