Differential Chemotherapeutic Sensitivity for Breast Tumors With “BRCAness”: A Review

Abstract

BRCA1 or BRCA2 mutations predispose to cancer development, primarily through their loss of role in the repair of DNA double-strand breaks. They play a key role in homologous recombination repair, which is a conservative, error-free DNA repair mechanism. When mutated, other alternative, errorprone mechanisms for DNA repair take over, leading to genomic instability. Somatic mutations are rare in sporadic breast tumors, but expression of BRCA1 and BRCA2 genes can be downregulated in other mechanistic ways. These tumors have similar features in terms of their phenotypic and genotypic profiles, which are normally regulated by these genes, and mutations lead to defective DNA repair capacity, called "BRCAness." Attempts have been made to exploit this differentially expressed feature between tumors and normal tissues by treatment with DNA-damaging chemotherapy agents. Cells with this functional BRCA deficiency should be selectively susceptible to DNA-damaging drugs. Preclinical and early clinical (primarily retrospective) evidence supports this approach. In contrast, there is emerging evidence of relative resistance of tumors containing BRCA1 or BRCA2 mutations (or BRCAness) to taxanes. In this review, we summarize the data supporting differentialchemotherapeuticsensitivityonthebasisofdefectiveDNA repair. If confirmed with available, clinically applicable techniques, this differential chemosensitivity could lead to treatment choices in breast cancer that have a more individualized biologic basis. The Oncologist 2013;18:909 -916 Implications for Practice: Women with germline BRCA mutations are more prone to develop breast, ovarian, and other cancers because of the inability to repair DNA damage effectively. These mutations cause a small minority of breast cancers, but studies have shown that such tumors respond better when treated with DNA-damaging chemotherapy agents. Evidence shows that nonmutated tumors also have defective DNA repair or "BRCAness" caused by other mechanisms and behave similarly to BRCAmutated tumors. Some clinical data support that tumors with BRCAness respond better to DNA-damaging chemotherapy. Preliminary data suggest that tumors with intact BRCA1 respond better to treatment with antitubulin agents. In this review, we discuss BRCAness and the clinical data supporting preferential responses to different chemotherapy agents. No standardized test to detect BRCAness exists yet, and various techniques are being developed because this test could affect chemotherapy choice.

Predictive biomarkers for triple negative breast cancer treated with platinum-based chemotherapy

“…BRCAness is defined as patients without BRCA mutations, but with epigenetic inactivation of BRCA, mutations in other genes, or post-translational modifications of key proteins involved in HR and pharmacological inhibitors of the HR, resulting in impairment of HR. 18,19 The BRCAness is identified in at least 25% of BRCA wild-type breast cancers and is more frequent in TNBC. 20,21 The BRCA1 promoter CpG island methylation is in approximately 30% of TNBC patients 22 and tumors with this methylation share the pattern of gene expression similar to inherited BRCA1-mutated breast cancers.…”

Histone deacetylase inhibitor treatment induces ‘BRCAness’ and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells

“…Previous reports have also demonstrated that the sporadic TNBC cells exhibiting similar DNA repair defects, i.e., BRCAness, are also sensitive to PARP inhibitors, cisplatin and other DNA-damaging chemotherapy [2, 19, 20]. Here, BRCAness may be caused by DNA methylation and depletion of BRCA1 expression [21], or due to mutation or depletion of other proteins involved in HR [22]. Based on this, clinical trials of PARP inhibitor in TNBC, including olaparib and veliparib, are ongoing [23].…”

BRCAness Predicts Resistance to Taxane-Containing Regimens in Triple Negative Breast Cancer During Neoadjuvant Chemotherapy

“…Therefore, because BRCAMut tumors cannot repair DSBs induced by agents such as bifunctional alkylators and platinum salts, they are hypersensitive to DSB-inducing agents and probably to PARP inhibitors. [11][12][13][14] Assessment of BRCAness using array comparative genomic hybridization (aCGH) or multiplex ligation-dependent probe amplification (MLPA) has recently been described. 15 Patients with BRCAness tumors survive longer when treated intensively with alkylating agents as adjuvant chemotherapy.…”