Olaparib monotherapy as primary treatment in unselected triple negative breast cancer

Eikesdal, Hans Petter; Yndestad, Synnøve; Elzawahry, Asmaa; Llop‐Guevara, Alba; Gilje, Bjørnar; Blix, Ellen; Espelid, Helge; Lundgren, Steinar; Geisler, Jürgen; Vagstad, Geirfinn; Venizelos, Andreas; Minsaas, Laura; Leirvaag, Beryl; Gudlaugsson, Einar; Vintermyr, Olav Karsten; Aase, Hildegunn Siv; Aas, Turid; Balmañà, Judith; Serra, Violeta; Janssen, Emiel A. M.; Knappskog, Stian; Lønning, Per Eystein

doi:10.1016/j.annonc.2020.11.009

Cited by 126 publications

(112 citation statements)

References 49 publications

(80 reference statements)

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“…The γH2AX score, i.e., the percentage of GMN + cells with more than two γH2AX foci/nucleus, was determined for each case. When applying a 25% γH2AX threshold, as described previously [42][43][44], 72/74 (97%) passed QC2 (Figures 1B and 2). We investigated whether differences could be observed between γH2AX scores of diagnostic FFPE specimens when cases were classified as either HR-Proficient (HRP) or HR-Deficient (HRD) based on the results of the RECAP test (RECAP-HRP and RECAP-HRD; Figure 2A and Figure S3).…”

Section: Diagnostic Ffpe Specimen Inclusion and Quality Control (Qc)supporting

confidence: 59%

The RAD51-FFPE Test; Calibration of a Functional Homologous Recombination Deficiency Test on Diagnostic Endometrial and Ovarian Tumor Blocks

Wijk

Kramer

Vermeulen

et al. 2021

Cancers

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PARP inhibitor (PARPi) sensitivity is related to tumor-specific defects in homologous recombination (HR). Therefore, there is great clinical interest in tests that can rapidly and reliably identify HR deficiency (HRD). Functional HRD tests determine the actual HR status by using the (dis)ability to accumulate RAD51 protein at sites of DNA damage as read-out. In this study, we further improved and calibrated a previously described RAD51-based functional HRD test on 74 diagnostic formalin-fixed paraffin-embedded (FFPE) specimens (RAD51-FFPE test) from endometrial cancer (EC n = 25) and epithelial ovarian cancer (OC n = 49) patients. We established optimal parameters with regard to RAD51 foci cut-off (≥ 2) and HRD threshold (15%) using matched endometrial and ovarian carcinoma specimens for which HR status had been established using a RAD51-based test that required ex vivo irradiation of fresh tissue (RECAP test). The RAD51-FFPE test detected BRCA deficient tumors with 90% sensitivity and RECAP-HRD tumors with 87% sensitivity, indicating that it is an attractive alternative to DNA-based tests with the potential to be applied in routine diagnostic pathology.

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Section: Diagnostic Ffpe Specimen Inclusion and Quality Control (Qc)supporting

confidence: 59%

The RAD51-FFPE Test; Calibration of a Functional Homologous Recombination Deficiency Test on Diagnostic Endometrial and Ovarian Tumor Blocks

Wijk

Kramer

Vermeulen

et al. 2021

Cancers

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“…6.3 ). TNBCs often harbor somatic BRCA or other HRR mutations, or BRCA genes may be silenced through promoter hypermethylation, which may result in susceptibility to PARP inhibitor therapy [ 137 ]. PARTNER is a three-stage phase 2/3 trial, designed to assess the safety, schedule selection, and efficacy of neoadjuvant olaparib in combination with platinum-based chemotherapy for patients with TNBC and/or gBRCA-mutated BC [ 138 , 139 ].…”

Section: Overview Of New Directions For Parp Inhibitorsmentioning

confidence: 99%

“…Based on 159 patients (target N = 527), preliminary safety data support the combination. A large phase 2 study, the PETREMAC trial, is also ongoing ( N = 200); olaparib is one of several treatment options being investigated in this trial for patients with TP53 -mutated or TP53 -wild-type BC [ 137 , 140 ]. The primary outcome measure of PETREMAC is the predictive and prognostic value of mutations in 300 cancer-related genes, assessed in BC tissue by next-generation sequencing before starting neoadjuvant therapy.…”

Section: Overview Of New Directions For Parp Inhibitorsmentioning

confidence: 99%

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An Overview of PARP Inhibitors for the Treatment of Breast Cancer

2021

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Loss-of-function mutations in BRCA1 and BRCA2 are detected in at least 5% of unselected patients with breast cancer (BC). These BC susceptibility genes encode proteins critical for DNA homologous recombination repair (HRR). This review provides an update on oral poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BC. Olaparib and talazoparib are PARP inhibitors approved as monotherapies for deleterious/suspected deleterious germline BRCA-mutated, HER2-negative BC. Olaparib is approved in the USA for metastatic BC and in Europe for locally advanced/metastatic BC. Talazoparib is approved for locally advanced/metastatic BC in the USA and Europe. In phase 3 trials, olaparib and talazoparib monotherapies demonstrated significant progression-free survival benefits compared with chemotherapy. Common toxicities were effectively managed by supportive treatment and dose interruptions/reductions. Veliparib combined with platinum-based chemotherapy has also shown promise for locally advanced/metastatic BC in a phase 3 trial. Differences in efficacy and safety across PARP inhibitors (olaparib, talazoparib, veliparib, niraparib, rucaparib) may relate to differences in potency of PARP trapping on DNA and cytotoxic specificity. PARP inhibitors are being investigated in early BC, in novel combinations, and in patients without germline BRCA mutations, including those with somatic BRCA mutations and other HRR gene mutations. Ongoing phase 2/3 studies include PARP inhibitors combined with immune checkpoint inhibitors for the treatment of triple-negative BC. Wider access to testing for BRCA and other mutations, and to genetic counseling, are required to identify patients who could benefit from PARP inhibitor therapy. The advent of PARP inhibitors has potential benefits for BC treatment beyond the locally advanced/metastatic setting.

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“…However, recent studies have shown that TNBC is heterogeneous and has multiple pathological subtypes ( 45 ). The molecularly targeted drug olaparib (a PARP inhibitor) has been approved for the treatment of BRCA-mutated TNBC ( 46 , 47 ). Given the broad applications of olaparib in clinical treatment, patients with TNBC have also exhibited resistance to olaparib ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

miR-27-3p Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to the Antitumor Agent Olaparib by Targeting PSEN-1, the Catalytic Subunit of Γ-Secretase

et al. 2021

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Olaparib has been used in the treatment of triple-negative breast cancer (TNBC) with BRCA mutations. In the present study, we demonstrated the effect of miR-27-3p on the γ-secretase pathway by regulating the sensitivity of TNBC cells to olaparib. miR-27-3p, a microRNA with the potential to target PSEN-1, the catalytic subunit of γ-secretase mediating the second step of the cleavage of the Notch protein, was identified by the online tool miRDB and found to inhibit the expression of PSEN-1 by directly targeting the 3’-untranslated region (3’-UTR) of PSEN-1. The overexpression of miR-27-3p inhibited the activation of the Notch pathway via the inhibition of the cleavage of the Notch protein, mediated by γ-secretase, and, in turn, enhanced the sensitivity of TNBC cells to the antitumor agent olaparib. Transfection with PSEN-1 containing mutated targeting sites for miR-27-3p or the expression vector of the Notch protein intracellular domain (NICD) almost completely blocked the effect of miR-27-3p on the Notch pathway or the sensitivity of TNBC cells to olaparib, respectively. Therefore, our results suggest that the miR-27-3p/γ-secretase axis participates in the regulation of TNBC and that the overexpression of miR-27-3p represents a potential approach to enhancing the sensitivity of TNBC to olaparib.

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Olaparib monotherapy as primary treatment in unselected triple negative breast cancer

Cited by 126 publications

References 49 publications

The RAD51-FFPE Test; Calibration of a Functional Homologous Recombination Deficiency Test on Diagnostic Endometrial and Ovarian Tumor Blocks

The RAD51-FFPE Test; Calibration of a Functional Homologous Recombination Deficiency Test on Diagnostic Endometrial and Ovarian Tumor Blocks

An Overview of PARP Inhibitors for the Treatment of Breast Cancer

miR-27-3p Enhances the Sensitivity of Triple-Negative Breast Cancer Cells to the Antitumor Agent Olaparib by Targeting PSEN-1, the Catalytic Subunit of Γ-Secretase

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