Impact of intraoperative radiation therapy and external beam radiation therapy on non-breast cancer mortality in early-stage breast cancer

Abstract Purpose: The TARGIT-A trial of kilovoltage intraoperative radiation therapy (IORT) versus external beam radiation therapy (EBRT) demonstrated a significant reduction in non-breast cancer mortality (nBCM) in women that received IORT, largely attributed to an increase in cardiac mortality in patients that received EBRT. Further, If EBRT does result in excess nBCM due to cardiac or other causes, then treatment with lumpectomy (Lump) alone or mastectomy (Mast) alone should result in lower rates of nBCM rates compared to Lump+EBRT. Our primary objective was to determine whether Lump+EBRT results in increased nBCM compared to Lump+IORT in women with early-stage breast cancer (BC) with a hypothesis that the two approaches should result in equivalent nBCM. We also tested the hypotheses that Lump+EBRT should have the same rates of nBCM as Lump alone or Mast alone. Materials/Methods: We used the Surveillance Epidemiology and End Results (SEER) database to identify women with early-stage BC treated with Lump alone, Lump+EBRT, Lump+IORT, or Mast alone from 2000-2016. SEER does not distinguish between kilovoltage IORT and electron IORT. We included patients with characteristics similar to the TARGIT-A study: age≥45 years; ductal carcinoma in situ (DCIS) or T1; lymph-node negative. We excluded patients that: received chemotherapy; received postmastectomy radiation therapy; had unknown cause of death; and had ≤1 month of follow-up. The primary endpoint was nBCM which is captured in the SEER database (patients were censored if they were alive or dead due to cancer at last follow-up). Cox-proportional hazards multivariate regression models were used to compare nBCM between Lump+EBRT and Lump+IORT adjusting for confounders that were statistically significant on univariate analysis. We secondarily compared nBCM in the Lump+EBRT vs. Lump population and Lump+EBRT vs. Mast population. Results: We identified 219,470 women that met the inclusion criteria: 121,776 Lump+EBRT; 1,735 Lump+IORT; 41,900 Lump; 54,059 Mast. Median follow-up time was 61 months for the entire cohort (IQR, 30-99 months) but was shorter for Lump+IORT patients (29 months) compared to the other groups (63 months Lump+EBRT; 62 months Mast; 57 months Lump). There were a total of 16,640 nBCM events: 6,210 Lump+EBRT; 5,708 Lump; 4,704 Mast; 18 Lump+IORT. The 5-year cumulative incidence of nBCM was 3.1% for Lump+EBRT vs. 1.6% for Lump+IORT (p=0.034). After adjustment for potential confounders (age, tumor location, marital status, race/ethnicity, DCIS vs. invasive, tumor grade, hormone receptor status, and receipt of axillary surgery), patients treated with Lump+IORT had a 38% relative reduction in the risk of nBCM compared to those treated with Lump+EBRT (HR=0.62, 95% CI 0.39-0.99, p=0.045). Other factors associated with increased nBCM included older age, divorced/single/widowed status (vs. married), Black race, high tumor grade, receipt of axillary lymph node dissection (vs. sentinel lymph node biopsy), no axillary surgery (vs. sentinel node biopsy), and ER-/PR- disease (vs. ER+ or PR+). In contrast, patients treated with Lulmp+EBRT had lower nBCM compared to those that received Lump alone (adjusted HR=0.55, 95% CI 0.53-0.57, p<0.0001) and compared to those that received Mast alone (adjusted HR=0.59, 95% CI 0.56-0.61, p<0.0001). Conclusion: In summary, contrary to our hypothesis, we found that Lump+IORT was associated with lower nBCM compared to Lump+EBRT possibly reflecting underlying selection bias. However, Lump+EBRT was not associated with an increased nBCM relative to patients treated with Lump alone or Mast alone. This suggests that the underlying mechanism for the reduced nBCM seen in patients treated with IORT in the TARGIT-A trial and this SEER analysis is not due to the potentially harmful effects of EBRT. Citation Format: Jose G Bazan, Jay Fisher, Sachin Jhawar, Erin Healy, Sasha Beyer, Julia R. White. Impact of intraoperative radiation therapy and external beam radiation therapy on non-breast cancer mortality in early-stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-09.