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Purpose The adoption of hypofractionated whole-breast irradiation (HF-WBI) remains low, in part because of concerns regarding its safety when used with a tumor bed boost or in patients who have received chemotherapy or have large breast size. To address this, we conducted a randomized, multicenter trial to compare conventionally fractionated whole-breast irradiation (CF-WBI; 50 Gy/25 fx + 10 to 14 Gy/5 to 7 fx) with HF-WBI (42.56 Gy/16 fx + 10 to 12.5 Gy/4 to 5 fx). Patients and Methods From 2011 to 2014, 287 women with stage 0 to II breast cancer were randomly assigned to CF-WBI or HF-WBI, stratified by chemotherapy, margin status, cosmesis, and breast size. The trial was designed to test the hypothesis that HF-WBI is not inferior to CF-WBI with regard to the proportion of patients with adverse cosmetic outcome 3 years after radiation, assessed using the Breast Cancer Treatment Outcomes Scale. Secondary outcomes included photographically assessed cosmesis scored by a three-physician panel and local recurrence-free survival. Analyses were intention to treat. Results A total of 286 patients received the protocol-specified radiation dose, 30% received chemotherapy, and 36.9% had large breast size. Baseline characteristics were well balanced. Median follow-up was 4.1 years. Three-year adverse cosmetic outcome was 5.4% lower with HF-WBI ( Pnoninferiority = .002; absolute risks were 8.2% [n = 8] with HF-WBI v 13.6% [n = 15] with CF-WBI). For those treated with chemotherapy, adverse cosmetic outcome was higher by 4.1% (90% upper confidence limit, 15.0%) with HF-WBI than with CF-WBI; for large breast size, adverse cosmetic outcome was 18.6% lower (90% upper confidence limit, −8.0%) with HF-WBI. Poor or fair photographically assessed cosmesis was noted in 28.8% of CF-WBI patients and 35.4% of HF-WBI patients ( P = .31). Three-year local recurrence-free survival was 99% with both HF-WBI and CF-WBI ( P = .37). Conclusion Three years after WBI followed by a tumor bed boost, outcomes with hypofractionation and conventional fractionation are similar. Tumor bed boost, chemotherapy, and larger breast size do not seem to be strong contraindications to HF-WBI.

Background As systemic therapy for metastatic breast cancer (BC) improves, the survival benefit from hormonal and targeted therapy urges treatment of brain metastases (BMs) with minimal toxicity and less systemic therapy interruption. Here we assessed clinical outcomes in BC patients who received upfront stereotactic radiosurgery (SRS). Methods We identified 236 patients who received upfront SRS with/without surgery for BMs from metastatic BC from 06/2007 to 05/2018. Twenty-four patients who received SRS for surgical cavity were excluded for analysis. Overall survival (OS) and salvage radiation-free survival (SRFS) were estimated using Kaplan-Meier analysis. Cox proportional hazard regression was used to identify prognostic factors. Results At a median follow-up time of 15.4 months (range, 0.8–119.6), the estimated median OS was 18.5 mo (95% CI, 14.9–21). Factors associated with OS on multivariate analysis (MVA) were molecular subtypes (12.2 months for triple-negative [n=68], 13.3 months for HR+/HER2- [n=66], 36.4 months for HR+/HER2+ [n=46], and 28.1 months for HER2+ [n=32], p=0.002), KPS >80 (p/= 4 [n=50], p=0.36). The 12-month salvage RT rate was 25% for WBRT and 26.4% for SRS. The median SRFS was 7.4 months (95% CI, 6.5‒8.3). Factors associated with SRFS on MVA were subtypes (p=0.002), KPS (p=0.011), and receipt of hormone therapy after diagnosis of BM (p=0.031). Conclusions The median OS for BC patients who developed BM is over 15 months. Molecular subtypes (HER2+ and HR+/HER2+), good KPS, and anti-HER2 or hormone therapy predicted better OS and SRFS. Prospective studies are needed to verify these results and refine the best treatment strategies for these patients.

Background: Adoption of HF-WBI remains low due in part to concerns regarding its safety when used with a tumor bed boost or in patients who have received chemotherapy or have large breast size. To address this, we conducted a randomized, multicenter trial to compare CF-WBI (50Gy/25fx+10-14Gy/5-7fx) to HF-WBI (42.56Gy/16fx+10-12.5Gy/4-5fx). Methods: From 2011 and 2014, 287 women with stage 0-II breast cancer, age ≥40 years, were randomized to CF-WBI or HF-WBI, stratified by chemotherapy and breast size. The primary outcome was the proportion of patients with adverse Breast Cancer Treatment Outcomes Scale (BCTOS) cosmetic score three years post-WBI, defined as a score of ≥2.5 (a score of 1 indicates no difference between the treated breast and contralateral breast, 2-slight difference, 3-moderate difference, 4-large difference). Secondary patient-reported outcomes included BCTOS functional status, BCTOS breast pain, Body Image Scale (BIS), and the FACT-B Trial Outcome Index (TOI). Additional secondary outcomes included photographically-assessed cosmesis scored by a 3-physician panel blinded to randomization arm using the RTOG scale, physician-assessed CTCAEv4.0, overall survival (OS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Chi-square, Fisher's exact, Wilcoxon's rank sum, logistic regression, and log-rank tests evaluated differences by treatment arm; survival was measured using the Kaplan-Meier method. All analyses were intention-to-treat. Results: Of 287 patients enrolled, 286 received the protocol-specified radiation dose. Thirty percent received chemotherapy (73% anthracycline, 92% taxane, 22% trastuzumab), 37% had large breast size (D cup or larger), and 44% were obese (BMI≥30). All baseline characteristics were well-balanced by treatment arm (P>0.05). Median follow-up is 4.1 years. For the primary outcome, adverse BCTOS cosmetic score at 3 years was noted in 13.6% (n=15/110) of CF-WBI and 8.2% (n=8/97) of HF-WBI patients (P=0.22). There were trends for lower risk of adverse BCTOS cosmetic score with HF-WBI, compared to CF-WBI, among patients who did not receive chemotherapy (OR=0.25, 95%CI 0.06-1.03; Pinteraction=0.07) or with large breast size (OR=0.26, 95%CI 0.07-0.98; Pinteraction=0.08). There were no patient subgroups where risk of adverse BCTOS cosmetic outcome was significantly higher with HF-WBI compared to CF-WBI. For secondary outcomes, there was no difference by treatment arm for BCTOS functional status (P=0.83), BCTOS breast pain (P=0.69), BIS (P=0.45), or FACT-B TOI (P=0.79). Poor-fair cosmetic outcome at 3 years assessed by the 3-physician panel was noted in 28.8% of CF-WBI patients and 35.4% of HF-WBI patients (P=0.31). In total, 19% CF-WBI patients and 20% of HF-WBI patients had a grade 2-3 toxicity at the three-year evaluation, with no difference by treatment arm (P=0.84). Five-year OS, LRFS, and DMFS were 99%, 98%, and 99%, respectively, with no difference by treatment arm (P=0.68, 0.37, 0.62). Conclusions: Three years after WBI followed by a tumor bed boost, outcomes with HF and CF are similar. Tumor bed boost, modern chemotherapy, and large breast size do not appear to be clinically meaningful contraindications to HF-WBI. Citation Format: Shaitelman SF, Lei X, Thompson A, Schlembach P, Arzu I, Bloom ES, Buchholz DJ, Chronowski GM, Dvorak T, Grade EJ, Hoffman KE, Kelly P, Perkins GH, Reed V, Shah S, Stauder MC, Strom EA, Tereffe W, Woodward WA, Baumann D, Amaya D, Guerra W, Morrison M, Hortobagyi G, Hunt KK, Buchholz TA, Smith BD. Three-year outcomes with hypofractionated (HF) versus conventionally fractionated (CF) whole breast irradiation (WBI) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-02.

Background Triple-negative breast cancer (TNBC) is an aggressive subtype with high propensity of developing brain metastases (BM). Clinical outcomes and prognostic factors after stereotactic radiosurgery (SRS) for BM were not well defined. Methods We identified 57 consecutive TNBC patients (pts) treated with single fraction SRS for BM during 05/2008–04/2018. Overall survival (OS) from BM diagnosis and freedom from BM progression (FFBMP) after initial SRS were evaluated. BM progression was defined as local and/or distant brain failure (LBF, DBF) after SRS. Kaplan-Meier analyses and Cox proportional hazard regression were used to estimate survival outcomes and identify prognostic factors. Results The median time to BM development from TNBC diagnosis was 23.7 months (mo) (range 0.7‒271.1). Median OS was 13.1 mo (95%CI 8.0‒19.5). On univariate analysis, Karnofsky performance score (KPS) >70 (p=0.03), number of BMs Conclusions TNBC pts with BM treated with SRS had an OS of 13.1 mo and FFBMP of 7.4 mo. Good KPS was an independent prognostic factor for OS. Further studies with more pts or conducted prospectively are needed to better understand and to improve treatment outcomes in this pt population.

Introduction Clinical trial enrollment has declined globally due to the COVID-19 pandemic. This underscores the importance of structured methods to continue critical medical research safely and efficiently. Methods We report the impact of a phased trial reopening strategy, remote research staffing, and telemedicine on cancer trial enrollment at one of the largest Radiation Oncology academic cancer centers. In Phase 1, trials investigating definitive therapeutic benefit were opened, followed by trials not increasing patient exposure or pulmonary toxicity risk in Phase 2. During Phase 2.5, multicenter trials reopened and limited research staff were allowed on-site. Results Despite initial enrollment declines during the early pandemic, the percentage of new patients enrolling in clinical trials from March to August 2020 was 8.8%, and represented an 10.5% relative increase from 2019. Monthly accrual enrollment from March to August 2019 ranged from 42-71 compared to enrollment during COVID-19 from 23-73 patients (p, At one of the largest academic cancer centers, the percentage of new patients enrolling in radiation oncology clinical trials during the 2020 COVID-19 pandemic showed a relative 10.5% increase from the same period in 2019. The use of a phased approach to trial reopening and adaptive techniques in telemedicine and remote staffing assist with maintaining accrual during the pandemic while preserving the integrity of trials and minimizing risk to patients and research staff.

Background: Triple-negative breast cancer (TNBC) has a high propensity for brain metastasis (BM) with poor prognosis. Stereotactic radiosurgery (SRS) has emerged as an effective treatment option for BM. However, clinical outcomes after SRS for BM from TNBC have not been well defined. We evaluated survival outcomes and prognostic factors among TNBC patients who received SRS for BMs.Methods: We retrospectively reviewed 99 patients with TNBC and BM who had received SRS at a single large-volume cancer center from May 2008 through April 2018. For the initial treatment of BM, 73 patients received SRS, 25 received whole-brain radiotherapy (WBRT), and 1 patient received surgery. Endpoints were overall survival (OS) from BM diagnosis, BM progression-free survival (BMPFS) from start of BM treatment, and times to intracranial local and distant failure from start of BM treatment. Both intracranial local and distant failure were considered BM progression. Local failure was defined as an increase in size of any treated lesions on imaging or assessment of treating physicians; enlargement attributable to radiation necrosis or post-radiation change was not counted as local failure. Kaplan-Meier analysis and Cox proportional hazard regression models were used to estimate survival curves and identify prognostic factors.Results: The median follow-up time from BM diagnosis was 12.7 months (95% confidence interval [CI] 1.3–52.1). The median age at BM diagnosis was 52 (range 24-82). The median interval between the diagnosis of primary breast cancer and BM was 25.8 months (95% CI 8.7–120.3). Of the 99 patients, 81 (81.8%) had 1-3 BMs and 18 (18.2%) had >3 BMs at diagnosis. The median OS time for all patients was 13.3 months (95% CI 10.3–16.4), and the cumulative survival rates were 55.1% at 1 year and 29.2% at 2 years. Factors independently associated with increased risk of death in multivariate analysis were Karnofsky performance score (KPS) ≤70 (p=0.01) and uncontrolled extracranial metastasis at BM diagnosis (p=0.05). No difference was found in OS according to type of initial treatment for BMs. Of the initial 99 patients, 12 were excluded from the evaluation of BMPFS, local and distant failure for missing follow-up imaging after initial treatment. The median BMPFS time was 7.2 months (95% CI 5.1–9.3). Of the 87 evaluable patients, 23 (26.4%) developed local recurrence after initial treatment, and among these 10 of 61 patients (16.4%) had received SRS and 13 of 25 patients (52%) had received WBRT. Patients initially treated with SRS had longer time to local failure than WBRT (50th percentile not reached vs. median 14.0 months, p=0.001). Multivariate analysis showed higher risk of local failure for patients who initially received WBRT versus SRS (hazard ratio [HR] 3.4, p=0.005). Forty-nine of 87 patients (56.3%) developed distant brain recurrence after initial treatment, and among these 35 of 61 patients (57.4%) had received SRS and 14 of 25 patients (56%) had received WBRT. No difference in risk of distant brain failure was found for patients initially treated with SRS versus WBRT (p=0.24). No difference was found in time to develop distant failure after initial treatment with SRS (median 18.4 months) versus WBRT (median 12.8 months, p=0.24).Conclusion: Patients with BM from TNBC had a median OS time of 13.3 months and a BMPFS time of 7.2 months. KPS≤70 and uncontrolled extracranial disease at the time of BM diagnosis were independent prognostic factors that increase risk of death. Patients initially treated with SRS had a longer time to develop intracranial local failure than those initially given WBRT, and this may be related to patient selection. Further prospective studies of larger numbers of patients with BM from TNBC are needed for a more accurate comparison of treatment modalities. Citation Format: Ran An, Yan Wang, Fuchenchu Wang, Chao Gao, Akshara Singareeka Raghavendra, Diana Amaya, Nuhad K Ibrahim, Jing Li. Survival outcomes and prognosis for patients with triple negative breast cancer who received stereotactic radiosurgery for brain metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-10.

Purpose: We sought to investigate if the use of HMG Co-A reductase inhibitors (statins) has an impact on outcomes among patients with triple negative breast cancer (TNBC). Methods: We reviewed the cases of women with invasive, non-metastatic TNBC, diagnosed 1997-2012. Clinical outcomes were compared based on statin use (defined as ever use during treatment vs. never use). We identified a subset of women for whom a 5-value lipid panel (5VLP) was available, including total cholesterol, low density lipoprotein, high density lipoprotein, very low density lipoprotein, and triglycerides. The Kaplan-Meier method was used to estimate median overall survival (OS), distant metastases-free survival (DMFS), and local-regional recurrence-free survival (LRRFS). A Cox proportional hazards regression model was used to test the statistical significance of prognostic factors. Results: 869 women were identified who met inclusion criteria, with a median follow-up time of 75.1 months (range 2.4-228.9 months). 293 (33.7%) patients used statins and 368 (42.3%) had a 5VLP. OS, DMFS, and LRRFS were not significant based on statin use or type. Controlling for the 5VLP values, on multivariable analysis, statin use was significantly associated with OS (HR 0.10, 95% CI 0.01-0.76), but not with DMFS (HR 0.14, 95% CI 0.01-1.40) nor LRRFS (HR 0.10 95% CI 0.00-3.51). Conclusions: Statin use among patients with TNBC is not associated with improved OS, although it may have a benefit for a subset of patients. Prospective assessment would be valuable to better assess the potential complex correlation between clinical outcome, lipid levels, and statin use.

Importance The most appropriate dose fractionation for whole-breast irradiation (WBI) remains uncertain. Objective To assess acute and 6-month toxic effects and quality of life (QOL) with conventionally fractionated WBI (CF-WBI) vs hypofractionated WBI (HF-WBI). Design, Setting, and Participants Unblinded randomized trial of CF-WBI (n = 149; 50.00 Gy/25 fractions + boost [10.00-14.00 Gy/5-7 fractions]) vs HF-WBI (n = 138; 42.56 Gy/16 fractions + boost [10.00-12.50 Gy/4-5 fractions]) following breast-conserving surgery administered in community-based and academic cancer centers to 287 women 40 years or older with stage 0 to II breast cancer for whom WBI without addition of a third field was recommended; 76% of study participants (n = 217) were overweight or obese. Patients were enrolled from February 2011 through February 2014 and observed for a minimum of 6 months. Interventions Administration of CF-WBI or HF-WBI. Main Outcomes and Measures Physician-reported acute and 6-month toxic effects using National Cancer Institute Common Toxicity Criteria, and patient-reported QOL using the Functional Assessment of Cancer Therapy for Patients with Breast Cancer (FACT-B). All analyses were intention to treat, with outcomes compared using the χ 2 test, Cochran-Armitage test, and ordinal logistic regression. Results Of 287 participants, 149 were randomized to CF-WBI and 138 to HF-WBI. Treatment arms were well matched for baseline characteristics, including FACT-B total score (HF-WBI, 120.1 vs CF-WBI, 118.8; P = .46) and individual QOL items such as somewhat or more lack of energy (HF-WBI, 38% vs CF-WBI, 39%; P = .86) and somewhat or more trouble meeting family needs (HF-WBI, 10% vs CF-WBI, 14%; P = .54). Maximum physician-reported acute dermatitis (36% vs 69%; P P P = .001), hyperpigmentation (9% vs 20%; P = .002), and fatigue (9% vs 17%; P = .02) during irradiation were lower in patients randomized to HF-WBI. The rate of overall grade 2 or higher acute toxic effects was less with HF-WBI than with CF-WBI (47% vs 78%; P P = .01), and patients randomized to HF-WBI reported less lack of energy (23% vs 39%; P P = .01). Multivariable regression confirmed the superiority of HF-WBI in terms of patient-reported lack of energy (odds ratio [OR], 0.39; 95% CI, 0.24-0.63) and trouble meeting family needs (OR, 0.34; 95% CI, 0.16-0.75). Conclusions and Relevance Treatment with HF-WBI appears to yield lower rates of acute toxic effects than CF-WBI as well as less fatigue and less trouble meeting family needs 6 months after completing radiation therapy. These findings should be communicated to patients as part of shared decision making. Trial Registration clinicaltrials.gov Identifier:NCT01266642