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Although relatively rare, soft tissue sarcoma after breast cancer treatment was linked most strongly to treatment with radiation, according to data from two large U.S. cohorts of breast cancer survivors.

Radiotherapy was associated with an 8.1-fold increased risk of developing a thoracic soft tissue sarcoma in one cohort (95% CI 1.1-60.4, P=0.0052) and 3.0-fold elevated risk in the other (95% CI 2.4-3.8, P<0.0001), reported Lene Veiga, PhD, of the National Cancer Institute in Bethesda, Maryland, and colleagues.

Elevated risk of thoracic angiosarcoma was also seen in patients who had breast-conserving surgery, received anthracyclines, and had a history of hypertension or diabetes at the time of breast cancer diagnosis, the researchers wrote in .

While these large analyses support the rarity of soft tissue sarcoma after breast cancer treatment, they also "raise important questions to guide efforts to minimise the risk of developing a secondary cancer after radiotherapy," noted Hope S. Rugo, MD, and Lisa Singer MD, PhD, both of the University of California San Francisco, in a .

"The findings from the current study further emphasise the importance of modifiable risk factors in the treatment of early stage breast cancer, personalising therapy to both biology and recurrence risk to minimise secondary cancers and other toxicities while optimising outcome," they wrote.

Several potential implications for clinical practice were suggested by the authors: "The growing evidence that anthracyclines can cause solid tumors, including soft tissue sarcomas, suggests that these risks need to be factored into the risk-benefit calculation."

Furthermore, the effect for hypertension and diabetes at the time of breast cancer diagnosis "is a novel finding, and the potential role of these comorbidities in the cause and prevention of this life-threatening disease warrants further investigation," they added. "These factors might be potential targets for future prevention strategies and identification of patients who should receive increased surveillance."

At 10 years after radiotherapy, the cumulative incidence of thoracic soft tissue sarcoma was 0.21% (95% CI 0.12-0.34) in one cohort of 15,940 women from Kaiser Permanente (KP) who were diagnosed with breast cancer between 1990 and 2016, and 0.15% (95% CI 0.13-0.17) in the Surveillance, Epidemiology, and End Results (SEER) 13 registries cohort of 457,300 women diagnosed with breast cancer from 1992 to 2016.

At a median follow-up of 9.3 years in the KP cohort, 19 women developed a thoracic soft tissue sarcoma (11 angiosarcomas, eight other subtypes), with 18 (94.7%) occurring in women treated with radiotherapy.

The researchers also found that the relative risk of angiosarcoma was elevated with:

• Anthracycline-based treatment (RR 3.6, 95% CI 1.0-13.3, P=0.058)
• History of hypertension (RR 4.8, 95% CI 1.3-17.6, P=0.017)
• History of diabetes (RR 5.3, 95% CI 1.4-20.8, P=0.036)

Alkylating agents were associated with an increased risk of developing other sarcomas (RR 7.7, 95% CI 1.2-150.8, P=0.026).

In the SEER cohort, 430 of 457,300 patients had subsequent thoracic soft tissue sarcomas (268 angiosarcomas and 162 other subtypes) after a median follow-up of 8.3 years. Again, most (77.9%) occurred after radiotherapy.

In this group of women, those who had breast-conserving surgery were at significantly higher risk of developing any type of thoracic soft tissue sarcoma (RR 2.3, 95% CI 1.7-3.1, P<0.0001) or angiosarcoma (RR 3.7, 95% CI 2.3-6.0, P<0.0001) than were women treated with mastectomy. Among patients who developed angiosarcoma, the relative risk with breast-conserving surgery plus radiotherapy versus mastectomy plus radiotherapy was 1.9 (95% CI 1.1-3.3, P=0.012).

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