DNA damage targeted therapy for advanced breast cancer

Abstract

Breast cancer (BC) is the most prevalent malignancy affecting women worldwide, including Portugal. While the majority of BC cases are sporadic, hereditary forms account for 5-10% of cases. The most common inherited mutations associated with BC are germline mutations in the BReast CAncer (BRCA) 1/2 gene (gBRCA1/2). They are found in approximately 5-6% of BC patients and are inherited in an autosomal dominant manner, primarily affecting younger women. Pathogenic variants within BRCA1/2 genes elevate the risk of both breast and ovarian cancers and give rise to distinct clinical phenotypes. BRCA proteins play a key role in maintaining genome integrity by facilitating the repair of double-strand breaks through the homologous recombination (HR) pathway. Therefore, any mutation that impairs the function of BRCA proteins can result in the accumulation of DNA damage, genomic instability, and potentially contribute to cancer development and progression. Testing for gBRCA1/2 status is relevant for treatment planning, as it can provide insights into the likely response to therapy involving platinum-based chemotherapy and poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitors (PARPi). The aim of this review was to investigate the impact of HR deficiency in BC, focusing on BRCA mutations and their impact on the modulation of responses to platinum and PARPi therapy, and to share the experience of Unidade Local de Saúde Santa Maria in the management of metastatic BC patients with DNA damage targeted therapy, including those with the Portuguese c.156_157insAlu BRCA2 founder mutation.

Keywords: BReast CAncer 1/2 gene; breast cancer; chemotherapy; homologous recombination; poly[adenosine diphosphate-ribose] polymerase.

Figure 1

Types of DNA damage and their repair systems. MMR: mismatch repair; NER: nucleotide excision repair; TLS: translesion synthesis; BER: base excision repair; ICLR: interstrand crosslink repair; HR: homologous recombination; NHEJ: non-homologous end joining

Figure 2

Main DNA repair pathways involved in platinum salts-induced DNA damage. SSBs are primarily repaired through the base excision repair (BER) pathway, requiring proficient DNA glycosylases to identify and cleave the damaged base. Following this, human apurinic/apyrimidinic endonuclease 1 (APE1) eliminates the abasic site, which can then be sealed by Polβ and ligases. In the instance of DSBs, HR assumes a critical role. The Mre11-Rad50-Nbs1 (MRN) complex detects the DSB, enlisting ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR), eventually leading to potential cell cycle arrest mediated by p53. Subsequently, ATM facilitates the recruitment of breast cancer susceptibility gene 1 (BRCA1), BRCA2, and partner and localizer of BRCA2 (PALB2), determining RAD51 loading and subsequent DNA synthesis. SSBs: single-strand breaks; DSBs: double-strand breaks; HR: homologous recombination; PT: platinum salts; FA: Fanconi anaemia Note. Adapted from “Platinum salts in patients with breast cancer: a focus on predictive factors,” by Garutti M, Pelizzari G, Bartoletti M, Malfatti MC, Gerratana L, Tell G, et al. Int J Mol Sci. 2019;20:3390 (https://www.mdpi.com/1422-0067/20/14/3390). CC BY.

Figure 3

The mechanism of action of poly[adenosine diphosphate (ADP)-ribose] polymerase (PARP) inhibitors (PARPi). PARPi mechanism involves interfering with PARP’s role in repairing single-strand breaks (SSBs) present in proliferating cells. Normally, PARP assists in SSB repair, primarily through PARP-dependent base excision repair (BER), vital for cell survival (A). However, PARP inhibitors disrupt this process by preventing PARP from binding to DNA breaks. Consequently, unrepaired SSBs may evolve into double-strand breaks (DSBs), causing cellular toxicity (B). Cells proficient in homologous recombination (HR) can mend these DSBs during replication, ensuring genome stability and cell survival. Conversely, cells lacking efficient HR mechanisms fail to repair DSBs, resulting in cell apoptosis. Red ×: blocking

Figure 4

Swimmers plot for metastatic breast cancer (BC) susceptibility gene 1/2 (BRCA1/2)-mutated BC patients treated with platinum drugs or poly[adenosine diphosphate (ADP)-ribose] polymerase inhibitor (PARPi) at Unidade Local de Saúde Santa Maria between May 2018 and June 2022. Each continuous horizontal line represents a line of treatment for metastatic disease. The origin of the X-axis is taken as the starting date of the first time that a platinum drug or PARPi is used in a metastatic setting. Negative time points represent the number of months before the use of the first PARPi or platinum compound, while positive time points represent the number of months since the use of the first PARPi or platinum compound. P: patient