Fusion-Negative Sarcoma Survivors Have Increased Risk of Second Malignancies

Survivors of fusion-negative (F−) sarcomas have a higher risk of developing a second malignant neoplasm than those who had fusion-positive (F+) sarcomas, according to a new study, which could offer guidance on surveillance of these survivors.

F+ sarcomas refer to a group of malignancies that carry reciprocal chromosomal translocations that yield oncogenic fusion transcripts, such as those seen in alveolar rhabdomyosarcoma and Ewing sarcoma. F− tumors, on the other hand, have abnormalities that follow no specific pattern.

“Sarcoma susceptibility in certain individuals has been linked to specific cancer-predisposing germline mutations that may be inherited or also may arise de novo,” wrote study authors led by Philip J. Lupo, PhD, of Baylor College of Medicine in Houston, Texas. Based on various earlier studies, the researchers hypothesized that F− sarcoma survivors were more likely to carry those cancer-predisposing abnormalities, and thus more likely to develop a second malignancy.

The new study included 4,822 survivors of F+ sarcomas and 3,963 survivors of F− tumors from the Surveillance, Epidemiology, and End Results (SEER) database. The results of the analysis were published online ahead of print in Cancer.

There were a total of 166 secondary malignant neoplasms (SMNs) identified among all the sarcoma survivors in the study; 113 of these were solid tumors, and 53 were lymphoma or leukemia.

There was a clear increase in risk for survivors of F− tumors: the cumulative incidence of SMNs in this group was 2.67%, compared with 2.08% in those with F+ tumors. The specific SMN diagnoses did not differ between the two groups, and acute myeloid leukemia/myelodysplastic syndrome accounted for approximately 20% of the SMNs in each group.

Compared to a reference population, the standardized incidence ratio for developing any SMN was 1.86 in F+ sarcoma survivors and 2.89 in F− sarcoma survivors. When compared to each other, the hazard ratio (HR) for developing an SMN in F− sarcoma survivors vs F+ survivors was 1.38 (95% CI, 1.01–1.89). Specifically for developing a secondary solid tumor, the HR was 1.50 (95% CI, 1.03–2.18). The risk remained higher for F− sarcoma survivors whether or not they had received radiotherapy-a known predictor of SMN risk-for the initial malignancy.

“We propose that sarcoma-predisposing germline mutations may contribute to tumor initiation and subsequent SMN risk in individuals with F− sarcomas, but not F+ sarcomas,” the authors concluded. “This may inform a growing body of evidence for tailored SMN surveillance among survivors of sarcoma based on germline mutational profiles.”