Radiation therapy and secondary malignancy in Li‐Fraumeni syndrome: A hereditary cancer registry study

Abstract

Background Li‐Fraumeni Syndrome (LFS) is a rare cancer‐predisposing condition caused by germline mutations in TP53. Conventional wisdom and prior work has implied an increased risk of secondary malignancy in LFS patients treated with radiation therapy (RT); however, this risk is not well‐characterized. Here we describe the risk of subsequent malignancy and cancer‐related death in LFS patients after undergoing RT for a first or second primary cancer. Methods We reviewed a multi‐institutional hereditary cancer registry of patients with germline TP53 mutations who were treated from 2004 to 2017. We assessed the rate of subsequent malignancy and death in the patients who received RT (RT group) as part of their cancer treatment compared to those who did not (non‐RT group). Results Forty patients with LFS were identified and 14 received RT with curative intent as part of their cancer treatment. The median time to follow‐up after RT was 4.5 years. Fifty percent (7/14) of patients in the curative‐intent group developed a subsequent malignancy (median time 3.5 years) compared to 46% of patients in the non‐RT group (median time 5.0 years). Four of seven subsequent malignancies occurred within a prior radiation field and all shared histology with the primary cancer suggesting recurrence rather than new malignancy. Conclusion We found that four of14 patients treated with RT developed in‐field malignancies. All had the same histology as the primary suggesting local recurrences rather than RT‐induced malignancies. We recommend that RT should be considered as part of the treatment algorithm when clinically indicated and after multidisciplinary discussion.

Second cancer risk in childhood cancer survivors treated with intensity‐modulated radiation therapy: An updated analysis of more than 10 years of follow‐up

“…All second tumors shared histology with the primary tumor, suggesting recurrence as opposed to radiation-induced malignancies; therefore, RT should still be considered in these patients when clinically indicated, as radiation-induced second malignancy is not inevitable. 25 Of the 17 patients who developed an SMN, all but one had been exposed to chemotherapy, and of those, 94% received an alkylating agent. Most chemotherapy-related cases of AML/MDS occur within 5 years of treatment regardless of RT exposure 26 ; therefore, the two hematologic malignancies that developed within 5 years after treatment in our cohort may be explained by their exposure to multiple chemotherapy agents.…”

Carbon ion radiotherapy eradicates medulloblastomas with chromothripsis in an orthotopic Li-Fraumeni patient-derived mouse model

“…Due to the germline TP53 mutation, local therapy intensification in these patients is limited by the risk of development of secondary malignancies, which could occur in 30%–50% of LFS cases, often within the radiation field. 11 , 12 Likewise, genotoxic chemotherapy can contribute to the development of subsequent tumors in the context of p53 dysfunction. 13 Therefore, maximal normal tissue sparing is a prerequisite for therapy intensification in this cancer entity.…”

Case Report : Li-Fraumeni Syndrome with Central Nervous System Tumors in Two Siblings

“…In our opinion, prognostic benefits of postoperative radiotherapy must be weighed against the risk of long-term secondary cancer if the tumor is highly malignant. In addition, the results of Hendrickson et al who studied 40 patients with LFS on radiotherapy and secondary malignant tumors were different from before, their data provide preliminary evidence to suggest RT should not be withheld in patients with LFS [ 26 ]. Recently, a strong link between TP53 mutations and hypermethylation at the promoter of the p53-associated microRNA miR-34A, which was found as a potential putative novel therapeutic target and a marker for clinical prognostication [ 27 ].…”