Breast cancer is one of the most common cancers among women in the U.S., and health care practitioners must balance treatment benefits against short-term and long-term risks. Although relatively rare, soft tissue sarcoma is a serious long-term risk of breast cancer radiotherapy with poor prognosis and high mortality. Since the early 1990s, data has indicated that incidence rates of these radiation-induced sarcomas have been increasing in the U.S. Unfortunately, there are few studies of soft tissue sarcoma in patients with breast cancer or the other factors contributing to this increased risk.
In a retrospective cohort study reported in The Lancet Oncology, Veiga and colleagues evaluated potential co-factors and the rates of thoracic soft tissue sarcoma in two complementary cohorts—the Kaiser Permanente (KP) cohort and the Surveillance, Epidemiology, and End Results (SEER) 13 registries cohort—consisting of women with breast cancer diagnosed from the early 1990s to 2016 (2022; https://doi.org/10.1016/S1470-2045(22)00561-7).
The KP cohort included 15,940 women diagnosed with breast cancer from January 1, 1990, to December 31, 2016, in KP Colorado, KP Northwest, or KP Washington with detailed treatment data and comorbidities. The KP breast cancer survivors cohort provides a distinctive prospect to assess the risk of subsequent thoracic soft tissue sarcoma in relation to treatment and other medical conditions (including hypertension and diabetes at or before breast cancer diagnosis from electronic medical records) in a general community health care setting.
Given the rarity of soft tissue sarcoma, the researchers supplemented the study by evaluating the risk of subsequent thoracic soft tissue sarcoma in breast cancer survivors treated during the same time period in the SEER 13 cancer registries. The SEER cohort included 457,300 women diagnosed with breast cancer from January 1, 1992, to December 31, 2016, within the 13 SEER registries across the U.S. with initial treatment data.
Eligibility criteria in both cohorts were female breast cancer survivors (Stage I-III) ages 20-84 years at diagnosis who had breast cancer surgery and survived for ≥1 year after diagnosis. The study included systematic follow-up for ensuing malignancies; rich treatment data (including radiotherapy fields, prescribed dose, and fractions); initial and subsequent chemotherapy, including specific agents (i.e., anthracycline, alkylating agents); and history of comorbidities (i.e., obesity and hypertension) before or at breast cancer diagnosis. The outcome of interest was any second thoracic soft tissue sarcoma (angiosarcomas and other subtypes) that developed ≥1 year after a breast cancer diagnosis. Risk factors for thoracic soft tissue sarcoma were assessed using multivariable Poisson regression models.
In the KP cohort, median follow-up was 9.3 years (interquartile range [IQR]=5.7-13.9 years) and 19 (0.1%) of 15,940 eligible, evaluable women developed a thoracic soft tissue sarcoma (11 angiosarcomas, 8 of other subtypes). Overall, most (94.7%; 18 of 19) thoracic soft tissue sarcomas occurred in women treated with radiotherapy (relative risk [RR]=8.1, 95% CI: 1.1-60.4, P=.0052). Thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma, but no associations with prescribed dose, fractionation, or boost were observed. Elevated risk for angiosarcoma was observed with receipt of anthracyclines (RR=3.6, 95% CI: 1.0-13.3, P=.058), and alkylating agents were associated with an increased risk of developing other sarcomas (RR=7.7, 95% CI: 1.2-150.8, P=0.026). The researchers also found that the relative risk of angiosarcoma was elevated for patients with a history of hypertension (RR=4.8, 95% CI: 1.3-17.6, P=.017) and a history of diabetes (RR=5.3, 95% CI: 1.4-20.8, P=.036).
In the parallel analysis of breast cancer survivors from the SEER cohort, the median follow-up was 8.3 years (IQR=4.3-13.9 years). Sarcomas developed in 430 (0.1%) of 457,300 eligible, evaluable women, including 268 angiosarcomas and 162 of other subtypes. Again, most (77.9%, 335 of 430) occurred after radiotherapy. Thus, radiotherapy was associated with a significantly increased risk of developing a thoracic soft tissue sarcoma (RR=3.0, 95% CI: 2.4-3.8, P<.0001).
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). Moreover, 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.
Encouragingly, at 10 years after receiving radiotherapy, the cumulative incidence of thoracic soft tissue sarcoma was 0.21 percent (95% CI: 0.12-0.34) in the KP cohort and 0.15 percent (95% CI: 0.13%-0.17%) in the SEER cohort and was associated with potentially modifiable risk factors.
For additional perspectives on the study, Oncology Times connected with lead study author, Lene H.S. Veiga, PhD, Staff Scientist in the Radiation Epidemiology Branch of the Division of Cancer Epidemiology & Genetics at the National Cancer Institute.
Oncology Times: What motivated you to pursue this research study? What were some of the drawbacks of previous studies to evaluate risk factors of soft tissue sarcoma in patients with breast cancer?
Veiga: “Breast cancer patients who are treated with radiotherapy are at higher risk of developing thoracic soft tissue sarcomas, which is a very rare but fatal disease. Also, incidence rates of these radiation-induced sarcomas are increasing in the U.S., possibly because of the increased use of radiotherapy to treat breast cancer over time. Nevertheless, there are very few recent studies of soft tissue sarcoma among breast cancer survivors. Given the rarity of soft tissue sarcomas, most of the previous studies were case series that did not include an internal control population or cancer registry studies that do not include treatment details or information on risk factors.
“The Kaiser Permanente Breast Cancer Survivors Cohort study is a retrospective, electronic medical record linkage study with complete follow-up, detailed treatment, and comorbidities which provides a unique opportunity to evaluate the risk of thoracic sarcoma in relation to treatment and other cofactors in a general health care setting.”
Oncology Times: What is a possible explanation for the association of hypertension and diabetes with breast lymphedema?
Veiga: “Although the precise mechanism is still unclear, several studies have shown that increased blood pressure is related to the dysfunction of lymph vessels via increased capillary filtration that increases the fluid load on an already compromised lymph drainage system after breast cancer surgery. Although hypertension has been associated with an increased risk of lymphedema, it remains unclear whether it is hypertension alone or hypertension treatment (e.g., calcium channel blockers) that increases the risk of lymphedema. A common mechanism of action for calcium channel blockers medication is the regulation of calcium signaling and smooth muscle contraction, which are key elements in normal lymphatic function. Calcium channel blockers have been shown to inhibit these contractions in lymph vessels. Therefore, it is possible that calcium channel blockers inhibit lymphatic transport in patients and contribute to lymphedema development in patients already exposed to other treatment-related risk factors.
“Diabetes generally causes damage to the arteries and capillaries, subsequently affecting both the arterial and lymphatic systems, resulting in disruption of the vascular barrier function. Animal studies have shown that diabetic mice have an enhanced permeability of the walls of the lymphatic vessels caused by low nitric oxide bioavailability. Therefore, the lymphatic dysfunction present in diabetes might be a possible explanation for the association of diabetes with breast lymphedema.”
Oncology Times: Based on the findings of the study, what are clinical implications and considerations to minimize secondary cancers and other toxicities while optimizing outcomes?
Veiga: “In our study, we found that breast cancer survivors who received radiotherapy [and] anthracyclines, had breast-conserving surgery, and had a history of hypertension or diabetes were at the greatest risk of developing thoracic soft tissue sarcoma. If the pathway to thoracic angiosarcoma development is through breast lymphedema, which is affected by common comorbidities, such as hypertension, obesity, and diabetes, then monitoring of patients who develop this acute side effect is possibly warranted. A number of strategies have been recommended to decrease the risk of lymphedema after breast cancer treatment, [and] it is important to implement these strategies in clinical settings.
“Another important clinical implication is the growing evidence that anthracyclines can cause solid tumors, including soft tissue sarcoma. Although the benefit of an anthracycline-based regimen in reducing breast cancer mortality has been established in clinical trials, the risk of subsequent cancer after anthracycline use needs to be considered in the context of a risk-benefit calculation.
“It is important to recognize that our cumulative absolute risk estimates, which were broadly consistent in both cohorts, show that these subsequent soft tissue sarcomas are still very rare.”
Oncology Times: What were some of the study limitations that you would like to address in future research?
Veiga: “In future research, we would like to evaluate the risk of thoracic soft tissue sarcoma in a much larger cohort of breast cancer survivors with additional information on other lymphedema risk factors, such as axillary lymph node dissection, lymphedema diagnosis, and antihypertensive medications. These additional pieces of information will elucidate if hypertension itself or antihypertensive medication increases the risk of lymphedema and the pathway for thoracic angiosarcoma development through breast lymphedema after breast cancer surgery. Additional information on the intensity and duration of chemotherapy drugs is also another limitation that we want to address in future studies to assess anthracycline dose response and thoracic angiosarcoma risk.
“Future studies should also expand this work to determine risk of thoracic sarcoma across racially and ethnically diverse cohorts, combination treatments, and other comorbid conditions to identify high-risk patient populations that may benefit from future prevention strategies and increased surveillance.”
Dibash Kumar Das is a contributing writer.