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
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 Status | Maxwell et al | SOLO2+Study 19 | ||||
---|---|---|---|---|---|---|
BRCA1 | BRCA2 | BRCA1/2 | BRCA1 | BRCA2 | BRCA1/2 | |
Yes | 48 | 27 | 75 | 214 | 97 | 311 |
No | 4 | 5 | 9 | 0 | 2 | 2 |
Total | 52 | 32 | 84 | 214 | 99 | 313 |
% non-LOH | 7.7 | 15.6 | 10.7 | 0 | 2 | 0.6 |
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