Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers

被引：25

作者：

Batalini, Felipe ^{[1
,2
,3
]}

Gulhan, Doga C. ^{[4
]}

Mao, Victor ^{[4
]}

Tran, Antuan ^{[4
]}

Polak, Madeline ^{[1
,5
]}

Xiong, Niya ^{[1
,6
]}

Tayob, Nabihah ^{[1
,6
]}

Tung, Nadine M. ^{[1
,2
]}

Winer, Eric P. ^{[1
,5
]}

Mayer, Erica L. ^{[1
,5
]}

Knappskog, Stian ^{[7
]}

Lonning, Per E. ^{[7
]}

Matulonis, Ursula A. ^{[1
,8
]}

Konstantinopoulos, Panagiotis A. ^{[1
,8
]}

Solit, David B. ^{[9
]}

Won, Helen ^{[9
]}

Eikesdal, Hans P. ^{[7
]}

Park, Peter J. ^{[4
]}

Wulf, Gerburg M. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Dept Med, Boston, MA 02215 USA

[2] Beth Israel Deaconess Med Ctr, Div Med Oncol & Canc Res Inst, Boston, MA 02215 USA

[3] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[4] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02215 USA

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[6] Dana Farber Canc Inst, Dept Data Sci, Boston, MA 02115 USA

[7] Univ Bergen, Dept Clin Sci, Bergen, Norway

[8] Dana Farber Canc Inst, Dept Gynecol Oncol, Boston, MA 02115 USA

[9] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

来源：

CLINICAL CANCER RESEARCH | 2022年 / 28卷 / 21期

基金：

美国国家卫生研究院;

关键词：

PHASE-II; GENOMIC INSTABILITY; MAINTENANCE; DEFICIENCY; THERAPY; CARBOPLATIN; MONOTHERAPY; LANDSCAPE; REPAIR; BRCA1;

D O I：

10.1158/1078-0432.CCR-22-0749

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: The identification of patients with homologous recombination deficiency (HRD) beyond BRCAJ/ 2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signa-ture 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing.Experimental Design: We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973).Results: We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demon-strated highly concordant results and superior performance in comparison with the genomic instability score.Conclusions: Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCAJ/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.

引用

页码：4714 / 4723

页数：10

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