Abstract 4355
Background
We conducted tumour testing in pts with germline mutations in BRCA1 and/or BRCA2 (gBRCAm) and HER2-negative mBC in the OlympiAD study (NCT02000622).
Methods
Tumour tissue of gBRCAm pts was analysed with Myriad myChoice HRD Plus, including determination of tumor (t) BRCAm, HRD score and gene-specific loss of heterozygosity (LOH).
Results
Tissue was available from 161/302 pts: tBRCAm status n = 143 (47%); HRD score n = 129 (43%); LOH n = 125 (41%). Concordance of gBRCAm and tBRCAm was 99% (141/142). Absence of LOH was observed in 7/125 pts (6%): 4/49 (8%) BRCA2m, 3/76 (4%) BRCA1m; 2 had a 2nd mutation event (Table). Low HRD scores (<42) were seen in 16% of pts (21/129), with higher rates in BRCA2m vs BRCA1m pts (14/51 [27%] vs 7/78 [9%]) and hormone receptor positive (HR+) vs triple negative (TN; 13/59 [22%] vs 8/70 [11%]). In olaparib (ola) pts with a BRCAm, ORR was 60% (6/10) and 57% (37/65) in pts with HRD score <42 and ≥42, respectively. Hazard ratio for PFS favoured ola vs treatment of physician’s choice (TPC) when HRD score was <42 or ≥ 42.Table: 1936P
Pts with absence of LOH
Treatment | Biopsy | Gene | Variant | HRD score | Hormone receptor status | 2nd event | RECIST response | PFS (months)† |
---|---|---|---|---|---|---|---|---|
Ola | Pri | BRCA2 | c.9097dupA (p.Thr3033Asnfs*11) | 31 | HR + | PR | 11.0‡ | |
Ola | Pri | BRCA2 | c.5946del (p.Ser1982Argfs*22) | 28 | HR + | PD | 1.3§ | |
Ola | Met | BRCA2 | c.658_659del (p.Val220Ilefs*4) | 12 | HR + | SD | 8.2§ | |
Ola | Pri | BRCA2 | c.7977-1G>C | 34 | HR + | CR | 11.0‡ | |
Ola | Met¶ | BRCA1 | c.188T>A (p.Leu63*) | 56 | HR + | S1580fs*2 | PR | 6.5§ |
TPC | Met¶ | BRCA1 | c.5266dupC (p.Gln1756Profs*74) | 73 | HR + | 494dupT and 528_535delins25 | PR | 5.9§ |
TPC | Pri | BRCA1 | c.1931del (p.Cys644Phefs*7) | 41 | TN | SD | 8.1§ |
†Overall median PFS was 7.0 months for ola vs 4.2 months for TPC;
‡Censor;
§Event;
¶Diagnosis to sample interval was ≥7 years. CR, complete response; Met, metastatic; PD, progressive disease; PR, partial response; Pri, primary; SD, stable disease
Conclusions
Tumour testing detected almost all gBRCAm in the study. In this mBC population, absence of LOH was uncommon, indicating a high rate of biallelic inactivation. There was no evidence for a reduction in ola efficacy in the small number of pts with BRCAm HER2-negative mBC whose tumors lack LOH and/or have HRD score <42.
Clinical trial identification
NCT02000622.
Editorial acknowledgement
Medical writing assistance was provided by Debbi Gorman, PhD, from Mudskipper Business, Ltd, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, U.S.A. (MSD).
Legal entity responsible for the study
AstraZeneca.
Funding
This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck & Co, Inc.
Disclosure
M. Robson: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Uncompensated: Daiichi-Sankyo; Advisory / Consultancy: McKesson; Advisory / Consultancy, Uncompensated: Merck; Advisory / Consultancy, Research grant / Funding (institution), Consulting/advisory: Uncompensated; other transfer of value (editorial services): Pfizer; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Invitae; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): Myriad; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution), Funded in part: Grant P30 CA008748: NIH/NCI Cancer Center Support. Z. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S. Dearden: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J.C. Barrett: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E.A. Harrington: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Timms: Shareholder / Stockholder / Stock options, Full / Part-time employment: Myriad. J. Lanchbury: Shareholder / Stockholder / Stock options, Full / Part-time employment: Myriad. W. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Allen: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Goessl: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E. Senkus: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): Clinigen; Honoraria (self), Travel / Accommodation / Expenses: Egis; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self): Sandoz; Honoraria (self), Research grant / Funding (institution): Samsung; Honoraria (self), Research grant / Funding (institution): Merck; Research grant / Funding (institution): Boehringer. S. Domchek: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Clovis Oncology; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): PharmaMar. D. Hodgson: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca.
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