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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.

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.

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.

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

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.

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.

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.

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.

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.

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

Introduction Breast cancer radiotherapy cures many women, but, as with other therapies, can cause late side-effects. Methods We undertook meta-analyses of individual patient data from the trials of breast cancer radiotherapy, relating various characteristics of the regimens tested to cause-specific mortality rate ratios (RRs) and second cancer incidence RRs. Doses to cardiac structures were calculated for trials with some heart disease death(s), lung doses were calculated for megavoltage trials with some lung cancer(s) in the second decade after radiotherapy, and oesophagus doses were calculated for megavoltage trials with some oesophageal cancer(s). Trial radiotherapy regimens were reconstructed for a woman with typical anatomy using virtual simulation and 3-dimensional CT planning (and, for a few regimens, manual planning). Results Information was available on 40,781 women in 75 evenly randomised comparisons of radiotherapy versus not. Median follow-up was 9.7 years and 20,345 died, 6064 without recurrence. Smoking information for included women was unavailable. Mean normal tissue radiation doses for irradiated women were: heart 6.3 Gy (range Allocation to radiotherapy increased non-breast-cancer mortality (RR=1.15, 95% CI 1.09–1.22, 2p Second cancer incidence was increased (RR=1.23, 1.12–1.36, 2p Conclusions Since these trials, normal tissue doses from breast cancer radiotherapy have at least halved so the excess relative risks will be at least halved. Background disease rates have also changed, so the absolute risks will be different for women today. Modelling the effects of such changes suggests that for women who have smoked throughout adult life and will continue smoking, even modern radiotherapy may cause an absolute lung cancer risk of a few per cent, making this the main late side-effect in smokers. However, for non-smokers (and ex-smokers) with healthy hearts who would, under current guidelines, be offered radiotherapy, the expected reduction in breast cancer mortality greatly outweighs any increase in other mortality. Citation Format: Taylor C, Correa C, Anderson S, Duane F, Ewertz M, Jagsi R, Pierce L, Swain S, Whelan T, Wang Z, Wang Y, Peto R, McGale P. Late side-effects of breast cancer radiotherapy: Second cancer incidence and non-breast-cancer mortality among 40,000 women in 75 trials. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-08.

7004 Background: The TAILORx study demonstrated women with an intermediate Oncotype DX score receive the same benefit with endocrine therapy (ET) compared to chemoendocrine therapy (CET). However, early discontinuation of adjuvant ET is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the full 5 years of recommended ET treatment. The aim of this study was to identify patient-level risk factors associated with early discontinuation of ET in the TAILORx study. Methods: TAILORx was coordinated by the ECOG-ACRIN Cancer Research Group. Participants were a subgroup of 954 women who completed additional measures on health-related quality of life (HRQoL) including endocrine symptoms (ES) physical well-being (PWB) and social well-being (SWB) prior to initiating ET, which categorized into three groups by tertile for analysis. All participants were diagnosed with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer who started ET within a year of study entry. Early discontinuation of ET, defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence, was assessed by clinician report. Rate of discontinuation was calculated using Kaplan-Meier estimates, and Cox-proportional hazards joint models were used to analyze the association between rates of adherence to ET with patient-level factors. Results: In a joint model, receipt of CET therapy (vs receipt of ET only; HR = .59, 95% CI .38-.94, p = .02) and age above 40 (versus age < = 40; HR = .30, 95% CI .14-.66, p = .003) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared to no history of depression (HR 1.82, 95% CI 1.19-2.77, p = 0.005), worse ES compared to better ES (HR 1.70, 95% CI 1.06-2.74, p = 0.03), worse PWB compared to better PWB (HR 2.12, 95% CI 1.30-3.45,p = 0.003), and worse SWB compared to better SWB (HR 1.94, 95% CI 1.20-3.13, p = 0.007) were individually and significantly associated with a higher probability of early discontinuation of ET, although none reached statistical significance when all were included in a joint model. Conclusions: Younger women are at risk for early discontinuation and modifiable characteristics such as HRQoL and history of depression are potential risk factors for early discontinuation of ET. These results support systematic screening for HRQoL and depressive symptoms to identify women at risk for discontinuation of ET. Clinical trial information: NCT00310180 .

The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score.We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death).Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25.Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).

Background Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses on effects of radiotherapy predated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis used GEP information with pooled individual-level data to evaluate the impact of omitting radiotherapy on recurrence and mortality. Methods We considered trials that evaluated or administered radiotherapy after lumpectomy in women with low-risk breast cancer. Women included had undergone lumpectomy and were treated with hormonal therapy for stage I, ER+ and/or PR+, HER2- breast cancer with Oncotype scores no greater than 18. Recurrence-free interval (RFI), type of RFI (locoregional or distant), and breast cancer-specific and overall survival were compared between no radiotherapy and radiotherapy using adjusted Cox models. All statistical tests were two-sided. Results The final sample included 1778 women from seven trials. Omission of radiotherapy was associated with an overall adjusted hazard ratio of 2.59 (95% confidence interval [CI] = 1.38 to 4.89, P = .003) for RFI. There was a statistically significant increase in any first locoregional recurrence (P = .001), but not distant recurrence events (P = .90), or breast cancer-specific (P = .85) or overall survival (P = .61). Five-year RFI rate was high (93.5% for no radiotherapy vs 97.9% for radiotherapy; absolute reduction = 4.4%, 95% CI = 0.7% to 8.1%, P = .03). The effects of radiotherapy varied across subgroups, with lower RFI rates for those with Oncotype scores of less than 11 (vs 11-18), older (vs younger), and ER+/PR+ status (vs other). Conclusions Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but does not appear to increase the rate of distant recurrence or death.

Purpose The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (BC) is unknown. Patients and Methods The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. Results From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). Conclusion As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

Regional nodal irradiation as a component of both postmastectomy and postlumpectomy radiation has been shown in numerous randomized trials and meta-analyses to have a significant impact on locoregional control, breast cancer mortality, and, in some cases, overall survival. A recent meta-analysis of postmastectomy radiation demonstrated a breast cancer mortality benefit in patients with involved axillary nodes, independent of the use of chemotherapy or the number of nodes involved. From a more current era, two recently reported randomized trials also demonstrated a benefit to regional nodal irradiation in early-stage breast cancer in which the majority of patients had one to three involved nodes or high-risk/medial location node-negative disease. These trials included patients who had undergone lumpectomy or mastectomy, and patients were randomly assigned to breast/chest wall irradiation alone or to breast/chest wall irradiation plus regional nodal irradiation. In both trials, radiation to the nodes was directed at the internalmammary, supraclavicular, and undissected levels II to III lymph nodes. Although neither trial reached the primary goal of demonstrating statistically significant improved survival, they both reported an improvement in disease-free and distant metastasis–free survival with regional nodal irradiation. The European Organisation for the Research and Treatment of Cancer (EORTC) trial demonstrated a nearly significant improvement in survival and a significant improvement in breast cancermortality, whereas theMA.20 trial demonstrated a survival improvement in a prespecified subgroup of patients who had hormone receptor–negativedisease. Because, in both studies, all regional lymphatics were targeted, the relative benefit specific to internal mammary irradiation could not be determined. Although controversies about the selection of patients for regional nodal irradiation remain, there is general consensus and acceptance of the fact that the risks and benefits of regional nodal irradiation should be discussed and considered in appropriately selected patients. However, significant debate and wide variability in practice persist regarding radiation field design and the relative benefit of targeting the internal mammary nodes. The retrospective data, both supporting and refuting the benefits of internal mammary radiation, suffer from the usual limitations of such studies, including selection biases, heterogeneous patient populations, variability of treatment over time, and other confounding factors that cannot be accounted for in retrospective series. Arguments against internal mammary irradiation and barriers to its use point to potential added cardiac and pulmonary toxicity with larger irradiated volumes, increased complexity of treatment setup, and low rates of detectable internal mammary recurrences. Proponents of internal mammary irradiation would argue that all prospective, randomized trials that demonstrated the benefits of regional nodal irradiation routinely included internal mammary irradiation and that, therefore, one cannot exclude specific targeting of the internal mammary nodes as a contributing factor to the improved outcomes reported in these studies and meta-analyses. In addition, with modern radiation treatment planning and the use of a wide range of radiation treatment modalities and techniques—including three-dimensional conformal techniques, intensity-modulated radiation therapy, combination of photons and electrons, deep inspiration breath holding, and even proton beam therapy in selected cases— acceptable radiation doses to the critical cardiac and pulmonary organs at risk for toxicity can be achieved in the majority of patients. These doses lead to an acceptably low risk for toxicity, such that the potential benefit outweighs the potential risks. One recently published randomized trial, which patients who received postmastectomy radiation were specifically randomly assigned to radiation of the internal mammary nodes or not showed an insignificant improvement in survival of 3.3%, from 59.3% to 62.6%, at 10 years in the group randomly assigned to internal mammary radiation. That trial, however, had a number of major limitations. There was, at the time of the study design, an overestimation of the degree of internal mammary involvement, and the number of patients to be included was estimated to detect a 10% difference in survival at 10 years. In retrospect, this was too optimistic, given subsequent meta-analysis that demonstrated a smaller 5% improvement in overall survival at 15 years with any postmastectomy radiation. Furthermore, the actual survival rate observed in the trial was considerably greater than the original design’s expected survival rate. Because of this, the trial was underpowered, and the authors acknowledged that the trial could not rule out a smaller, more realistic potential benefit in survival; they concluded that “we cannot reliably recommend for or against internal mammary irradiation after mastectomy.” In the article that accompanies this editorial, Thorsen et al report the results of the Danish Breast Cancer Cooperative Group (DBCG) internal mammary node (IMN) study, an important

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials yielded rate ratios (RRs) for second primary cancers and cause-specific mortality and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (and ex-smokers), the benefits of radiotherapy far outweigh the risks. Hence, smoking can determine the net effect of radiotherapy on mortality, but smoking cessation substantially reduces radiotherapy risk.

The 15th St. Gallen International Breast Cancer Conference 2017 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Treatments were assessed in light of their intensity, duration and side-effects, seeking where appropriate to escalate or de-escalate therapies based on likely benefits as predicted by tumor stage and tumor biology. The Panel favored several interventions that may reduce surgical morbidity, including acceptance of 2 mm margins for DCIS, the resection of residual cancer (but not baseline extent of cancer) in women undergoing neoadjuvant therapy, acceptance of sentinel node biopsy following neoadjuvant treatment of many patients, and the preference for neoadjuvant therapy in HER2 positive and triple-negative, stage II and III breast cancer. The Panel favored escalating radiation therapy with regional nodal irradiation in high-risk patients, while encouraging omission of boost in low-risk patients. The Panel endorsed gene expression signatures that permit avoidance of chemotherapy in many patients with ER positive breast cancer. For women with higher risk tumors, the Panel escalated recommendations for adjuvant endocrine treatment to include ovarian suppression in premenopausal women, and extended therapy for postmenopausal women. However, low-risk patients can avoid these treatments. Finally, the Panel recommended bisphosphonate use in postmenopausal women to prevent breast cancer recurrence. The Panel recognized that recommendations are not intended for all patients, but rather to address the clinical needs of the majority of common presentations. Individualization of adjuvant therapy means adjusting to the tumor characteristics, patient comorbidities and preferences, and managing constraints of treatment cost and access that may affect care in both the developed and developing world.

TPS602 Background: Biomarker low risk, ER positive (+), HER2 negative (-) breast cancer with low burden nodal involvement may be associated with good outcomes (Woodward 2016, Mamounas 2017). There is conflicting data regarding the efficacy of regional radiotherapy after breast conserving surgery (BCS) or mastectomy in these patients (Kyndi 2008, Whelan 2015, Poortmans 2015, Liu 2015). Our hypothesis is that the risk of recurrence in patients with biomarker low risk, ER+, Her2- breast cancer and involvement of 1-3 lymph nodes where regional RT is omitted will not be inferior to the risk of recurrence in patients treated with regional RT. Methods: MA39 is a Canadian Cancer Trials Group led, NCTN sponsored, randomized phase III study comparing breast cancer recurrence free interval (BCRFI) in patients with ER+, Her2-, LN 1-3+ breast cancer that is low risk as defined by Oncotype Dx Recurrence Score < 18. Secondary objectives include a comparison of DFS, breast cancer mortality, OS, locoregional and distant recurrence free intervals, toxicity, arm volume and mobility measurements, patient reported outcomes and cost effectiveness. Key eligibility criteria include: age ≥ 40 years; BCS or mastectomy with axillary dissection and 1-3 positive axillary nodes; BCS and SLNB alone and 1-2 positive axillary nodes; mastectomy and SLNB alone and only 1 positive axillary node; planned endocrine therapy ≥ 5 years; adjuvant chemotherapy allowed. Statistical design: The primary analysis will be a test of non-inferiority (NI) in the intention to treat population. If the upper bound of a one-sided 95% interval for the hazard ratio for BCRFI is < 1.4, NI will be declared. Using a one-sided α of 0.05 and a power of 87%, it is anticipated that 278 events are required. With an expected 5 years of accrual and 4.5 years of follow-up, 2140 patients are needed for the final sample size. Conduct to Date: Study activation May 30 2018. Participation as of February 2019: Registrations 64 Randomizations 26. CIRB approval for continuation of MA.39 was received on January 11 2019. Clinical trial information: NCT03488693.

529 Background: The effect of metformin on sex hormones (SHs) levels that may impact breast cancer (BC) outcome, is unclear. We evaluated the effect of metformin on SHs in a subgroup of women enrolled in the placebo-controlled MA.32 trial, a phase III randomized study of nondiabetic subjects with T1-3, N0-3 BC randomized to receive metformin 850 mg po bid or placebo for 5 years. Methods: Our substudy was conducted on the group of post-menopausal women with estrogen receptor (ER) and progesterone receptor (PR) negative BC and not receiving endocrine treatment enrolled in the trial. Post-menopausal was defined as prior bilateral oophorectomy or > 12 months since last menses without prior hysterectomy. Fasting blood and adherence to study drug at baseline and 6 months was required. Sex hormone binding globulin (SHBG), free testosterone and estradiol serum levels were evaluated using Roche Modular competitive ECLIA (electrochemiluminescense immunoassay). We compared change from baseline to 6 months in estradiol, SHBG and free testosterone between study arms using Wilcoxon sum rank tests and regression models to adjust for baseline BMI and weight change. Results: 304 women were eligible, 135 metformin vs 169 placebo; tumor stage and prior (neo)adjuvant chemotherapy (98% in both arms) and HER2 targeted treatment were well balanced between arms. At baseline mean age was 58.2±6.9 vs 57.6±7.9 years, mean BMI 26.9±4.9 vs 28.6±6.2 Kg/m2, median estradiol 29.82 vs 31.01 pmol/L, SHBG 80.6 vs 73.7 nmol/L and free testosterone 0.02 vs 0.03 nmol/L in metformin vs placebo patients, respectively. In univariable analysis, median estradiol decreased significantly between baseline and 6 months on the metformin vs placebo arm (-4.81 vs 0 pmol/L, p = < 0.0001); this difference remained significant after controlling for baseline BMI (p = 0.0001) and weight change (mean weight change -1.8±3.5 vs 0.4±3.5 Kg, p = < 0.0001 for metformin vs placebo respectively) between baseline and 6 months (p = 0.0007). In contrast, there was no significant change in SHBG or free testosterone (median change SHBG -5.5 vs -5.9 nmol/L, p = 0.33; median change free testosterone 0 vs 0 nmol/L, p = 0.33 for metformin vs placebo respectively). Conclusions: Metformin lowered estradiol levels, independent of weight change in non-diabetic post-menopausal women with ER and PR negative BC enrolled onto MA.32 trial. This observation suggests a new metformin action that has potential relevance to BC management.

Background Whole breast irradiation (WBI) after lumpectomy reduces the risk of local recurrence, thereby avoiding subsequent mastectomy. It is a key component of breast conserving therapy. WBI is usually given in daily fractions over 3-6 weeks. With accelerated partial breast irradiation (APBI), radiation is delivered over a week or less to the surgical cavity with a margin of normal tissue. It was introduced to provide treatment in a shorter more convenient form. 3D-CRT is an attractive approach as it is non-invasive and uses standard techniques for external beam RT that are widely available. The objective of the RAPID trial was to determine if APBI using 3D-CRT was not inferior to WBI following breast conserving surgery (BCS). Methods Women ≥40 years of age with axillary node-negative invasive ductal carcinoma, or ductal carcinoma in situ (DCIS) ≤3cm treated by BCS with clear margins of excision were eligible. Randomization was stratified for age (< or ≥50y), histology (DCIS alone or invasive breast cancer), tumor size (< or ≥1.5cm), ER status (+/-) if invasive disease, and treatment center. Patients were allocated to APBI using 3D-CRT (38.5Gy in 10 fractions delivered twice daily) or WBI (42.5Gy in 16 daily fractions or 50Gy in 25 daily fractions; boost radiation was permitted). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Important secondary outcomes included radiation toxicity and nurse assessed adverse cosmesis (fair or poor on global assessment). The trial was designed to show that the 5-year IBTR rate in the APBI arm was not inferior to the WBI arm by more than 1.5% (hazard ratio [HR] ≤ 2.02) with 85% power and a one-sided alpha of 5%. Results From February 2006 to July 2011, 2135 patients from sites in Canada, Australia, and New Zealand were randomly assigned: 1070 to APBI and 1065 to WBI. The median follow-up was 8.6 years. The mean age of the study population was 61 years; 82% of patients had invasive breast cancer and 18% had DCIS only. For invasive cancers: 60% were < 1.5cm and 90% were ER positive. For DCIS tumors: 68% were < 1.5cm. A total of 65 IBTRs were observed. For the APBI patients, the 5-year and 8-year cumulative rates of IBTR were 2.3% and 3.0%, respectively. The corresponding data for the WBI patients were 1.7% and 2.8%. The HR for APBI versus WBI was 1.27, 90% confidence interval, 0.84 to 1.91. Acute radiation toxicity (occurring within 3 months of treatment start) e.g. radiation dermatitis and breast swelling was less in patients treated with APBI compared with WBI (≥ Grade 2, 28% vs 45%, p Conclusions The APBI regimen used in our trial was non-inferior to WBI in preventing local recurrence. Although it was associated with less acute toxicity, an increase in late normal tissue toxicity and adverse cosmesis was observed with APBI. Citation Format: Whelan T, Julian J, Levine M, Berrang T, Kim D-H, Gu CS, Germain I, Nichol A, Akra M, Lavertu S, Germain F, Fyles A, Trotter T, Perera F, Balkwill S, Chafe S, McGowan T, Muanza T, Beckham W, Chua B, Olivotto I. RAPID: A randomized trial of accelerated partial breast irradiation using 3-dimensional conformal radiotherapy (3D-CRT) [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 GS4-03.

Partial breast irradiation was introduced to reduce treatment times, improve convenience of radiotherapy and reduce radiation exposure to the breast and surrounding normal tissues. A number of techniques have been developed including interstitial brachytherapy, single catheter-based brachytherapy, intraoperative therapy, and 3 dimensional conformal or intensity modulated radiotherapy. The toxicity profile of partial breast irradiation has been dependent on the different techniques used. In general acute toxicity has been less than that observed with whole breast irradiation, particularly for intraoperative approaches where radiotherapy is delivered at the time of breast conserving surgery. Reports of late toxicity have varied. The majority of trials have observed no increase in late toxicity with interstitial brachytherapy and intraoperative treatment when compared to whole breast irradiation. Some studies of 3D conformal radiotherapy have reported an increase in late radiation toxicity such as telangiectasia of the skin and subcutaneous fibrosis of the breast. Limited data are available on cosmetic outcome and quality of life. Again, results to date have varied with some studies reporting similar cosmetic results and others indicating an increase in adverse cosmesis with partial breast irradiation when compared to whole breast irradiation. This presentation will review mature results from completed trials and discuss radiobiological inferences and implications for clinical decision making. Citation Format: Whelan T. Treatment morbidity and quality of life considerations [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 ES4-2.

Background There is uncertainty as to which lymph node regions should be irradiated following breast cancer surgery. Systematic review of radiation dosimetry indicates that in randomised trials of nodal radiation therapy (RT) versus not, radiation delivery was qualitatively better in modern trials compared to older trials. Methods We undertook an individual patient data meta–analysis of randomised trials assessing the benefits and risks of RT to different lymph node regions including the axilla, supraclavicular fossa (SCF) and internal mammary chain (IMC). Eligible studies started before 2009, and included a randomisation, or pseudo–randomisation (by left–versus–right sided tumours), in which the only difference between treatment groups was the use, or extent, of nodal irradiation. Surgery/RT to the breast was the same in both arms. Analyses used standard log–rank methods, and were stratified by study, age, nodal status and year of follow–up. – Studies were categorised according to estimated mean heart dose in the nodal RT arm and whether regimens were likely to have delivered ≥85% of prescribed dose to target nodal regions. Results Information was available on 13,132 women in 14 comparisons of nodal RT versus not. There were 3260 recurrences, 2545 deaths from breast cancer and 4147 deaths overall. Eight trials starting 1961–1978, with median follow–up 9.2 (interquartile [IQR] range 3.4–17.5) years, had estimated >8 Gy mean heart dose and likely nodal dose Six studies starting 1989–2003, with a mean follow–up 9.1 [IQR 7.0–11.0] years, had likely nodal dose ≥85%, and estimated mean heart dose Conclusions RT to regional lymph nodes in older (1961–78) studies increased the overall risk of death, probably explained by radiation exposure of the lungs and heart. Nodal RT in more recent (1989–2003) studies reduced breast cancer recurrence, breast cancer mortality and overall mortality without increasing non–breast cancer mortality. The proportional benefits from today's RT may be larger. Absolute benefits for individual women will depend on their absolute recurrence and breast cancer mortality risks. Citation Format: Dodwell D, Taylor C, McGale P, Coles C, Duane F, Gray R, Kühn T, Hennequin C, Oliveros S, Wang Y, Overgaard J, Poortmans P, Whelan T. Regional lymph node irradiation in early stage breast cancer: An EBCTCG meta-analysis of 13,000 women in 14 trials [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 GS4-02.

Background: TAILORx patient-reported outcomes (PRO) quantify symptoms and health-related quality of life (HRQL) from C+E beyond E alone from the patient's perspective, thus can inform decision-making for women in the intermediate risk group for whom chemotherapy may still be considered. Methods: TAILORx participants with OncoType DX Recurrence Scores 11-25 were randomly assigned to E or C+E. All TAILORx participants enrolled 1/2010-10/2010 (N=612) completed PROs measuring fatigue, endocrine symptoms, cognitive impairments (PCI), and fear of recurrence at baseline, 3, 6, 12, 24 and 36 months. HRQL was assessed at baseline, 12, and 36 months. Linear regression (LR) examined PRO scores among the per-protocol sample. Results: Overall, participants reported significantly more fatigue, endocrine symptoms and PCI at 3, 6, 12, 24 and 36 months compared to baseline and those randomized to C+E reported a greater magnitude of change baseline-3 months compared to those randomized to E alone (Table 1). Overall, by 12 months symptoms were comparable between groups. Pre-menopausal women had comparable symptoms at 24 and 36 months. Post-menopausal women randomized to C+E had greater endocrine symptoms at 24 and 36 months and greater fatigue at 6 and 24 months. Fear of recurrence was comparable between arms during treatment and follow-up. Multiple linear regression identified increased fatigue (LR slope β=0.67), endocrine symptoms (β =0.14), and PCI (β=0.11) as significant predictors of decreased HRQL across arms (p< 0.001). HRQL was comparable between E and C+E at 12- and 36-months. Mean PRO change scores from baseline by treatment arm and menopausal status in per protocol population Months 36122436N=Overall454469458384343n=Pre-menopausal153151150118103n=Post-menopausal301318308266240FACIT-Fatigue Overall sample C+E-8.77-4.37-4.01-4.27-3.67E-2.48-1.97-2.14-1.49-1.83LMED-5.32***-1.55-1.01-1.76-0.90Pre-M C+E-8.01-3.26-2.99-2.45-1.60E-3.87-1.66-1.32-2.52-2.11LMED-3.11-0.82-1.121.021.46Post-M C+E-9.22-4.97-4.55-5.14-4.67E-1.87-2.10-2.52-1.09-1.71LMED-6.42***-1.99*-1.16-3.02*-2.01FACT-Endocrine Symptoms Overall sample C+E-5.56-5.63-6.96-6.81-7.14E-3.61-4.24-5.62-5.31-5.17LMED-1.62*-0.97-1.08-1.05-1.69Pre-M C+E-7.62-8.34-7.94-8.29-8.96E-5.96-6.19-8.95-10.39-10.84LMED-1.44-1.631.062.272.18Post-M C+E-4.39-4.19-6.45-6.10-6.28E-2.55-3.41-4.10-3.23-2.87LMED-1.49-0.45-2.04-2.39*-3.17**Significance between mean change scores *p Conclusions: TAILORx is the first trial to examine patient-reported fatigue, endocrine symptoms, PCI and HRQL among breast cancer patients randomized to endocrine therapy alone vs chemoendocrine therapy, thus allowing us to quantify acute and long-term symptoms uniquely attributable to chemotherapy. As expected, chemotherapy is associated with greater fatigue, endocrine symptoms and PCI acutely during treatment, and for post-menopausal women with greater long-term endocrine symptoms. Increased symptoms were associated with poorer HRQL. Long-term HRQL was comparable between groups. Citation Format: Wagner LI, Gray RJ, Garcia S, Whelan TJ, Tevarweerk A, Yanez B, Carlos R, Gareen I, McCaskill-Stevens W, Cella D, Sparano JA, Sledge, Jr. GW, On behalf of the TAILORx Study Team. Symptoms and health-related quality of life on endocrine therapy alone (E) versus chemoendocrine therapy (C+E): TAILORx patient-reported outcomes results [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 GS6-03.

With the emergence of radiosurgery as a new radiotherapeutic technique, health care decision makers are required to incorporate community need, cost and patient preferences when allocating radiosurgery resources. Conventional patient utility measures would not reflect short term preferences and would therefore not inform decision makers when allocating radiosurgery treatment units. The goal of this article is to demonstrate the feasibility of cost-benefit analysis to elicit the yearly net monetary benefit of robotic radiosurgery. To calculate the yearly incremental cost of robotic radiosurgery as compared to fixed gantry radiosurgery we used direct local cost data. We assumed a standard 10 year replacement and 5% amortization rate. Decision boards summarizing the clinical scenario of brain metastases and the difference between robotic and fixed gantry radiosurgery in terms of immobilization, comfort and treatment time were then presented to a sample of 18 participants. Participants who preferred robotic radiosurgery were randomly assigned to either a low ($1) or high ($5) starting point taxation based willingness-to-pay algorithm. The yearly incremental cost of providing robotic radiosurgery was $99,177 CAD. The mean community yearly willingness-to-pay for robotic radiosurgery was $2,300,000 CAD, ρ = 0.03. The calculated yearly net societal benefit for robotic radiosurgery was $2,200,823 CAD. Among participants who preferred robotic radiosurgery there was no evidence of starting point bias, ρ = 0.8. We have shown through this pilot study that it is feasible to perform cost-benefit analysis to evaluate new technologies in Radiation Oncology. Cost-benefit analysis offers an analytic method to evaluate local preferences and provide accountability when allocating limited healthcare resources.

Purpose The optimal fractionation schedule of post lumpectomy radiation therapy remains controversial. The objective of this study was to describe the fractionation of post-lumpectomy radiation therapy (RT) in Ontario, before and after the seminal Ontario Clinical Oncology Group (OCOG) trial, which showed the equivalence of 16- and 25-fraction schedules. Methods and Materials This was a retrospective cohort study conducted by linking electronic treatment records to a population-based cancer registry. The study population included all patients who underwent lumpectomy for invasive breast cancer in Ontario, Canada, between 1984 and 2008. Results Over the study period, 41,747 breast cancer patients received post lumpectomy radiation therapy to the breast only. Both 16- and 25-fraction schedules were commonly used throughout the study period. In the early 1980s, shorter fractionation schedules were used in >80% of cases. Between 1985 and 1995, the proportion of patients treated with shorter fractionation decreased to 48%. After completion of the OCOG trial, shorter fractionation schemes were once again widely adopted across Ontario, and are currently used in about 71% of cases; however, large intercenter variations in fractionation persisted. Conclusions The use of shorter schedules of post lumpectomy RT in Ontario increased after completion of the OCOG trial, but the trial had a less normative effect on practice than expected.

Withdrawn by Author Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-02.

Background: In 2000, cyclophosphamide(C), epirubicin(E) and fluorouracil (F) (CEF) and doxorubicin (A) and C followed by paclitaxel (T) (AC/T) given every three weeks were commonly used regimens in Canada and the USA to treat women with node positive or high risk node negative operable breast cancer. In a previous trial in women with locally advanced breast cancer, 3 months of dose-dense EC was equivalent to six months of CEF. We hypothesized that the addition of 3 months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. In a randomized trial in women with early breast cancer we compared CEF, dose dense EC/T and AC/T. An interim analysis (JCO, 2010) conducted when 50% of the events for the relapse-free-survival (RFS) analysis were observed, demonstrated that AC/T administered every 3 weeks was significantly inferior to CEF or EC/T. The results of the final RFS including CEF versus EC/T will be presented. Methods: Women, 60 years or younger, with operable axillary node positive or high risk node negative breast cancer were randomized to adjuvant CEF, EC/T or AC/T. CEF was given for 6 cycles and consisted of: C 75 mg/m2 orally on Days 1–14, and E 60 mg/m2 and F 500 mg/m2, IV on Days 1 and 8. CEF patients received concurrent antibiotic prophylaxis. EC/T consisted of 6 cycles of EC every 14 days; E 120 mg/m2 and C 830 mg/m2, both IV on Day 1 with filgrastim 5 [ug]/kg/day subcutaneous from Days 2–13 and epoetin alpha 40,000 units subcutaneous once weekly. After completion of EC, 4 cycles of T 175 mg/m2 every 21 days with filgrastim and epoetin alpha were given. The AC/T regimen consisted of A 60 mg/m2 and C 600 mg/m2 IV every 21 days for 4 cycles. This was followed by T 175 mg/m2 every 21 days for 4 cycles. The final analysis for RFS was planned when 453 events were observed permitting the detection of a hazard ratio (HR) of 1.43 between CEF and AC/T and a HR of 1.43 between EC/T and the best of the other two arms. Quality of Life data using the EORTC C-30 and the Breast Cancer Chemotherapy questionnaires were collected throughout the study. The results will be available at the time of the presentation. Results: A total of 2104 women were enrolled between December 2000 and April 2005. The required 453 events for the RFS analysis were observed by the clinical cut-off date of March 30, 2012. At this point 369 deaths had been observed. The median follow-up is 87.5 months. Outstanding data and queries are currently being collected and reviewed with an expected database lock and final analysis mid August, 2012. Febrile neutropenia remains higher on the CEF and EC/T arms while more neuropathy was seen in the taxane containing regimens. Conclusions: Although the two regimens considered a standard of care at the time the study was initiated are no longer widely used, the trial results will enhance our understanding of the magnitude of benefit of taxane following an anthracycline, the significance of cumulative anthracycline dose, and the role of dose density/ intensity as backbone of conventional chemo regimens. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-01.

Purpose A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). Methods A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. Recommendations The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer–specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

To develop a patient decision aid (PtDA) for older women with Stage I, pathologically node negative, estrogen receptor-positive progesterone receptor-positive breast cancer who are considering adjuvant radiotherapy after lumpectomy and to examine its impact on patients' decision making.A PtDA was developed and evaluated in three steps according to the Ottawa Decision Support Framework: (1) needs assessment (n = 16); (2) Pilot I to examine PtDA acceptability (n = 12); and (3) Pilot II, a pretest posttest (n = 38) with older women with estrogen receptor-positive progesterone receptor-positive breast cancer after lumpectomy who were receiving adjuvant radiation therapy. Measures included patients' satisfaction with the PtDA, self-reported decisional conflict, level of distress, treatment-related knowledge, and choice predisposition.The PtDA is a booklet that details each adjuvant treatment option's benefits, risks, and side effects tailored to the patient's clinical profile; includes a values clarification exercise; and includes steps to guide patients towards their decision. On the basis of qualitative comments and satisfaction ratings, all women thought that the PtDA was helpful and informative. In comparison with their baseline scores, patients had a statistically significant (p0.05) reduction in decisional conflict (adjusted mean difference [AMD], -7.18; 95% confidence interval [CI], -13.50 to 12.59); increased clarity of the benefits and risks (AMD, -10.86; CI, -20.33 to 21.49); and improved general treatment knowledge (AMD, 8.99; CI, 2.88-10.28) after using the PtDA. General trends were also reported in the patients' choice predisposition scores that suggested potential differences in treatment decision after PtDA use.This study provides evidence that this PtDA may be a helpful educational tool for this group of women. The quality of care for older breast cancer patients may be enhanced by the use of a tailored PtDA to help patients be better informed about their treatment options.

Background: Decision Aids (DA) are developed with the intent to support people in making specific and deliberate choices by improving information transfer about different outcomes. Previous research has shown that DAs can increase patient knowledge regarding treatment options, reduce decisional conflict, and increase patient satisfaction with the decision-making process. However, no DAs have been developed to help older breast cancer patients decide whether or not to undergo adjuvant RT. We developed and tested a DA for older women with stage I,ER/PR positive breast cancer considering adjuvant treatment post-lumpectomy and we examined its impact on treatment decision-making process. Methods and Materials: A DA was developed and evaluated in three steps following the Ottawa Decision Aid Framework: 1) Needs assessment (N=16); 2) Pilot I, to examine the DA's acceptability (N=12); and 3) Pilot II, a pre-test post-test (N=38) with older women with ER/PR responsive breast cancer post-lumpectomy who were receiving adjuvant RT. Measures included questionnaires to assess patient's satisfaction with the DA, patients’ self-reported decisional conflict (DC), level of distress, treatment-related knowledge, and choice predisposition Results: The DA is a booklet that details each adjuvant treatment option's benefits, risks and side-effects tailored to their clinical profile; includes a value clarification exercise; and steps to guide them towards their own treatment decision. All women felt the DA was helpful and informative. Compared with baseline scores, patients had a statistically significant (p < .05) reduction in DC (adjusted mean difference [AMD], −7.18; 95% confidence interval [CI], −13.50 to 12.59); increased clarity of the treatment benefits and risks (AMD, −10.86, CI, −20.33 to 21.49; and improved general treatment knowledge (AMD, 8.99, CI, 2.88 to 10.28) after using the DA. General trends were also reported in patient's choice predisposition scores suggesting potential differences in treatment decision after DA use. Discussion: This study provides evidence that this DA may be a helpful educational tool for this group of women. The quality of care for older breast cancer patients may be enhanced by using a tailored DA to help the patient be informed of their treatment options and to prepare for decision-making. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-15-03.