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

5074 General Poster Session (Board #22B), Sun, 8:00 AM-12:00 PM
Proliferation pathway aberration frequencies in BRCA1- and BRCA2mutated
ovarian cancers. Presenting Author: Deborah A. Zajchowski,
Clearity Foundation, San Diego, CA
Background: Large-scale genomic analyses of high-grade, advanced-stage
serous ovarian cancers by The Cancer Genome Atlas (TCGA) project
revealed aberrations in genes comprising key proliferation and survival
pathways (RB-E2F, RAS, PI3K) in the majority of tumors. Patients with
germline BRCA1/2-mutations have more favorable prognoses than non-
BRCA carriers, and recent work suggests that BRCA2 carriers do better than
BRCA1. We hypothesized that concurrent proliferation pathway aberrations
and BRCA1/2 mutations in tumors might play a role in patient outcome.
Methods: Mutation, copy number, and clinical data for 309 TCGA-profiled
serous ovarian tumors were downloaded from the MSKCC cBIO web portal.
Each tumor was scored as aberrant for a pathway if any gene (RB: RB1,
CDKN2A, CCND1, CCND2, E2F3, CCNE1; PI3K: PIK3CA, PTEN, AKT1,
AKT2; RAS: KRAS, BRAF, NF1) in that pathway was mutated, amplified, or
deleted. Results: 205 of 309 tumors had an aberration in at least one of
these pathways. The frequency of pathway alteration differed significantly
in BRCA1 (82%, 28/34), BRCA2 (52%, 17/33) and BRCA1/2 WT (66%,
160/242) tumors (BRCA1 vs. BRCA2: Fisher’s p� 0.0096). BRCA1
tumors more frequently contained alterations in multiple pathways than
BRCA2 or WT tumors (41% vs. 24% or 25%, respectively). RB-E2F
pathway alteration frequency was significantly different (BRCA1: 56%,
BRCA2: 18%, WT: 43%, p�0.0043), but no significant differences in
PI3K and RAS pathway aberration frequencies (BRCA1%: 41, 38; BRCA2%:
36, 27; WT% 28, 27), respectively, were observed. In agreement with the
previous report, BRCA2 patients had significantly better overall survival
(OS) than either BRCA1 or WT patients (median OS months for BRCA1:
35.9, BRCA2 45.4, BRCA1/2 WT 27.8; p�0.001). Presence of pathway
alterations was not significantly associated with OS in BRCA1, BRCA2, or
WT patients in this cohort. Conclusions: These results show a negative
association between BRCA2 mutations and aberrations in key proliferation
and survival pathways. Beyond BRCA1 and BRCA2 genetic mutations, the
elevated frequency of pathway alteration in BRCA1 vs. BRCA2 tumors
highlights differences that may be important for patient prognosis as well
as therapy responses.
5076 General Poster Session (Board #22D), Sun, 8:00 AM-12:00 PM
Inflammatory and nutritional markers as predictors of longer hospital stay
and suboptimal residual disease (RD) in ovarian cancer (OVCA). Presenting
Author: Michelle Torres, Mayo Clinic, Rochester, MN
Background: Advanced OVCA should be managed aggressively, and extensive
surgery has been the most accepted initial treatment. Medically unfit
patients or those with extensive disease, in which complete cytoreduction
is unlikely, may not benefit from upfront radical surgery, and neoadjuvant
chemotherapy might be an appropriate alternative. Thus, reliable preoperative
indicators of surgical outcome are necessary for considering primary
surgery vs. neoadjuvant chemotherapy. Our aim is to determine if Creactive
protein (CRP), IL-6, albumin and Glasgow Prognostic Score (GPS –
score based on CRP and albumin) correlate with overall survival (OS),
length of hospital stay (LOS), surgical morbidity, and suboptimal cytoreduction.
Methods: We randomly selected 50 stages III/IV OVCA who underwent
surgery as a primary treatment between July 2002 and June 2009 at Mayo
Clinic with serum albumin levels and frozen serum available. CRP and IL-6
were measured in stored serum. Univariate and multivariate regression
models were fit to evaluate associations with each of the outcomes. Results:
Among the 50 patients, the mean age was 67.7 years. 34% had
pretreatment albumin �3.5 g/ml, 22.4% had CRP level �10 mg/l, 26.5%
had IL-6 �24 pg/ml and 45% had abnormal GPS score. At 1, 3 and 5 years
following surgery, the OS was 75.6%, 49.8% and 36.9%, respectively. RD
(0, �1, �1cm; p�0.001) was the only independent predictor of OS. Also,
IL-6 (p�0.028) and stage (p�0.046) were independently associated with
LOS, but no inflammatory or nutritional markers were significant associated
with post surgical complications. Stage IV (p�0.019) and elevated CRP
(p�0.044) were independent predictors of suboptimal surgery (RD �
1cm). Conclusions: One-third of the patients in our series had low serum
albumin at the time of the OVCA diagnosis, and at least one-fourth had
elevated inflammatory markers. Advanced stage and elevated inflammatory
markers (CRP and IL-6) were independent predictors of longer hospital stay
and suboptimal debulking. These pilot data, if confirmed in a larger
population, may help in the selection of candidates for neoadjuvant
chemotherapy.
Gynecologic Cancer
345s
5075 General Poster Session (Board #22C), Sun, 8:00 AM-12:00 PM
Secondary surgery with intraoperative chemohyperthermia in recurrent
ovarian adenocarcinoma. Presenting Author: Jean Marc Bereder, University
Hospital Archet 2, Nice, France
Background: Optimal treatment of peritoneal recurrences in ovarian cancer
is debating with second line chemotherapies. We proposed association of
secondary surgery with heated intraperitoneal per operative chemotherapy
(HIPEC). The aim of study is to determine prognostic factors in a single
center cohort. Methods: Retrospective study of consecutive 169 patients
with peritoneal recurrence from ovarian cancer were performed to evaluate
HIPEC and to identify prognostic factors. Peritoneal Cancer Index (PCI)
assess tumor load and completeness cytoreductive score (CCS) were used
to give quality of resection CCS0 (no visible tumor), CCS1 (persistent
diffuse lesions � 2.5mm), CCS2 (2.5mm �CC2� 25mm) and over CCS3
status. HIPEC is performed with platinum based regimen. Endpoint was
survival. Cox’s regression model was used for multivariate survival analysis
and extending Cox model for modelling survival data. Results: We have
operated on 197 procedures (HIPEC) in 169 patients from 2000 to 2011.
Mean age was 58 years old range [28-75]. Median PCI was 10. After
completion of resection, allocation of CCS was CCS0�120, CCS1�70,
CCS2 & CCS3 �7. Procedure related mortality was 1% and morbidity 21%,
mean length of hospital stay was 17 days range [7-51]. 3 and 5 years
overall survival were respectively 64.7% and 37.4 %. Median survival was
47.6 months and the median disease free survival was 20 months. PCI
�10 (even if complete resection performed) and CCS2&3 were worse
prognostic factors (HR respectively � 2.64 IC 95% [1.29-5.36] and �
3.31 IC 95 % [1.55-7.08]). Modelling of these factors, is very strong to
predict risk of death over the 2 first years after HIPEC. Conclusions: The
chemo-hyperthermia is a standardized and reproducible feasible method.
Less extensive disease and the quality of cytoreduction remain an independent
factor of better outcome. To date HIPEC allows to reach the longest
median time survival in peritoneal recurrent ovarian cancer. Modelling
survival data is useful to know the risk of dying.
5077 General Poster Session (Board #22E), Sun, 8:00 AM-12:00 PM
Association of SNP genotype in ABCB1 with completion of intraperitoneal
chemotherapy in ovarian and primary peritoneal cancer. Presenting Author:
Sergio Enderica Gonzalez, Mayo Clinic, Rochester, MN
Background: A standard of care (SOC) for the adjuvant treatment of ovarian
and primary peritoneal cancer is a platinum-based intravenous (IV) chemotherapy
doublet. Intraperitoneal (IP) chemotherapy is also a SOC, but the
high incidence of grade 3/4 adverse events has limited its acceptance
among clinicians. To identify genetic markers for completion of IP
chemotherapy, we analyzed SNPs in four genes known to play a role in
metabolism of platinum or taxane drugs. Methods: Patients diagnosed with
primary or recurrent stage III or IV epithelial ovarian or primary peritoneal
cancer who had primary or secondary debulking surgery at Mayo Clinic
(Rochester, MN) between January 2007 and February 2009 followed by IP
chemotherapy were included in this study. A cycle was defined as IV
paclitaxel (135mg/m2 ) on day one, IP cisplatin (100mg/ m2 ) on day two,
and IP paclitaxel (60mg/ m2 ) on day eight. With prior consent from the
patient, peripheral blood was obtained before treatment for extraction of
germline DNA. Using a custom Illumina BeadXpress 96-plex panel, SNPs
in GSTM1 (N�7), ABCB1 (N�57), CYP3A4 (N�7), and CYP2C8 (N�25)
were genotyped. The association between SNPs in these subsets of genes
and completion of IP chemotherapy was analyzed using linear regression.
Results: Thirty-seven patients were included in this study and 16 (43.2%)
completed IP chemotherapy. Twenty-two out of the fifty-seven ABCB1
SNP’s were associated with the number of cycles (p�0.15). There were no
significant associations for GSTM1, CYP3A4 and CYP2C8 SNP’s. The
minor A allele at missense SNP rs2229109 in the ABCB1 gene was present
in five (31.2%) who completed treatment and only one (4.8%) who did not
(p�0.007). However, the later was due to catheter complication. There was
no association between rs2229109 and overall or progression-free survival.
Conclusions: Our findings suggest that SNP rs2229109 in ABCB1 gene is
associated with completion of IP chemotherapy, and potentially, less
toxicity from chemotherapy. Thus, these patients may be optimal candidates
for IP chemotherapy. Further studies in a larger population are
needed.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.