Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Proffered paper session - Translational research

1081 - Pan-cancer assessment of BRCA1/2 genomic alterations (GAs) by comprehensive genomic profiling (CGP) of tissue and circulating tumor DNA (ctDNA).

Date

20 Oct 2018

Session

Proffered paper session - Translational research

Topics

Targeted Therapy;  Translational Research

Tumour Site

Presenters

Neeraj Agarwal

Citation

Annals of Oncology (2018) 29 (suppl_8): viii14-viii57. 10.1093/annonc/mdy269

Authors

N. Agarwal1, E.S. Sokol2, P. Lara Jr.3, J.S. Ross4, V.A. Miller2, A.W. Welsh5, J.P. Gregg3, G.M. Frampton2, S.M. Ali2, J. Chung2

Author affiliations

  • 1 Oncology/ Internal Medicine, Huntsman Cancer Institute, 84112 - Salt Lake City/US
  • 2 Genetics, Foundation Medicine, Inc., Cambridge/US
  • 3 Medicine, University of California, Davis, Sacramento/US
  • 4 Medicine, SUNY Upstate Medical University, Syracuse/US
  • 5 Medicine, Memorial Sloan Kettering Cancer Center, Lambertville/US
More

Resources

Login to access the resources on OncologyPRO.

If you do not have an ESMO account, please create one for free.

Abstract 1081

Background

Whether somatic or germline, biallelic BRCA1/2 loss of function (LOF) results in homologous recombination deficiency (HRD) and is associated with sensitivity to PARP inhibitors (PARPi) in ovarian and breast cancer. We evaluate the pan-cancer landscape of BRCA1/2 GAs in tissue and ctDNA.

Methods

Hybrid capture-based CGP was performed in a CLIA/CAP lab using a tissue-based assay (FoundationOne) of 315 cancer-related genes or a blood-based ctDNA assay of 62 genes (FoundationACT), including the complete exonic regions of BRCA1 and BRCA2. Genomic profiles were available for >90,000 tissue and >5,000 ctDNA samples.

Results

We identified pathogenic BRCA GAs in 5% of tissue and 6% of ctDNA specimens, with BRCA GAs most frequently identified in ovarian carcinoma (15%), prostate (11%), breast (9%), endometrial (6%), and colorectal [CRC] (4%). Somatic-like BRCA GAs were most frequent in CRC (85%), non-small cell lung cancer [NSCLC] (64%), and prostate cancer (56%), but were also frequent in breast (32%) and ovarian cancers (42%). In tissue-based testing, we observe high frequencies of BRCA loss-of-heterozygosity (LOH) in ovarian and breast carcinomas (94% and 82% of BRCA point GAs), intermediate levels in prostate and pancreatic carcinomas (69% and 66%), and low levels in NSCLC, melanoma, and CRC (40%, 20%, 18%). BRCA LOF was associated with an elevated % genomic LOH in most tumor types (ovarian, breast, pancreatic, NSCLC, CRC, melanoma, and prostate; p < 1e-10). An index case of a prostatic carcinoma with homozygous BRCA alteration, and a genomic LOH score in the top quintile, showed a robust response to a PARPi. Comparison of tissue versus ctDNA revealed highly similar BRCA alteration frequencies (r = 0.94) across disease groups. ctDNA concordance with BRCA-altered tissue (n = 56) was 73% (41/56) overall, and concordance was associated with ctDNA fraction.

Conclusions

The frequencies of BRCA GAs observed here suggest HRD-targeted therapies warrant further investigation in carcinomas beyond ovarian, breast, and prostate. CGP of ctDNA may be a convenient and highly sensitive method for identifying such cases although it may need to be complemented with tissue testing for bi-allelic assessment of BRCA loci.

Clinical trial identification

Legal entity responsible for the study

Huntsman Cancer Institute.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

N. Agarwal: Consultant or advisor: Pfizer, Exelixis, Cerulean Pharma, Medivation/Astellas, Eisai, Merck, Novartis, EMD Serono, Clovis Oncology, Genentech/Roche, Bristol-Myers Squibb, AstraZeneca, and Nektar; Research funding: Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Medivation, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, Tracon Pharma, Rexahn Pharmaceuticals, Amgen. E.S. Sokol: Employment: Foundation Medicine, Inc. P. Lara Jr.: Consultant or advisor: Exelixis, Pfizer, Novartis, AstraZeneca, Bayer, Genentech/Roche, Celgene, Janssen Biotech, Bristol-Myers Squibb, Abbvie, Turnstone Bio; Research funding: Millennium, Polaris, GlaxoSmithKline, Genentech/Roche, Aragon Pharmaceuticals, Janssen Biotech, Heat Biologics, Tracon Pharma, Merck, Pharmacyclics, Incyte; Honoraria: Pfizer. J.S. Ross: Employment, leadership, stock, other ownership interests, research funding: Foundation Medicine, Inc. V.A. Miller: Employment, leadership, stock, other ownership interests: Foundation Medicine, Inc.; Patents, royalties, other intellectual property: Periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center. A.W. Welsh: Employment, travel, accommodations, expenses, stock, other ownership interests: Foundation Medicine, Inc. J.P. Gregg: Consultant or advisor: AstraZeneca, Bristol-Myers Squibb, Abbvie, Roche; Speakers' bureau: AstraZeneca, Foundation Medicine, Inc. G.M. Frampton: Employment, stock, other ownership interests: Foundation Medicine, Inc. S.M. Ali: Employment, patents, royalties, other intellectual property: Foundation Medicine, Inc.; Stock, other ownership interests: Exelixis, Blueprint Medicines, Agios; An immediate family member: Patent royalties: Seres Health. J. Chung: Employment, stock, other ownership interests: Foundation Medicine, Inc.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.