The therapeutic ratio is preserved for radiotherapy or cisplatin treatment in BRCA2-mutated prostate cancers

Abstract

Prostate cancers in patients with a mutation in BRCA2 have earlier disease onset and an aggressive course, often necessitating the use of systemic therapy. However, these tumours are DNA repair-defective and could respond favourably to Parp inhibitors or DNA-damaging agents, depending on the therapeutic ratio (ratio of tumour response to normal tissue toxicity). We describe 3 patients treated with precision radiotherapy or cisplatin who responded favourably to both agents, yet did not suffer undue toxicity. We review the concept of treating such patients with agents that are selectively toxic to repair-deficient tumours. BackgroundMen with an inherited mutation in BRCA2 face an increased risk of prostate cancer 1,2 and the course of their disease is often aggressive.3-5 BRCA2 is a tumour suppressor protein involved in the repair of DNA double-strand breaks via homologous recombination (HR). Tumour tissues derived from BRCA2 mutation carriers (e.g., male or female breast cancers, ovarian cancer and prostate cancer being the most common) may respond differently to radiotherapy (RT) and chemotherapy when compared to tumours with normal BRCA2 and HR protein function. In the normal tissues of BRCA1 or BRCA2 carriers, one BRCA1 or BRCA2 allele remains (heterozygote) and the normal cells maintain HR; however, there is a loss of BRCA1/2 expression in tumours from these patients and therefore functional HR is usually lost. Although the data are varied, some studies have suggested that HR-defective cell lines and xenografts can be more sensitive to ionizing radiation (IR), cisplatin, mitomycin C (MMC), etoposides, melphalan and poly(ADP-ribose) polymerase inhibitors (PARPi). 6,7These cell lines, however, have also been reported to be variably sensitive or even resistant to taxane-based chemotherapy (e.g., docetaxel). [8][9][10][11][12][13][14][15][16][17] These data suggest that patients with a BRCA2 mutation with tumours defective in HR may be targeted by agents, such as RT, cisplatin, anthracyclines or PARPi. This is based on the concept of their inability to repair DNA double strand breaks, DNA cross links or genetic synthetic lethality, respectively. 8,9,11,18 Indeed, a recent clinical trial has shown efficacy of the PARPi named olaparib (AZD2281), in women with ovarian or breast cancer that have mutations in BRCA1/2. 19 In this trial, there was report of a single prostate cancer patient with a BRCA2 mutation who responded to PARPi with a sustained >50% reduction in PSA. To date, the clinical response of men, specifically with known BRCA2 mutations to DNA-damaging chemotherapy, has not yet been reported.Whether normal tissues from male BRCA1/2 carriers are more sensitive to radiotherapy and chemotherapy is not known. We describe 3 patients with prostate cancer and an inherited mutation in BRCA2 who were treated with precision RT or chemotherapy (i.e., cisplatin or anthracylcines which should be more efficacious in patients with HR defective tumours). Given that patients 1 and 3 were from families with a known...

Involvement of homologous recombination in the synergism between cisplatin and poly (ADP‐ribose) polymerase inhibition

“…Poly (ADP-ribose) polymerase inhibitors were originally developed to selectively target HR-defective cells, and have been tested as a monotherapy and in combination with an alkylating agent and cisplatin in patients with certain solid tumors. (36)(37)(38)(39) In this study, 3-AB, as a single agent, had minimal cytotoxic efficacy (Fig. 1a), and only modest increases of cH2AX and RAD51 focus formation in response to 3-AB were observed in the ESCC cells, as compared to the untreated controls (Figs 1b,4a).…”

PTEN Deletion in Prostate Cancer Cells Does Not Associate with Loss of RAD51 Function: Implications for Radiotherapy and Chemotherapy

“…As a potentially important biomarker of DNA repair status, recent reports have suggested that tumor cells that lack PTEN have a marked reduction in RAD51-dependent HR and are therefore sensitive to PARPi in vitro and in vivo (18-20). This suggests that many sporadic tumors could be amenable to PARPi-specific treatments or other agents that are highly toxic to HR-deficient tumor cells such as mitomycin C (MMC), cis-platinum (cDDP) and ionizing radiation (IR) (21-23). Novel trials utilizing PARPi in prostate and other cancers could therefore stratify patients on the basis of intact or abrogated function of the HR, FA, DDR (MRE11-ATM) and now, PTEN pathways (24-26).…”

Radiation-Induced Colitis in a Pancreatic Cancer Patient With a Germline BRCA2 Mutation: A Case Report

“…In multiple reports consisting of germline BRCA mutated patients with breast cancer treated with radiation, no increased rates of acute or late toxicities were noted compared with sporadic breast cancer. 14 , 16 In addition, one case report by Vesprini et al 26 of 3 men with prostate cancer and germline BRCA2 mutations found no adverse short- or long-term gastrointestinal or genitourinary side effects after treatments with radiation and chemotherapy. Furthermore, cell lines generated from one of these BRCA2 mutated patients indicated no difference in clonogenic survival after radiation compared with normal fibroblast strains.…”