Annals of Oncology

abstracts
113P
Characteristics of homologous recombination deficiency
(HRD) in paired primary and recurrent high-grade serous
ovarian cancer (HGSOC)
J. Patel 1 , J. Sehouli 2 , K. Timms 3 , C. Solimeno 3 , J. Reid 3 , J. Lanchbury 3 , I. Braicu 2 ,
S. Darb-Esfahani 2 , M. Ganapathi 1 , R. Ganapathi 1
1 Pharmacology, Levine Cancer Institute, Charlotte, NC, USA, 2 Department of
Gynecology, Charité / University Hospital Berlin, Berlin, Germany, 3 Clinical
Research, Myriad Genetics Inc, Salt Lake City, UT, USA
Background: Recently, a 3-biomarker homologous recombination deficiency (HRD)
score has been shown to predict response to DNA damaging therapies in patients with
HGSOC, where patients with a high HRD score (≥42) and/or BRCA1/2 mutation show
improved response. In order to evaluate whether changes in tumor biology can impact
the prognostic value of this HRD score, we investigated the characteristics of HRD in
paired primary and recurrent HGSOC specimens.
Methods: HRD scores were evaluated in paired primary and recurrent specimens of
HGSOC from 55 patients treated with adjuvant carboplatin and paclitaxel. BRCA1/2
mutation and BRCA1 methylation (including loss of heterozygosity (LOH) status), and
HRD scores were characterized using tumor DNA-based assays.
Results: Here we present the results of the initial analysis performed for the first 25
patients. Data for 19 complete primary-recurrent pairs were available for comparative
analysis (7/50 samples failed HRD analysis). BRCA mutations were detected in 12% (3/
25) of tumors, all of which occurred in BRCA1 and contained LOH at BRCA1. There
was no mutation reversion in recurrent samples. Overall, 9 primary-recurrent pairs had
high HRD scores, including all 3 mutant pairs. There was a high degree of correlation
for all HRD scores in primary and recurrent samples (Pearson correlation coefficient
0.953). Scores for recurrent tumor samples were somewhat more likely to be higher
than in the primary (mean = 2.6), but the difference was not significant
(p-value = 0.11). The complete analysis will include data from paired primary and
recurrent tumors from an additional 30 patients. This will allow more thorough
investigation of how changes in the genomic profile of primary and recurrent tumors
may impact the HRD score.
Conclusions: Here we show that the 3-biomarker HRD score was not impacted by
changes in the genomic profile of paired primary and recurrent tumor samples. This
suggests that that testing recurrent HGSOC tumors will not alter treatment strategies
relative to analysis of the primary tumor. Additional analysis will reveal whether the
trends observed in this initial analysis are maintained in a larger cohort.
Legal entity responsible for the study: N/A
Funding: Myriad Genetics
Disclosure: J. Patel: Consultant, BTG; Research Funding, Myriad Genetics; Travel,
accommodations. J. Sehouli, S. Darb-Esfahani, M. Ganapathi, R. Ganapathi: Research
Funding, Myriad Genetics, Inc. K. Timms, C. Solimeno, J. Reid: Myriad employee,
salary and stock options. J. Lanchbury: Employee of Myriad Genetics, Inc. Receives
salary and stock options as compensation. I. Braicu: Research Funding, Myriad
Genetics, Inc.
114P
Prognostic biomarkers in locally advanced cervical cancer
(Cx Ca) treated with chemoradiation (CRT)
Y. Kanjanapan 1 , S. Deb 2 , R. Young 3 , M. Bressel 4 , L. Mileshkin 1 , D. Rischin 1 ,
M. Hofman 5 , K. Narayan 6 , S. Siva 6
1 Medical Oncology, Peter MacCallum Cancer Center, Melbourne, Australia,
2 Anatomical Pathology, Peter MacCallum Cancer Center, Melbourne, Australia,
3 Translational Research Laboratory, Peter MacCallum Cancer Center, Melbourne,
Australia, 4 Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer
Center, Melbourne, Australia, 5 Cancer Imaging, Peter MacCallum Cancer Center,
Melbourne, Australia, 6 Radiation Oncology, Peter MacCallum Cancer Center,
Melbourne, Australia
Background: Definitive chemoradiation (CRT) is standard therapy for locally
advanced cervical cancer (Cx Ca). However, there is a lack of biomarkers to identify
patients at increased risk of relapse. Post-therapy 18 F-fluoro-deoxyglucose positron
emission tomography (PET) response correlates with outcome, but cannot inform
treatment planning. We tested metabolic (glucose transporter [Glut-1]), hypoxic
(hypoxia inducible factor [HIF-1a] and carbonic anhydrase [CA-9]) and proliferative
(Ki-67) markers for prognostic utility in Cx Ca.
Methods: 60 FIGO stage Ib to IVa Cx Ca patients treated with CRT had formalin-fixed
paraffin-embedded tumour tissue from pre treatment biopsies. Immunohistochemistry
was performed for Glut-1, HIF-1a and CA-9, to generate a histoscore (0-12) by
multiplying intensity (0 absent, 1 mild, 2 moderate and 3 intense staining) by a
categorical percentage score (0 for none, 1 for 1-24%, 2 for 25-49%, 3 for 50-74% and 4
for ≥75% of cells staining), for each biomarker in each tumour sample. Ki-67 was
scored by percentage of positive cells amongst 1000 representative tumour cells. For
each biomarker, the cohort was dichotomized and survival estimated by the
Kaplan-Meier method and compared using logrank testing.
Results: High Glut-1 expression was associated with inferior progression-free survival
(PFS), (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.0 – 7.9, p = 0.049) and
overall survival (OS), (HR 5.0, 95% CI 1.3 – 19.2, p = 0.011) on multifactor analysis
adjusting for stage, node positivity, tumour volume and uterine corpus invasion. High
Glut-1 correlated with increased risk of distant failure (HR 14.6, 95% CI 1.9 - 112.9,
p = 0.001) but not with local failure (HR 2.1, 95% CI 0.5 - 8.9, p = 0.48). Low Glut-1
was associated with higher complete metabolic response rate on post-therapy PET scan
(odds ratio 3.4, 95% CI 1.0 – 12.3, p = 0.048). Ki-67 was significantly associated with
PFS only (HR 1.19 per 10 units increase, 95% CI 1.01 – 1.41, p = 0.033). Biomarkers for
hypoxia were not associated with outcome.
Conclusions: High Glut-1 expression in pre-treatment Cx Ca biopsies is associated
with worse outcome post CRT. If prospectively validated, Glut-1 may be used to select
Cx Ca patients who may benefit from a more intensive treatment regimen.
Legal entity responsible for the study: Division of Medical Oncology, Peter
MacCallum Cancer Centre
Funding: Funding for statistical support from the Division of Medical Oncology, Peter
MacCallum Cancer Centre, Melbourne, Australia
Disclosure: All authors have declared no conflicts of interest.
115P
The molecular landscape of genome instability in prostate
cancer (PC)
K. Timms 1 , J. Cuzick 2 , C. Neff 1 , J. Reid 1 , C. Solimeno 1 , Z. Sangale 1 , D. Pruss 1 ,
A. Gutin 1 , J. Lanchbury 1 , S. Stone 1
1 Clinical Research, Myriad Genetics Inc, Salt Lake City, UT, USA, 2 Cancer
prevention, Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine,
Barts and The London School of Medicine, London, UK
Background: Prostate cancer is a leading cause of cancer death in men. A recent study
suggests that prostate tumors with defects in DNA damage repair (DDR) genes may
respond to PARP inhibitor therapy. In breast and ovarian cancer a homologous
recombination deficiency (HRD) score optimally defines treatment groups for DNA
damaging therapy. This study investigates mutations in DDR genes and molecular
signatures for HRD, microsatellite instability (MSI), and high mutation load (HML) in PC.
Methods: DNA was extracted from 50 radical prostatectomies and 45 transurethral
resections of the prostate, and analyzed using a next generation sequencing assay
targeting 43 genes, and genomic regions used to generate HRD, HML, and MSI scores.
Results: DDR genes were considered non-functional if both alleles were mutated and/
or deleted. If the second allele is intact these genes were considered defective but
functional. Non-functional DDR genes (CDK12, PALB2, RPA1, ATM, and BRCA2)
were observed in 7 tumors. 11 tumors were observed with DDR gene defects in 8
additional genes. DDR gene mutation status was significantly associated with high
Gleason score (n = 84; p = 0.0028). Mean HRD scores were higher in tumors with
non-functional DDR genes (n = 7) compared to non-mutant tumors (n = 49) (31.7 vs.
14.6; p = 0.0039), but not in tumors with defective DDR genes (n = 11) (14.0 vs. 14.6;
p = 0.92). HRD scores were associated with high Gleason score (Gleason ≤7
mean = 11.3; Gleason >7 mean = 20.9; p = 0.00064). 3 MSI positive tumors were
identified, all had Gleason scores >7.
Conclusions: HRD scores, non-functional DDR genes (but not DDR gene defects), and
MSI are all associated with higher Gleason scores in PC. A significant proportion of
aggressive prostate tumors carry molecular signatures associated with response to therapies
targeting DDR deficiencies or to immunotherapeutics. This study demonstrates the
importance of assessing both alleles when identifying prostate tumors with DDR gene
mutations. In this study an HRD score of ≥20 captures three times as many potential
responders to HRD-dependent therapies compared to non-functional DDR gene
mutations. Further studies are required to investigate response to targeted therapies in PC.
Legal entity responsible for the study: N/A
Funding: Myriad Genetics
Disclosure: K. Timms, C. Neff, J. Reid, C. Solimeno, D. Pruss, S. Stone, Z. Sangale,
A. Gutin, J. Lanchbury: Myriad Employee, salary and stock options. J. Cuzick:
Consulting/Advisory-Becton Dickinson.
116P
Annals of Oncology
Correlation of mutant P53 protein expression and Ki67 index
with tumor response to concurrent chemoradiation in locally
advanced head and neck cancer
P.B. Shanmuga, K.T. Bhowmik, K. Periasamy
Radiotherapy, Vardhman Mahavir Medical College & Safdarjung Hospital
(VMMC-SJH), New Delhi, India
Background: Concurrent chemoradiotherapy (CRT) remains mainstay of management
in locally advanced head and neck squamous cell cancers. Despite advancements in
treatment delivery, there is heterogeneity in treatment outcome and only marginal
improvement in survival rates. This study was done to find out the correlation of
mutant P53 protein expression and Ki67 index with the treatment response to
concurrent chemoradiotherapy.
Methods: 55 patients of stage III-IVA non-nasopharyngeal head and neck squamous
cell carcinoma were enrolled and the expression of mutant P53 protein and Ki67 index
in the tumor were analysed. All patients were treated with concurrent
chemoradiotherapy using conventional planning to a dose of 66Gy in 33 fractions and
2 cycles of Inj cisplatin 100mg/m 2 as concurrent chemotherapy. The degree of mutant
P53 protein expression and Ki67 index were correlated with the response to concurrent
chemoradiotherapy, examined within three months of treatment completion with
RECIST1.1 criteria.
vi34 | abstracts Volume 27 | Supplement 6 | 2016