Olaparib for Metastatic Breast Cancer in Patients with a Germline <i>BRCA</i> Mutation

Robson, Mark E.; Im, Seock Ah; Senkus, Elżbieta; Xu, Binghe; Domchek, Susan M.; Masuda, Norikazu; Delaloge, Suzette; Li, Wei; Tung, Nadine; Armstrong, Anne; Wu, Weiwen; Goessl, Carsten; Runswick, Sarah; Conte, Pierfranco

doi:10.1056/nejmoa1706450

Cited by 2,517 publications

(2,224 citation statements)

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“…Both studies showed improvement of median PFS with the PARP inhibitor of ~ 3 months and greater tolerability, with no overall survival benefit evident as yet. Among patients with measurable disease, the objective response rates were approximately 60% with the PARP inhibitor compared to approximately 30% in physician choice (need to check talazaparib) [18,19]. The FDA approved olaparib for the treatment of germline BRCA1/2 metastatic breast cancer in January 2018.…”

Section: Germline Brca1 and Brca2 Mutation Status As A Hr Deficiencymentioning

confidence: 99%

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Telli

Stover

Loi

et al. 2018

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. Methods We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Results Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. Conclusions HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

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Section: Germline Brca1 and Brca2 Mutation Status As A Hr Deficiencymentioning

confidence: 99%

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Telli

Stover

Loi

et al. 2018

Breast Cancer Res Treat

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show abstract

“…However, in further lines it can be reasonable to consider a treatment with a PARP inhibitor, although data are not consistent, whilst the EMBRACA trial with talazoparib demonstrated an equal and significant efficacy in both triple-negative metastatic breast cancer patients and hormone receptor (HR)-positive metastatic breast cancer patients (hazard ratio for PFS in HR-positive 0.47, 95% CI 0.32–0.71), the parallel OlympiAD trial showed a significant benefit of olaparib in triple-negative breast cancer only (hazard ratio for PFS in HR-positive 0.82, 95% C.I. 0.55–1.26) [4, 5]. Summarizing the results of both trials, the trend seems to be more in favor of using PARP inhibitors also in HR-positive metastatic breast cancer if a germline BRCA mutation has been found.…”

Section: Question 4: Should All Patients With Luminal Metastatic Breamentioning

confidence: 99%

Luminal Metastatic Breast Cancer

et al. 2019

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“…Earlier this year, the FDA approved the BRACAnalysis CDx test for use in identifying patients with breast cancer with deleterious or suspected deleterious germline BRCA mutation (gBRCAm) who may be eligible for olaparib. The effectiveness of the BRACAnalysis CDx test was established based on the OlympiAD trial population [1]. There is emerging evidence that a significant number of patients with BRCA1/BRCA2 wild-type (wt) breast cancer is also deficient in homologous recombination, and it is likely that these patients may derive a similar benefit from drugs targeting DNA repair pathways, necessitating the development of a companion diagnostic to identify these sporadic BRCA-like tumors.…”

Section: Question 1: Do You Think That We Have the Optimal Drug Compamentioning

confidence: 99%