Second nonbreast malignancies after conservative surgery and radiation therapy for early-stage breast cancer

Abstract Purpose: Breast cancer patients treated with conservative surgery and radiation therapy are at risk of developing second nonbreast malignancies (SNBMs). The purpose of this study was to determine the incidence of all SNBMs and SNBMs by specific location among long-term survivors and to compare the risk of these events to the age-specific incidence of malignances as first cancers in the Surveillance Epidemiology and End-Results Program (SEER) population. Methods and Materials: We analyzed the likelihood of SNBM development for 1884 patients with clinical Stage I or II breast cancer treated with gross excision and ≥60 Gy (median 63) to the breast between 1970 and 1987. Fifty-seven percent received supraclavicular/axillary radiation (median dose 45 Gy, range 20–60) and 28% received systemic therapy. The median age at diagnosis was 52 years. The median clinical tumor size was 2 cm. Patients were considered at risk of an SNBM until the development of the first of distant metastases or contralateral breast cancer or death or, if alive and disease-free, until the last follow-up visit. The expected numbers of cancers were obtained from the SEER database, using the age-specific incidence for white women within 5-year age groups and 5-year calendar intervals. The median time at risk for an SNBM was 10.9 years (range 0.2–27.9). Results: By 8 years of follow-up, 432 patients (23%) had developed distant metastases, 295 patients (16%) a local/regional recurrence, and 159 (8%) a contralateral primary. Of the 1884 patients in our cohort, 147 (8%) developed an SNBM compared with the 127.7 expected from SEER. This corresponds to an absolute excess of 1% of the study population and a relative increase of 15% greater than that expected from SEER ( p = 0.05). Within the first 5 years, the observed and expected rates of SNBMs were identical (47 vs. 46.9). After 5 years, 24% more SNBMs were observed than expected (100 vs. 80.8, p = 0.02). Among patients p = 0.02). For patients ≥50 years, 7% more SNBMs were observed than expected (107 vs. 99.7, p = 0.25). Lung SNBMs were observed in 33 women, 52% more than the 21.67 predicted by SEER ( p = 0.01). Most of the lung SNBMs occurred >5 years after treatment ( n = 23) and in women who were >50 years at the time of their breast cancer diagnosis ( n = 27). The observed incidence of ovarian cancer was significantly greater than expected among patients p = 0.004) but was not different than expected for patients ≥50 years (5 vs. 5.3, p = 0.61). Among the 7 sarcomas, 3 developed in the radiation field. Conclusions: SNBMs occur in a substantial minority (8%) of patients treated with conservative surgery and radiotherapy. However, the absolute excess risk compared with the general population is very small (1%). This excess risk is only evident after 5 years. In particular, a slightly increased incidence of lung SNBMs and a somewhat larger increase in ovarian cancer among younger patients was found. Our data suggest that preventive strategies to reduce the incidence of certain cancers (e.g., smoking cessation and prophylactic oophorectomy) and/or continued monitoring for SNBMs to increase the likelihood of early detection and treatment may be prudent in this population.