Our center is a large tertiary care center that treated approximately 8700 breast cancer patients with radiotherapy in the 20-year period included in this study. We are also a referral center for sarcoma patients diagnosed at outside centers. We are specialized in sarcoma management, employing a multidisciplinary approach which includes surgical oncology, medical oncology and radiation oncology. To our knowledge, this is one of the first studies exploring RIS of the breast in a cohort of patients diagnosed and treated with modern techniques between 2000 to 2020.
In our study, we found 19 patients with RIS of the breast over the 20-year period. If we used the 8700 patients that were diagnosed and treated for breast cancer at our centre over this period as a comparison, this would result in an incidence of 0.2%. Taghian et al. examined 7000 breast cancer patients treated between 1954–1983 in France [14]. They found 11 patients that developed secondary sarcoma, resulting in a cumulative incidence of 0.2% at 10 years. However, noticeably different radiotherapy techniques were used in this historic cohort, as some patients received total body irradiation in addition to breast radiotherapy, resulting in a higher total radiotherapy dose [14]. In their 2002 publication, Yap et al. used SEER data to identify breast cancer patients who underwent RT from 1973–1997 (n = 275 000) [15]. The cumulative incidence of developing RIS in patients who received radiotherapy was 0.32% at 15 years, compared to 0.23% in patients who did not receive radiotherapy [15]. In a more recent analysis of the SEER database, Snow et al. found the incidence of RIS of the breast to be 0.02% at a median follow-up of 9.6 years [11]. A major limitation of SEER data is that it does not report data on radiation treatment or systemic treatment received [11, 15]. The SEER data analysis also excluded patients for whom data were missing, therefore likely underestimating the true incidence. With 19 breast RIS patients in our study period, our 0.2% incidence would appear higher than the recent SEER analysis, but is comparable to historical data [14, 15]. However, had we not included the small number of patients that were not initially treated for their breast cancer at our center, our center-specific incidence would be slightly lower. Due to the retrospective nature of our study, it is impossible to establish the true denominator, limiting our calculation of true incidence during this time period.
While less than 10% of secondary malignancies are radiation-induced, the relative risk of developing RIS varies by treatment site and was found to be correlated with higher dose, younger age and increased time since diagnosis in one review [19]. Dose is an important factor, with risk increasing linearly after 40Gy [19]. The risk of sarcoma was 30.6 times higher for doses more than 44Gy compared to doses less than 15Gy in breast cancer patients in one study [20]. All of the patients included in our analysis in which radiotherapy dose was known received doses of at least 40Gy, consistent with standards of care for breast radiotherapy.
Breast cancer patients were found to have the highest incidence of RIS compared to other primary solid cancers in a recent review of SEER data [11]. Hereditary breast cancer syndromes (Li Fraumeni, Retinoblastoma, Nijmegen breakage syndrome) and BRCA are thought to play a role [21]. Kadouri et al. reviewed 473 BRCA and p53 mutation carriers and found the rate of RIS to be 0.43% (n = 7 women), but the overall rate is still low and not significantly different compared to all breast cancer patients with RIS reported in other studies [21]. Schlosser et al. retrospectively reviewed 230 women with BRCA mutations who underwent RT for breast cancer and found the incidence of secondary malignancies to be 0.32 per 1000 women-years [22]. However, of the six women who developed secondary malignancies, none were RIS [22]. In our study, we identified one patient with a TP53 mutation. However, it is difficult to draw conclusions on hereditary breast cancer and incidence of RIS given the rarity of both.
While this study yields important insights into the incidence and outcomes of RIS of the breast, it has several limitations. Firstly, inherent to its retrospective nature, data was missing, for example pertaining to previous radiation treatment details for patients that were treated at outside institutions. Two patients were lost to follow-up, further limiting our data analysis. Furthermore, we included data from electronic health records only, and therefore did not have access to paper charts which may have been used in the early 2000s. Given that this is single institutional data and incidence of breast RIS is rare, the total number of patients included in our analysis is small. This small number of patients renders it difficult to draw conclusions on risk factors associated with poorer outcomes. Our overall survival was favorable, with a 2-year disease-specific survival of 88.9%. Our PFS of 56.1% at 2 years illustrates that a large proportion of patients recur locally or distantly despite aggressive multimodality treatment, suggesting that longer follow-up time is needed for survival data maturation.