Olaparib Use in Patients With Metastatic Breast Cancer Harboring Somatic BRCA1/2 Mutations or Mutations in Non-BRCA1/2, DNA Damage Repair Genes

Walsh, Elaine M.; Mangini, Neha; Fetting, John H.; Armstrong, Deborah K.; Chan, Isaac S.; Connolly, Roisín M.; Fiallos, Katie; Lehman, Jennifer; Nunes, Raquel; Petry, Dana; Reynolds, Jeffrey; Shah, Mirat; Smith, Karen L.; Visvanathan, Kala; Lauring, Josh; Park, Ben Ho; Stearns, Vered; Wolff, Antonio C.

doi:10.1016/j.clbc.2021.12.007

Cited by 6 publications

(7 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There were also appreciable numbers of patients in the United States (18%) and the EU4 (10%), but not Israel, who received s BRCA1/2 mut-only testing. Although patients with metastatic breast cancer with an s BRCA1/2 mut have been shown to respond to PARPi [ 23 , 24 ], PARPi have not been approved to treat this patient group. The ESMO international consensus guidelines indicate that the therapeutic implications of s BRCA1/2 mut in patients with breast cancer need further evaluation and should not be used for decision-making in clinical practice [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

BRCA1/2 Mutation Testing in Patients with HER2-Negative Advanced Breast Cancer: Real-World Data from the United States, Europe, and Israel

Mahtani

Niyazov

Arondekar

et al. 2022

Cancers

View full text Add to dashboard Cite

Poly(adenosine diphosphate-ribose) polymerase inhibitors are approved to treat patients harboring a germline breast cancer susceptibility gene 1 or 2 mutation (BRCA1/2mut) with human epidermal growth factor receptor 2—negative (HER2−) advanced breast cancer (ABC). This study evaluated differences in patient demographics, clinical characteristics, and BRCA1/2mut testing within the United States (US), European Union 4 (EU4; France, Germany, Italy, and Spain), and Israel in a real-world population of patients with HER2− ABC. Oncologists provided chart data from eligible patients from October 2019 through March 2020. In the US, EU4, and Israel, 73%, 42%, and 99% of patients were tested for BRCA1/2mut, respectively. In the US and the EU4, patients who were not tested versus tested for BRCA1/2mut were more likely to have hormone receptor—positive (HR+)/HER2− ABC (US, 94% vs. 74%, p < 0.001; EU4, 96% vs. 78%, p < 0.001), less likely to have a known family history of BRCA1/2-related cancer (US, 6% vs. 19%, p = 0.002; EU4, 10% vs. 28%, p < 0.001), and were older (US, 68.9 vs. 62.5 years, p < 0.001; EU4, 66.7 vs. 58.0 years, p < 0.001). Among tested patients, genetic counseling was received by 45%, 53%, and 98% with triple-negative breast cancer, and 36%, 36%, and 98% with HR+/HER2− ABC in the US, EU4, and Israel, respectively. Efforts should be made to improve BRCA1/2 testing rates in the US and Europe.

show abstract

Section: Discussionmentioning

confidence: 99%

BRCA1/2 Mutation Testing in Patients with HER2-Negative Advanced Breast Cancer: Real-World Data from the United States, Europe, and Israel

Mahtani

Niyazov

Arondekar

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…All s BRCA1/2 mutation carriers responded to Olaparib, while other HRR-associated mutation carriers did not respond to PARP inhibition. Median PFS was 6.5 months with s BRCA1/2 mutations, compared to the 3 months of those patients with non- BRCA HRR mutations [ 71 ]. However, the number of reported cases was low.…”

Section: Breast Cancermentioning

confidence: 99%

Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors

Szentmartoni,

Mühl,

Csanda

et al. 2024

Biomedicines

View full text Add to dashboard Cite

Ten percent of patients with breast cancer, and probably somewhat more in patients with ovarian cancer, have inherited germline DNA mutations in the breast and ovarian cancer genes BRCA1 and BRCA2. In the remaining cases, the disease is caused by acquired somatic genetic and epigenetic alterations. Targeted therapeutic agents, such as poly ADP-ribose polymerases (PARP) inhibitors (PARPi), have emerged in treating cancers associated with germline BRCA mutations since 2014. The first PARPi was FDA-approved initially for ovarian cancer patients with germline BRCA mutations. Deleterious variants in the BRCA1/BRCA2 genes and homologous recombination deficiency status have been strong predictors of response to PARPi in a few solid tumors since then. However, the relevance of somatic BRCA mutations is less clear. Somatic BRCA-mutated tumors might also respond to this new class of therapeutics. Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.

show abstract

Section: Parp Inhibitors In Breast Cancers With Ddr Alterations Other...mentioning

confidence: 99%

“…A retrospective report on seven metastatic breast cancer patients who received off label olaparib showed that the four patients with somatic BRCA1/ BRCA2 mutations achieved a partial response and had a median PFS of 6.5 months (55). The three patients with other mutations (one patient with somatic ATM mutation, one patient with germline ATM mutation and one with germline BARD1 mutation) did not respond to olaparib and had a median PFS of 3 months (55). In unselected patients with triple-negative breast cancers receiving neo-adjuvant olaparib in the phase II PETREMAC trial, patients with germline mutations in BRCA1, BRCA2 and PALB2 genes showed responses to the drug (56).…”

Section: Parp Inhibitors In Breast Cancers With Ddr Alterations Other...mentioning

confidence: 99%

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

Voutsadakis

Stravodimou

2023

Anticancer Res

View full text Add to dashboard Cite

Homologous recombination repair (HRR) is the cellular mechanism for error-free repair of double strand DNA (dsDNA) breaks. Cancer cells with mutations in both alleles of genes encoding for proteins involved in HRR, such as BRCA1 and BRCA2, have defects in the repair process. As a result, these cells repair dsDNA breaks with alternative mechanisms, such as non-homologous end joining. In breast cancers with germline mutations in BRCA1 and BRCA2 genes, HRR defects result in sensitivity to PARP inhibitors, drugs that interfere with the function of PARP enzyme and promote trapping of the enzyme on DNA and stalling of the process of repairing single strand breaks. HRR defects also lead to sensitivity to DNA damaging chemotherapy due to the inability of cells to repair chemotherapy induced DNA lesions. Besides germline mutations in BRCA1 and BRCA2, somatic mutations in these genes or germline and somatic mutations or other genetic and epigenetic alterations of other genes involved in homologous recombination (HR) may produce HRR defects leading to sensitivity to PARP inhibitors. However, studies are less conclusive, a fact that may relate to the common lack of bi-allelic loss of function in these cases, as opposed to cancers with germline BRCA1 or BRCA2 defects that usually acquire bi-allelic loss of function. In addition, there is heterogeneity between the different HRR genes and the severity of the resulting HRR defects, as measured by HR defect assays. This review article examines the landscape of HRR gene mutations in breast cancer and the possible therapeutic implications of HRR defects other than germline BRCA1 and BRCA2 mutations for targeted therapies. Identification of a wider range of breast cancers with HRR defects may expand the subset of patients that derive benefit from PARP inhibitors and other DDR-targeting drugs in the clinic.

show abstract

Olaparib Use in Patients With Metastatic Breast Cancer Harboring Somatic BRCA1/2 Mutations or Mutations in Non-BRCA1/2, DNA Damage Repair Genes

Cited by 6 publications

References 44 publications

BRCA1/2 Mutation Testing in Patients with HER2-Negative Advanced Breast Cancer: Real-World Data from the United States, Europe, and Israel

BRCA1/2 Mutation Testing in Patients with HER2-Negative Advanced Breast Cancer: Real-World Data from the United States, Europe, and Israel

Predictive Value and Therapeutic Significance of Somatic BRCA Mutation in Solid Tumors

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes BesidesBRCA1andBRCA2as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies

Contact Info

Product

Resources

About