Ipsilateral Breast Tumor Recurrence Research Articles

Loco-regional outcomes of adjusted breast radiotherapy with conventional fractionation after breast conserving surgery: De-escalation of whole breast irradiation dose.

We compared the cumulative incidence of ipsilateral breast tumor recurrence (IBTR) between 2 whole breast irradiation (WBI) dose range with conventional fractionation.We retrospectively reviewed 1122 patients who received WBI at 2 institutions between 2004 and 2012. One institution delivered WBI 41.4 to 45 Gy followed by boost 14 to 18 Gy (adjusted group), while the other delivered WBI 50 to 50.4 Gy followed by boost 10 Gy (standard group).The median follow-up period was 85 months. The 10-year cumulative incidence in all patients was 6.1% (95% confidence interval [CI]: 4.3%–8.4%) for IBTR and 3.0% (95% CI: 1.7%–4.8%) for regional recurrence. The 10-year cumulative incidence of IBTR was not significantly influenced by WBI dose (6.3% in the adjusted group vs 5.2% in the standard group, P = .136). Comparable IBTR rates between the 2 groups were observed regardless of clinical and pathological factors. The WBI dose was not significantly associated with the 10-year cumulative incidence of regional recurrence in these groups (3.5% in the adjusted group vs 0.5% in the standard group, P = .214).De-escalated WBI doses while intensifying tumor bed boost did not compromise local and regional outcomes compared to standard group.

Multifocality in ipsilateral breast tumor recurrence - A study in ablative specimens

BackgroundThe incidence and clinical significance of multifocality in ipsilateral breast tumor recurrence (IBTR) after breast-conserving therapy (BCT) are unclear. With growing interest in repeat BCT, this information has become of importance. This study aimed to gain insight in the incidence of multifocality in IBTR, to identify patient- and tumor-related predicting factors and to investigate the prognostic significance of multifocality. MethodsTwo hundred and fifteen patients were included in this analysis. All had an IBTR after BCT and were treated by salvage mastectomy and appropriate adjuvant therapy. Predictive tumor- and patient-related factors for multifocality in IBTR were identified using X2 test and univariate logistic regression analyses. Prognostic outcomes were calculated using Kaplan Meier analysis and compared using the log rank test. ResultsMultifocality was present in 50 (22.9%) of IBTR mastectomy specimens. Axillary positivity in IBTR was significantly associated with multifocality in IBTR. Chest wall re-recurrences occurred more often after multifocal IBTR (14% versus 7% after unifocal IBTR, p = 0.120). Regional re-recurrences did not differ significantly between unifocal and multifocal IBTR (8% vs. 6%, p = 0.773). Distant metastasis after salvage surgery occurred more frequently after multifocal IBTR (15% vs. 24%, p = 0.122). Overall survival was 132 months after unifocal IBTR and 112 months after multifocal IBTR (p = 0.197). ConclusionThe prevalence of multifocality in IBTR is higher than in primary breast cancer. Axillary positivity in IBTR was associated with a multifocal IBTR. Chest wall re-recurrences and distant metastasis were, although not statistically significant, more prevalent after multifocal IBTR.

Aberrant Lymphatic Drainage in the Contralateral Axilla in Patients with Isolated Ipsilateral Breast Tumor Recurrence

The management and implications of aberrant lymphatic drainage in the contralateral axilla during repeat sentinel lymph node biopsy (SLNB) in patients with isolated ipsilateral breast tumor recurrence (IBTR) are not well understood. We analyzed the outcomes of contralateral SLNB in cases of isolated IBTR compared to ipsilateral SLNB. We conducted a retrospective review of cases reported at Samsung Medical Center between 1995 and 2015. All patients with isolated IBTR that underwent ipsilateral and contralateral SLNB with clinically negative lymph nodes but lymphatic drainage on the ipsilateral or contralateral axilla were included. Among 233 patients with isolated IBTR, 31 patients underwent repeat SLNB, 11 underwent ipsilateral SLNB, and nine underwent contralateral SLNB. None of the patients showed contralateral axillary metastasis in cases with isolated IBTR in the absence of clinically suspicious drainage on the contralateral axilla. Contralateral drainage was associated with a longer interval to IBTR (68.4 vs.18.6 months, p = 0.001) and the overall median follow-up duration (102.6 vs. 45.4 months, p = 0.002). There was no significant difference in the recurrence after the second operation (1 of 11 vs. 1 of 9, p = 1.000). Only one patient in both groups experienced recurrence after the second operation. Two patients (22.2%) who underwent contralateral SLNB had lymphedema. We demonstrate that no patient had contralateral metastasis in patients with isolated IBTR in the absence of clinically suspicious drainage in the contralateral axilla. Further study is warranted to better understand and optimize the management of these rare and challenging cases.

Efficacy of radiation boost after breast-conserving surgery for breast cancer with focally positive, tumor-exposed margins.

Many patients with positive margins following breast-conserving surgery (BCS) undergo re-excisions that aim to remove residual disease from the breast, which brings a tremendous emotional burden in addition to financial consequences. We sought to determine whether re-excisions could be safely avoided without compromising local control and survival by using whole-breast radiation therapy (WBRT) with a tumor bed boost in patients with early-stage breast cancer with focally positive, tumor-exposed margins after BCS. All patients with ductal carcinoma in situ (DCIS) and/or invasive breast cancer (IBC) who had pathologically tumor-exposed margins following BCS, without re-excision and treated with WBRT with tumor bed boost between March 2005 and December 2011, were included. The radiotherapy consisted of WBRT at a dose of 50 Gy in 25 fractions, followed by a tumor bed boost with an additional dose of 16 Gy in eight fractions. A total of 125 patients fulfilled the eligibility criteria; of the 125 patients, 1 had bilateral breast cancer, resulting in 126 cases. Invasive disease was found in 102 (81%) cases and purely ductal carcinoma in situ (DCIS) disease in 24 (19%) cases. The 10-year ipsilateral breast tumor recurrence (IBTR) -free survival, progression-free survival (PFS), and 10-year overall survival (OS) rates were 95%, 92.5% and 96%, respectively. Patients with early-stage breast cancer who receive BCS and have focally positive, tumor-exposed margins can avoid re-excision by undergoing WBRT followed by a sufficient dose of tumor bed boost, without negatively impacting local control and survival.

Abstract P2-16-27: Risk factors of ipsilateral breast tumor recurrence in primary breast cancer patients who achieved pathological complete response after neoadjuvant chemotherapy

Abstract Background: Pathologic complete response (pCR) is an early surrogate marker of long-term survival in human epidermal growth factor receptor 2-positive (HER2+) and triple negative breast cancer (TNBC). However, it is difficult to predict patients who should avoid breast-conserving therapy (BCT) even after achieving pCR by neoadjuvant chemotherapy (NAC) with respect to ipsilateral breast tumor recurrence (IBTR). We aimed to assess the risk of IBTR in pCR patients who underwent BCT after NAC. Patients and methods: We retrospectively reviewed clinicopathological characteristics of 178 TNBC or HER2+ primary breast cancer patients with pCR who underwent BCT after NAC in 2 institutes between 2002 and 2017. Histological type and grade were defined according to the World Health Organization classification system. Estrogen receptor (ER), progesterone receptor (PR), and HER2 status were determined from the surgical specimens. ER and PR were assessed by immunohistochemical staining. HER2 was considered positive if reported as 3+ on immunohistochemical staining or if those tumors reported as 2+ were amplified on fluorescence in situ hybridization (FISH). pCR was defined as no involvement of invasive ductal carcinoma in breast and lymph nodes. All patients who had node-positive before NAC had axillary lymph node dissection even if assessed as clinically node-negative after NAC (ycN0). The 5-year IBTR-free survival was estimated in each subtype. The risk factors of IBTR, including the age at diagnosis, clinical T-stage, clinical N-stage, histological grade, neoadjuvant regimen, pathological N-status, and postoperative chemotherapy, were estimated using the log-rank test for univariate analysis. P-values < 0.05 were considered statistically significant. Results: A median age of the 178 patients at diagnosis was 52 years (range, 30-72 years). At a median follow-up period of 5.4 years (range, 0.2-15.4 years), 5 patients (3%) had developed IBTR. Among the 178 patients, 82 patients had TNBC and 96 patients had HER2+ breast cancer. NAC with a combination of anthracycline and taxane regimens was sequentially delivered to 163 of the 178 patients (92%). In 96 HER2+ patients, trastuzumab containing regimen were done in 69 (72%) in NAC setting and 79 (82%) in adjuvant setting. Sentinel lymph node biopsy without axillary lymph node dissection was performed 98 (55%) of the patients. Seventy-nine (44%) had received axillary lymph node dissection. Subtype (ER+/HER2+, ER-/HER2+, or TNBC) after achieving pCR was not associated with 5-year IBTR (P= 0.6). In multivariate analysis, Clinical N-stage (N1 or more) was the only independent clinicopathological factor of associated 5-year IBTR in TNBC (P = 0.04). In HER2+ breast cancer, postoperative trastuzumab has a similar trend for 5-year IBTR (P = 0.07). Conclusions: We showed that clinical node-positive before NAC in TNBC and no receiving trastuzumab in HER2+ breast cancer were prognostic factor of 5-year IBTReven after achieving pCR. Citation Format: Naoko Matsuda, Naoki Hayashi, Ryu Tokui, Takahiro Nakayama, Hideko Yamauchi, Makoto Ishitobi. Risk factors of ipsilateral breast tumor recurrence in primary breast cancer patients who achieved pathological complete response after neoadjuvant chemotherapy [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 P2-16-27.

Abstract P6-10-24: High stromal platelet derived growth factor receptor beta predicts absence of benefit of radiotherapy after breast conserving surgery in breast ductal carcinoma in situ within the SweDCIS randomized trial

Abstract Background: With the introduction of mammography the detection of breast ductal carcinoma in situ (DCIS) has increased four- to sevenfold. Local recurrences occur only in a minority of patients. Radiotherapy (RT) is presently used without biomarker guidance. Therefore, novel biomarkers predicting benefit of radiotherapy are warranted to prevent overtreatment. Studies on RT response-predictive biomarkers in DCIS have focused on tumor cell features and often neglected the tumor-associated stroma, despite growing evidence of its active influence on treatment response including RT. The platelet derived growth factor receptors alpha and beta (PDGFRa and -b) signaling pathways are major regulators of stroma cells. Recent studies have indicated a loss of PDGFRa in the tumor-associated stroma of DCIS while PDGFRb remains high and patients with PDGFRa(low)/PDGFRb(high) expression had a significant increased risk for any tumor recurrence. A limitation of this study was though the usage of a population-based cohort, thus not allowing firm conclusions on the impact of the marker on natural course of the disease or benefit to treatment. Purpose: To explore if stromal expression of PDGFRb serves as prognostic as well as response-predictive biomarker for RT benefit with regard to ipsilateral breast tumor recurrence (IBTR) and overall survival (OS) for DCIS patients within a large and clinically well-annotated randomized trial. Method: Immunohistochemical staining of PDGFRb was performed on full tissue sections of 705 patients from the SwedDCIS cohort, a randomized RT trial after breast-conserving surgery. Stromal PDGFRb expression was evaluated by two independent raters in up to ten high power fields within the tumor associated stroma region and scored as 0/negative, 1/low average stroma intensity, 2/moderate average stroma intensity or 3/high average stroma intensity. An average PDGFRb score was calculated for each tumor. The final data was split at median defining PDGFRb low and high patient groups. Outcomes were analyzed at 10 years of follow-up. Results: High stromal PDGFRb was correlated with young age (p=0.003 Spearman’s Rank correlation). In multivariable Cox regression including RT, age, size, screen detection and tumor margin status, the PDGFRb high patient group showed a trend to worse prognosis with regard to IBTR (HR 1.40, CI95% 0.96-2.04, p=0.08) and OS (HR 1.76, CI95% 1.00-3.09, p=0.05). Benefit of radiotherapy on IBTR (in situ and invasive) was absent in the PDGFRb high patient group (HR 0.76, CI95% 0.47-1.22, p=0.25)), but clearly detected in the PDGFRb low group (HR 0.29, CI95% 0.15-0.55, p<0.001) in a multivariable analysis including age, size, screen detection and tumor margin status. Interaction between RT and PDGFRb was significant (p=0.020). No differences in OS after RT were observed within the PDGFR-defined patient groups. RT benefit was also restricted to the PDGFRb low patient group in separate analyses for in situ IBTR (PDGFRb low group HR 0.27, CI95% 0.12-0.60, p=0.001, versus PDGFRb high group HR 0.66, CI95% 0.34-1.29, p=0.22) or invasive IBTR (PDGFRb low group HR 0.33, CI95% 0.11-0.98, p=0.045, versus PDGFRb high group HR 0.88, CI95% 0.45-1.73, p=0.71). Significant interactions between PDGFRb group and RT were not detected in these sub-analyses (p=0.11 for in situ and p=0.15 for invasive IBTR). Conclusion: These data suggests high stromal PDGFRb as a marker of potential clinical utility for RT resistance regarding IBTR in DCIS patients. Furthermore, the study supports the hypothesis of a fibroblast-mediated modulation of RT-sensitivity in DCIS cells. Experimental model studies, investigating the biological mechanisms and potential therapeutic relevance are therefore highly motivated. Citation Format: Carina Strell, Dick Folkvaljon, Erik Holmberg, Per Karlsson, Jonas Bergh, Troy Bremer, Lars A. Akslen, Fredrik Wärnberg, Arne Östman. High stromal platelet derived growth factor receptor beta predicts absence of benefit of radiotherapy after breast conserving surgery in breast ductal carcinoma in situ within the SweDCIS randomized trial [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 P6-10-24.

Abstract P4-12-06: Long-term follow-up of patients with invasive breast cancer treated with catheter-based accelerated partial breast irradiation following lumpectomy

Abstract Introduction: A large number of breast cancer patients who are eligible for breast-conserving therapy (radiation following complete resection via lumpectomy) elect to undergo mastectomy to avoid radiation - with treatment length being the most significant deterrent. The development of accelerated partial breast irradiation (APBI) tailored treatment to target tissue at greatest risk of recurrence, balancing treatment-associated benefits with radiation exposure risk while shortening therapy duration from 6 weeks to 5 days. This study analyzed rates of ipsilateral breast tumor recurrence (IBTR) in patients with invasive breast cancer treated with resection followed by APBI delivered via catheter-based brachytherapy. Methods: Retrospective data was collected on 406 patients with primary invasive breast cancer diagnosed from January 2007 to February 2014, treated with lumpectomy and adjuvant APBI catheter-based brachytherapy. Follow-up data was available for 390 patients (97.5%). Mean and median follow-up were 80.9 and 83.5 months respectively. 193 patients (49.4%) had at least 7 years of follow-up. Results: 21 patients (5.4%) were found to have an IBTR. Of these patients, 14 (66.7%) experienced an IBTR in the same quadrant as their index cancer. 7 patients (33.3%) experienced an IBTR in a different quadrant. Only one patient (4.8%) experienced an IBTR within the first two years after conclusion of their primary treatment. Of the entire cohort, 7 patients (1.8%) were found to have a metastatic recurrence (one which occurred within the first two years after primary treatment) and 7 patients (1.8%) experienced new primary cancers diagnosed in their contralateral breasts. Conclusion: The results of this investigation demonstrate catheter-based brachytherapy APBI delivered after breast-conserving surgery carries a relatively low risk for IBTR in patients with invasive breast cancer. We support its' use as an effective and valid alternative for selected early breast cancer patients desiring a significantly shorter, more convenient course of treatment in the adjuvant setting without increased risk of recurrence. Citation Format: Cynthia Chen, Chi Chi Do-Nguyen, Lisa Poole, Lina Sizer, William B Carter, Thomas G. Frazier. Long-term follow-up of patients with invasive breast cancer treated with catheter-based accelerated partial breast irradiation following lumpectomy [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 P4-12-06.

Abstract PD6-10: A high ratio of CD8/FOXP3 predicts an unfavorable response to postoperative radiotherapy after breast-conserving surgery: Results from the randomized SweBCG91RT trial

Abstract Purpose: The effect of postoperative radiotherapy (RT) based on the immune phenotype of tumor-infiltrating lymphocytes (TILs) has not been investigated. The purpose of this study was to analyze how the balance between CD8+ T cells and T regulatory cells (FOXP3+), which have opposite effects on the anti-tumoral defense, affects the risk of ipsilateral breast tumor recurrence (IBTR) and of any recurrence as well as the interaction with RT in a large randomized RT trial. Methods: In the SweBCG91RT trial, patients with breast cancer stage I and II were randomized to breast conserving surgery (BCS) and postoperative RT or BCS only and followed for a median time of 15.2 years. Tumor blocks were retrieved and stromal TILs were assessed through hematoxylin-eosin stained slides. CD8+ T cells and T regulatory cells were evaluated through staining for CD8 and FOXP3 and the percentage of stroma occupied by CD8+ T cells and T regulatory cells respectively was then calculated. Cutoffs at 5% and 2.5% were used to define high levels of CD8+ T cells (CD8High) and T regulatory cells (FOXP3High), respectively. In total, 943 patients were analyzed. Results: Among patients who did not receive RT, an increased risk of IBTR and of any recurrence was seen in the CD8Low/FOXP3Low (HR 2.64, CI95% 1.26-5.56, p=0.010 and HR 2.52, CI95% 1.34-4.77, p=0.004, respectively) and CD8High/FOXP3High (HR 1.94, CI95% 0.81-4.63, p=0.135 and HR 2.76, CI95% 1.36-5.57, p=0.005, respectively) groups compared to CD8High/FOXP3Low (HR 1.0) in multivariable analyses including grade and age. The effect of RT on risk of IBTR was more pronounced in the groups with CD8Low/FOXP3Low (HR 0.37, CI95% 0.24-0.57, p<0.001) and CD8High/FOXP3High (HR 0.43, CI95% 0.16-1.13, p=0.086) compared to CD8High/FOXP3Low (HR 0.92, CI95% 0.25-3.40, p=0.905). A potentially unfavorable effect of RT on the risk of any recurrence was observed in the CD8High/FOXP3Low (HR 1.74, CI95% 0.75-4.06, p=0.20) group in contrast to the effect of RT in patients with CD8High/FOXP3High (HR 0.53, CI95% 0.28-1.01, p=0.054) and CD8Low/FOXP3Low (HR 0.48, CI95% 0.34-0.68, p<0.001). A significant interaction between immune phenotype and the effect of RT was found for any recurrence (p=0.024) but not for IBTR (p=0.66). Conclusions: Our findings suggest that patients with a favorable immune phenotype (CD8High/FOXP3Low) may not derive any benefit from adjuvant RT which could be explained by an interaction through which RT may suppress an activated immune response. These results may have an impact on decisions regarding postoperative RT in early breast cancer. Citation Format: Axel Stenmark Tullberg, Henri AJ Puttonen, Erik Holmberg, Dan Lundstedt, Fredrika Killander, Emma Niméus, Anikó Kóvacs, Per Karlsson. A high ratio of CD8/FOXP3 predicts an unfavorable response to postoperative radiotherapy after breast-conserving surgery: Results from the randomized SweBCG91RT trial [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 PD6-10.

Abstract P3-08-08: Prognostic and predictive impact of stroma cells defined by platelet derived growth factor receptor beta in early breast cancer: Results from the randomized SweBGR91RT trial

Abstract Background: Although preclinical studies have indicated that stroma cells can modulate the radiosensitivity of tumor cells, non-leukocytic stroma cells have not yet been explored as potential predictive markers for radiotherapy (RT) through systematic analyses of clinical samples. Platelet-derived growth factor receptor beta (PDGFRb) is a key regulator of fibroblasts, pericytes and smooth muscle cells. A high expression of PDGFRb in tumor-associated stroma has previously been associated with worse recurrence free and breast cancer specific survival as well as reduced tamoxifen sensitivity in invasive breast cancer. Purpose: To analyze the prognostic and predictive impact of stromal PDGFRb regarding ipsilateral breast tumor recurrence (IBTR) and any recurrence in a large randomized RT trial. Methods: Stromal PDGFRb expression was assessed by immunohistochemical staining of tissue microarrays (TMAs) with 958 tumors from the SweBCG91RT trial (Swedish Breast Cancer Group 91 Radiotherapy). The trial enrolled node-negative, stage I or IIA breast cancer patients, who were randomized to postoperative RT or not after breast conserving surgery. Stained TMAs were evaluated by two independent raters for PDGFRb staining intensity (0/negative; 1/low; 2/moderate; 3/high) and positive stroma fraction (0/0%; 1/1-10%; 2/11-50; 3/51-75%; 4/76-100%). The evaluations of both raters were averaged and the product between the two scoring metrics was formed. For final analysis the data was split in tertiles, as predefined, and referred to as PDGFRb low, medium or high score group. Outcomes were analyzed at 10 years of follow-up. Results: A high PDGFRb score was correlated with ER negativity (p=0.003,), young age (p<0.001), large tumor size (p=0.058) and high histological grade (p=0.067) in Spearman’s Rank test. With regard to prognosis, a significantly increased risk for any recurrence was detected in univariable analysis for patients with a medium (HR 1.57, CI95% 1.11-2.23, p=0.011) or high PDGFRb score (HR 1.49, CI95% 1.06-2.10, p=0.021) compared to the PDGFRb low score group. The significance remained for the PDGFRb medium (HR 1.47, CI95% 1.03-2.11, p=0.034) but not the PDGFRb high score group (HR 1.32, CI95% 0.93-1.88, p=0.125) in a multivariable analysis including grade, age and RT. The benefit of RT regarding the risk of IBTR was significant in the PDGFRb low (HR 0.28, CI95% 0.12-0.65, p=0.003) and medium (HR 0.32, CI95% 0.16-0.61, p=0.001) score groups but not in the PDGFRb high (HR 0.61, CI95% 0.35-1.07, p=0.086) score group in a multivariable analysis including grade and age. The risk reduction from RT regarding any recurrence was also less pronounced in the PDGFRb high (HR 0.73, CI95% 0.48-1.12, p=0.149) score group compared to the PDGFRb low (HR 0.57, CI95 0.32-1.03, p=0.065) and medium (HR 0.46, CI95% 0.28-0.75, p=0.002) score groups in multivariable analysis. No significant interaction between RT and PDGFRb expression could however be detected for IBTR (p=0.14) or any recurrence (p=0.33). Conclusion: A higher PDGFRb score conferred a negative prognosis with increased risk of any recurrence in univariable analyses, which in part can be explained by its association with ER negativity, young age and grade. A predictive effect of RT benefit from PDGFRb could not be confirmed although a tendency toward less benefit was observed in the patient group with the highest PDGFRb score. Citation Format: Carina Strell, Reidunn J Edelmann, Axel Stenmark Tullberg, Per Malmström, Mårten Fernö, Arne Östman, Erik Holmberg, Per Karlsson. Prognostic and predictive impact of stroma cells defined by platelet derived growth factor receptor beta in early breast cancer: Results from the randomized SweBGR91RT trial [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 P3-08-08.

Abstract P4-13-07: Oncoplastic breast conservation surgery for patients with large breast cancers undergoing primary or post-NACT breast conservation surgery is safe and effective

Abstract Introduction: Majority of women diagnosed with breast cancers (BC) have self-detected large tumors (mean tumor size >4 cm). There are number of myths and misconceptions regarding safety of breast conservation surgery (BCS), which, coupled with the fear of re-operation for infiltrated margins lead to poor acceptance of BCS by Indian BC patients. Practice of oncoplastic breast surgery (OBS), neo-adjuvant chemotherapy (NACT) and intra-op frozen section (FS) margins assessment have helped us achieve safe, single stage breast conservation even for patients with large tumors. In this retrospective study, we evaluated the OBS techniques used in patients undergoing primary or post-NACT BCS and compared the outcomes in terms of ipsilateral breast tumor recurrence (IBTR) and overall survival (OS) between patient groups that underwent OBS-BCS, non-OBS BCS and mastectomy. Methods: Retrieving data from a prospectively maintained database, all patients treated for stages I-III BC between 2009 & 2018 at a specialty breast surgery unit were reviewed. Patient demographics, TNM stage, pathology, OBS technique, margin re-excision, and outcomes in terms of IBTR and OS, were evaluated; and compared with non-OBS BCS and mastectomy patients. Results: Of 1884 (Median age 50 years, 59% post-menopausal, T3-18%, T4b-7%) who underwent curative breast surgery, 1424 (75%) underwent mastectomy. Rest 460 (24.4%) underwent BCS, of which 43% underwent OBS BCS. Fifty-two patients (26.6%) underwent post-NACT BCS, of which 27.5% had pathological complete response (pCR). OBS techniques used were volume displacement in 169 (86.4%) and volume replacement (mini LD/LD flap) in 29 (13.6%). The OBS techniques used constituted Level-1 OBS in 33% and level-2 OBS in 66%. Procedures performed included round block / modified Benelli-10.6%, batwing mastopexy- 6%, wise pattern reduction mammoplasty+contralateral symmetrization-4%, and other procedures-9.5% (medial mammoplasty, inverted T/vertical scar mastopexy, J or L mammoplasty, parallelogram excision, Z plasty). Intraop FS histology detected infiltrated margins in 11.6% of patients undergoing OBS-BCS, which were re-excised/ converted to mastectomy in the same sitting, thus avoiding a re-operation. In comparison, 17% patients who underwent non-OBS BCS had margin infiltration. Cosmetic outcomes and patient satisfaction were better in OBS BCS patients. Peri-op complications including partial nipple necrosis, skin necrosis, seroma, wound dehiscence and infection occurred in 17%. IBTR occurred in 4% of OBS-BCS patients, compared to 7% patients who underwent non-OBS BCS. Over 36 mo median follow-up, stagewise OS was similar in patient groups undergoing mastectomy, OBS BCS or non-OBS BCS. Conclusion: Employing OBS techniques has enabled us offer BCS for EBC and large or locally advanced BC. These techniques facilitate safe BCS of patients undergoing primary or post-NACT breast surgery, with relatively lower margin infiltration and local recurrence rates, comparable survival and higher patient satisfaction of their cosmetic outcomes, compared to patients undergoing mastectomy or conventional/ non-OBS BCS. Table: Types of oncoplastic procedures used in patients undergoing primary or post-NACT Oncoplastic breast surgical breast conservation surgeryNo.of patientsPercentageLevel I16181.3 %Level II(MiniLD/ LD/ Contralateral Symmetrisation)3718.6%Volume Displacement16985.3%Volume Replacement2913.6%Ipsilateral breast tumor recurrence84.02% Citation Format: Gaurav Agarwal, VC Ramya, Anjali Mishra, Gyan Chand, Sabaretnam Mayilvahanan, Vinita Agrawal, Narendra Krishnani, Namita Mohindra, Punita Lal. Oncoplastic breast conservation surgery for patients with large breast cancers undergoing primary or post-NACT breast conservation surgery is safe and effective [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 P4-13-07.

Abstract P1-17-10: Breast pain is a common complaint after breast cancer treatment but not a sign of recurrence

Abstract Background: Mastalgia, breast pain without other signs or symptoms, is a very common complaint, yet occurs in only approximately 5% of patients with breast cancer. Most clinicians are aware of this lack of association with cancer. Mastalgia is also a common complaint after breast cancer treatment. This symptom is very worrisome to many women, and when seen in the office, clinicians tend to give in to the fear of patients and order various tests. In 2017, we presented an abstract at SABCS that showed that breast pain was not associated with breast cancer diagnosis. Many attendees were interested in the incidence of breast pain after breast cancer treatment. The current study was performed to evaluate the incidence and significance of mastalgia after breast cancer treatment. Methods: Maricopa Medical Center, the county safety net hospital in Phoenix, Arizona serves a patient base which is 34.5% non-English speaking. The majority of these patients are uninsured or underinsured. A total of 1635 breast cancer patients were seen at least once at the Breast Clinic from June 1, 2006 to December 31, 2018. Sociodemographic variables were collected on all patients. All patients who were treated for breast cancer and then presented with a complaint of breast pain during follow up were evaluated. Additionally, all patients who complained of a breast mass but were found to have pain with no mass were evaluated in a similar fashion. Results: A total of 1577 patients were seen during the time period. The mean age of the patients was age 52. Of the patients, 144 presented with or developed metastatic disease prior to their operation. 116 patients transferred their care to another facility. Of the remaining patients, 36% of patients (474 of 1317) presented with a complaint of breast pain during their follow up after breast cancer treatment. Of the patients with breast pain, 16 had an ipsilateral breast tumor recurrence or contralateral breast cancer diagnosis, however, none of the patients presented with breast pain. The breast pain occurred after treatment was completed. Nine patients presented with a palpable mass and seven patients presented with abnormal imaging. In contrast, 6.0% patients (51 of 843) without breast pain developed an ipsilateral breast tumor recurrence, chest wall recurrence, or contralateral breast cancer. 35 patients presented with a painless breast mass and the remaining 26 recurrences or contralateral breast cancer were found on routine imaging. Local recurrence or contralateral breast cancer were more common in patients without breast pain during follow up (p = 0.036). The two most common factors related to any breast cancer recurrence and death were noncompliance with recommended treatment and presentation with T4 (Stage 3B) breast cancer. Conclusions: Mastalgia is a very common complaint in patients seen for follow up after breast cancer treatment. Patients and providers may believe a complaint of breast pain warrants further workup and often results in additional, repeat, or interval imaging. With normal physical examination and routine imaging, however, breast pain alone does not appear to be an indication of breast cancer recurrence. Additional or repeat imaging as well as laboratory tests do not appear beneficial in patients with breast pain. Reassurance and patient education is necessary to avoid continued use of unnecessary medical resources. Citation Format: Ian Komenaka, Anushi Shah, Tina Wong, Daniela Cocco, Chiu-Hsieh Hsu, Jesse Nodora, Waqas Arslan, Maria Elena Martinez. Breast pain is a common complaint after breast cancer treatment but not a sign of recurrence [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 P1-17-10.

Abstract OT3-09-04: A randomized phase II study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS)

Abstract A randomized phase II study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) Breast radiotherapy (RT) for DCIS has been studied only in the adjuvant setting, following lumpectomy surgery. Adjuvant RT reduced invasive recurrences by 52% in the combined analysis of the two largest DCIS trials NSABP B-17/B-24, and reduced recurrences even for low or intermediate grade DCIS in the RTOG 9804 trial (recurrence 0.9% with RT versus 6.7% without RT). The mechanism of action is hypothesized to be elimination of occult disease and/or inhibition of neoplastic transformation in normal breast tissue. Trial Design To understand the ablative effects of RT on pure DCIS, we are conducting a prospective randomized trial comparing histopathological findings of surgical excision (Arm 1) to neoadjuvant partial breast irradiation (neoRT) followed by delayed surgical excision (Arm 2) for patients with core needle biopsy proven DCIS. Arm 1 will provide a reference group for upstaging to invasive cancer, molecular markers and pathological-radiological correlations. Arm 2 participants will receive 6 Gy daily x 5 to the intact tumor with a 0.5 cm margin of normal tissue. Surgical excision will be delayed 12-16 weeks to allow for the radioablative effects to occur and radiation-induced inflammation to subside. Specific Aims To determine if neoRT can completely ablate at least 30% of pure DCISTo determine if DCIS subtypes exhibit differential sensitivity to neoRTTo determine the radiation-induced treatment effects; wound complication rates; radiological Eligibility Women 18 years of age or older with DCIS diagnosed on vacuum assisted core needle biopsy who intend to receive breast conserving surgery are eligible, excluding those with a prior history of ipsilateral breast cancer. The imaging abnormality must be mammographic microcalcifications and/or MRI non-mass enhancement measuring <3 cm and not completely removed by core needle biopsy. Statistics A total of 50 patients will be recruited. Upstaging to invasive cancer is anticipated to be approximately 10% in the reference group. With 25 subjects in each arm, we will have 80% power to detect a 30% or higher improvement in the DCIS complete response rate following neoRT. Accrual Opened to accrual June 1, 2019 Contact wapnir@stanford.edu Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011;103(6):478-488. doi:10.1093/jnci/djr027. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015;33(7):709-715. doi:10.1200/JCO.2014.57.9029. Citation Format: Irene Wapnir, Wendy DeMartini, Kimberly Allison, Kimberly Stone, Frederick Dirbas, Carol Marquez, Debra Ikeda, Sunita Pal, Jacqueline Tsai, Rachel Yang, Robert West, Alex McMillan, Melinda Telli, Kathleen Horst. A randomized phase II study comparing surgical excision versus NeOadjuvant Radiotherapy followed by delayed surgical excision of Ductal carcinoma In Situ (NORDIS) [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 OT3-09-04.

Prognostic study for isolated local recurrence operated with salvage excision in hormone-receptor-positive patients with invasive breast cancer after primary breast surgery

BackgroundThis study aimed to identify the factors that predict distant recurrence and survival outcome after patients with primary positive hormone receptor-positive (HR+) invasive breast cancer undergo complete excision for isolated local recurrence (ILR). MethodsFrom January 2000 to December 2009, we performed a retrospective review of our database and identified 51 patients with HR + invasive breast cancer who underwent complete excision for ILR as a component of salvage therapy. The distant metastasis-free survival (DMFS) and overall survival (OS) from the time of ILR were calculated using the Kaplan–Meier method, and a Cox regression model was used for multivariate analysis. ResultsOf the 51 cases of ILR, 28 were of ipsilateral breast tumor recurrence and 23 were of chest wall recurrence. By receiver operating characteristic curve analyses, the cut-off time point for time to ILR was determined to be 29 months. According to time to ILR (≤29 vs. >29 months) and primary tumor size (≤2 vs. >2 cm), patients were divided into four risk groups as variables for analysis. On multivariate analysis, two independent prognostic factors for DMFS and OS after ILR were identified: risk groups (ILR≤29 months with primary tumor size >2 cm vs. ILR>29 months with primary tumor size ≤ 2 cm, HR = 8.53 for DMFS and HR = 11.18 for OS) and primary tumor grade (2/3 vs. 1, HR = 6.10 for DMFS and 4.27 for OS). ConclusionWe demonstrated that poor DMFS and OS are associated with high risk group defined as short time to ILR (≤29 months) with primary tumor size (>2 cm) and higher primary tumor grade (2/3) among patients with HR + invasive breast cancer treated with complete excision for ILR. Therapeutic strategies for ILR based on hormone therapy with new agents should be explored in future prospective studies, especially for patients with poor outcome.

Ipsilateral breast tumor recurrence in early stage breast cancer patients treated with breast conserving surgery and adjuvant radiation therapy: Concordance of biomarkers and tumor location from primary tumor to in-breast tumor recurrence

BACKGROUNDPatients with an in-breast tumor recurrence (IBTR) after breast-conserving therapy have a high risk of distant metastasis and disease-related mortality. Classifying clinical parameters that increase risk for recurrence after IBTR remains a challenge.AIMTo describe primary and recurrent tumor characteristics in patients who experience an IBTR and understand the relationship between these characteristics and disease outcomes.METHODSPatients with stage 0-II breast cancer treated with lumpectomy and adjuvant radiation were identified from institutional databases of patients treated from 2003-2017 at our institution. Overall survival (OS), disease-free survival, and local recurrence-free survival (LRFS) were estimated using the Kaplan Meier method. We identified patients who experienced an isolated IBTR. Concordance of hormone receptor status and location of tumor from primary to recurrence was evaluated. The effect of clinical and treatment parameters on disease outcomes was also evaluated.RESULTSWe identified 2164 patients who met the eligibility criteria. The median follow-up for all patients was 3.73 [interquartile range (IQR) 2.27-6.07] years. Five-year OS was 97.7% (95%CI: 96.8%-98.6%) with 28 deaths; 5-year LRFS was 98.0% (97.2-98.8) with 31 IBTRs. We identified 37 patients with isolated IBTR, 19 (51.4%) as ductal carcinoma in situ and 18 (48.6%) as invasive disease, of whom 83.3% had an in situ component. Median time from initial diagnosis to IBTR was 1.97 (IQR: 1.03-3.5) years. Radiotherapy information was available for 30 of 37 patients. Median whole-breast dose was 40.5 Gy and 23 patients received a boost to the tumor bed. Twenty-five of thirty-two (78.1%) patients had concordant hormone receptor status, HER-2 receptor status, and estrogen receptor (ER) (P = 0.006) and progesterone receptor (PR) (P = 0.001) status from primary to IBTR were significantly associated. There were no observed changes in HER-2 status from primary to IBTR. The concordance between quadrant of primary to IBTR was 10/19 [(62.2%), P = 0.008]. Tumor size greater than 1.5 cm (HR = 0.44, 95%CI: 0.22-0.90, P = 0.02) and use of endocrine therapy upfront (HR = 0.36, 95%CI: 0.18-0.73, P = 0.004) decreased the risk of IBTR.CONCLUSIONAmong patients with early stage breast cancer who had breast conserving surgery treated with adjuvant RT, ER/PR status and quadrant were highly concordant from primary to IBTR. Tumor size greater than 1.5 cm and use of adjuvant endocrine therapy were significantly associated with decreased risk of IBTR.

Validation of a Novel Nomogram for Prediction of Local Relapse after Surgery for Invasive Breast Carcinoma.

Around 7% of women who undergo breast-conserving surgery (BCS) or mastectomy are at risk of developing ipsilateral breast tumor recurrence (IBTR). When assessing risks that, like that of IBTR, depend on multiple clinicopathological variables, nomograms are the predictive tools of choice. In this study, two independent nomograms were constructed to estimate the individualized risk of IBTR after breast surgery. In this retrospective study, 18,717 consecutive patients with primary invasive breast cancer were enrolled. The training set used for building the nomograms comprised 15,124 patients (11,627 treated with BCS and 3497 with mastectomy), while the validation set included 3593 women (2565 BCS and 1028 mastectomy). Median follow-up time was 8years in the training set and 6years in the validation set. Multivariable Cox proportional hazards regression was used to identify independent factors for IBTR. Two separated nomograms were constructed on multivariate models for BCS and mastectomy. The factors that associated with IBTR after either BCS or mastectomy were identified. The two multivariable models were used to build nomograms for the prediction of IBTR 1year, 5years, and 10years after BCS or after mastectomy. Five-year and 10-year IBTR rates in the BCS training set were equal to 3.50% and 7.00%, respectively, and to 5.39% and 7.94% in the mastectomy training set. The nomograms were subsequently validated with c-index values of 0.77 and 0.69 in the BCS and mastectomy validation sets, respectively. The nomograms presented in this study provide clinicians and patients with a valuable decision-making tool for choosing between different treatment options for invasive breast cancer.

Outcomes and risk of subsequent breast events in breast-conserving surgery patients with BRCA1 and BRCA2 mutation.

PurposePrevious studies provide inconsistent interpretations of the effect of inherited genetic factors on the survival and prognosis of patients with breast cancer. The aim of this study was to examine the effect of germline BRCA1 and BRCA2 mutation on survival and subsequent breast events in Chinese women who underwent breast‐conserving surgery.MethodsA retrospective review of the clinical and pathological records was performed in patients diagnosed with primary invasive breast cancer between 2005 and 2018 in the cancer registry database. Clinicopathological data and data regarding treatment and outcomes, including date and site of disease progression, were collected. The survival outcomes and independent risk factors were conducted using SPSS.ResultsOverall, a total of 501 patients who underwent breast‐conserving surgery were identified and subjected to analyses, of which 63 cases with BRCA1 or BRCA2 mutation. The median age at diagnosis was 41 (range, 24‐74) for carriers and 37 (range, 17‐84) for noncarriers. After a median follow‐up time of 61 months (range, 8‐161) and 70 months (range, 0‐153), respectively, in carriers and noncarriers, the overall survival (P = .173) and disease‐free survival (P = .424) were not significantly different. Analogously, there was no significant difference between the two groups about the outcomes of ipsilateral breast tumor recurrence (P = .348), yet the contralateral breast cancer (CBC) was overt worse than noncarriers (P < .001). When adjusted to confounding factors, BRCA mutation was the only independent risk factors to CBC (HR = 7.89, P = .01).ConclusionIn this study, BRCA mutation carriers have higher risk of CBC. And, BRCA mutation is the only independent risk factor to CBC. Therefore, intensive surveillance and follow‐up as well as more effective individual prevention are urgent. Decisions on alternatively effective prevention, especially the prevention of CBC, are urgent and should take into account patient prognosis and preferences.

Adjuvant whole breast radiotherapy with simultaneous integrated boost to tumor bed with intensity modulated radiotherapy technique in elderly breast cancer patients.

BackgroundAdjuvant whole breast radiotherapy is the standard of care for breast cancer patients after partial mastectomy. Intensity-modulated radiation therapy (IMRT) has been reported to reduce acute toxicities compared to conventional radiotherapy. IMRT with simultaneous integrated boost (SIB) technique can deliver higher doses to tumor bed and irradiate whole breast with a lower dose level to shorten overall treatment duration. This study presents the long-term results of adjuvant IMRT with SIB in elderly breast cancer patients who received partial mastectomy.MethodsFrom January 2007 to January 2018, 93 elder breast cancer patients (≥65-year-old) who received IMRT with SIB technique after partial mastectomy were reviewed retrospectively. The axillary areas were managed with either sentinel lymph node biopsies or axillary lymph node dissection. The dose to whole breast was 50.4 Gy in 28 fractions in all patients and the dose to tumor bed was 61.6 to 66.4 Gy in 28 fractions. The primary end point is locoregional control. Secondary end points include: overall survival, breast cancer-specific survival, distant-metastases-free survival, disease-free survival, and acute and chronic toxicities.ResultsThe median follow-up was 56.1 months. One patient had ipsilateral breast tumor recurrence, 3 patients had regional lymph node recurrence, and 9 patients had distant metastases. Death occurred in 5 patients, including 3 patients died of breast cancer progression. Five-year overall survival is 96.3% and 5-year locoregional recurrence-free survival is 96.4%. The 5-year breast cancer specific survival and 5-year distant metastases-free survival is 97.5% and 87.2%, respectively. Seven patients developed second primary cancer after RT. Eighty-one point seven percent patients had acute grade 1 dermatitis while 18.3% suffered from grade 2 dermatitis. The incidence of grade 1 pneumonitis and grade 1 stomatitis was 4.3% and 8.6%, respectively.ConclusionsAdjuvant IMRT with SIB technique is a safe and effective treatment strategy for elderly breast cancer patients after partial mastectomy.

Neoadjuvant systemic therapy does not compromise local control after breast-conserving surgery: a single-center, propensity score matching study in China.

BackgroundTo investigate ipsilateral breast tumor recurrence (IBTR) in patients who have undergone breast-conserving surgery (BCS) after neoadjuvant systematic therapy (NST).MethodThree hundred and twenty-one patients undergoing BCS after NST and 2,534 patients undergoing initial BCS from June 2008 to June 2017 at Fudan University Shanghai Cancer Center were retrospectively enrolled, and statistical analyses, including propensity score matching, were applied to compare IBTR-free survival. The main factors related to IBTR in the NST group were estimated utilizing univariate and multivariate analyses.ResultsAfter propensity score matching, the 3-year IBTR-free survival rates were 93.7% (95% CI, 90.6–96.8%) in the NST group and 96.9% (95% CI, 94.9–98.9%) in the matched initial BCS group at a median follow-up period of 58 months. IBTR-free survival did not differ statistically between the two groups (P=0.154). According to multivariate analysis in the NST group, tumor-infiltrating lymphocytes (TILs), epidermal growth factor receptor 2 (HER2) status and pathologic ductal carcinoma in situ (DCIS) constituent were the factors related to IBTR after BCS.ConclusionsBCS after NST and initial BCS have equivalent IBTR-free survival. BCS after NST is a safe and effective therapy in terms of IBTR.

Minimally invasive tumor bed implant (MITBI) and peri-operative high-dose-rate brachytherapy (PHDRBT) for accelerated minimal breast irradiation (AMBI) or anticipated boost (A-PHDRBT-boost) in breast-conserving surgery for ductal carcinoma in situ.

PurposeTo evaluate our institutional experience of minimally invasive tumor bed implantation (MITBI) during breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) to deliver peri-operative high-dose-rate brachytherapy (PHDRBT) as accelerated minimal breast irradiation (AMBI) or anticipated boost (A-PHDRBT-boost).Material and methodsPatients older than 40, with clinical and radiological unifocal DCIS < 3 cm were considered potential candidates for accelerated partial breast irradiation (APBI) and were implanted during BCS using MITBI-technique. Patients who in final pathology reports showed free margins and no other microscopic tumor foci, received AMBI with PHDRBT (3.4 Gy BID in 5 days). Patients with adverse features received A-PHDRBT-boost with post-operative external beam radiotherapy (EBRT).ResultsForty-one patients were implanted, and 36 were treated and analyzed. According to final pathology, 24 (67%) patients were suitable for AMBI and 12 (33%) were qualified for A-PHDRBT-boost. Reoperation rate for those with clear margins was 16.6% (6/36); this rate increased to 33% (4/12) for G3 histology, and 66% (4/6) were rescued using AMBI. Early complications were documented in 5 patients (14%). With a median follow-up of 97 (range, 42-138) months, 5-year rates of local, elsewhere, locoregional, and distant control were all 97.2%. 5-year ipsilateral breast tumor recurrence rates (IBTR) were 5.6% (2/36), 8.3% (2/24) for AMBI, and 0% (0/12) for A-PHDRBT-boost patients. Both instances of IBTR were confirmed G3 tumors in pre-operative biopsies; no IBTR was documented in G1-2 tumors. Cosmetic outcomes were excellent/good in 96% of AMBI vs. 67% in A-PHDRBT-boost (p = 0.034).ConclusionsThe MITBI-PHDRBT program allows selection of patients with excellent prognoses (G1-2 DCIS with negative margins and no multifocality), for whom AMBI could be a good alternative with low recurrence rate, decrease of unnecessary radiation, treatment logistics improvement, and over-treatment reduction. Patients whose pre-operative biopsy showed G3 tumor, presents with inferior local control and more risk of reoperation due to positive margins.

External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial

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. 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. 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<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). 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. Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.