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Poster display

1377 - Germline and somatic multi-gene sequencing in patients (pts) with advanced high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC)

Date

10 Oct 2016

Session

Poster display

Presenters

Neda Stjepanovic

Citation

Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392

Authors

N. Stjepanovic1, M. Wilson1, V. Mandilaras1, B. Clarke2, H. Berman2, R.H. Kim1, S. Lheureux1, S. Randall Armel1, J. McCuaig1, A. Volenik1, R. Demsky1, H. Chow1, M. Mysura3, L. Siu1, P. Bedard1, S. Kamel-Reid3, T. Stockley3, A. Oza1

Author affiliations

  • 1 Division Of Medical Oncology & Hematology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 2 Department Of Pathology And Laboratory Medicine, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
  • 3 Genome Diagnostics, Laboratory Medicine Program, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
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Resources

Abstract 1377

Background

Genomic similarities of HGSOC and TNBC include germline pathogenic variants (GPV) in BRCA1/2 and somatic mutations in homologous recombination (HR) genes. Non-BRCA GPV in HGSOC and TNBC pts have also been identified through multi-gene Next Generation Sequencing (NGS). Somatic multi-gene analysis can identify pts with acquired HR mutations for trials with novel targeted drugs, like PARP inhibitors.

Methods

Study cohort included HGSOC and TNBC pts unselected for family history or age at diagnosis, enrolled in an institutional molecular screening program (NCT01505400). DNA extracted from matched blood and tumor samples (FFPE) was additionally tested using a lab-developed NGS Hereditary Cancer Panel of 52 cancer predisposition genes, including 11 HR genes. Medical records were reviewed for clinical course, pathology and prior germline testing results. All pts consented for research on banked samples and return of GPV by a genetic counsellor.

Results

Of 58 analyzed pts 48 (83%; 8/17 TNBC and 40/41 HGSOC) had prior germline testing, which revealed GPV in 17 pts: BRCA1 (12 pts), BRCA2 (4 pts) and PALB2 (1 pt). We identified previously unknown GPV in five pts (9%; see table) and a potentially clinically relevant RAD51 variant in a previously known germline BRCA1 carrier with HGSOC.

Pt Cohort New GPV Prior germline testing
1 TNBC BRCA2 Patient declined
2 TNBC BRCA1 + CHEK2 Provincial testing criteria not met
3 HGSOC CHEK2 BRCA1/2 wild type (WT)
4 HGSOC PALB2 BRCA1/2 WT
5 HGSOC FANCC BRCA1/2 WT
Among 22 GPV carriers, three HGSOC pts (14%) also had somatic mutations in HR genes (BRCA1, FANCD2), in addition to their GPV that were present in the tumor. Of 36 germline WT pts, five HGSOC pts (14%) had somatic mutations in HR genes (BRCA1/2, FANCD2), including one who achieved a partial response on a clinical trial with a PARP inhibitor.

Conclusions

Comprehensive germline and tumor analysis with 52 gene panel in advanced HGSOC and TNBC found previously unidentified GPV in 9% of pts and somatic mutations in HR genes in 14% of germline WT pts. This increases options for targeted therapeutics with investigational agents, such as PARP inhibitors.

Clinical trial identification

Legal entity responsible for the study

Princess Margaret Cancer Centre

Funding

AstraZeneca

Disclosure

M. Wilson, S. Lheureux: Consulting/Advisory for AstraZeneca. L. Siu: Consulting-Advisory: Oncoethix, Novartis, Daiichi Sankyo, Boehringer, Merck/Family Member-Leadership: Agios; Ownership Interests: Agios,Entremed/Research. Funding: Abraxis, Celgene, BMS, Genentech/Roche, GSK, Merck, Novartis, Pfizer, MedImmune, AstraZeneca, Boehringer. P. Bedard: Consulting/Advisory: Pfizer, Genentech/Roche, Sanofi Research Funding: Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, SERVIER, GlaxoSmithKline, Oncothyreon, Novartis, SignalChem, PTC Therapeutics. A. Oza: Consulting/Advisory: Amgen, Verastem, Clovis Oncology, Immunovaccine Honoraria: WebRx Research Funding: AstraZeneca, Roche, Merck, AstraZeneca Travel, Accommodations, Expenses: AstraZeneca. All other authors have declared no conflicts of interest.

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