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Current and New Novel Combination Treatments for Metastatic Triple-Negative Breast Cancer.

ABSTRACT: Triple-negative breast cancer (TNBC) has a worse prognosis and remains the most challenging breast cancer subtype to treat. This is largely related to the heterogeneity of this disease and the lack of reliable oncological targets. In this review, we discuss the current standard-of-care treatment options for metastatic TNBC, including recent advances with the use of immunotherapy, PARP inhibitors and antibody-drug conjugates. This review also explores new agents and novel combinations arising in the field for the treatment of advanced TNBC.

SUBMITTER: Pauls M

PROVIDER: S-EPMC9323790 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Current and New Novel Combination Treatments for Metastatic Triple-Negative Breast Cancer.

Pauls Mehrnoosh M Chia Stephen S LeVasseur Nathalie N

Current oncology (Toronto, Ont.) 20220707 7

Triple-negative breast cancer (TNBC) has a worse prognosis and remains the most challenging breast cancer subtype to treat. This is largely related to the heterogeneity of this disease and the lack of reliable oncological targets. In this review, we discuss the current standard-of-care treatment options for metastatic TNBC, including recent advances with the use of immunotherapy, PARP inhibitors and antibody-drug conjugates. This review also explores new agents and novel combinations arising in ...[more]

PMID: 35877237

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Project description:Triple negative tumors represent 15% of breast cancer and are characterized by the lack of estrogen receptors, progesterone receptor, and HER2 amplification or overexpression. Approximately 25% of patients diagnosed with triple negative breast cancer carry a germline BRCA1 or BRCA2 mutation. They have an aggressive biology, and chemotherapy has been the mainstay of treatment for a long time. Despite intensive therapies, prognosis is still poor, and many patients will eventually relapse or die due to cancer. Therefore, novel targeted agents that can increase the treatment options for this disease are urgently needed. Recently, a new class of molecules has emerged as a standard of care for patients with triple negative breast cancer and germline BRCA1 or BRCA2 mutation: poly (ADP-ribose) (PARP) inhibitors. In the first part of the review, we summarize and discuss evidence supporting the use of PARP inhibitors. Currently, two PARP inhibitors have been approved for triple negative metastatic breast cancer-olaparib and talazoparib-based on two phase III trials, which showed a progression-free survival benefit when compared to chemotherapy. Safety profile was manageable with supportive therapies and dose reductions/interruptions. In addition, other PARP inhibitors are currently under investigation, such as talazoparib, rucaparib, and veliparib. Subsequently, we will discuss the potential role of PARP inhibitors in the future. Clinical research areas are investigating PARP inhibitors in combination with other agents and are including patients without germline BRCA mutations: ongoing phase II/III studies are combining PARP inhibitors with immunotherapy, while phases I and II trials are combining PARP inhibitors with other targeted agents such as ATM and PIK3CA inhibitors. Moreover, several clinical trials are enrolling patients with somatic BRCA mutation or patients carrying mutations in genes, other than BRCA1/2, involved in the homologous recombination repair pathway (e.g., CHECK2, PALB2, RAD51, etc.).

Project description:IntroductionRapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of everolimus also known as RAD001 (oral mammalian target of rapamycin (mTOR) inhibitor) and carboplatin may have activity in metastatic triple-negative breast cancer (TNBC).MethodsThe primary objective of this study was to determine clinical benefit rate (CBR), that is (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting ≥6 months) and the toxicity of everolimus/carboplatin in women with metastatic TNBC. Prior carboplatin was allowed. Treatment consisted of intravenous carboplatin area under the curve (AUC) 6 (later decreased to AUC 5 and subsequently to AUC 4) every 3 weeks with daily 5 mg everolimus.ResultsWe enrolled 25 patients in this study. Median age was 58 years. There were one CR, six PRs, seven SDs and eight PDs (progression of disease). CBR was 36% (95% confidence interval (CI) 21.1 to 57.4%). One SD was achieved in a patient progressing on single agent carboplatin. The median progression free survival (PFS) was 3 months (95% CI 1.6 to 4.6 months) and overall survival (OS) was 16.6 months (95% CI 7.3 months to not reached). There were seven patients (28%) with ≥ grade 3 thrombocytopenia; three (12%) with grade 3 neutropenia (no bleeding/febrile neutropenia) and one (4%) with grade 3 anemia. Greater hematological toxicity was seen in the first seven patients treated with carboplatin AUC5/6. After the amendment for starting dose of carboplatin to AUC 4, the regimen was well tolerated with only one out of 18 patients with grade 3 neutropenia and two patients with grade 3 thrombocytopenia. There was only one case of mucositis.ConclusionEverolimus-carboplatin was efficacious in metastatic TNBC. Dose limiting hematological toxicity was observed when AUC5/6 of carboplatin was combined with everolimus. However, carboplatin AUC 4 was well tolerated in combination with everolimus with continuing responses.Trial registrationsClinicalTrials.gov NCT01127763.

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Current and New Novel Combination Treatments for Metastatic Triple-Negative Breast Cancer.

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Current and New Novel Combination Treatments for Metastatic Triple-Negative Breast Cancer.

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