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Prospect for Application of PARP Inhibitor in Patients with HER2 Negative Breast Cancer.

ABSTRACT: Human epidermal growth factor receptor (HER2) negative metastatic breast cancer (BC) accounts for 73% of BC. The molecular analysis of this disease is essential for potential options for targeted therapy. Several promising clinical strategies are being evaluated which includes endocrine therapy, modified chemotherapy, angiogenesis inhibitors, immune checkpoint inhibitors, and anti-androgens. New therapeutic approaches are being developed that target BC patients with germline mutations in either BRCA1, BRCA2 as well as BRCAness, a condition in which tumors have molecular similarity to BRCA-mutated tumors. Poly (ADP-ribose) polymerase inhibitors (PARPi) which are effective therapy in germline BRCA1 and BRCA2 mutations, are also observed to be effective in somatic mutations. Germline mutations in the homologous recombination pathway genes could also contribute to PARPi sensitivity. PARPi act as chemo- and radio-sensitizers by limiting the DNA-damage response and potentiating the activity of chemo- and radio-therapy when used alone or in combination with chemotherapy. Apart from PARPi as monotherapy, additional researches are ongoing in combination with cytotoxic chemotherapeutics and targeted agents in HER2 negative BC. This review aims at the most recent developments in the targeted therapy, summarizes the recent clinical trials outcomes, along with the overview of ongoing clinical trials in HER2 negative patients with BRCA1/2 mutations and sporadic tumors with BRCAness.

SUBMITTER: Shao N

PROVIDER: S-EPMC6535782 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Prospect for Application of PARP Inhibitor in Patients with HER2 Negative Breast Cancer.

Shao Nan N Shi Yawei Y Yu Liang L Ye Runyi R Shan Zhen Z Zhang Zhanqiang Z Zhang Yunjian Y Lin Ying Y

International journal of biological sciences 20190310 5

Human epidermal growth factor receptor (HER2) negative metastatic breast cancer (BC) accounts for 73% of BC. The molecular analysis of this disease is essential for potential options for targeted therapy. Several promising clinical strategies are being evaluated which includes endocrine therapy, modified chemotherapy, angiogenesis inhibitors, immune checkpoint inhibitors, and anti-androgens. New therapeutic approaches are being developed that target BC patients with germline mutations in either ...[more]

PMID: 31182917

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Project description:Breast cancer is the most commonly diagnosed cancer (estimated 2.3 million new cases in 2020) and the leading cause of cancer death (estimated 685,000 deaths in 2020) in women globally. Breast cancers have been categorized into four major molecular subtypes based on the immunohistochemistry (IHC) expression of classic hormone and growth factor receptors including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as a proliferation marker Ki-67 protein expression. Triple-negative breast cancer (TNBC), a breast cancer subtype lacking ER, PR, and HER2 expression, is associated with a high metastatic potential and poor prognosis. TNBC accounts for approximately only 15%-20% of new breast cancer diagnoses; it is responsible for most breast cancer-related deaths due to the lack of targeted treatment options for this patient population, and currently, systemic chemotherapy, radiation, and surgical excision remain the major treatment modalities for these patients with TNBC. Although breast cancer patients in general do not have a robust response to the immunotherapy, a subset of TNBC has been demonstrated to have high tumor mutation burden and high tumor-infiltrating lymphocytes, resembling the features observed on melanoma or lung cancers, which can benefit from the treatment of immune checkpoint inhibitors (ICIs). Therefore, the immunogenic nature of this aggressive disease has presented an opportunity for the development of TNBC-targeting immunotherapies. The recent US Food and Drug Administration approval of atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced, or metastatic TNBC has led to a new era of immunotherapy in TNBC treatment. In addition, immunotherapy becomes an active research area, both in the cancer biology field and in the oncology field. In this review, we will extend our coverage on recent discoveries in preclinical research and early results in clinical trials from immune molecule-based therapy including cytokines, monoclonal antibodies, antibody-drug conjugates, bi-specific or tri-specific antibodies, ICIs, and neoantigen cancer vaccines; oncolytic virus-based therapies and adoptive immune cell transfer-based therapies including TIL, chimeric antigen receptor-T (CAR-T), CAR-NK, CAR-M, and T-cell receptor-T. In the end, we will list a series of the challenges and opportunities in immunotherapy prospectively and reveal novel technologies such as high-throughput single-cell sequencing and CRISPR gene editing-based screening to generate new knowledges of immunotherapy.

Project description:To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2(-/low) breast cancers.HER2-expressing BCSCs (HER2(+)/CD44(+)/CD24(-/low)) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24(-/low) BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program.Compared with HER2-negative BCSCs, HER2(+)/CD44(+)/CD24(-/low) cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2(+)/CD44(+)/CD24(-/low) cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24(-/low) BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified.This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2(-/low) breast cancer.

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Prospect for Application of PARP Inhibitor in Patients with HER2 Negative Breast Cancer.

Publications

Prospect for Application of PARP Inhibitor in Patients with HER2 Negative Breast Cancer.

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