Locus-specific loss of heterozygosity (LOH) in BRCA1/2 mutated (mBRCA) ovarian tumors from the SOLO2 (NCT01874353) and Study 19 (NCT00753545) clinical trials.

Authors

null

Kirsten Timms

Myriad Genetics, Salt Lake City, UT

Kirsten Timms , Jessica S Brown , Darren R. Hodgson , J Carl Barrett , Tsveta Milenkova , Jonathan A. Ledermann , Charlie Gourley , Eric Pujade-Lauraine , Michael Perry , Alexander Gutin , Victor Abkevich , Jerry S Lanchbury

Organizations

Myriad Genetics, Salt Lake City, UT, Translational Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, United Kingdom, AstraZeneca, Cambridge, United Kingdom, Translational Science, Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, University College London Cancer Institute, London, United Kingdom, University of Edinburgh Cancer Research UK Centre, MRC IGMM, Edinburgh, United Kingdom, Universite Paris-Descartes, AP-HP, Paris, France, Myriad Genetics, Inc., Salt Lake City, UT

Research Funding

Pharmaceutical/Biotech Company

Background: The PARP inhibitor olaparib is approved in the US for patients with mBRCA (germline) advanced ovarian cancer, and in the EU for platinum-sensitive relapsed mBRCA (germline or somatic) ovarian cancer. A recent study reported retention of a normal allele in 7% of germline BRCA1 mutant ovarian tumors and 16% of germline BRCA2 ovarian tumors, and suggested that absence of locus-specific LOH may be a biomarker of primary resistance to DNA damaging agents (Maxwell KN et al, Nature Commun. 2017;22:319). Methods: mBRCA tumors were identified from two trials with patients with platinum sensitive relapsed ovarian cancer: SOLO2 (NCT01874353), Study 19 (NCT00753545). Analysis was performed on tissue obtained at the time of diagnosis. LOH status was assigned using a genomic instability algorithm, and confirmed via human review. Both processes evaluated relative read count and allele dosage data from 54,000 independent SNPs. Results: 210 mBRCA tumors (144 BRCA1, 66 BRCA2) were identified in the SOLO2 cohort. 103 mBRCA (70 BRCA1, 33 BRCA2) were identified in the study 19 cohort. There was lack of locus-specific LOH observed in 1 BRCA2 mutant in each trial. There was no statistically significant difference in the frequency of locus-specific LOH between the two cohorts. The frequencies of locus-specific LOH in the combined SOLO2 and Study 19 cohort were statistically significantly different to that reported by Maxwell et al (Table) for BRCA1, BRCA2, and combined BRCA1/2 mutants (p = 0.001, 0.01, 0.00002, respectively). Conclusions: Locus-specific LOH in mBRCA tumors from the SOLO2 and Study19 cohorts was almost universal; however it is possible that selection for platinum sensitivity enriched for tumors with loss of both alleles. These data support the use of germline or tumor BRCA1/2 testing as a means of identifying patients likely to respond to olaparib treatment in platinum-sensitive ovarian cancer. Further analysis of this phenomenon in additional cohorts will be presented. Clinical trial information: SOLO2 (NCT01874353), Study 19 (NCT00753545).

LOH StatusMaxwell et al
SOLO2+Study 19
BRCA1BRCA2BRCA1/2BRCA1BRCA2BRCA1/2
Yes48277521497311
No459022
Total52328421499313
% non-LOH7.715.610.7020.6

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Abstract Details

Meeting

2018 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Gynecologic Cancer

Track

Gynecologic Cancer

Sub Track

Ovarian Cancer

Clinical Trial Registration Number

SOLO2 (NCT01874353), Study 19 (NCT00753545).

Citation

J Clin Oncol 36, 2018 (suppl; abstr 5563)

DOI

10.1200/JCO.2018.36.15_suppl.5563

Abstract #

5563

Poster Bd #

290

Abstract Disclosures