24
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      DNA repair deficiency biomarkers and the 70-gene ultra-high risk signature as predictors of veliparib/carboplatin response in the I-SPY 2 breast cancer trial

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Veliparib combined with carboplatin (VC) was an experimental regimen evaluated in the biomarker-rich neoadjuvant I-SPY 2 trial for breast cancer. VC showed improved efficacy in the triple negative signature. However, not all triple negative patients achieved pathologic complete response and some HR+HER2− patients responded. Pre-specified analysis of five DNA repair deficiency biomarkers (BRCA1/2 germline mutation; PARPi-7, BRCA1ness, and CIN70 expression signatures; and PARP1 protein) was performed on 116 HER2− patients (VC: 72 and concurrent controls: 44). We also evaluated the 70-gene ultra-high risk signature (MP1/2), one of the biomarkers used to define subtype in the trial. We used logistic modeling to assess biomarker performance. Successful biomarkers were combined using a simple voting scheme to refine the ‘predicted sensitive’ group and Bayesian modeling used to estimate the pathologic complete response rates. BRCA1/2 germline mutation status associated with VC response, but its low prevalence precluded further evaluation. PARPi-7, BRCA1ness, and MP1/2 specifically associated with response in the VC arm but not the control arm. Neither CIN70 nor PARP1 protein specifically predicted VC response. When we combined the PARPi-7 and MP1/2 classifications, the 42% of triple negative patients who were PARPi7-high and MP2 had an estimated pCR rate of 75% in the VC arm. Only 11% of HR+/HER2− patients were PARPi7-high and MP2; but these patients were also more responsive to VC with estimated pathologic complete response rates of 41%. PARPi-7, BRCA1ness and MP1/2 signatures may help refine predictions of VC response, thereby improving patient care.

          Biomarkers: Gene expression tests predict response to PARP inhibitor combined with carboplatin

          Several predictive gene signatures can help identify breast cancer patients likely to respond to veliparib, an investigational PARP inhibitor, combined with the chemotherapy agent carboplatin. A team led by Denise Wolf, Christina Yau, and Laura van ‘t Veer from the University of California, San Francisco, used data from the I-SPY 2 trial to assess the predictive value of six different biomarkers in determining which women with early stage and locally advanced, aggressive breast cancer would have no signs of disease after veliparib—carboplatin treatment. They found three biomarkers with predictive value: a 7-gene expression signature that predicts breast cancer cell line sensitivity to another PARP inhibitor called olaparib; a 77-gene expression signature that detects molecular features shared with BRCA1-mutant tumours; and a 70-gene signature of recurrence risk called MammaPrint.

          Related collections

          Most cited references29

          • Record: found
          • Abstract: found
          • Article: not found

          Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.

          Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations. In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged >or=18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442. Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4). Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer. AstraZeneca. Copyright 2010 Elsevier Ltd. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.

            Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.

              Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer. In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included in the primary efficacy analysis. This trial is registered at ClinicalTrials.gov, number NCT00679783. 91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22-64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14-38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%]). Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed. AstraZeneca. Copyright © 2011 Elsevier Ltd. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                denise.wolf@ucsf.edu
                cyau@buckinstitute.org
                VantveerL@cc.ucsf.edu
                Journal
                NPJ Breast Cancer
                NPJ Breast Cancer
                NPJ Breast Cancer
                Nature Publishing Group UK (London )
                2374-4677
                25 August 2017
                25 August 2017
                2017
                : 3
                : 31
                Affiliations
                [1 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Laboratory Medicine, , University of California, San Francisco, ; San Francisco, CA 94115 USA
                [2 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Surgery, , University of California, San Francisco, ; San Francisco, CA 94115 USA
                [3 ]Berry Consultants, LLC, Austin, TX 78746 USA
                [4 ]GRID grid.423768.c, Agendia, Inc., ; 1098XH Amsterdam, The Netherlands
                [5 ]ISNI 0000 0004 1936 8032, GRID grid.22448.38, Center for Applied Proteomics and Molecular Medicine, , George Mason University, ; Fairfax, Virginia 22030 USA
                [6 ]GRID grid.430814.a, Division of Molecular Pathology, , Netherlands Cancer Institute, ; Amsterdam, The Netherlands
                [7 ]QuantumLeap Healthcare Collaborative, San Francisco, CA 94143 USA
                [8 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Division of Hematology Oncology, , University of Pennsylvania, ; Philadelphia, PA 19104 USA
                [9 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Radiology, , University of California, San Francisco, ; San Francisco, CA 94115 USA
                [10 ]ISNI 0000 0000 9206 2401, GRID grid.267308.8, Division of Pathology, , University of Texas, ; MD Anderson, Houston, TX 77030 USA
                [11 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Medicine, , University of Minnesota, ; Minneapolis, MN 55455 USA
                [12 ]ISNI 0000 0001 2297 6811, GRID grid.266102.1, Department of Medicine, , University of California, San Francisco, ; San Francisco, CA 94115 USA
                [13 ]ISNI 0000 0004 1936 7822, GRID grid.170205.1, Department of Medicine, , University of Chicago, ; Chicago, IL 60637 USA
                Author information
                http://orcid.org/0000-0002-4502-0035
                Article
                25
                10.1038/s41523-017-0025-7
                5572474
                28948212
                b2eb5246-a9fa-40fa-a508-bd1e2f0d4945
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 December 2016
                : 24 May 2017
                : 5 June 2017
                Categories
                Article
                Custom metadata
                © The Author(s) 2017

                Comments

                Comment on this article

                scite_

                Similar content116

                Cited by38

                Most referenced authors904