Cancer Res Treat.  2022 Jan;54(1):54-64. 10.4143/crt.2020.1247.

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

• Kim KH
• Kim HS
• Kim Ss
• Shim HS
• Yang AJ
• Lee JJB
• Yoon HI
• Ahn JB
• Chang JS

• KMID: 2524587
• DOI: http://doi.org/10.4143/crt.2020.1247

Abstract

Purpose
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 Methods
Patients 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.
Results
Of the 97 patients, five patients harbored mutation only in ATM, 22 in only BRCA1/2, and six in both ATM and BRCA1/2 (ATM^mtBRCA^mt). Propensity score matching was performed to select the control group without mutations (ATM^wtBRCA^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^mtBRCA^mt lesions (p=0.007), which was mostly durable. Furthermore, the cumulative 1-year LRR was the lowest in ATM^mtBRCA^mt lesions and the highest in ATM^wtBRCA^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=0.680).
Conclusion
Tumors 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.

Keyword

Radiotherapy; DNA repair; Radiosensitivity

Figure

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  Fig. 1 Serial tumor response in patients treated with radiotherapy. (A) A representative patient diagnosed with Adenocarcinoma in Rectosigmoid Junction was initially treated with systemic chemotherapy and was referred for progression in aortocaval lymph node. A total dose of 45 Gy in 25 fractions was delivered to the lesion and the patient exhibited a marked response at 12-weeks post-radiotherapy and no recurrence at 185 weeks. A biliary stent was inserted after radiotherapy for bile drainage. (B) The same patient presented with a peritoneal metastatic lesion after 2 years and was treated with a total dose of 50 Gy in 25 fractions. The treated lesion also showed marked reduction in size and no recurrence at 48 weeks. (C) Change in the longest tumor diameter over time compared to the baseline of lesions subjected to radiotherapy.

• 

  Fig. 2 Treatment response of patients treated with radiotherapy according to mutational status. (A) A waterfall plot of the percentage changes in radiotherapy-treated lesions compared to measurements in pre-radiotherapy lesions. The bottom panel represents the primary tumor site, radiotherapy (RT) site, radiotherapy dose (EQD2), best response (BR), and mutation status of ATM, BRCA1, BRCA2, TP53, and PALB2. The line at 20% and −30% indicate the threshold for progressive disease and objective response per Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1. Two patients with partial response (PR) per RECIST exhibited a complete metabolic response according to Positron Emission Tomography Response Criteria in Solid Tumors. CR, complete response; CUP, cancer of unknown primary; GI, gastrointestinal; GYN, gynecologic; PD, progression of disease; SD, stable disease. (B) A swimmer plot representing the duration of response of patients who exhibited an objective response. Arrows indicate an ongoing response at the time of data censoring.

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  Fig. 3 Local recurrence rate of treated lesions. Shown are the local recurrence rate (LRR) for ATMwtBRCAwt (n=46), ATMmtBRCAwt (n=8), ATMwtBRCAmt (n=27), and ATMmtBRCAmt (n=10) groups.

Reference

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