Clinical Outcomes of Hypofractionated Whole Breast Irradiation in Early Stage, Biologically High-Risk Breast Cancer.

PURPOSE: Adoption of hypofractionated whole breast irradiation (HWBI) for patients with early-stage, biologically high-risk breast cancer remains relatively low. We compared clinical outcomes of conventionally fractionated whole breast irradiation (CWBI) versus moderate HWBI in this patient population. METHODS AND MATERIALS: We queried a prospectively maintained database for patients with early-stage (T1-2, N0, M0) breast cancer who received whole breast irradiation with either CWBI or moderate HWBI at a single institution. We included only patients with biologically high-risk tumors (defined as either estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 negative, human epidermal growth factor receptor 2 amplified, and/or patients with a high-risk multigene assay) who received systemic chemotherapy. Inverse probability of treatment weighting was used to compare treatment cohorts and to estimate 5-year time to event endpoints. Hazard ratios (HR) and 95% confidence interval (CI) were determined based on Cox proportional hazards model. RESULTS: We identified 300 patients, of whom 171 received CWBI and 129 received HWBI. There was a statistically significant difference in median age at diagnosis, 59 years for CWBI versus 63 years for HWBI (P = .004), and in median follow-up time, 97 months for CWBI versus 55 months for HWBI (P < .001). After accounting for differences in patient and tumor characteristics with inverse probability of treatment weighting, we found similar 5-year freedom from local recurrence (HR, 0.76; 95% CI, 0.14-4.1), freedom from regional recurrence (HR, 3.395% CI 0.15-69), freedom from distant metastasis (HR 3.9, 95% CI 0.86-17), and disease-free survival (HR 0.84; 95% CI, 0.3-2.4), between those treated with CWBI and those treated with HWBI. Results were similar among each of the 3 high-risk subtypes. CONCLUSIONS: Our data support the use of moderate HWBI in patients with early-stage, biologically high-risk breast cancer.

Dose to the Left Anterior Descending Artery Correlates With Cardiac Events After Irradiation for Breast Cancer.

PURPOSE: Although global heart dose has been associated with late cardiac toxic effects in patients who received radiation therapy for breast cancer, data detailing the clinical significance of cardiac substructure dosimetry are limited. We investigated whether dose to the left anterior descending artery (LAD) correlates with adverse cardiac events. METHODS AND MATERIALS: We identified 375 consecutively treated female patients from 2012 to 2018 who received left-sided breast or chest wall irradiation (with or without regional nodal irradiation). Medical records were queried to identify cardiac events after radiation therapy. Mean and maximum LAD and heart doses (LAD Dmean, LAD Dmax, heart Dmean, and heart Dmax) were calculated and converted to 2-Gy equivalent doses (EQD2). Univariate and multivariable Cox regression analyses were performed to determine association with cardiac toxic effects. Potential dose thresholds for each of the 4 dose parameters were identified by receiver operating characteristic (ROC) curve analysis, after which Kaplan-Meier analysis was performed to compare cardiac event-free survival based on these constraints. RESULTS: Median follow-up time was 48 months. Thirty-six patients experienced a cardiac event, and 23 patients experienced a major cardiac event. On univariate and multivariable analyses, increased LAD Dmean, LAD Dmax, and heart Dmean were associated with increased risk of any cardiac event and a major cardiac event. ROC curve analysis identified a threshold LAD Dmean EQD2 of 2.8 Gy (area under the ROC curve, 0.69), above which the risk for any cardiac event was higher (P = .001). Similar results were seen when stratifying by LAD Dmax EQD2 of 6.7 Gy (P = .005) and heart Dmean EQD2 of 0.8 Gy (P = .01). CONCLUSIONS: Dose to the LAD correlated with adverse cardiac events in this cohort. Contouring and minimizing dose to the LAD should be considered for patients receiving radiation therapy for left-sided breast cancer.

Left anterior descending artery avoidance in patients receiving breast irradiation.

PURPOSE: Dose to the left anterior descending artery (LAD) may be significant in patients receiving left-sided irradiation for breast cancer. We investigated if prospective contouring and avoidance of the LAD during treatment planning were associated with lower LAD dose. METHODS AND MATERIALS: We reviewed dosimetric plans for 323 patients who received left whole breast or chest wall irradiation with or without internal mammary node (IMLN) coverage between 1/2014 and 1/2019 at a single institution. The LAD was contoured prospectively for 155 cases, and techniques were utilized to minimize LAD dose. Dose-volume-histograms from these patients were compared to those of 168 patients for whom the LAD was contoured retrospectively after treatment completion. EQD2 was calculated to account for fractionation differences. RESULTS: Compared to cases where the LAD was contoured retrospectively (n = 126), prospective LAD contouring (n = 124) was associated with lower unadjusted median max and mean LAD doses for 250 patients receiving whole-breast irradiation (WBI) without IMLN coverage: 8.5 Gy vs 5.2 Gy (p < 0.0001) and 3.6 Gy vs 2.7 Gy (p < 0.0001), respectively. EQD2 median max and mean LAD doses were also lower with prospective LAD contouring: 5.2 Gy vs 3.0 Gy (p < 0.0001) and 1.9 Gy vs 1.5 Gy (p < 0.0001), respectively. Compared to cases where the LAD was contoured retrospectively (n = 42), prospective LAD contouring (n = 31) was associated with lower max LAD doses for 73 patients with IMLN coverage: 20.4 Gy vs 14.3 Gy (p = 0.042). There was a nonsignificant reduction in median mean LAD dose: 6.2 Gy vs 6.1 Gy (p = 0.33). LAD doses were reduced while maintaining IMLN coverage (mean V90%Rx >90%). CONCLUSIONS: Prospective contouring and avoidance of the LAD were associated with lower max and mean LAD doses in patients receiving WBI and with lower max LAD doses in patients receiving IMLN treatment. Further reduction in LAD dose may require stricter optimization weighting or compromise in IMLN coverage.

Omission of Axillary Lymph Node Dissection is Associated with Inferior Survival in Breast Cancer Patients with Residual N1 Nodal Disease Following Neoadjuvant Chemotherapy.

BACKGROUND: The appropriateness of substituting sentinel lymph node dissection (SLND) and regional nodal irradiation (RNI) for axillary lymph node dissection (ALND) in patients with residual lymph node (LN) disease following neoadjuvant chemotherapy (NAC) is unknown. We used the National Cancer Database (NCDB) to compare survival following SLND and ALND in breast cancer patients with residual LN disease. METHODS: We analyzed NCDB patients, treated between 2006 and 2014, with cT1-3, cN1, cM0 breast cancer and residual disease in 1-3 axillary LNs (ypN1) following NAC. Patients were grouped into those who received SLND (defined as removal of ≤ 4 LNs) and RNI, or ALND and RNI. Patients were matched for all patient, tumor, and treatment characteristics. RESULTS: We identified 1313 eligible patients in the ALND group and 304 patients in the SLND group. For the matched cohorts, SLND was associated with significantly lower survival in both univariate and doubly robust multivariable analyses (MVA) (HR 1.7, 95% CI 1.3-2.2, P < 0.001 for MVA), with estimated 5-year OS of 71%, compared with 77% in the ALND group (P = 0.01). Exploratory subgroup analyses showed that SLND was comparable with ALND in patients with luminal A or B tumors with a single metastatic LN (HR 1.03, 95% CI 0.59-1.8, (P = 0.91). CONCLUSIONS: Our analysis suggests that, while an ALND may not be needed for patients with limited residual nodal burden and biologically favorable tumors, SLND should not be routinely substituted for ALND in patients with ypN1 disease following NAC until its efficacy is confirmed by prospective trials.

Post-mastectomy radiotherapy is associated with improved overall survival in T3N0 patients who do not receive chemotherapy.

BACKGROUND AND PURPOSE: There is limited retrospective evidence addressing the utility of post-mastectomy radiotherapy (PMRT) in patients with T3N0 breast cancer. We performed a retrospective analysis of the National Cancer Database (NCDB) comparing overall survival (OS) in T3N0 patients treated with mastectomy alone (MTX) or with PMRT. MATERIALS AND METHODS: We performed a matched-cohort analysis of NCDB breast cancer patients with pT3N0 disease who did not receive NAC, or cT3N0 patients who received NAC treated between 2006 and 2014. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights. RESULTS: We identified 13,901 eligible patients. In the pT3N0 cohort, median follow-up was 47 months for the MTX group and 50 months for the PMRT group. In the cT3N0 cohort, median follow-up was 44 months for the MTX group and 46 months for the PMRT group. OS was higher in pT3N0 patients treated with PMRT compared to MTX: 7-year OS of 74% vs. 65% (P < 0.001). Doubly robust multivariable analysis showed an association between PMRT and improved OS (HR 0.78, 95% CI 0.68-0.89, P < 0.001). There was no benefit to PMRT in patients who received adjuvant chemotherapy (AC). In the NAC cohort, PMRT did not change OS, with 7-year OS of 78% with MTX and 79% with PMRT. There was a trend of improved OS with PMRT in patients with residual disease in the breast and lymph nodes (HR 0.70, 95% CI 0.46-1.07). CONCLUSION: PMRT improves OS in patients with pT3N0 disease, but the benefit appears limited to those who do not receive AC. PMRT does not improve OS in patients with cT3N0 disease who receive NAC, but there might be a benefit in patients with a poor response to chemotherapy. However, longer follow-up may be needed to make a definitive conclusion about the benefit of PMRT in patients who receive chemotherapy.

Mapping of Metastatic Level I Axillary Lymph Nodes in Patients with Newly Diagnosed Breast Cancer.

PURPOSE: We examined the distribution of pretreatment nodal metastases to the level I axilla (Ax-L1) to assess the appropriateness of current breast atlases and provide guidelines in relationship to easily identifiable anatomic landmarks for accurate delineation of this lymph node (LN) basin. METHODS AND MATERIALS: Patients with newly diagnosed breast cancer and biopsy-proven metastatic Ax-L1 LNs were identified. We related the location of each LN to its most adjacent rib and its distance from the bottom of the humeral head, axillary vessels, and a line connecting the anterior aspects of the pectoralis and latissimus dorsi muscles (P-L line). LNs were mapped onto a representative planning computed tomography scan, and their distribution was used to validate the current Radiation Therapy Oncology Group, European Society for Radiotherapy and Oncology, and Radiotherapy Comparative Effectiveness breast atlases. Furthermore, we examined metastases to a subregion encompassing the superolateral Ax-L1, irradiation of which correlates highly with lymphedema. RESULTS: We identified 106 eligible patients with 107 biopsied LNs. All LNs fell between the second and fifth ribs (mean, 3.8 ± 0.56). Mean distance from the inferior aspect of the humeral head was 4.3 ± 1.6 cm (range, 0.3-8.4). Mean distance from the inferior aspect of the axillary vessels was 2.9 ± 1.5 cm (range, -0.6 to 5.4). Mean distance from the P-L line was 0.01 ± 1.9 cm (range, -2.2 to 2.4); negative and positive values denote medial or lateral to the P-L line. A Radiation Therapy Oncology Group-compliant Ax-L1 consensus contour, created from contours by 4 attending breast radiation oncologists, partially or fully missed 45% of mapped LNs. European Society for Radiotherapy and Oncology- and Radiotherapy Comparative Effectiveness-compliant Ax-L1 similarly missed 46% and 34% of mapped LNs, respectively. LNs were most frequently missed in the lateral direction. The superolateral Ax-L1 encompassed 9.3% of the mapped LNs. CONCLUSIONS: A significant percentage of at-risk Ax-L1 tissue falls outside current contouring atlases. We propose expansion of the recommended Ax-L1 borders, most notably in the lateral direction.

Breast conserving therapy is associated with improved overall survival compared to mastectomy in early-stage, lymph node-negative breast cancer.

BACKGROUND AND PURPOSE: Recent retrospective studies suggest improved overall survival (OS) with breast conserving therapy (BCT), including breast conserving surgery and adjuvant whole breast radiotherapy, compared to mastectomy in the modern era. The patient subset most likely to benefit from BCT remains unclear, and the role of Oncotype DX Recurrence Score (RS) in this context is unknown. We compared BCT to mastectomy in early-stage, node-negative breast cancer. We further explored outcomes after stratification by RS and age. MATERIALS AND METHODS: We performed a matched-cohort analysis of National Cancer Database (NCDB) patients with pT1-2, pN0, cM0 breast cancer treated between 2006 and 2014 with BCT or mastectomy. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights. RESULTS: We identified 144,263 eligible patients treated with BCT and 87,379 patients treated with mastectomy. After IPTW-matching, OS was higher with BCT compared to mastectomy: 5-year OS of 94.4% vs. 91.8% (P < 0.001) and 7-year OS of 90% vs. 85.2% (P < 0.001). Doubly robust multivariable analysis showed an association between BCT and improved OS (HR 0.66, 95% CI, 0.64-0.69, P < 0.001). In a subset analysis, BCT was associated with improved OS in patients with RS >25, but not patients with RS ≤25. When stratified by age, only patients >50 years had improved OS with BCT. CONCLUSION: BCT is associated with improved OS compared to mastectomy in women with early-stage, node-negative breast cancer. The improvement in OS with BCT appears to be most pronounced in patients with high RS and >50 years of age. Prospective validation of these findings is required.

Recent Time Trends and Predictors of Heart Dose From Breast Radiation Therapy in a Large Quality Consortium of Radiation Oncology Practices.

PURPOSE: Limited data exist regarding the range of heart doses received in routine practice with radiation therapy (RT) for breast cancer in the United States today and the potential effect of the continual assessment of the cardiac dose on practice patterns. METHODS AND MATERIALS: From 2012 to 2015, 4688 patients with breast cancer treated with whole breast RT at 20 sites participating in a state-wide consortium were enrolled into a registry. The importance of limiting the cardiac dose has been emphasized in the consortium since 2012, and the mean heart dose (MHD) has been reported by each institution since 2014. The effects on the MHD were estimated for both conventional and accelerated fractionation using regression models, with technique (intensity modulated RT [IMRT] vs 3-dimensional conformal RT), deep inspiration breath hold use, patient position (supine vs prone), nodal RT (if delivered), and boost (yes vs no) as covariates. RESULTS: For left-sided breast cancer treated with conventional fractionation, the median MHD in 2012 was 2.19 Gy versus 1.65 Gy in 2015 (P<.001). The factors that significantly increased the MHD for conventional fractionation were increased separation relative to 22 cm (1.5%/1 cm), supraclavicular or infraclavicular nodal RT (17.1%), internal mammary nodal RT (40.7%), use of a boost (20.9%), treatment year before 2015 (7.7%), and use of IMRT (20.8%). For left-sided BC treated with accelerated fractionation, the median MHD in 2012 was 1.70 Gy versus 1.22 Gy in 2015 (P<.001). The factors that significantly increased the MHD for accelerated fractionation were separation (1.7%/1 cm), use of a boost (20.0%), year before 2015 (8.5%), and use of IMRT (19.2%). The factors for both conventional fractionation and accelerated fractionation that significantly reduced the MHD were the use of deep inspiration breath hold and prone positioning. CONCLUSIONS: The MHD for left-sided breast cancer decreased during a recent 4-year period, coincident with an increased focus on cardiac sparing in the radiation oncology community in general and a state-wide consortium specifically. These data suggest a positive effect of systematically monitoring the heart dose delivered.

Seven-Year Outcomes Following Accelerated Partial Breast Irradiation Stratified by ASTRO Consensus Groupings.

OBJECTIVES: Limited long-term data exist regarding outcomes for patients treated with accelerated partial breast irradiation (APBI), particularly, when stratified by American Society for Radiation Oncology (ASTRO) Consensus Statement (CS) risk groups. The purpose of this analysis is to present 5- and 7-year outcomes following APBI based on CS groupings. MATERIALS AND METHODS: A total of 690 patients with early-stage breast cancer underwent APBI from 1993 to 2012, receiving interstitial brachytherapy (n=195), balloon-based brachytherapy (n=290), or 3-dimensional conformal radiotherapy (n=205) at a single institution. Patients were stratified into suitable, cautionary, and unsuitable groups with 5-year outcomes analyzed. Seven-year outcomes were analyzed for a subset with follow-up of ≥2 years (n=625). RESULTS: Median follow-up was 6.7 years (range, 0.1 to 20.1 y). Patients assigned to cautionary and unsuitable categories were more likely to have high-grade tumors (21% to 25% vs. 9%, P=0.001), receive chemotherapy (15% to 38% vs. 6%, P<0.001), and have close/positive margins (9% to 11% vs. 0%, P<0.001). There was no difference in ipsilateral breast tumor recurrence at 5 or 7 years: 2.2%, 1.2%, 2.8% at 5 years (P=0.57), and 2.2%, 1.9%, 4.6% at 7 years (P=0.58) in the suitable, cautionary, and unsuitable groups, respectively. As compared with the suitable group, increased rates of distant metastases were noted for the unsuitable and cautionary groups at 5 years (P=0.04). CONCLUSIONS: No differences in rates of ipsilateral breast tumor recurrence were seen at 5 or 7 years when stratified by ASTRO CS groupings. Modest increases in distant recurrence were noted in the cautionary and unsuitable groups. These findings suggest that the ASTRO CS groupings stratify more for systemic recurrence and may not appropriately select patients for whole versus partial breast irradiation.