Increased Radiosensitivity of Solid Tumors Harboring ATM and BRCA1/2 Mutations

Abstract

Preclinical data indicate that response to radiotherapy (RT) depends on DNA damage repair. In this study, we investigated the role of mutations in genes related to DNA damage repair in treatment outcome after RT. Materials and MethodsPatients with solid tumor who participated in next generation sequencing panel screening using biopsied tumor tissue between October 2013 and February 2019 were reviewed and 97 patients that received RT were included in this study. Best response to RT and the cumulative local recurrence rate (LRR) were compared according to absence or presence of missense, nonsense, and frameshift mutations in ATM and/or BRCA1/2. ResultsOf the 97 patients, five patients harbored mutation only in ATM, 22 in only BRCA1/2, and six in both ATM and BRCA1/2 (ATM mt BRCA mt ). Propensity score matching was performed to select the control group without mutations (ATM wt BRCA wt , n=33). In total, 90 RT-treated target lesions were evaluated in 66 patients. Highest objective response rate of 80% was observed in ATM mt BRCA mt lesions (p=0.007), which was mostly durable. Furthermore, the cumulative 1year LRR was the lowest in ATM mt BRCA mt lesions and the highest in ATM wt BRCA wt lesions (0% vs. 47.9%, p=0.008). RT-associated toxicities were observed in 10 treatments with no significant difference among the subgroups (p=0.68). ConclusionTumors with ATM and BRCA1/2 mutations exhibited superior tumor response and local control after RT compared to tumors without these mutations. The results are hypothesis generating and suggest the need for integrating the tumor mutation profile of DNA repair genes during treatment planning.

Dramatic response to local radiotherapy in a refractory metastatic mediastinal yolk sac tumor patient harboring a germline BRCA2 frameshift mutation: a case report

“… 27 Recently, a study by Kim et al demonstrated that solid tumors harboring BRCA1/2 variations exhibited increased sensitivity to radiotherapy compared to those without these alterations. 9 Our case is consistent with the findings of Kim et al in this regard.…”

“…Previous studies have demonstrated that mutations in DDR genes, including BRCA1/2 , potentially enhance radiosensitivity in patients with diverse solid tumors. 9 However, DDR-gene mutations, as predictive biomarkers for radiotherapy in primary mediastinal YSTs, have not yet been explored.…”

“… 8 Recently, studies have demonstrated that DDR-gene mutations potentially predict an enhanced response to radiotherapy in patients with diverse solid tumors. 9 …”

Case Report: MR-Guided Adaptive Radiotherapy, Some Room to Maneuver

“…In contrast, our patient had almost a 50% reduction in target volume, potentially due to the longer span in overall treatment time. The reduction may have also been associated with his BRCA2 mutation status as there are reports of increased radiosensitivity in normal and tumor cells of BRCA mutation carriers ( 18 ).…”

Ovarian Cancer Radiosensitivity: What Have We Understood So Far?

“…BRCA1 and BRCA2 play a pivotal role in HR, and a higher risk of contralateral breast cancer was described in patients with germline mutation who underwent adjuvant RT after breast surgery [ 47 ]. Kim et al [ 48 ] described a significantly higher objective response and a lower local recurrence rate in patients with BRCA mutation treated with RT and a dramatic and durable response when there was also a concomitant ATM mutation (1-year local recurrence rate at 0% in BRCA + ATM mutated vs. 47.9% in wild type, p = 0.008) without an increased toxicity rate.…”