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Partial breast irradiation (PBI) is the delivery of radiation therapy (RT) limited to the tumor bed after breast conserving surgery. The results of recent trials of PBI compared with whole breast irradiation (WBI) have suggested conflicting results with respect to local control and toxicity. The purpose of this meta-analysis was to assess effectiveness of PBI and to compare the different techniques.A meta-analysis of aggregate data from published randomized trials was performed to examine the effectiveness of PBI compared with WBI in patients with invasive breast cancer and ductal carcinoma in situ. Relevant data were extracted. The primary outcome was any ipsilateral breast event (invasive or noninvasive). Secondary outcomes included acute and late toxicity. The results of randomized trials were pooled using a fixed effects model and the inverse variance method.Fifteen trials involving 16,474 patients were identified. The majority of enrolled patients were60 years of age and had T1N0 grade 1 to 2 disease treated with hormone therapy. The percent of ipsilateral breast events was higher in patients treated with PBI compared with WBI (5.0% vs 2.8%; risk ratio [RR], 1.72; 95% confidence interval [CI], 1.47-2.02). Heterogeneity (P = .0002) was observed between the 4 PBI techniques: external beam RT without computed tomography (CT) planning (RR, 2.06; 95% CI, 1.36-3.12); brachytherapy (RR, 1.21; 95% CI, 0.65-2.25); intraoperative RT (RR, 2.79; 95% CI, 2.08-3.73); and external beam RT with CT planning (RR, 1.25; 95% CI, 0.99-1.58). When external beam RT without CT planning and intraoperative RT trials were excluded, the percent of ipsilateral breast events was 3.3% versus 2.6%, respectively (RR, 1.25; 95% CI, 1.00-1.55; P = .05), and no heterogeneity was observed (P = .92). Overall, acute toxicity was less with PBI, and the effect on late toxicity varied by technique.Overall, WBI was more effective than PBI, but the effectiveness of PBI was technique related. PBI was less effective when given by external beam RT without CT planning or intraoperative therapy. Although PBI given by multicatheter brachytherapy or external beam RT with CT planning tended to be statistically less effective than WBI, the absolute difference between groups for ipsilateral breast events was very small (1%), supporting these approaches for women considering PBI.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS.METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236).FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; pINTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results.FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

Background: MET has been associated with beneficial anti-cancer effects in epidemiologic and preclinical research. It may act indirectly by reversing obesity associated physiologic changes or directly via mitochondrial mediated effects on LKB1/AMPK/mTOR and other mechanisms. MA.32 investigated the effect of MET vs PLAC (in addition to standard therapy) on adjuvant BC outcomes. Design: Randomized, placebo-controlled double-blind Phase III clinical trial conducted within the NCI US National Clinical Trials Network, NCRI (UK) BG, IBCSG. Methods: Between 2010-2013 BC patients < 75 yo without diabetes (DM) with high risk T1-3, N0-3 M0 BC regardless of ER, PgR, HER2 and with adequate cardiac, renal and hepatic function were randomized (stratified for ER/PgR + vs -, BMI < vs > 30 kg/m2, HER2 +ve vs -ve, any vs no chemo) within 1 year of BC diagnosis to MET 850 mg po bid or PLAC bid for 5 years. Dose was reduced for toxicity with re-escalation when possible. Subjects were followed for Invasive Disease-Free Survival (IDFS primary outcome; events included invasive local/regional recurrences, distant recurrences, new ipsilateral/contralateral invasive BCs, new non-breast primary cancers, any death), Overall Survival (OS), Distant Relapse Free Survival (DRFS), BC Specific Survival (BCSS), BC Free Interval (BCFI), contralateral BC and cardiovascular (CV) events/new DM. 3582 subjects were required for 80% power to detect HR 0.76 (431 events). In 2011, entry was restricted to higher risk BC, leading to 80% power to detect HR 0.785 (544 events). In 2016, after the 2nd interim analysis at 29.5 months median F/U, the DSMB recommended (i) the intervention be continued with primary analysis triggered at 544 events be conducted in ER/PgR +ve (any HER2) subjects only and (ii) ER/PgR -ve subjects stop study drug for futility but blinding and follow-up continue. In 2021, a time driven analysis in ER/PgR +ve BC was approved (465 events providing 80% power to detect the original HR 0.76). Time to event survival described by the Kaplan-Meier method. Two-sided log-rank tests adjusting for stratification factors were primarily used to compare IDFS between arms. Cox proportional hazards models were used to identify and adjust for factors significantly related to IDFS. Results: 3649 subjects were enrolled. In the 2533 ER/PgR +ve subjects included in the primary analysis, baseline mean (± SD) age was 52.7 (±9.9 yrs); mean BMI 28.8 (±6.4) kg/m2. Baseline tumor characteristics were balanced: T stage 1/2/3/4 = 832/1351/349/1; N stage 0/1/2/3 = 964/1097/449/23; HER2+ 429. 1901 (75%) received XRT. 2150 (84.9%) received (neo)adj chemo, 2223 (87.8%) (neo)adj hormones and 434 (17.1%) HER2 targeted therapy. Any Grade ≥ 3 toxicity was similar in MET and PLAC arms (21.7% and 18.7%, P = 0.06). Median follow-up was 96.2 (range 0.2-121.0) months with 465 IDFS events (234 MET, 231 PLAC, 76% due to BC). Efficacy results are shown below. MET vs PLACMET vs PLACIDFSOSPopulation Included# subjectsHR (95% CI)HR (95% CI)PRIMARY ANALYSISER/PgR +ve (any HER2)*25331.01 (0.84-1.21). P=0.920.89 (0.64-1.23). P=0.46ER/PgR -ve (any HER211161.01 (0.79-1.30. P=0.92)0.89 (0.64-1.23). P=0.46Exploratory. AnalysisHER2 +ve (any ER/PgR)6200.64 (0.43-0.95. P=0.0260.53 (0.30-0.98. P=0.0398**in ER/PgR pos BC HRs were similar for BCFI, DRFS, BCSS (ranging from 0.98-1.09)Conclusions: MET did not improve IDFS or other BC outcomes in ER/PgR positive or ER/PgR negative BC and should not be used as adjuvant treatment. Exploratory findings suggesting benefit in HER2+ve BC should be further investigated. Funded by: CCSRI, NCI (US), CBCF, BCRF, CRUK, Hold’Em for Life Charity, Apotex (Canada) Citation Format: Pamela J. Goodwin, Bingshu E Chen, Karen A Gelmon, Timothy J Whelan, Marguerite Ennis, Julie Lemieux, Jennifer A Ligibel, Dawn L Hershman, Ingrid A Mayer, Timothy J Hobday, Judith M Bliss, Priya Rastogi, Manuela Rabaglio-Poretti, Som D. Mukherjee, Robert R Mackey, Vandana G Abramson, Conrad Oja, Robert Wesolowski, Alastair M Thompson, Daniel W Rea, Paul M Stos, Lois E Shepherd, Vuk Stambolic, Wendy R Parulekar. CCTGMA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438) [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 GS1-08.

Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was −1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.

Introduction: Luminal A breast cancer is associated with low proliferation, indolent disease biology and limited benefit from chemotherapy. The LUMINA prospective study recently demonstrated a very low 5 year local recurrence rate (2.3%) in women ≥55 years with grade I-II, T1N0 luminal A breast cancer (defined as ER ≥ 1%, PR>20%, HER2 negative and Ki67 index ≤ 13.25%) treated with breast conservation surgery and endocrine therapy without radiation, supporting the safe omission of radiation in this molecularly defined low risk group. Here, we report the protocol for multicentre Ki67 scoring, the embedded integral companion diagnostic employed in LUMINA. Methodology: Ki67 immunohistochemistry was performed on full-face sections at one of the 3 labs and scored by pathologists using an adaptation of the International Ki67 Working Group (IKWG) method. Prior to the start of the study, quality assurance and quality control programs were set up to standardize staining and scoring protocols. All pathologists completed the IKWG training and calibration exercise using a tissue microarray-based series of 18 breast cancers. Inter-laboratory variability was assessed annually during the study period on a set of 9 breast cancer cases with a range of Ki67 scores that purposely over-represented the 13.25% threshold. Stained slides were scanned and images annotated to demarcate invasive carcinoma. Next, 5 random, non-overlapping, 1 mm virtual cores were generated via software and 100 nuclei assessed per core using a keyboard-based counting aid. Ki67 index was derived as the percentage of all counted tumor nuclei that are positively stained. For cases with high Ki67 heterogeneity, additional virtual cores were generated and scored and a 95% confidence interval (CI) of Ki67 index was estimated. The goal was to confidently assign a case as luminal A (≤13.25%) or B (> 13.5%). If the 95% CI crossed 13.25% a recount was performed by an additional pathologist. Results: Quality Assurance Programs: Mean Ki67 index across all cases, labs and years was 13% with high concordance across specimens and score ranges. Observed intra-class correlation coefficients (ICC) were ≥ 0.9, showing near perfect agreement in quantitative Ki67 evaluation. About the 13.25% cutpoint, the observed Kappa statistics were ≥ 0.7 indicating excellent agreement for assignment of luminal A vs. B status. A sub-study was conducted to compare the method of randomly selected virtual fields with the IKWG ‘global weighted score’ method for visual assessment of full-face sections. For this purpose, the 9 quality control cases were reassessed by the same pathologist using the updated IKWG method. Results showed an ICC of 0.96 (0.95% CI: 0.91-0.98) indicating that the Ki67 score generated by the methodology employed in LUMINA trial is highly concordant with the IKWG scoring methodology validated for use on full face sections. Ki67 index summary statistics across LUMINA: Of the 724 eligible cases, 69% (n=500) were assigned as luminal A (median Ki67=7.5%; IQR 5.2-9.8%) and 31% (n=224) as luminal B (median Ki67=19%; IQR 17-23%). Median pathologist scoring time was 4 minutes/case; 45% of cases required scoring of > 5 virtual cores. Per protocol, 39% cases where the initial CI crossed 13.25% were rescored by additional pathologist for final luminal A consensus assignment. Conclusions: Ki67 is a practical biomarker for identifying molecularly defined low-risk luminal A cancers. Our structured quality assurance approach for the trial led to excellent reproducibility and concordance among decentralized labs, supporting applicability of a distributed, inexpensive methodology beyond clinical trial settings and in resource restricted environments. Citation Format: Torsten Nielson, Samuel Leung, Nazia Riaz, Zuzana Kos, Anita Bane, Timothy J. Whelan. Ki67 Assessment Protocol: Companion Diagnostic Biomarker for LUMINA Prospective Cohort Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-04-02.

Background: The benefit of regional nodal irradiation (RNI) in patients with low burden metastatic axillary disease was established in MA.20 showing that patients randomized to receive adjuvant whole breast irradiation (WBI) plus RNI experienced a significantly better disease free survival (DFS) and distant disease free survival (DDFS) compared to those who received WBI alone and this advantage was maintained in the hormone receptor negative subgroup. Stromal tumor infiltrating lymphocytes (sTILs) have shown prognostic and predictive value in HER2 positive and triple negative breast cancers. To date, clinical importance of immune infiltrates as prognostic and predictive biomarkers in the context of benefit from RNI has not been shown. Methods: 1064 full-face hematoxylin and eosin (H&E) stained sections and formalin fixed paraffin embedded primary tumor blocks assembled into 16 tissue microarrays (TMAs) in quadruplicates linked with clinical data were accessible from the original 1832 patients in the MA.20 trial for this retrospective-prospective translational study conducted according to the REMARK guidelines. sTILs were assessed on scanned images of H&E sections according to the International Immuno-Oncology Working Group method, and on TMAs by CD8 immunohistochemistry (IHC) using a validated assay. Biomarkers were scored by pathologists blinded to the clinical data and analyzed as continuous and categorical variables using prespecified median cutpoints. The median follow-up was 9.5 years. Cox proportional regression modelling was used after adjusting for clinicopathological factors and treatments. Hazard ratios (HR) with 95% confidence intervals (CI) were reported for the primary endpoint of DFS and secondary endpoint of DDFS. Predictive value was assessed by the interaction test between the treatment arm and the biomarkers in the full cohort and an IHC defined non-luminal A subgroup. Results: 1035 cases were evaluable for sTILs on H&E sections. Of these 52.6% (n=544) cases with ≥10% sTILs displayed a significant correlation with age < 50 years, grade III, tumor size >2cm, hormone receptor negative status, and non-luminal A subgroup (p < 0.05). Of the 857 evaluable cases on TMAs, CD8+sTILs (≥16) were observed in 49.8% (n=427) cases and showed a significant association with grade III, ER negativity and non-luminal A status (p < 0.05). For the full cohort, H&E sTILs assessed as a continuous parameter, were not prognostic for DFS (HR 0.993; 95% CI 0.984-1.003; p=0.18) but provided prognostic information for DDFS (HR 0.988; 95% CI 0.977-0.999; p=0.04) in multivariate analyses. H&E sTILs did not show predictive value as a continuous variable. Similarly, using the prespecified cutpoint (≥10%), H&E sTILs were neither prognostic nor predictive. Increasing level of CD8+sTILs was associated with significantly improved DFS (HR 0.99; 95% CI 0.983-0.998; p=0.02) and DDFS (HR 0.98; 95% CI 0.97-0.99; p=0.002) in multivariate analyses. For the full cohort, CD8+sTILs as a continuous variable, showed a significant improvement in DDFS for patients randomized to WBI and RNI (HR 0.979; 95%CI 0.959-0.999; p(interaction) =0.04) compared to WBI alone and a trend (HR 0.977; 95%CI 0.954-1.001; p(interaction) =0.06) for better outcome was observed for the non-luminal A subgroup. CD8+sTILs at the prespecified cutpoint (≥16) were not prognostic or predictive. Conclusions: Pre-treatment tumoral infiltration with stromal lymphocytes provided positive prognostic information for DFS (CD8+sTILs) and DDFS (H&E sTILs and CD8+sTILs) when examined as a continuous variable but failed to do so at prespecified cutpoints. While CD8+sTILs as a continuous variable predicted benefit from RNI, significant prediction results were not seen for prespecified cutpoint or related biomarker H&E sTIL. These results require further validation. Citation Format: Nazia Riaz, Bingshu Chen, Anita Bane, Dongxia Gao, Elisabeth Stovgaard, Zuzana Kos, Samuel Leung, Elahe Shenasa, Wendy Parulekar, Shelley Chambers, Torsten Nielson, Timothy J. Whelan. Prognostic and Predictive Capacity of Tumor Infiltrating Lymphocytes in the MA.20 regional radiotherapy trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-16.

Importance Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration ClinicalTrials.gov Identifier: NCT01101438.

Purpose of Review Accelerated partial breast irradiation (APBI) is an alternative approach to breast conserving therapy (BCT) where radiation (RT) is delivered over a shorter period of time compared with whole breast irradiation (WBI), resulting in improved patient convenience and cost savings. APBI can be delivered using brachytherapy, intraoperative RT, or conformal external beam radiation therapy (EBRT) techniques. In this review, the authors appraise the latest modern randomized controlled trials (RCTs) of APBI and discuss the application of the data to clinical practice. Recent Findings The OCOG-RAPID and NSABP B-39/RTOG 0413 trials recently reported long-term outcomes of APBI. The OCOG-RAPID trial delivered 38.5 Gy/10 fractions twice daily (at least 6 h apart using EBRT) or WBI and demonstrated non-inferiority of APBI compared with WBI (8-year cumulative rate of ipsilateral breast tumor recurrence (IBTR) was 3% after APBI or 2.8% after WBI, HR 1.27, 90%CI: 0.84–1.91). While acute toxicity was reduced, late toxicity and breast cosmesis were worse with APBI. The NSABP B-39 trial included higher risk patients and was unable to demonstrate equivalence between APBI (38.5 Gy/10 fractions delivered twice daily using EBRT or brachytherapy techniques) and WBI. However, 10-year IBTR rates were low: 4.6% vs. 3.9%, respectively, HR 1.22, 90%CI: 0.94–1.58. The University of Florence demonstrated low rates of local recurrence at 10 years and overall excellent breast cosmetic outcomes when APBI was delivered using EBRT to a dose of 30 Gy/5 fractions delivered on non-consecutive days. Summary Recent RCTs of APBI have shed light on important factors for the integration of APBI into clinical practice, including patient selection and treatment delivery. APBI should be limited to patients with low-risk ductal carcinoma in situ or early stage (T1) invasive ductal cancer with clear margins of excision, estrogen receptor positivity, and node negative disease. Ongoing research should focus on the optimal dose/fractionation for delivery of EBRT-based APBI.

To assess the acute toxicity and quality of life (QOL) of hypofractionation compared with conventional fractionation for whole breast irradiation (WBI) after breast-conserving surgery.Women with node-negative breast cancer who had undergone breast-conserving surgery with clear margins were randomly assigned to conventional WBI of 5000 cGy in 25 fractions over 35 days or hypofractionated WBI of 4256 cGy in 16 fractions over 22 days. Acute skin toxicity and QOL were assessed at baseline and 2, 4, 6, and 8 weeks from the start of treatment for a subgroup of patients. QOL was assessed at baseline and 4 weeks posttreatment for all patients. In the acute toxicity substudy, repeated measures modeling was used to investigate treatment by time interactions over the 8-week period for acute toxicity and QOL mean change score. QOL mean change score from baseline to 4 weeks posttreatment was compared for all patients.In the acute toxicity substudy, 161 patients participated. In the main trial, 1152 patients participated. Acute skin toxicity was initially similar between groups but was less with hypofractionation compared with conventional fractionation toward the end of the 8-week period (P.001). QOL at 6 weeks from the start of treatment was improved with hypofractionation for the skin side effects, breast side effects, fatigue, attractiveness, and convenience domains (all P.05). In the main trial, hypofractionation resulted in improved overall QOL and QOL attributed to skin side effects, breast side effects, and attractiveness (all P.01).Hypofractionated WBI compared with conventional WBI resulted in less acute toxicity and improved QOL. This further supports the benefits of hypofractionation.

Background: Guidelines recommend that breast radiation (RT) can be omitted for patients with a low risk of local recurrence (LR) after breast-conserving surgery (BCS) for DCIS. The inability to identify women at low risk of LR ( Methods: Prospective cohort study of women with low/moderate risk pure DCIS treated with BCS. Cases with age 2.5cm, multifocality, or prior breast cancer were excluded. Baseline CPFs, the DS and risk of LR were collected. Pre-assay, the radiation oncologist provided an estimate of 10-year LR risk without RT and a preliminary recommendation for RT. Post-assay, final recommendations were recorded. The primary outcome was change in treatment recommendation by the radiation oncologist. Target sample size was 220 to provide data on 200 evaluable patients with adequate precision. Results: 217 patients were evaluable: mean age, 63 years and mean tumor size, 1.1 cm. Nuclear grade was low in 26 (12%), intermediate in 116 (53%), and high in 75 (35%) of patients. Mean DS = 32; 140 (64%) low (15% in 128 (59%) cases. Post-assay, estimated 10-yr LR risk after BCS was 15% in 49 (22%) (RT recommended in 98%). Conclusion: The use of the DCIS Score combined with CPFs identifies more women with an estimated low ( Table 1.Post-assay 10-yr LR risk15%(N=101)(N= 67)(N=49)Pre-assay estimated 10-yr LR risk• 15% (N=128)424739RT recommended• Yes17 (17%)44 (66%)48 (98%)• No83 (83%)23 (34%)1 (2%) Citation Format: Eileen Rakovitch, Anne Koch, Laval Grimard, Hany Soliman, Christiaan Stevens, Francisco Perera, Iwa Kong, Senti Senthelal, Margaret Anthes, Ericka Wiebe, Jeffrey Cao, Mira Goldberg, Sally Smith, Luciana Spadafora, Sameer Parpia, Timothy Whelan. Refined local recurrence risk estimates based on a multigene expression assay combined with clinicopathological features significantly impacts radiotherapy recommendation in patients with low/intermediate risk DCIS treated with breast-conserving surgery [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-16-01.

Purpose: Current guidelines recommend for women (≥65 years at diagnosis) with early stage (T1N0), hormone receptor (HR+) breast cancer (BC) treated with breast-conserving surgery (BCS) that treatment with 5 years of endocrine therapy (ET) alone with omission of radiation (RT) is acceptable. Population studies however report that many women continue to receive RT. The use of RT may reflect preferences due to the convenience of modern RT and/or concerns of the adverse effects of ET. Adjuvant treatment with RT alone may be an attractive option, but further data on the outcomes and morbidity following mono adjuvant therapy with either RT alone or ET alone is needed. We established a contemporary population-based cohort of women ≥65 years with HR+ T1N0 BC treated by BCS. We report the risk of local recurrence, any secondary breast events and adverse treatment-related effects following single modality adjuvant therapy with RT or ET alone. Methods: We identified all women aged ≥65 years at diagnosis with HR+ T1N0 BC diagnosed in Ontario from 2010-2016, treated with BCS and adjuvant RT alone or ET alone (tamoxifen or aromatase inhibitors (AI)). The administration of ET was ascertained from the Ontario Drug Benefit database. Cases were coded as having received either tamoxifen or AI according to the first prescription. Cases with Her2+ BC or those who did not undergo nodal surgery were excluded. Outcomes were ascertained using deterministic linkages of administrative databases. Propensity-weighted scores (PS) were calculated using baseline factors (diagnosis year, age, Charlson comorbidity score, nodal surgery type, grade, socioeconomic status, HR category). Kaplan Meier curves and PS-adjusted multivariable Cox regression were used to evaluate risks of ipsilateral LR, any in-breast event (ipsilateral or contralateral), and adverse treatment-related outcomes (venous thromboembolism (VTE), osteoporotic fracture, vaginal bleeding requiring hysteroscopy or curettage, ischemic heart events, second malignancy. Results: The cohort includes 1054 that received BCS + adjuvant RT and 497 that received BCS + adjuvant ET alone (N= 201 tamoxifen; N=296 AI). Median follow-up time was 5 years. LR occurred in 0.9% (n=10) after RT alone and 2.8% (n=14) after ET alone (p=0.005). Rates of any in-breast event were 3.2% and 3.4%, respectively (p=0.8). Adjusting for PS, treatment with ET alone was associated with an increased risk of LR (HR= 2.79, 95% CI: 1.20, 6.49, p=0.02), no difference in the risk of any in-breast event (HR=0.96, 95% CI: 0.53, 1.77, p=0.9) and a higher risk of VTE (HR=1.8, 95% CI: 1.0, 3.2, p=.05) compared to those treated with RT alone. Women treated with tamoxifen alone had a 5-fold increased risk of vaginal bleeding (HR=4.7, 95%CI: 2.2, 10.0, p Conclusions: Women ≥65 years with HR+ EBC treated with single modality adjuvant therapy with RT or ET alone experience low risks of recurrence and morbidity. In this population-based study, RT alone compared to ET alone was associated with a lower risk of LR and less adverse events. Table 1. 5-year rates of adverse eventp-valueAny Fracture0.3• RT only11.9• tamoxifen9.5• aromatase inhibitor13.3Osteoporotic Fracture0.1• RT only5.8• tamoxifen2.8• aromatase inhibitor7.3Hysteroscopy/Curettage Citation Format: Mira Goldberg, Rinku Sutradhar, Lawrence Paszat, Timothy Whelan, Sumei Gu, Cindy Fong, Eileen Rakovitch. Single modality adjuvant therapy with radiation (RT) alone or endocrine therapy (ET) alone in women ≥65 years with early stage, hormone receptor positive breast cancer treated with breast-conserving surgery: A population-based analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-01.

Purpose: Clinical guidelines recommend that for women ≥65 years with stage T1N0 breast cancer (BC) treated with breast-conserving surgery (BCS) that breast RT may be omitted and treatment with ET alone is acceptable. However, population-based studies report that up to two-thirds of women with T1N0 BC do not complete 5 years of ET. The effect of non-adherence to ET on recurrence risks in women treated with ET alone is unclear. We established a contemporary population-based cohort of women aged ≥65 years with stage T1N0, hormone receptor positive, breast cancer treated with single modality adjuvant ET or RT alone. We examined the effect of non-adherence in those treated with ET alone and compared the outcomes (ipsilateral LR, any breast event and any invasive in-breast event) of women who were non-adherent to those who were adherent to ET or those treated with RT alone. Methods: A population-based cohort of women diagnosed with T1N0 BC from 2010-2016, aged ≥65 years at diagnosis, treated with BCS and single modality adjuvant therapy with RT alone or ET alone was identified from the Ontario Cancer Registry. ER-/PR-, ER unknown/PR unknown, HER2+ cases and those without sentinel node biopsy or axillary dissection were excluded. Treatment and outcomes were ascertained using deterministic linkages of administrative databases. Receipt of adjuvant ET was identified using dispensing records from the Ontario Drug Benefit Claims database. Adherence percentage at any specific time was calculated by dividing the number of days dispensed (up to that time) by the number of days since diagnosis. This was updated every 3 months for each woman receiving ET. Adherence to ET was captured as a 3-level time-varying covariate (RT only, Results: The cohort includes 1551 women; 1054 women treated with BCS + adjuvant RT alone and 497 treated with BCS + adjuvant ET alone. The median follow-up time was 5 years. Almost half (45.7%) of cases prescribed ET alone were 80% adherent and 0.9% in those treated with RT alone (p80% adherent to ET. There was no significant difference in outcomes between those treated with ET who were >80% adherent during their follow-up time and those treated with RT alone. Conclusions: Almost half of women older than 65 years with stage T1N0 breast cancer treated with breast-conserving surgery and adjuvant ET alone are Citation Format: Mira Goldberg, Rinku Sutradhar, Lawrence Paszat, Timothy Whelan, Sumei Gu, Cindy Fong, Eileen Rakovitch. Non-adherence to endocrine therapy is associated with a significant increased risk of local recurrence in women ≥65 years with stage T1N0 breast cancer treated with adjuvant endocrine therapy alone after breast-conserving surgery [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-06.

Purpose: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast. Materials and methods: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/− TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems. Results: 1608 women were enrolled from 11 countries between 2007 and 2014. 85–90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p ≥ 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p ≥ 0.30). Conclusions: Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS.

IMPORTANCE: Racial disparities in survival outcomes among Black women with hormone receptor–positive breast cancer have been reported. However, the association between individual-level and neighborhood-level social determinants of health on such disparities has not been well studied. OBJECTIVE: To evaluate the association between race and clinical outcomes (ie, relapse-free interval and overall survival) adjusting for individual insurance coverage and neighborhood deprivation index (NDI), measured using zip code of residence, in women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of 9719 women with breast cancer in the Trial Assigning Individualized Options for Treatment, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor–positive, ERBB2-negative, axillary node–negative breast cancer. The present data analysis was conducted from April 1 to October 22, 2021. MAIN OUTCOMES AND MEASURES: A multivariate model was developed to evaluate the association between race and relapse-free interval and overall survival adjusting for insurance and NDI level at study entry, early discontinuation of endocrine therapy 4 years after initiation, and clinicopathologic characteristics of cancer. Median follow-up for clinical outcomes was 96 months. RESULTS: A total of 9719 women (4.2% [n = 405] Asian; 7.1% [n = 693] Black; 84.3% [n = 8189] White; 4.4% [n = 403] others/not specified) were included; 9.1% of included women [n = 889] were Hispanic or Latino. Median (SD) age was 56 (9.2) years. In multivariate models, Black race compared with White race was associated with statistically significant shorter relapse-free interval (hazard ratio [HR], 1.39; 95% CI, 1.05-1.84; P = .02) and overall survival (HR, 1.49; 95% CI, 1.10-2.99; P = .009), adjusting for insurance and NDI level at study entry and other factors. Although uninsured status was not associated with clinical outcomes, patients with Medicare (HR, 1.30; 95% CI, 1.01-1.68; P = .04) and Medicaid (HR, 1.44; 95% CI, 1.01-2.05; P = .05) had shorter overall survival compared with those with private insurance. Participants living in neighborhoods in the highest NDI quartile experienced shorter overall survival compared with those in the lowest quartile (HR, 1.34; 95% CI, 1.01-1.77; P = .04), regardless of self-identified race. CONCLUSIONS AND RELEVANCE: The findings of this post hoc analysis of a randomized clinical trial suggest that Black women with breast cancer have significantly shorter relapse-free interval and overall survival compared with White women. Early discontinuation of endocrine therapy, clinicopathologic characteristics, insurance coverage, and NDI do not fully explain the observed disparity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00310180

Adjuvant whole breast irradiation after breast-conserving surgery is a well-established treatment standard for early invasive breast cancer. Screening, early diagnosis, refinement in surgical techniques, the knowledge of new and specific molecular prognostic factors, and now the standard use of more effective neo/adjuvant systemic therapies have proven instrumental in reducing the rates of locoregional relapses. This underscores the need for reliably identifying women with such low-risk disease burdens in whom elimination of radiation from the treatment plan would not compromise oncological safety. This review summarizes the current evidence for radiation de-intensification strategies and details ongoing prospective clinical trials investigating the omission of adjuvant whole breast irradiation in molecularly defined low-risk breast cancers and related evidence supporting the potential for radiation de-escalation in HER2+ and triple-negative clinical subtypes. Furthermore, we discuss the current evidence for the de-escalation of regional nodal irradiation after neoadjuvant chemotherapy. Finally, we also detail the current knowledge of the clinical value of stromal tumor-infiltrating lymphocytes and liquid-based biomarkers as prognostic factors for locoregional relapse.

Summary Background Whole breast irradiation delivered once per day over 3–5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. Methods We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5–8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov , NCT00282035 . Findings Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3–9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9–4·0) in the APBI group and 2·8% (1·8–3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84–1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p Interpretation External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. Funding Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

Background TAILORx (Trial Assigning Individualized Options for Treatment) prospectively assessed fatigue and endocrine symptoms among women with early-stage hormone receptor-positive breast cancer and a midrange risk of recurrence who were randomized to endocrine therapy (E) or chemotherapy followed by endocrine therapy (CT+E). Methods Participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue, the Patient-Reported Outcomes Measurement Information System-Fatigue Short Form, and the Functional Assessment of Cancer Therapy-Endocrine Symptoms at the baseline and at 3, 6, 12, 24, and 36 months. Linear regression was used to model outcomes on baseline symptoms, treatment, and other factors. Results Participants (n = 458) in both treatment arms reported greater fatigue and endocrine symptoms at early follow-up in comparison with the baseline. The magnitude of change in fatigue was significantly greater for the CT+E arm than the E arm at 3 and 6 months but not at 12, 24, or 36 months. The CT+E arm reported significantly greater changes in endocrine symptoms from the baseline to 3 months in comparison with the E arm; change scores were not significantly different at later time points. Endocrine symptom trajectories by treatment differed by menopausal status, with the effect larger and increasing for postmenopausal patients. Conclusions Adjuvant CT+E was associated with greater increases in fatigue and endocrine symptoms at early time points in comparison with E. These differences lessened over time, and this demonstrated early chemotherapy effects more than long-term ones. Treatment arm differences in endocrine symptoms were more evident in postmenopausal patients. Lay summary Participants in TAILORx (Trial Assigning Individualized Options for Treatment) with early-stage hormone receptor-positive breast cancer and an intermediate risk of recurrence were randomly assigned to endocrine or chemoendocrine therapy. Four hundred fifty-eight women reported fatigue and endocrine symptoms at the baseline and at 3, 6, 12, 24, and 36 months. Both groups reported greater symptoms at early follow-up versus the baseline. Increases in fatigue were greater for the chemoendocrine group than the endocrine group at 3 and 6 months but not later. The chemoendocrine group reported greater changes in endocrine symptoms in comparison with the endocrine group at 3 months but not later.

Background: Wholebreast irradiation (WBI) after breast conserving surgery for DCIS reduces therisk of local recurrence including invasive recurrence. The objective of BIG3-07/TROG 07.01 is to test radiation dose escalation to the tumor bed (tumorbed boost) and fractionation sensitivity of whole breast irradiation (WBI) inpatients with non-low risk DCIS treated with breast conserving therapy. Methods: BIG3-07/TROG 07.01 is an international, multicenter, randomized, controlled, phase 3 trial. Eligible women were ≥18 years ofage with completely resected non-low risk DCIS defined as age Results: BetweenJune 2007 and June 2014, 1608 patients were randomized to have no boost (805patients) or boost (803 patients) after WBI. Conventional WBI was given in 831 patients(no boost in 416 patients; boost in 415 patients). Hypofractionated WBI wasgiven in 777 patients (no boost in 389 patients; boost in 388 patients). Adjuvantendocrine therapy was planned in 106 patients (13%) in the no boost group and105 patients (13%) in the boost group. Median follow-up was 6.6 years. The 5-yearfree-from- local recurrence rates were 93% in the no boost group and 97% in theboost group (hazard ratio, 0.47; 95% confidence interval [CI], 0.31 to 0.72;P Conclusions: Inwomen with non-low risk DCIS treatedwith breast conserving surgery, the addition of tumor bed boost followingconventional or hypofractionated WBI reduced local recurrence rates. There wasno difference in local recurrence rates between conventional WBI andhypofractionated WBI. (Registered with ClinicalTrials.gov, NCT00470236.) Citation Format: Boon Hui Chua, Emma Link, Ian Kunkler, Ivo Olivotto, Antonia Helen Westenberg, Timothy Whelan, Guenther Gruber, Breast International Group (BIG)-aisbl, Trans Tasman Radiation Oncology Group, Scottish Cancer Trials Breast Group, Canadian Cancer Trials Group, European Organization for Research and Treatment of Cancer, International Breast Cancer Study Group, Cancer Trials Ireland. A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01) [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 GS2-04.

Background Circulating levels of cancer antigen (CA) 15–3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15–3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer. Methods A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15–3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15–3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided. Results Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor–positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15–3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15–3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15–3 = 7.7% vs 2.0%, P .11). Conclusions Our observation that metformin reduces CA 15–3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15–3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.

Regional nodal irradiation for women with breast cancer is known to be an important risk factor for the development of upper extremity lymphedema, but tools to accurately predict lymphedema risks for individual patients are lacking. This study sought to develop and validate a nomogram to predict lymphedema risk after axillary surgery and radiation therapy in women with breast cancer.Data from 1832 women accrued on the MA.20 trial between March 2000 and February 2007 were used to create a prognostic model with National Cancer Institute Common Toxicity Criteria Version 2.0 grade 2 or higher lymphedema as the primary endpoint. Multivariable logistic regression estimated model performance. External validation was performed on data from a single large academic cancer center (N = 785).In the MA.20 trial cohort, 3 risk factors were predictive of lymphedema risk: body mass index (adjusted odds ratio, 1.05 per unit body mass index; 95% confidence interval [CI], 1.03-1.08, P.001), extent of axillary surgery (adjusted odds radio for 8-11 lymph nodes removed, 3.28 [95% CI, 1.53-7.89] P = .004; 12-15 lymph nodes, 4.04 [95% CI, 1.76-10.26] P = .002; ≥16 nodes, 5.08 [95% CI, 2.26-12.70] P.001), and extent of nodal irradiation (adjusted odds radio for limited, 1.66 [95% CI, 1.08-2.56] P = .02; for extensive, 2.31 [95% CI, 1.28-4.10] P = .004). A nomogram was created from these data that predicted lymphedema risk with reasonable accuracy confirmed by both internal (concordance index, 0.69; 95% CI, 0.64-0.74) and external validation (concordance index, 0.71; 95% CI, 0.66-0.76).The nomogram created from the MA.20 randomized trial data using clinical information may be useful for lymphedema screening and risk stratification for therapeutic intervention trials.

A better understanding underlying radiation (RT) response after breast-conserving surgery (BCS) is needed to mitigate over-treatment of DCIS. The hazard ratio (HR) measures the effect of RT but assumes the effect is constant over time. We examined the hazard function adjusted for adherence to surveillance mammography to examine variations in LR risk and the effect of RT over time. Crude hazard estimates for the development of LR in a population cohort of DCIS treated by BCS ± RT were computed. Multivariable extended Cox models and hazard plots were used to examine the association between receipt of RT and risk of each outcome adjusted for baseline covariates and adherence to mammography. Population cohort includes 3262 women treated by BCS; 1635 received RT. Median follow-up was 13 years. LR developed in 364 women treated by BCS alone and 274 treated with RT. LR risk peaked at 2 years, declined until year 7, and then remained steady. The peak hazard of LR was associated with adverse features of DCIS. Early LR risk was attenuated in patients treated with RT but late annual risks of LR and invasive LR were similar among the two treatment groups. On multivariate analysis, RT was associated with a reduction in early LR risk (HR = 0.52, 95% CI 0.43–0.63, p

Background: Black race is associated with worse outcomes in localized hormone receptor (HR)-positive breast cancer in population-based and in clinical trial cohorts, whether using self-identified race (Albain et al. JNCI 2009 [PMID: 19584328; Sparano et al. JNCI 2012 [PMID: 22250182) or genetically-identified race (Schneider et al. J Precision Oncol 2017 [PMID: 29333527]). This disparity persists after adjustment for treatment delivery parameters (Hershman et al. JCO 2009 [PMID:19307504]). We evaluated clinicopathologic characteristics, treatment delivered and clinical outcomes in the Trial Assigning Individualized Options for Treatment (TAILORx) by race and ethnicity (Sparano et al. NEJM 2018 [PMID: 29860917]). Methods: The analysis included 9719 evaluable TAILORx participants. The association between clinical outcomes and race (white, black, Asian, other/unknown) and ethnicity (Hispanic vs. non-Hispanic) was examined, including invasive disease-free survival (iDFS), distant relapse-free interval (DRFI), relapse-free interval (RFI), and overall survival (OS). Proportional hazards models were fit including age (5 categories), tumor size (>2 cm vs. Results: The study population included 8189 (84%) whites, 693 (7%) blacks, 405 (4%) Asians, and 432 (4%) with other/unknown race. Regarding ethnicity, 7635 (79%) were non-Hispanic, 889 (9%) Hispanic, and 1195 (12%) unknown. There was no significant difference in RS distribution (p=0.22) in blacks compared with whites, or in median (17 vs. 17) or mean RS (19.1 vs. 18.2). There was likewise no difference in Hispanic vs. non-Hispanic ethnicity for RS distribution (p=0.72) or median (17 vs. 17) or mean RS (18.5 vs. 18.0). Black race (39% vs. 30%) and Hispanic ethnicity (39% vs. 30%) were both associated with younger age ( Race (black vs.white) and clinical outcomes in proportional hazards modelsClinical endpointEntire Population (N=693 black) Hazard ratio for eventRS 11-25 (N=471 black) Hazard ratio for eveniDFS1.33 (p=0.005)1.49 (p=0.001)DRFI1.21 (p=0.28)1.60 (p=0.02)RFI1.39 (p=0.02)1.80 (p Conclusions: In patients eligible and selected for participation in TAILORx, black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy. This adds to an emerging body of evidence suggesting a biologic basis or other factors contributing to racial disparities in HR-positive breast cancer that requires further evaluation. Citation Format: Albain K, Gray RJ, Sparano JA, Makower DF, Pritchard KI, Hayes DF, Geyer, Jr. CE, Dees EC, Goetz MP, Olson, Jr. JA, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge, Jr. GW. Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-07.

Background: Palbociclib is approved for treatment of ER+, HER2- ABC at a standard dose of 125 mg po daily 3 weeks on/1 week off (STD). We evaluated the efficacy, safety, quality of life (QOL) and compliance of a 100 mg continuous daily dose (CDD) of palbociclib based on modeling data that suggested efficacy and tolerability. Methods: Canadian Cancer Trials Group (CCTG) led a randomized phase II trial (CCTG MA38) to estimate the efficacy of palbociclib 100 mg po on CDD schedule (Arm 1) relative to 125 mg po STD schedule (Arm 2) with physician choice endocrine therapy. Eligible patients had ER+, HER2- ABC, post progression on first line metastatic endocrine therapy or progressed while on/within 12 months of completion of adjuvant endocrine therapy. One line of palliative chemotherapy in ABC was allowed. Stratification factors were: visceral metastases, duration of prior endocrine therapy and planned endocrine therapy. Primary Outcome measure was investigator reported PFS; secondary outcome measures included: RR, OS, safety (CTCAE V4.0), and QOL (EORTC QLQ-C30). The sample size was 180 to enable estimation of the HR between arms with the upper bound of the 90% CI 1.36 times the estimated HR and the lower bound is 0.74 times the estimated HR. Results: 180 patients were enrolled across Canada from Dec 2015 to Feb 2017. The database was locked April 16 2018 after prespecified PFS events reached at a median follow-up of 19 months for all patients. For the whole population: median age was 60.5 years (21% ≥ 70 years); ECOG 0/1 95%; postmenopausal 91%; visceral metastases 67%. Planned endocrine therapy: aromatase inhibitor 33%, fulvestrant 57%, tamoxifen 10%. Efficacy analyses CDD vs STD: PFS stratified univariate HR 0.93 (90% CI 0.66-1.30); multivariate Cox model analysis (covariates ECOG PS, age, histology, grade): HR 0.92 (90% CI 0.67-1.25). Median PFS CDD: 9.33 months (90% CI 6.93-13.90) and STD: 11.30 months (90% CI 8.08- 13.83) Secondary analyses CDD vs STD: OS stratified univariate HR: 1.07 (90% CI 0.67-1.69); multivariate HR 1.14 (90%CI 0.75-1.75); median OS for CDD: 20.73 months (90% CI 19.29-23.30) and 21.39 months (90% CI 19.65 to 26.68) for STD. RR and median duration of response: 11.1% vs 12.4% (p=0.84) and 126 vs 169 days (p=0.86), respectively. Palbociclib drug exposure CDD vs STD: median daily dose (mg) 87 vs 125; median dose intensity (mg/week) 571.2 vs 613.5; ≥ 90% planned dose intensity, 41% vs 54%. Dose modification (withhold and/or reduction) rate CDD vs STD for neutropenia was 70% vs 40%. Grade 3/4 neutropenia 69% vs 53%; febrile neutropenia 3% each arm. Non-hematological toxicity profiles were comparable for both arms. No significant differences were seen in QOL domains. Conclusion: Palbociclib is active and tolerable when administered on either a 100 mg CDD or a 125 mg STD schedule. CDD schedule had higher rates of grade 3/4 neutropenia and dose modifications. Post approval evaluation of alternate dosing schedules for targeted therapies provides useful information regarding drug activity, toxicity and adherence. Citation Format: Parulekar WR, Joy AA, Gelmon K, Mates M, Desbiens C, Clemons M, Taylor S, Lemieux J, Bartlett J, Whelan T, Ayoub J-P, Cescon D, Bordeleau L, Rahim Y, Winch C, Chen BE. Randomized phase II study comparing two different schedules of palbociclib plus second line endocrine therapy in women with estrogen receptor positive, HER2 negative advanced/metastatic breast cancer: CCTG MA38 (NCT02630693) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD1-10.

Purpose: PAM50-defined breast cancer intrinsic subtypes and risk-of-relapse (ROR) scores are prognostic and predictive of endocrine therapy, and some chemotherapy. We investigated the prognostic and predictive effect of PAM50 classifications by chemotherapy type. Methods: NCIC CTG MA.21 randomized 2104 patients to doxorubicin, cyclophosphamide and paclitaxel (AC/T); dose-intense cyclophosphamide, epirubicin and flurouracil (CEF); or dose-dense, dose-intense epirubicin, cyclophosphamide and paclitaxel (EC/T). Patients were ≤60 years, with node-positive or high-risk node-negative disease, with median 8-year follow-up. Intrinsic subtypes and ROR were determined from RNA extracted from formalin-fixed paraffinembedded sections by the NanoString PAM50 test. Univariate effects on relapse-free survival (RFS) were assessed with stratified log-rank test; multivariate analyses utilized stratified Cox regression. Results: Among 1094 cases completing PAM50 intrinsic subtyping, 27% were classified as luminal A, 23% luminal B, 18% HER2E, and 32% basal-like. CEF and EC/T were superior to AC/T (p=0.01). Higher continuous ROR was multivariately associated with worse RFS (p=0.03), although categorical ROR was neither prognostic nor predictive. Intrinsic subtypes had a significant multivariate prognostic effect on RFS (p=0.002). Compared with luminal A, hazard ratios were: luminal B=1.48 (95% CI= 0.92-2.37); HER2E=2.68 (95% CI=1.60-4.48); basallike=1.97 (95% CI=1.10-3.53). Intrinsic subtypes were not predictive of treatment benefit (AC/T vs EC/T+CEF); however, subgroup analysis indicated subtypes (non-luminal vs. luminal) were predictive of taxane benefit (EC/T vs. CEF; p=0.05). Conclusion: Both NanoString PAM50 subtypes and continuous ROR had significant prognostic effects on RFS for breast cancer patients treated with CEF, EC/T and AC/T. Non-luminal tumors differentially responded to EC/T (with taxane) over CEF.

Identification of women with DCIS who have a very low risk of local recurrence risk (LRR) after breast-conserving surgery (BCS) is needed to de-escalate therapy. We evaluated the impact of 10-year LRR estimates after BCS, calculated by the integration of a 12-gene molecular expression assay (Oncotype Breast DCIS Score®) and clinicopathological features (CPFs), on its ability to change radiation oncologists’ recommendations for RT after BCS for DCIS. Prospective cohort study of women with DCIS treated with BCS. Eligibility criteria were as follows: age > 45 years, tumor ≤ 2.5 cm, and margins ≥ 1 mm. Radiation oncologists provided 10-year LRR estimates without RT and recommendation for RT pre- and post-assay. Primary outcome was change in RT recommendation. 217 patients were evaluable, with mean age = 63 years, mean tumor size = 1.1 cm, and mean DCIS Score = 32; 140 (64%) were in the low-risk (

Purpose Metastatic epidural spinal cord compression (MESCC) is a devastating complication of advanced malignancy, which can result in neurologic complications and significant deterioration in overall function and quality of life. Most patients are not candidates for optimal surgical decompression and as a result, receive urgent 3D conformal radiotherapy (3DCRT) to prevent or attempt to reverse neurologic progression. Multiple trials indicate that response and ambulatory rates after 3DCRT are inferior to surgery. The advent of stereotactic body radiation therapy (SBRT) has created a method with which a “radiosurgical decompression” boost may facilitate improve outcomes for MESCC patients. Methods We are conducting a pilot study to investigate SBRT boost after urgent 3D CRT for patients with MESCC. The aim of the study is to establish feasibility of this two-phase treatment regimen, and secondarily to characterize post-treatment ambulation status, motor response, pain control, quality of life and survival. Discussion We describe the study protocol and present a case report of one patient. A quality assurance review was conducted after the first seven patients, and resultant dose-constraints were revised to improve safety and feasibility of planning through more conservative organ at risk constraints. There have been no severe adverse events (grade 3–5) to date. We have illustrated clinical and dosimetric data of an example case, where a patient regained full strength and ambulatory capacity. Conclusions Our study aims to determine if SBRT is a feasible option in addition to standard 3DCRT for MESCC patients, with the goal to consider future randomized trials if successful. Having a robust quality assurance process in this study ensures translatability going forward if future trials with multicenter and increased patient representation are to be considered. Trial registration clinicaltrials.gov; registration no. NCT03529708; https://clinicaltrials.gov/ct2/show/NCT03529708; First posted May 18, 2018.

PURPOSE Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI. METHODS Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors. RESULTS FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant. CONCLUSION Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.

Background Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. Methods The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Results Of 9719 eligible women with hormone receptor–positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Conclusions Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.

Importance The 21-gene assay recurrence score is increasingly used to personalize treatment recommendations for systemic therapy in postmenopausal women with estrogen receptor (ER)– or progesterone receptor (PR)–positive, node-positive breast cancer; however, the relevance of the 21-gene assay to radiotherapy decisions remains uncertain. Objective To examine the association between recurrence score and locoregional recurrence (LRR) in a postmenopausal patient population treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone. Design, Setting, and Participants This cohort study was a retrospective analysis of the Southwest Oncology Group S8814, a phase 3 randomized clinical trial of postmenopausal women with ER/PR-positive, node-positive breast cancer treated with tamoxifen alone, chemotherapy followed by tamoxifen, or concurrent tamoxifen and chemotherapy. Patients at North American clinical centers were enrolled from June 1989 to July 1995. Medical records from patients with recurrence score information were reviewed for LRR and radiotherapy use. Primary analysis included 316 patients and excluded 37 who received both mastectomy and radiotherapy, 9 who received breast-conserving surgery without documented radiotherapy, and 5 with unknown surgical type. All analyses were performed from January 22, 2016, to August 9, 2019. Main Outcomes and Measures The LRR was defined as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. Time to LRR was tested with log-rank tests and Cox proportional hazards regression for multivariate models. Results The final cohort of this study comprised 316 women with a mean (range) age of 60.4 (44-81) years. Median (interquartile range) follow-up for those without LRR was 8.7 (7.0-10.2) years. Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (hazard ratio [HR], 2.36; 95% CI, 1.02-5.45;P = .04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051). Conclusions and Relevance This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.

Introduction The purpose of this guideline is to offer recommendations on fractionation for whole breast irradiation (WBI) with or without a tumor bed boost and guidance on treatment planning and delivery. Methods and materials The American Society for Radiation Oncology (ASTRO) convened a task force to address 5 key questions focused on dose-fractionation for WBI, indications and dose-fractionation for tumor bed boost, and treatment planning techniques for WBI and tumor bed boost. Guideline recommendations were based on a systematic literature review and created using a predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength. Results For women with invasive breast cancer receiving WBI with or without inclusion of the low axilla, the preferred dose-fractionation scheme is hypofractionated WBI to a dose of 4000 cGy in 15 fractions or 4250 cGy in 16 fractions. The guideline discusses factors that might or should affect fractionation decisions. Use of boost should be based on shared decision-making that considers patient, tumor, and treatment factors, and the task force delineates specific subgroups in which it recommends or suggests use or omission of boost, along with dose recommendations. When planning, the volume of breast tissue receiving >105% of the prescription dose should be minimized and the tumor bed contoured with a goal of coverage with at least 95% of the prescription dose. Dose to the heart, contralateral breast, lung, and other normal tissues should be minimized. Conclusions WBI represents a significant portion of radiation oncology practice, and these recommendations are intended to offer the groundwork for defining evidence-based practice for this common and important modality. This guideline also seeks to promote appropriately individualized, shared decision-making regarding WBI between physicians and patients.

Background We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates. Methods The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively. Results Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results. Conclusions The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient.

Purpose: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses of radiotherapy benefits pre-dated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis utilized GEP information with individual-level data from seven clinical trials to evaluate the impact of omitting radiotherapy on recurrence and mortality. Patients and Methods: The pooled observational data included women who had undergone breast conservation surgery for stage I, ER+ and/or PR+/HER2- cancers with clinicopathologically estimated 21-Gene Recurrence Scores (RS) of ≤ 18, and did not receive chemotherapy (n= 1,684). The primary endpoint was 10-year invasive or DCIS recurrence free-interval (IRFI-DCIS), including breast cancer death and was estimated using adjusted Cox models. Secondary outcomes were breast-cancer specific and all-cause survival. Covariates included for all models were age, tumor size, grade, hormonal status, type of hormonal therapy, risk score, and trial. Results: Ten-year IRFI-DCIS was high (96.6% with radiotherapy vs. 91.6% without), for an absolute difference of 5%. Omission of radiotherapy (vs. radiotherapy) was associated with an overall adjusted hazard ratio of 2.6 (95% confidence interval 1.5-4.5) for any first event. There was only a significant increase in risk of loco-regional; not, distant recurrence, breast cancer–specific or overall survival. The effect of radiotherapy varied across subgroups, with lower first event rates for those with estimated RS of Conclusion: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest absolute increase in loco-regional recurrence, but does not appear to increase risk of distant recurrence or death. Citation Format: Jayasekera JC, Schechter C, Jagsi R, White J, Chapman J-AW, Whelan T, Sparano JA, Anderson SJ, Fyles A, Sauerbrei W, Zellars RC, Li Y, Song J, Julian T, Berry D, Feuer EJ, Luta G, Mandelblatt JS. Effects of radiotherapy on breast cancer outcomes among stage I, low-Recurrence risk, hormone-Sensitive breast cancer: Pooled analysis of individual data from phase III trials [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 P2-11-01.

PURPOSE/OBJECTIVE(S) APBI is the delivery of radiotherapy (RT) to the tumor bed after breast conserving surgery (BCS) often given over a week or less. An attractive approach to deliver APBI is by external beam 3DCRT or IMRT. Previous studies have suggested that external beam APBI delivered twice-a-day can lead to increased late effects and poor breast cosmesis. The objective of our trial was to determine if two doses for APBI given once-a-day over 1-week result in acceptable long-term morbidity. MATERIALS/METHODS Eligible patients were > 50 years with DCIS or invasive breast cancer < 3 cm treated by BCS with negative margins and negative axillary nodes. Consenting patients were planned to receive APBI with 3-5 non-coplanar fields using a 3DCRT or IMRT and randomized to 27.5Gy or 30Gy each given in 5 fractions once-a-day over 5-8 days. Cosmetic evaluation with the EORTC Cosmetic Rating System was performed at baseline and 2 years by: a study nurse directly assessing the breast, and a group of oncologists unaware of RT regimen assessing photographs. Patient assessment of cosmesis was also performed at 3 years. Patients were followed for toxicity using the NCI CTCAE and recurrence. The primary outcome was adverse cosmesis (fair or poor global score) by photographic assessment at 2 years. The rate of adverse cosmesis with standard whole breast irradiation was 17% in our previous trial. Based on this consideration and one-sided α of 5% for each group, the upper bound of a one-sided 95% (two-sided 90%) confidence interval (CI) had to be < 23% for the treatment to be acceptable; 140 patients were required for each group. The proportion of patients with adverse cosmesis at 2 years and cosmetic deterioration from baseline to 2 years (excellent/good to fair/poor) with corresponding two-sided 90% CIs were estimated using the Wilson score method. The proportion of patients with any late breast toxicity (edema, induration, and telangiectasia) grades 2-3 at 2 years and local recurrence (LR) were also determined. RESULTS Of the 281 patients: 139 were randomized to 27.5Gy and 142 to 30.0Gy. Median follow-up was 3 years. The mean age was 65 years; mean tumor size was 1.2cm. With respect to photographic assessment both schedules met our criteria for acceptability (Table 1). Adverse cosmesis assessed by nurse or patient and toxicity appeared to be less for 27.5Gy compared to 30Gy. No LRs were observed for 27.5Gy and one LR was observed for 30Gy. CONCLUSION According to the study design 27.5Gy and 30Gy resulted in acceptable cosmetic outcomes. In light of recent studies, the lower dose may be preferable in terms of late adverse effects but requires further evaluation.

Importance Early discontinuation of adjuvant endocrine therapy (ET) is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the recommended full 5 years of ET treatment. Objective To identify the association between early discontinuation of ET in the Trial Assigning Individualized Options for Treatment (TAILORx) and modifiable risk factors, polypharmacy, and types of additional medications such as antidepressants and opioids. Design, setting, and participants This post hoc analysis includes a subgroup of 954 patients with breast cancer in TAILORx, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer and started ET within a year of study entry. Analyses were conducted in the intent-to-treat population. Statistical analysis took place from January 15, 2020, to April 6, 2021. Main outcomes and measures Participants completed measures on cancer-related health-related quality of life including physical well-being and social well-being prior to initiating ET. Early discontinuation of ET was defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence. Kaplan-Meier estimates were used to calculate discontinuation, and Cox proportional hazards regression joint prediction models were used to analyze the association between rates of adherence to ET with patient-level factors. Results A total of 954 women (mean [SD] age, 56.6 [8.9] years) were included in this analysis. In a joint model, receipt of chemoendocrine therapy (vs receipt of ET only; hazard ratio [HR], 0.57; 95% CI, 0.35-0.92; P = .02) and age older than 40 years (vs ≤40 years; HR for 41-50 years, 0.39; 95% CI, 0.18-0.85; P = .02; HR for 51-60 years, 0.28; 95% CI, 0.13-0.60; P = .001; HR for 61-70 years, 0.40; 95% CI, 0.18-0.86; P = .02; and HR for >70 years, 0.23; 95% CI, 0.07-0.77; P = .02) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared with no history of depression (HR, 1.82; 95% CI, 1.19-2.77; P = .005), worse physical well-being compared with better physical well-being (HR, 2.12; 95% CI, 1.30-3.45; P = .002), and worse social well-being compared with better social well-being (HR, 1.94; 95% CI, 1.20-3.13; P = .006) were individually and significantly associated with a higher probability of early discontinuation of ET. Only antidepressant use at study baseline was associated with early discontinuation (HR, 1.87; 95% CI, 1.23-2.84; P = .003). Conclusions and relevance In this post hoc analysis of a randomized clinical trial, baseline patient-reported health-related quality of life components, such as poor social well-being, poor physical well-being, and comorbid depression, were significant risk factors for early discontinuation of endocrine therapies. These results support systematic screening for patient-reported outcomes and depressive symptoms to identify women at risk for discontinuation of ET. Trial registration ClinicalTrials.gov Identifier: NCT00310180.

Background We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. Methods Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. Results In pre-/peri-/early post-menopausal chemotherapy trials (N = 2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P = 0.85) after 5 years although it was associated with worse BCFI (P = 0.03) and DSS (P = 0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P = 0.01; 0.01) and OS (P = 0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N = 672), patients with higher baseline BMI had worse BCFI (P = 0.02) after 1 year, worse DSS (P = 0.05; 0.004) after 1 and 5 years and worse OS (P = 0.01) after 5 years. Increased BMI did not impact BCFI (P = 0.90) after 5 years, although it was associated with worse BCFI (P = 0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N = 8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P = 0.02) after 1 year. With the administration of trastuzumab (N = 1395) baseline BMI and BMI change did not significantly impact outcomes. Conclusions Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. Clinical Trials numbers CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573.

Background and purpose Radiation therapy (RT) for breast cancer has evolved considerably over the past two decades. A concise list of optimal care indexes is lacking. The purpose of this project was to generate a suite of quality of care indicators for breast cancer RT. Materials and methods A modified Delphi approach was used including a comprehensive literature and guideline review (1995–2015), an initial review of potential quality indicators (QIs) by a steering committee, a survey of Canadian Radiation Oncologists, and a face-to-face consensus development meeting with breast cancer experts to develop a list of breast RT quality indicators. Results The literature review identified 163 potential QIs, which was reduced to 73 by the steering committee. After all rounds of the Delphi process the final suite included 33 QIs. Of these, 28 (85%) received at least 80% acceptance from the Radiation Oncologists who participated in the final online survey. Conclusions A suite of measureable RT quality indicators to be considered during management of invasive breast cancer was developed. These indicators could be used to assess the quality and consistency of breast cancer RT practices.

Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples.VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels 181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels 222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables.237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (15μmol/L). At 6 months, one patient (metformin) had MMA0.4μmol/L and 3 (2 metformin, 1 placebo) had HC 15μmol/L.There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.

Background: Triple Negative Breast Cancer (TNBC) is often associated with a poor prognosis. However TNBC is a heterogeneous group of tumors and while some patients have a poor prognosis others appear to do well long-term. There are currently no clinical or pathologic tumor features that distinguish poor from good outcome. Some TNBCs have infiltration with immune cells and the degree of this infiltration correlates with prognosis. Objectives: 1) To comprehensively examine immune factors associated with outcome in a cohort of TNBC patients, and 2) to develop an immune gene signature that can stratify patients into low and high risk groups. Methods: We profiled RNA from 22 TNBCs (10 who had experienced a recurrence) from our institutional cohort using the PanCancer Immune Profiling Panel from NanoString. This panel consists of an extensive list of 770 genes designed to evaluate the immune microenvironment of tumors. The genes fall into a number of functional categories including; 1. Genes that identify specific immune cells, 2. Cytokines that promote an effective immune response and others that are associated with immunosuppression, 3. Chemokines, which attract immune cells into the tumor, 4. Genes that assess both the activation and inhibition of immune cell function, 5. Genes that identify tumor specific antigens. Analysis was performed in the nSolver Advanced Analysis Program. Results: Using unsupervised hierarchical clustering of genes that were highly differentially expressed, the tumors were classified into 3 immune groups with distinct clinical outcomes. Group 1 ('Immune Excluded'), consisted of tumors with the lowest levels of expression of the immune markers assessed, suggesting that these tumors have a low or absent immune infiltrate; 7 of 7 patients in this group recurred. Group 2 ('Immune Activated') contains tumors that had the highest levels of anti-tumoral immune cell genes and their activation markers. This we interpret to represent a tumor group with a robust anti-tumor immune response; 0 of the 6 patients in this group recurred. In comparison Group 3 ('Immune Low') had moderate to low levels of expression of the majority of immune genes assessed. This we interpret to represent a group of tumors with limited immune cells present; 3 of 9 patients in this group recurred. Lastly, when comparing scores for immune cells, patients that recurred had lower scores for cytotoxic cells, CD8 T cells, Th1 cells and B cells. Conclusion: In this pilot study high expression of anti-tumoral immune genes correlated with good outcome, whereas lower/absent expression of these genes correlated with poor outcome. We are currently extending these findings to our entire cohort of 180 TNBC patients. Citation Format: Gillgrass AE, Pond GR, Levine MN, Whelan TJ, Hassell JA, Bane AL. The immune response in triple negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-12-09.

Background and purpose: We report the long-term outcomes in patients enrolled in a multicenter randomized controlled trial comparing Intensity Modulated Radiation Therapy (IMRT) with standard wedge radiotherapy. Materials and methods: Trial participants were assessed to compare long-term side effects between treatment arms. The primary endpoint was chronic breast pain assessed by trained observers blinded to treatment allocation. Secondary endpoints included cosmesis and quality of life measures. Results: Median follow-up time was 9.8 years and 241 patients were available for assessment. There was no significant difference in chronic pain between treatment arms (OR = 0.74, range 0.432-1.271). There were also no differences for the secondary endpoints. Univariate and multivariate analyses identified young age (p = 0.013) and pain during RT (p < 0.001) to be associated with chronic pain. Acute moist desquamation was associated with late subcutaneous fibrosis (p = 0.003) and telangiectasia (p = 0.039). Pain during RT was associated with a long-term poorer self-assessed cosmetic outcome (p < 0.001) and quality of life (p < 0.001). Conclusions: Breast IMRT cannot be recommended for all patients to reduce long-term side effects. However, late toxicities were significantly correlated with acute side effects, which are increased in patients having poor dose distribution. Breast IMRT may hence be useful for selected patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies.

Randomized trials studying endocrine therapy (ET) with and without radiation therapy (RT) following breast-conserving surgery (BCS) have detected differences in local recurrence (LR) but not survival among elderly women with hormone receptor positive stage I breast cancer (BC). We assembled a population-based cohort of such women to examine the use and outcomes associated with or without the administration of adjuvant radiotherapy (RT) or ET. Women aged ≥ 65 years with stage I BC treated with BCS in Ontario between 2010 and 2016, their treatments and outcomes were ascertained using deterministic linkages of administrative databases. Multivariable Cox regression models were used to evaluate risks of ipsilateral LR and of any first in-breast event, categorizing women by their treatment. 5076 women were treated with BCS followed by RT + ET (n = 1964), RT alone (n = 1325), ET alone (n = 719), or no adjuvant treatment (n = 1068). Median follow-up was 5 years. LR occurred in 0.9% after adjuvant RT + ET, 1.4% after RT alone, 3.1% after ET alone, and 9.4% after BCS alone (p

Key Points Question Is adjuvant radiation associated with a reduction in breast cancer mortality in patients treated for ductal carcinoma in situ? Findings Using a matched approach in a large cohort of patients treated for ductal carcinoma in situ, treatment with lumpectomy and radiotherapy was associated with a significantly reduced risk of breast cancer–specific mortality compared with treatment with lumpectomy alone (hazard ratio, 0.77; 95% CI, 0.67-0.88) or mastectomy alone (hazard ratio, 0.75; 95% CI, 0.65-0.87). Meaning Adjuvant radiation is associated with a small but significant breast cancer survival benefit in patients with ductal carcinoma in situ that cannot be accounted for by enhancing local control., This cohort study uses data from the Surveillance, Epidemiology, and End Results (SEER) 18 database to compare rates of survival among women with ductal carcinoma in situ (DCIS) who were treated with radiotherapy after lumpectomy vs lumpectomy or mastectomy alone., Importance Patients with ductal carcinoma in situ (DCIS) are treated with radiotherapy to reduce their risk of local invasive recurrence after breast-conserving surgery. However, the association of radiotherapy with breast cancer survival in patients with DCIS has not yet been clearly established. Objective To determine the extent to which radiotherapy is associated with reduced risk of breast cancer mortality in a large cohort of patients treated for DCIS, using a propensity score–based matching approach. Design, Setting, and Participants This cohort study of women who had first primary DCIS diagnosed between 1998 and 2014 used data from the Surveillance, Epidemiology, and End Results 18 registries database. Information on age and year of diagnosis, ethnicity, income, tumor size, tumor grade, estrogen receptor status, all treatments (surgery and radiation), and outcomes (invasive local recurrence and death from breast cancer) was abstracted for 140 366 women diagnosed with first primary DCIS. Three separate comparisons were performed using 1:1 matching: lumpectomy with radiation vs lumpectomy alone; lumpectomy alone vs mastectomy; and lumpectomy with radiation vs mastectomy. Exposures Use of radiotherapy and/or extent of surgery. Main Outcomes and Measures Crude and adjusted 15-year breast cancer–specific mortality. Results Of the 140 366 patients with DCIS in the cohort (109 712 [78.2%] white; mean [SD] age, 58.8 [12.3] years), 35 070 (25.0%) were treated with lumpectomy alone, 65 301 (46.5%) were treated with lumpectomy and radiotherapy, and 39 995 (28.5%) were treated with mastectomy. The actuarial 15-year breast cancer mortality rate was 2.33% for patients treated with lumpectomy alone, 1.74% for patients treated with lumpectomy and radiation, and 2.26% for patients treated with mastectomy. The adjusted hazard ratios for death were 0.77 (95% CI, 0.67-0.88) for lumpectomy and radiotherapy vs lumpectomy alone (29 465 propensity-matched pairs), 0.91 (95% CI, 0.78-1.05) for mastectomy alone vs lumpectomy alone (20 832 propensity-matched pairs), and 0.75 (95% CI, 0.65-0.87) for lumpectomy and radiotherapy vs mastectomy (29 865 propensity-matched pairs). Conclusions and Relevance In patients with DCIS, treatment with lumpectomy and radiotherapy was associated with a significant reduction in breast cancer mortality compared with either lumpectomy alone or mastectomy alone. This suggests that the survival benefit of radiation is likely not due to local control, but rather to systemic effects.

Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor–positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor–positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.

Canadian Cancer Society Research Institute [021039, 015469]; National Cancer Institute [CA180888, CA189953, CA180828, CA13612, CA37981, CA077202, CA180863, CA67753, CA189805, CA16116, CA180802]; Canadian Cancer Trials Group [CA077202, CA180863]; ECOG-ACRIN Cancer Research Group [CA180820, CA21115]; Novartis Pharmaceuticals; Avon Foundation; AstraZeneca; Pfizer; Roche; Amgen; Novartis; Glaxo-SmithKline; Eisai; Genomic Health; NanoString; Genentech; BioMarin

This study aims to evaluate the reduction of cardiac radiation dose and volume with deep inspiration breath hold (DIBH) technique compared to free breathing (FB) in patients with left-sided breast cancer. The study also aims to evaluate whether the benefits of DIBH vary in patients who had whole breast radiotherapy (RT) after breast-conserving surgery (BCS) and those who had chest wall RT post-mastectomy (M). FB and DIBH plans were generated for 15 consecutive post-BCS patients and 17 post-M patients who underwent RT with DIBH using varian real-time position management (RPM) system. Cardiac shields were used in all post-BCS plans, provided that clinical treatment volume coverage was not compromised, while chest wall coverage took priority in post-M plans. The prescribed dose was 50 Gy in 25 fractions for the whole breast or the chest wall. Parameters of interest were cardiac V5, mean LAD dose, maximum LAD dose, and mean heart dose. The impact of DIBH was compared in post-BCS and post-M patients using paired t tests. To gauge clinically meaningful outcome, the proportion of patients with V5