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Background: Accrual to oncology clinical trials remains a challenge, particularly during the COVID-19 pandemic. For late phase clinical trials funded by the National Cancer Institute, the development of these research protocols is a resource-intensive process; however, mechanisms to optimize patient accrual after trial activation are underdeveloped across the National Clinical Trial Network (NCTN). Low patient accrual can lead to the premature closure of clinical trials and can ultimately delay the availability of new, potentially life-saving therapies in oncology., Objective: The purpose of this study is to formally create an easily implemented tool kit of resources for investigators of oncology clinical trials within the NCTN, specifically the NRG Oncology cooperative group, in order to optimize patient accrual., Methods: NRG Oncology sought to formally develop a tool kit of resources to use at specific time points during the lifetime of NRG Oncology clinical trials. The tools are clearly described and involve the facilitation of engagement of the study principal investigator with the scientific and patient advocate community during the planning, activation, and accrual periods. Social media tools are also leveraged to enhance such engagement. The principal investigator (PI) tool kit was created in 2019 and thereafter piloted with the NRG Oncology/Alliance NRG-LU005 phase II or III trial in small-cell lung cancer. The PI tool kit was developed by the NRG Oncology Protocol Operations Management committee and was tested with the NRG/Alliance LU005 randomized trial within the NCTN., Results: NRG Oncology/Alliance NRG-LU005 has seen robust enrollment, currently 127% of the projected accrual. Importantly, many of the tool kit elements are already being used in ongoing NRG Oncology trials, with 56% of active NRG trials using at least one element of the PI tool kit and all in-development trials offered the resource. This underscores the feasibility and potential benefits of deploying the PI tool kit across all NRG Oncology trials moving forward., Conclusions: While clinical trial accrual can be challenging, the PI tool kit has been shown to augment accrual in a low-cost and easily implementable fashion. It could be widely and consistently deployed across the NCTN to improve accrual in oncology clinical trials., Trial Registration: ClinicalTrials.gov NCT03811002; https://clinicaltrials.gov/ct2/show/NCT03811002., (©Kristin A Higgins, Alexandra Thomas, Nancy Soto, Rebecca Paulus, Thomas J George, Thomas B Julian, Sharon Hartson Stine, Merry Jennifer Markham, Maria Werner-Wasik. Originally published in JMIR Cancer (https://cancer.jmir.org), 25.08.2022.)

Purpose: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy., Method: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS)., Results: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group., Conclusion: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100., Trial Registration: ClinicalTrials.gov: NCT00087178., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results., Methods: Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments., Results: Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms., Conclusion: Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life., Competing Interests: Lori J. GoldsteinStock and Other Ownership Interests: CureVacHonoraria: Daiichi Sankyo, Roche/Genentech, Amgen, Mylan, Merck, Eisai, Immunomedics, Exact SciencesConsulting or Advisory Role: Genentech, Genomic Health, Merck, Mylan, Immunomedics, Amgen, Eisai, Exact SciencesResearch Funding: Merck (Inst), Genentech/Roche (Inst)Other Relationship: Daiichi Sankyo David CellaStock and Other Ownership Interests: FACIT.orgConsulting or Advisory Role: AbbVie, GlaxoSmithKline, Pfizer, Astellas Pharma, Novartis, Bristol Myers Squibb, Asahi Kasei, Ipsen, Mei PharmaResearch Funding: Novartis (Inst), Ipsen (Inst), Pfizer (Inst), PledPharma (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Regeneron (Inst), Clovis Oncology (Inst) Mark BasikHonoraria: Roche CanadaResearch Funding: Pfizer, LabCorp Mehra GolshanConsulting or Advisory Role: AbbVie, BertisResearch Funding: Breast Cancer Research Foundation Christine A. LeeConsulting or Advisory Role: OlympusSpeakers' Bureau: AstraZeneca/Merck, OncoCyte Joseph A. SparanoStock and Other Ownership Interests: MetaStatConsulting or Advisory Role: Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, Merrimack, Adgero Biopharmaceuticals, Cardinal Health, Pfizer, GlaxoSmithKline, CStone Pharmaceuticals, Epic Sciences, Daiichi Sankyo, BMSiSpeakers' Bureau: Eisai, CertaraResearch Funding: Prescient Therapeutics (Inst), Deciphera (Inst), Genentech/Roche (Inst), Merck (Inst), Novartis (Inst), Novartis (Inst), Merrimack (Inst), Radius Health (Inst), Olema Pharmaceuticals (Inst)Travel, Accommodations, Expenses: Menarini Silicon Biosystems, Roche/Genentech, Adgero Biopharmaceuticals, Myriad Genetics, Pfizer, AstraZeneca, Rhenium Medical Gildy V. BabieraStock and Other Ownership Interests: PolyPidHonoraria: Insightec, GleolanConsulting or Advisory Role: Insightec, Gleolan, Theracal, Polypid, NektarPatents, Royalties, Other Intellectual Property: Patent Holder for DNX 2401 and DNX2440 Owned by DNAtrixTravel, Accommodations, Expenses: Gleolan, Insightec Sarika JainEmployment: G1 TherapeuticsStock and Other Ownership Interests: G1 Therapeutics Carla S. FisherConsulting or Advisory Role: Biom'UpTravel, Accommodations, Expenses: Biom'Up Amye J. TevaarwerkOther Relationship: Epic Systems Lynne I. WagnerStock and Other Ownership Interests: Johnson & Johnson, Lilly, Gilead SciencesConsulting or Advisory Role: Celgene, AthenexTravel, Accommodations, Expenses: Celgene George W. SledgeLeadership: Syndax, Tessa TherapeuticsStock and Other Ownership Interests: Syndax, Tessa Therapeutics, PionyrConsulting or Advisory Role: Symphogen, Synaffix, Syndax, Verseau Therapeutics, GRAIL, AstraZeneca, G1 TherapeuticsResearch Funding: Genentech/Roche (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Verseau Therapeutics, Tessa TherapeuticsNo other potential conflicts of interest were reported.

Purpose: Preclinical studies report that trastuzumab (T) can boost radiotherapy (RT) effectiveness. The primary aim of the B-43 trial was to assess the efficacy of RT alone vs concurrent RT plus T in preventing recurrence of ipsilateral breast cancer (IBTR) in women with ductal carcinoma in situ (DCIS)., Patients and Methods: Eligibility: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, DCIS resected by lumpectomy, known estrogen receptor (ER) and/or progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) status by centralized testing. Whole-breast RT was given concurrently with T. Stratification was by menopausal status, adjuvant endocrine therapy plan, and nuclear grade. Definitive intent-to-treat primary analysis was to be conducted when either 163 IBTR events occurred or all accrued patients were on study ≥ 5 years., Results: There were 2,014 participants who were randomly assigned. Median follow-up time as of December 31, 2019, was 79.2 months. At primary definitive analysis, 114 IBTR events occurred: RT arm, 63 and RT plus T arm, 51 (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.17; P value = .26). There were 34 who were invasive: RT arm, 18 and RT plus T arm, 20 (HR, 1.11; 95% CI, 0.59 to 2.10; P value = .71). Seventy-six were DCIS: RT arm, 45 and RT plus T arm, 31 (HR, 0.68; 95% CI, 0.43 to 1.08; P value = .11). Annual IBTR event rates were: RT arm, 0.99%/y and RT plus T arm, 0.79%/y. The study did not reach the 163 protocol-specified events, so the definitive analysis was triggered by all patients having been on study for ≥ 5 years., Conclusion: Addition of T to RT did not achieve the objective of 36% reduction in IBTR rate but did achieve a modest but statistically nonsignificant reduction of 19%. Nonetheless, this trial had negative results. Further exploration of RT plus T is needed in HER2-positive DCIS before its routine delivery in patients with DCIS resected by lumpectomy., Competing Interests: Melody A. CobleighConsulting or Advisory Role: Roche/Genentech, Immunomedics, Genomic Health, Puma Biotechnology, Seattle GeneticsResearch Funding: Macrogenics, Radius Health, Genentech/Roche, Seattle Genetics, Zymeworks, SynthonPatents, Royalties, Other Intellectual Property: Genomic HealthTravel, Accommodations, Expenses: Genentech, Immunomedics, Puma Biotechnology, Seattle Genetics Stewart J. AndersonConsulting or Advisory Role: Jazz Pharmaceuticals Kalliopi P. SiziopikouHonoraria: Ventana Medical Systems, Lilly, Merck Douglas W. ArthurStock and Other Ownership Interests: Advanced Radiation Therapy Rachel RabinovitchStock and Other Ownership Interests: Abbott Laboratories, Bristol-Myers Squibb, Intuitive Surgical, IDEXX LaboratoriesResearch Funding: Prelude Therapeutics Dennis L. CarterEmployment: Rocky Mountain Cancer Centers Melissa S. DillmonStock and Other Ownership Interests: Johnson & JohnsonConsulting or Advisory Role: Puma Biotechnology Vivek S. KavadiEmployment: US Oncology Network Matthew L. HillStock and Other Ownership Interests: AstraZeneca, Newlink Genetics, Kazia Therapeutics, Leap Therapeutics, OncoSec, MEI Pharma, PLx Pharma, Radius Health, Crispr Therapeutics, Cassava Sciences Sushil BeriwalHonoraria: Varian Medical Systems, XOFT Eleftherios P. MamounaHonoraria: Genentech/Roche, Genomic Health, PreciscaConsulting or Advisory Role: Genomic Health, BioTheranostics, Roche/Genentech, Merck, Daiichi Sankyo, Puma Biotechnology, PreciscaSpeakers' Bureau: Genomic Health, Genentech/RocheTravel, Accommodations, Expenses: Genomic Health, Genentech/RocheNo other potential conflicts of interest were reported.

Purpose: Accrual to clinical trials that challenge well-established treatment paradigms represents a unique challenge. Physician opinions on investigation of a novel approach to breast cancer treatment, in which patients with complete response to neoadjuvant chemotherapy are offered omission of lumpectomy, are unknown. NRG-CC006 sought to describe physician attitudes toward a novel approach to breast cancer treatment., Methods: We recruited 18 participants in the fields of surgery, medical oncology, and radiation oncology to participate in the semi-structured telephone interviews. Main outcomes are qualitative themes associated with omission of surgery., Results: Of 18 interview participants, specialty and gender were evenly represented across surgery, medical oncology, and radiation oncology. Qualitative themes included general attitudes toward treatment de-escalation, stakeholder considerations, and trial/protocol considerations. The vast majority of participants expressed interest in investigation of omission of surgery, with all participants endorsing need for further investigation into treatment de-escalation. Stakeholder considerations in opening such a trial emphasized need for multidisciplinary involvement and, particularly, the unique role of surgeons as gatekeepers in breast cancer treatment. Finally, participants endorsed a need for further foundational studies to develop ways to predict complete pathologic response to chemotherapy without surgical intervention., Conclusions: Physicians expressed interest in investigating a novel approach to breast cancer treatment that would omit surgery in complete responders to neoadjuvant chemotherapy. Multidisciplinary input, and specifically surgeon engagement, will be key to the success of future investigations. Ongoing work to develop approaches to predict pathologic complete response accurately is needed to achieve the promise of this idea. ClinTrials #: BR005: NCT03188393 June 13, 2017.

Surgery has always been the backbone of breast cancer management. Throughout the past century, there have been great advances in chemotherapy regimens, especially in the neo-adjuvant setting. As a result of this progress, a patient's disease can be potentially down-staged and thus surgical intervention can therefore be de-escalated for the breast as well as the axilla. Current clinical trials are evaluating the role of imaging and core needle biopsy as predictive tools for the efficacy of neo-adjuvant chemotherapy. Results from these trials may help to clarify how the intricate relationship among imaging, pathology, radiotherapy, and surgery will affect the future management of patients undergoing neo-adjuvant chemotherapy for invasive breast cancer., (© 2019 Wiley Periodicals, Inc.)

Background: Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation., Methods: We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov, NCT00103181., Findings: Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5-11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94-1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7-5·7) in the APBI group versus 3·9% (3·1-5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group., Interpretation: APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women., Funding: National Cancer Institute, US Department of Health and Human Services., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: Lymphedema is a potential complication of breast cancer treatment. This longitudinal substudy aimed to prospectively assess arm measurements and symptoms following neoadjuvant chemotherapy and axillary dissection in the ACOSOG/Alliance Z1071 trial to characterize the optimal approach to define lymphedema., Methods: Z1071 enrolled patients with cT0-4, N1-2, M0 disease treated with neoadjuvant chemotherapy. All patients underwent axillary dissection. Bilateral limb volumes, circumferences, and related symptoms were assessed pre-surgery, 1-2 weeks post-surgery, and semiannually for 36 months. Lymphedema definitions included volume increase ≥ 10% or limb circumference increase ≥ 2 cm. Symptoms were assessed by the Lymphedema Breast Cancer Questionnaire., Results: In 488 evaluable patients, lymphedema incidence at 3 years by ≥ 10%-volume-increase was 60.3% (95% CI 55.0-66.2%) and by ≥ 2 cm-circumference increase was 75.4% (95% CI 70.8-80.2%). Symptoms of arm swelling and heaviness decreased from post-surgery for the first 18 months and then were relatively stable. The 3-year cumulative incidence of arm swelling and heaviness was 26.0% (95% CI 21.7-31.1%) and 30.9% (95% CI 26.3-36.3%), respectively. There was limited agreement between the two measurements (kappa 0.27) and between symptoms and measurements (kappa coefficients ranging from 0.05-0.09)., Conclusions: Lymphedema incidence by limb volume and circumference gradually increased over 36 months post-surgery, whereas lymphedema symptoms were much lower. These findings underscore the importance of prospective surveillance and evaluation of both limb measurements and symptom assessment. Lymphedema incidence rates varied by definition. We recommend that ≥ 10% volume change criterion be used for lymphedema evaluation for referral for specialist care., Trial Registration: NCT00881361.

Purpose: CDK4/6 inhibitors are used to treat estrogen receptor (ER)-positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy., Patients and Methods: Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the  MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase., Results: Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (-4.1 v -2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of -97.4% versus -88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (-0.80 v -0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia., Conclusion: Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.

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: To analyze the effect of post-radiation therapy (XRT) mammographic timing and radiation technique in relation to additional downstream workup for 569 breast conservation therapy patients treated with adjuvant XRT after their initial surveillance mammogram (MMG)., Methods and Materials: From January 2011 to December 2014, 569 breast cancer patients treated with breast conservation surgery and adjuvant XRT with a follow-up MMG were reviewed. Patients were stratified by the time interval until their first post-XRT MMG, and by XRT technique-whole breast (472), accelerated partial breast (96), conventional fractionation (373), hypofractionation (94), surgical cavity boosts (407), or no boost (66). The primary endpoint was further imaging after the initial MMG., Results: Additional workup for those receiving an MMG within 3 months of completing XRT was 51% (73 of 143), compared with 40% (84 of 210) with MMG between 3 and 6 months and 34.5% (75 of 216) with MMG after 6 months (P=.04). Radiation boost to the postoperative bed was associated with further downstream imaging, whereas accelerated partial-breast irradiation and hypofractionated treatment were not., Conclusions: Breast conservation therapy patients who underwent screening MMG before 6 months after completion of XRT were more likely to undergo downstream workup, including additional biopsies. Accelerated and hypofractionated radiation techniques were not associated with supplementary workup. Further study is needed to assess appropriate selection of high-risk patients and possible negative implications of earlier post-XRT screening MMG., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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.

Background: The long-term effects of chemotherapy are sparsely reported. Peripheral neuropathy (PN) is one of the most frequent toxicities associated with taxane use for the treatment of early-stage breast cancer. We investigated the impact of the three different docetaxel-based regimens and patient characteristics on long-term, patient-reported outcomes of PN and the impact of PN on long-term quality of life (QOL)., Methods: The National Surgical Adjuvant Breast and Bowel Project Protocol B-30 was a randomized trial comparing sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T) (AC→T), concurrent ACT, or AT in women with node-positive, early-stage breast cancer. The AC→T group had a higher cumulative dose of T. PN was one of the symptoms assessed in a QOL substudy. Statistical methods included simple and mixed ordinal logistic regression and general linear models. All statistical tests were two-sided., Results: Of 1512 patients, 41.9% reported PN two years after treatment initiation. Treatment with AT and ACT was associated with less severe long-term PN compared with AC→T (odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.35 to 0.58; OR = 0.59, 95% CI = 0.46 to 0.75). Preexisting PN, older age, obesity, mastectomy, and greater number of positive nodes were also associated with higher risk of long-term PN. Patients who reported worse PN symptoms at 24 months had statistically significantly worse QOL (Ptrend < .001)., Conclusions: The administration of docetaxel is associated with long-term PN. The lower rate of long-term PN in AT and ACT patients might be an important consideration in supporting choosing these therapies for individuals with preexisting neuropathic symptoms or other risk factors for neuropathy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: The 21-gene recurrence score (RS) predicts outcome and benefit from adjuvant chemotherapy benefit in breast cancer patients treated with adjuvant endocrine therapy. In the NSABP B-28 study, we evaluated the 21-gene RS for its prognostic impact and its ability to predict benefit from paclitaxel (P) in node-positive, estrogen receptor-positive (ER+) breast cancer patients treated with adjuvant chemotherapy plus tamoxifen., Methods: The B-28 trial compared doxorubicin/cyclophosphamide (AC) with AC followed by P in 3060 patients. Tamoxifen for 5 years was also given to patients > 50 years and those < 50 years with ER+ and/or progesterone receptor-positive (PR+) tumors. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Median follow-up time was 11.2 years., Results: In univariate analyses, RS was a significant predictor of outcome. In multivariate analyses, RS remained a significant independent predictor of outcome beyond clinico-pathologic factors, age, and type of surgery (p < 0.001). In the study population (n = 1065), the disease-free survival (DFS) hazard ratio (HR) with adding P to AC was 0.87 (95% CI 0.72-1.05; p = 0.14). RS was not a significant predictor of P benefit: for DFS, HRs for adding P to AC in RS low, intermediate, and high subgroups were 1.01 (95% CI 0.69-1.47; p = 0.99), 0.84 (95% CI 0.62-1.14; p = 0.26), and 0.81 (95% CI 0.60-1.10; p = 0.21), respectively (interaction p = 0.64). Similar findings were observed for the other study endpoints., Conclusions: RS maintains significant prognostic impact in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen. However, RS did not significantly predict benefit from adding paclitaxel to AC chemotherapy. (Trial Registration: PDQ: NSABP-B-28).

Background: Women with node-positive breast cancer are at high risk for recurrence. We evaluate the impact of approximated tumor subtype and response to chemotherapy on long-term outcomes in a node-positive cohort receiving neoadjuvant chemotherapy., Methods: ACOSOG Z1071 enrolled cT0-4N1-2 breast cancer patients treated with neoadjuvant chemotherapy from 2009 to 2011. Factors impacting breast cancer-specific survival (BCSS) and overall survival (OS) were analyzed., Results: Median follow-up of 701 eligible patients was 4.1 years (0.4-6.5). Ninety patients (12.8%) died from breast cancer. Approximated subtype and chemotherapy response were significantly associated with BCSS and OS (P < 0.0001). BCSS and OS were highest in patients who achieved pathologic complete response (pCR) (P < 0.0001 and P < 0.0001, respectively).Five-year BCSS was highest in human epidermal growth factor receptor 2 (HER2)-positive disease [95.8%; 95% confidence interval (CI): 87.7-98.6], followed by hormone receptor-positive/HER2-negative (80.4%; 95% CI: 73.2-85.9) and lowest in triple-negative (TNBC) (74.8%; 95% CI: 66.6-81.2; P < 0.0001). Similar patterns were seen in OS.In TNBC (n = 174), 5-year BCSS was higher in patients with pCR versus residual disease (89.8%; 95% CI: 78.8-95.3 vs 65.8%; 95% CI: 54.5-74.9; P = 0.0013). In hormone receptor-positive/HER2-negative (n = 318) disease, BCSS was 100% in patients with pCR and 78.3% (95% CI: 70.4-84.3) in those with residual disease (P = 0.018). In HER2-positive disease (n = 204) there was no difference between pCR and residual disease (96.0%; 95% CI: 83.6-99.1 vs 95.8%; 95% CI: 81.4-99.1; P = 0.77)., Conclusions: In node-positive breast cancer patients treated with neoadjuvant chemotherapy, BCSS and OS were associated with approximated subtype and chemotherapy response and were lowest in TNBC patients with residual disease. Five-year BCSS was > 95% in HER2-positive disease independent of chemotherapy response.

Purpose: Postmastectomy chest wall radiation therapy has historically used bolus to increase dose at the skin surface. Despite the theoretical benefits of bolus, the clinical implications of locoregional tumor control, cosmesis, and the incidence of radiodermatitis are less well characterized. We hypothesized that treatment in the presence or absence of bolus results in equivalent chest wall recurrence rates, but its presence results in more severe acute dermatologic toxicity., Methods and Materials: Locally advanced breast cancer patients undergoing chest wall radiation therapy were retrospectively reviewed from 2005 to 2015 (n = 106; 53 with bolus, 53 without). Outcomes including local failure, acute skin toxicity, and treatment interruptions were recorded. Median age was 59 years (range, 28-91) and median follow-up was 34 months. Histology was invasive ductal carcinoma (73%), invasive lobular carcinoma (20%), inflammatory (6%), and neuroendocrine (1%). Fifty-nine percent were T3/T4 primary tumors and 29.2% had clinical/pathologic skin involvement. Node-positive patients accounted for 80.2%. Chemotherapy was administered in 84.0%. All patients had 3-dimensional conformal radiation therapy and received a median dose of 61Gy (range, 50-63 Gy)., Results: Local failure was 6.6% (n = 7) overall, with 4 failures in the bolus group and 3 in the no bolus group. No pathological factors were associated with local failure. Acute grade 2 and 3 skin toxicities (37 vs 22) and treatment interruptions (20 vs 3) were more common in the bolus group (P < .05). Mean treatment interruption (14.5 vs 5 days) was longer for patients receiving bolus. Patients undergoing treatment interruption were more likely to fail locally than patients not requiring a treatment interruption (17.4% vs 3.6%, P = .0322)., Conclusions: Bolus omission in adjuvant chest wall radiation therapy may be a reasonable approach to avoid acute skin toxicity and treatment interruptions while preserving local control; however, further study will be needed to reach a definitive conclusion., (Copyright © 2016. Published by Elsevier Inc.)

The National Surgical Adjuvant Breast and Bowel Project (NSABP) has made significant contributions in reducing the extent of breast surgery and in improving outcomes of patients with early-stage breast cancer through the conduct of large randomized clinical trials evaluating local and systemic therapy. In 2014, the NSABP merged with two other US National Cancer Institute-funded cooperative groups, the Radiation Therapy Oncology Group (RTOG) and the Gynecologic Oncology Group (GOG), to form NRG Oncology. The combined organization has 218 member institutions with more than 600 affiliate centers located throughout the United States, Canada, Puerto Rico, and other international sites. Over the past half century, the NSABP has entered more than 150,000 women into clinical trials of breast cancer treatment and breast cancer prevention. Many of these trials have been instrumental in establishing new standards of care for patients with breast cancer.

Background: The 21-gene recurrence score (RS) predicts risk of locoregional recurrence (LRR) in node-negative, estrogen receptor (ER)-positive breast cancer. We evaluated the association between RS and LRR in node-positive, ER-positive patients treated with adjuvant chemotherapy plus tamoxifen in National Surgical Adjuvant Breast and Bowel Project B-28., Methods: B-28 compared doxorubicin/cyclophosphamide (AC X 4) with AC X 4 followed by paclitaxel X 4. Tamoxifen was given to patients age 50 years or older and those younger than age 50 years with ER-positive and/or progesterone receptor-positive tumors. Lumpectomy patients received breast radiotherapy. Mastectomy patients received no radiotherapy. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Cumulative incidence functions and subdistribution hazard regression models were used for LRR to account for competing risks including distant recurrence, second primary cancers, and death from other causes. Median follow-up was 11.2 years. All statistical tests were one-sided., Results: There were 80 LRRs (7.5%) as first events (68% local/32% regional). RS was low: 36.2%; intermediate: 34.2%; and high: 29.6%. RS was a statistically significant predictor of LRR in univariate analyses (10-year cumulative incidence of LRR = 3.3%, 7.2%, and 12.2% for low, intermediate, and high RS, respectively, P < .001). In multivariable regression analysis, RS remained an independent predictor of LRR (hazard ratio [HR] = 2.59, 95% confidence interval [CI] = 1.28 to 5.26, for a 50-point difference, P = .008) along with pathologic nodal status (HR = 1.91, 95% CI = 1.20 to 3.03, for four or more vs one to three positive nodes, P = .006) and tumor size (HR = 1.28, 95% CI = 1.05 to 1.55, for a 1 cm difference, P = .02)., Conclusions: RS statistically significantly predicts risk of LRR in node-positive, ER-positive breast cancer patients after adjuvant chemotherapy plus tamoxifen. These findings can help in the selection of appropriate candidates for comprehensive radiotherapy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy., Methods: The double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (<60 vs ≥60 years) and patients and investigators were masked to treatment allocation. The primary outcome was breast cancer-free interval, defined as time from randomisation to any breast cancer event (local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00053898, and is complete., Findings: Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9·0 years (IQR 8·2-10·0). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0·73 [95% CI 0·56-0·96], p=0·0234). A significant time-by-treatment interaction (p=0·0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0·0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism--a known side-effect of tamoxifen-for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group., Interpretation: Compared with tamoxifen, anastrozole treatment provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age. This finding means that women will benefit from having a choice of effective agents for ductal carcinoma in situ., Funding: US National Cancer Institute and AstraZeneca Pharmaceuticals LP., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The NSABP B-35 trial compared 5 years of treatment with anastrozole versus tamoxifen for reducing subsequent occurrence of breast cancer in postmenopausal patients with ductal carcinoma in situ. This report assesses the effect of these drugs on quality of life and symptoms., Methods: The study was done at 333 hospitals in North America. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole breast irradiation were randomly assigned to receive either tamoxifen (20 mg/day) or anastrazole (1 mg/day) for 5 years, stratified by age (<60 years vs ≥60 years). Patients and investigators were masked to treatment allocation. Patients completed questionnaires at baseline and every 6 months thereafter for 6 years. The primary outcomes were SF-12 physical and mental health component scale scores, and vasomotor symptoms (as per the BCPT symptom scale). Secondary outcomes were vaginal symptoms and sexual functioning. Exploratory outcomes were musculoskeletal pain, bladder symptoms, gynaecological symptoms, cognitive symptoms, weight problems, vitality, and depression. We did the analyses by intention to treat, including patients who completed questionnaires at baseline and at least once during follow-up. This study is registered with ClinicalTrials.gov, NCT00053898., Findings: Between Jan 6, 2003, and June 15, 2006, 3104 patients were enrolled in the study, of whom 1193 were included in the quality-of-life substudy: 601 assigned to tamoxifen and 592 assigned to anastrozole. We detected no significant difference between treatment groups for: physical health scores (mean severity score 46·72 for tamoxifen vs 45·85 for anastrozole; p=0·20), mental health scores (52·38 vs 51·48; p=0·38), energy and fatigue (58·34 vs 57·54; p=0·86), or symptoms of depression (6·19 vs 6·39; p=0·46) over 5 years. Vasomotor symptoms (1·33 vs 1·17; p=0·011), difficulty with bladder control (0·96 vs 0·80; p=0·0002), and gynaecological symptoms (0·29 vs 0·18; p<0·0001) were significantly more severe in the tamoxifen group than in the anastrozole group. Musculoskeletal pain (1·50 vs 1·72; p=0·0006) and vaginal symptoms (0·76 vs 0·86; p=0·035) were significantly worse in the anastrozole group than in the tamoxifen group. Sexual functioning did not differ significantly between the two treatments (43·65 vs 45·29; p=0·56). Younger age was significantly associated with more severe vasomotor symptoms (mean severity score 1·45 for age <60 years vs 0·65 for age ≥60 years; p=0·0006), vaginal symptoms (0·98 vs 0·65; p<0·0001), weight problems (1·32 vs 1·02; p<0·0001), and gynaecological symptoms (0·26 vs 0·22; p=0·014)., Interpretation: Given the similar efficacy of tamoxifen and anastrozole for women older than age 60 years, decisions about treatment should be informed by the risk for serious adverse health effects and the symptoms associated with each drug. For women younger than 60 years old, treatment decisions might be driven by efficacy (favouring anastrozole); however, if the side-effects of anastrozole are intolerable, then switching to tamoxifen is a good alternative., Funding: US National Cancer Institute, AstraZeneca Pharmaceuticals., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Ductal carcinoma in situ of the breast has rapidly increased in incidence over the past several decades secondary to an increased use of screening mammography. Local treatment options for women diagnosed with ductal carcinoma in situ include mastectomy or breast-conserving therapy. Although several randomized trials have confirmed a >50% reduction in the risk of local recurrence with the administration of radiation therapy (RT) compared with breast-conserving surgery alone, controversy persists regarding whether or not RT is needed in selected "low-risk" patients. Over the past two decades, two prospective single-arm studies and one randomized trial have been performed and confirm that the omission of RT after surgery is associated with higher rates of local recurrence even after selecting patients with optimal clinical and pathologic features. Importantly, these trials have failed to consistently and reproducibly identify a low-risk cohort of patients (based on clinical and pathologic features) that does not benefit from RT. As a result, adjuvant RT is still advocated in the majority of patients, even in low-risk cases. Future research is moving beyond traditional clinical and pathologic risk factors and instead focusing on approaches such as multigene assays and biomarkers with the hopes of identifying truly low-risk patients who may not require RT. However, recent studies confirm that even low-risk patients identified from multigene assays have higher rates of local recurrence with local excision alone than would be expected with the addition of RT.

Objective: To establish a safety profile for amnion-derived cellular cytokine solution following topical application in patients undergoing whole breast radiotherapy for breast cancer., Materials and Methods: Twenty female patients with early-stage breast cancer were enrolled in 2 separate cohorts of an institutional review board-approved phase I protocol. Cohort 1 consisted of 10 patients who received topical amnion-derived cellular cytokine solution to the breast immediately following the first 10 fractions of whole breast radiotherapy. Cohort 2 consisted of 10 additional patients who fit the same criteria as the initial cohort but received topical amnion-derived cellular cytokine solution following the development of at least grade I breast erythema. Blood samples were tested for the presence of proteins in amnion-derived cellular cytokine solution as well as routine hematologic functions., Results: Amnion-derived cellular cytokine solution did not induce overproduction of any cytokines sampled, and there was no evidence of "cytokine storm." It also showed no significant absorption systemically following topical delivery. No patients developed an adverse event. There were no patterns of changes in vital signs or clinical laboratory tests that were related to the treatment regimen., Conclusion: In this safety trial, the topical application of amnion-derived cellular cytokine solution in both intact and denuded, irradiated skin was found to be safe, and showed no evidence of systemic absorption. No cosmetic changes were identified long term. Patient blood chemistry was not adversely affected, indicating the absence of an anaphylactic response and no evidence "cytokine storm" was identified. Amnion-derived cellular cytokine solution is safe to use topically in clinical protocols.

The surgical management of breast cancer has changed considerably since the use of the Halstedian radical mastectomy early in the 20th century. Over the last 50 years, several landmark clinical trials from the USA and Europe have resulted in a paradigm shift in the management of breast cancer toward less radical forms of surgery with the combined use of multi-modality treatments including systemic chemotherapy, endocrine therapy, and radiotherapy. Advances in such research have established a new worldwide standard of care for breast cancer surgical management and treatment, which has become more patient centric and which places a higher emphasis on cosmesis and improved patient quality of life. In this chapter, we review the landmark clinical trials that have influenced surgical management for non-invasive and invasive breast cancer and that serve to guide current clinical practices to date., (© 2014 Wiley Periodicals, Inc.)

Purpose: To report our long-term experience with balloon brachytherapy in retreatment of the breast after ipsilateral breast tumor recurrence., Methods and Materials: Between March 2004 and June 2012, 18 patients previously treated with external beam radiotherapy were retreated using either the MammoSite (Hologic Corporation, Marlborough, MA), MammoSite ML (Hologic Corporation), or the Contura (Bard Peripheral Vascular, Inc., Tempe, AZ) brachytherapy devices. Sixteen patients were treated for an ipsilateral breast tumor recurrence after breast conservation surgery and postoperative irradiation (11 with infiltrating ductal carcinoma [IDC] and 6 with ductal carcinoma in situ [DCIS]), whereas 2 patients developed an in-field breast cancer likely associated with Hodgkin disease mantle irradiation (27 and 17 years prior, respectively). The recurrent histology of seven was IDC, with seven others recurring as DCIS, three as a combination of IDC/DCIS, and one as infiltrating lobular carcinoma. All patients received a twice-daily tumor dose of 3400 cGy at 340 cGy per fraction. Acute and chronic side effects were graded by the Common Terminology Criteria for Adverse Events, version 4.0. Cosmesis was graded by both the Harvard Cosmesis Scale and the Allegheny General Modification of the Harvard Scale., Results: With a mean of followup of 39.6 months, only 2 patients developed a local recurrence. One patient developed an inflammatory recurrence from what was identified as a moderately differentiated T1N0M0 estrogen receptor-positive recurrence, and the second developed a recurrence immediately adjacent to the implant site. Both patients were treated locally by salvage mastectomy. The patient who developed an inflammatory recurrence rapidly developed visceral metastases including brain lesions and succumbed to her progressive disease. The second patient was successfully salvaged with uncomplicated mastectomy, and she survives to this date. One patient developed a chronic abscess in the sinus tract of the balloon, which required mastectomy, and one developed a post-treatment infection in the catheter tract, which was successfully treated with oral antibiotics. Cosmesis as graded by the Harvard cosmesis criteria and the Allegheny General Modification Score diminished one grade in only 2 patients. All other patients had stable cosmetic scores., Conclusions: Use of balloon brachytherapy devices in the treatment of the previously irradiated breast is feasible and may provide adequate local control and acceptable cosmesis in carefully selected patients. Further study and refinement of this therapy is required for more definitive results., (Copyright © 2014 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Breast-conserving therapy consisting of segmental mastectomy followed by whole-breast irradiation (WBI) has become widely accepted as an alternative to mastectomy as a treatment for women with early-stage breast cancer. WBI is typically delivered over the course of 5-6 weeks to the whole breast. Hypofractionated whole-breast irradiation and accelerated partial breast irradiation have developed as alternative radiation techniques for select patients with favorable early-stage breast cancer. These radiation regimens allow for greater patient convenience and the potential for decreased health care costs. We review here the scientific rationale behind delivering a shorter course of radiation therapy using these distinct treatment regimens in this setting as well as an overview of the published data and pending trials comparing these alternative treatment regimens to WBI., (© 2014 Wiley Periodicals, Inc.)

NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust.

Importance: Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies., Objective: To determine the false-negative rate (FNR) for SLN surgery following chemotherapy in women initially presenting with biopsy-proven cN1 breast cancer., Design, Setting, and Patients: The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial enrolled women from 136 institutions from July 2009 to June 2011 who had clinical T0 through T4, N1 through N2, M0 breast cancer and received neoadjuvant chemotherapy. Following chemotherapy, patients underwent both SLN surgery and ALND. Sentinel lymph node surgery using both blue dye (isosulfan blue or methylene blue) and a radiolabeled colloid mapping agent was encouraged., Main Outcomes and Measures: The primary end point was the FNR of SLN surgery after chemotherapy in women who presented with cN1 disease. We evaluated the likelihood that the FNR in patients with 2 or more SLNs examined was greater than 10%, the rate expected for women undergoing SLN surgery who present with cN0 disease., Results: Seven hundred fifty-six women were enrolled in the study. Of 663 evaluable patients with cN1 disease, 649 underwent chemotherapy followed by both SLN surgery and ALND. An SLN could not be identified in 46 patients (7.1%). Only 1 SLN was excised in 78 patients (12.0%). Of the remaining 525 patients with 2 or more SLNs removed, no cancer was identified in the axillary lymph nodes of 215 patients, yielding a pathological complete nodal response of 41.0% (95% CI, 36.7%-45.3%). In 39 patients, cancer was not identified in the SLNs but was found in lymph nodes obtained with ALND, resulting in an FNR of 12.6% (90% Bayesian credible interval, 9.85%-16.05%)., Conclusions and Relevance: Among women with cN1 breast cancer receiving neoadjuvant chemotherapy who had 2 or more SLNs examined, the FNR was not found to be 10% or less. Given this FNR threshold, changes in approach and patient selection that result in greater sensitivity would be necessary to support the use of SLN surgery as an alternative to ALND., Trial Registration: clinicaltrials.gov Identifier: NCT00881361.

Advances in methods used to diagnose breast cancer have resulted in the increased detection of ductal carcinoma in situ; most of these are detected by screening mammograms and are confirmed by core needle biopsy. Currently, classification schemas are moving toward a molecular approach. Treatment options for patients with ductal carcinoma in situ are multiple and take into consideration end points such as local, regional or distant recurrence, overall survival and quality of life. Treatment methods continue to be controversial and debated in the oncology community. The quality of local control is multifactorial and depends on adequate surgical clearance, biological characteristics of the tumor, clinical presentation and the possibility of radiation therapies.

Purpose: Final dosimetric findings of a completed, multi-institutional phase 4 registry trial using the Contura Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer are presented., Methods and Materials: Three dosimetric plans with identical target coverage were generated for each patient for comparison: multilumen multidwell (MLMD); central-lumen multidwell (CLMD); and central-lumen single-dwell (CLSD) loading of the Contura catheter. For this study, a successful treatment plan achieved ideal dosimetric goals and included the following: ≥ 95% of the prescribed dose (PD) covering ≥ 95% of the target volume (TV); maximum skin dose ≤ 125% of the PD; maximum rib dose ≤ 145% of the PD; and V150 ≤50 cc and V200 ≤ 10 cc., Results: Between January 2008 and February 2011, 23 institutions participated. A total of 318 patients were available for dosimetric review. Using the Contura MLB, all dosimetric criteria were met in 78.93% of cases planned with MLMD versus 55.38% with the CLMD versus 37.66% with the CLSD (P ≤.0001). Evaluating all patients with the full range of skin to balloon distance represented, median maximum skin dose was reduced by 12% and median maximum rib dose by 13.9% when using MLMD-based dosimetric plans compared to CLSD. The dosimetric benefit of MLMD was further demonstrated in the subgroup of patients where skin thickness was <5 mm, where MLMD use allowed a 38% reduction in median maximum skin dose over CLSD. For patients with rib distance <5 mm, the median maximum rib dose reduction was 27%., Conclusions: Use of the Contura MLB catheter produced statistically significant improvements in dosimetric capabilities between CLSD and CLMD treatments. This device approach demonstrates the ability not only to overcome the barriers of limited skin thickness and close rib proximity, but to consistently achieve a higher standard of dosimetric planning goals., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The impact of arm morbidity following breast cancer surgery on patient-observed changes in daily functioning and health-related quality of life (HRQoL) has not been well-studied., Objective: To examine the association of objective measures such as range of motion (ROM) and lymphedema, with patient-reported outcomes (PROs) in the arm and breast, upper extremity function, activities, and HRQoL., Methods: The National Surgical Adjuvant Breast and Bowel Project Protocol B-32 was a randomized trial comparing sentinel node resection (SNR) with axillary dissection (AD) in women with node-negative breast cancer. ROM and arm volume were measured objectively. PROs included symptoms; arm function; limitations in social, recreational, occupational, and other regular activities; and a global index of HRQoL. Statistical methods included cross-tabulations and multivariable linear regression models., Results: In all, 744 women provided at least 1 postsurgery assessment. About one-third of the patients experienced arm mobility restrictions. A similar number of patients avoided the use of the arm 6 months after surgery. Limitations in work and other regular activities were reported by about a quarter of the patients. In this multivariable analysis, arm mobility and sensory neuropathy were predictors of patient-reported arm function and overall HRQoL. Predictors for activity limitations also included side of surgery (dominant vs nondominant). Edema was not significant after adjustment for sensory neuropathy and ROM., Limitations: Arm mobility and edema were measured simultaneously only once during the follow-up (6 months)., Conclusion: Clinical measures of sensory neuropathy and restrictions in arm mobility following breast cancer surgery are associated with self-reported limitations in activity and reductions in overall HRQoL.

Purpose: The limited information on predictors of locoregional recurrence (LRR) after neoadjuvant chemotherapy (NC) has resulted in controversy about the optimal use of adjuvant radiotherapy and the timing of sentinel lymph node biopsy., Patients and Methods: We examined patterns and predictors of LRR as first event in combined analysis of two National Surgical Adjuvant Breast and Bowel Project (NSABP) neoadjuvant trials. NC was either doxorubicin/cyclophosphamide (AC) alone or AC followed by neoadjuvant/adjuvant docetaxel. Lumpectomy patients received breast radiotherapy alone; mastectomy patients received no radiotherapy. Pathologic complete response was defined as the absence of invasive tumor in the breast. Multivariate analyses were used to identify independent predictors of LRR. The primary end point was time to LRR as first event., Results: In 3,088 patients, 335 LRR events had occurred after 10 years of follow-up. The 10-year cumulative incidence of LRR was 12.3% for mastectomy patients (8.9% local; 3.4% regional) and 10.3% for lumpectomy plus breast radiotherapy patients (8.1% local; 2.2% regional). Independent predictors of LRR in lumpectomy patients were age, clinical nodal status (before NC), and pathologic nodal status/breast tumor response; in mastectomy patients, they were clinical tumor size (before NC), clinical nodal status (before NC), and pathologic nodal status/breast tumor response. By using these independent predictors, groups at low, intermediate, and high risk of LRR could be identified. Nomograms that incorporate these independent predictors were created., Conclusion: In patients treated with NC, age, clinical tumor characteristics before NC, and pathologic nodal status/breast tumor response after NC can be used to predict risk for LRR and to optimize the use of adjuvant radiotherapy.

While any study can be criticized, the results of Z0011 clearly show that sentinel lymph node biopsy (SLNB) alone without axillary lymph node dissection (ALND) results in extremely low locoregional recurrence and excellent overall survival comparable to completion ALND. The observed results in this trial with SLNB alone were excellent. A prospective randomized study with results such as Z0011 should alter therapy. The skilled clinician must utilize his or her experience and the prospective randomized data of this study to improve patient care for women with breast cancer. On the other hand, ALND continues to be the standard of care for positive nodes in the axilla, with lymph node status as the most important prognostic indicator in overall survival (OS) and disease-free survival (DFS) in the management of early stage breast cancer. The advent of sentinel lymph node resection (SLNR) is challenging this notion. There is evidence to support the need for regional control of the axilla as a preventative means for locoregional recurrence and improvement in DFS. ALND is both a diagnostic and therapeutic approach that not only decreases rates of locoregional recurrence, but also guides further treatment strategies. Currently, there are no definable criteria that completely prevent patients from benefiting from ALND in the setting of metastatic disease to the axilla. It is, therefore, clear that ALND should be strongly considered in the management of the SLN-positive axilla. SLNR has its role in the management of early stage breast cancer, but whether SLNR alone should replace ALND is yet to be determined.

Purpose: The NSABP (National Surgical Adjuvant Breast and Bowel Project) B-24 study demonstrated significant benefit with adjuvant tamoxifen in patients with ductal carcinoma in situ (DCIS) after lumpectomy and radiation. Patients were enrolled without knowledge of hormone receptor status. The current study retrospectively evaluated the relationship between receptors and response to tamoxifen., Patients and Methods: Estrogen (ER) and progesterone receptors (PgR) were evaluated in 732 patients with DCIS (41% of original study population). An experienced central laboratory determined receptor status in all patient cases with available paraffin blocks (n = 449) by immunohistochemistry (IHC) using comprehensively validated assays. Results for additional patients (n = 283) determined by various methods (primarily IHC) were available from enrolling institutions. Combined results were evaluated for benefit of tamoxifen by receptor status at 10 years and overall follow-up (median, 14.5 years)., Results: ER was positive in 76% of patients. Patients with ER-positive DCIS treated with tamoxifen (v placebo) showed significant decreases in subsequent breast cancer at 10 years (hazard ratio [HR], 0.49; P < .001) and overall follow-up (HR, 0.60; P = .003), which remained significant in multivariable analysis (overall HR, 0.64; P = .003). Results were similar, but less significant, when subsequent ipsilateral and contralateral, invasive and noninvasive, breast cancers were considered separately. No significant benefit was observed in ER-negative DCIS. PgR and either receptor were positive in 66% and 79% of patients, respectively, and in general, neither was more predictive than ER alone., Conclusion: Patients in NSABP B-24 with ER-positive DCIS receiving adjuvant tamoxifen after standard therapy showed significant reductions in subsequent breast cancer. The use of adjuvant tamoxifen should be considered for patients with DCIS.

Purpose: The impact of using the Contura multilumen balloon (MLB) (SenoRx, Inc., Irvine, CA) breast brachytherapy catheter's vacuum port in patients treated with accelerated partial breast irradiation (APBI) was analyzed., Methods and Materials: Data from 32 patients at two sites were reviewed. Variables analyzed included the seroma fluid (SF):air volume around the MLB before and after vacuum port use and on its ability to improve (1) the eligibility of patients for APBI and (2) dose coverage of the planning target volume for evaluation (PTV&#95;EVAL) in eligible patients., Results: The median SF/air volume before vacuum removal was 6.8 cc vs. 0.8 cc after vacuum removal (median reduction in SF/air volume was 90.5%). Before vacuum port use, the median SF/air volume expressed as percentage of the PTV&#95;EVAL was 7.8% (range, 1.9-26.6) in all patients. After application of the vacuum, this was reduced to 1.2%. Before vacuum port use, 10 (31.3%) patients were not considered acceptable candidates for APBI because the SF/air volume:PTV&#95;EVAL ratio (SF:PTV) was greater than 10% (range, 10.1-26.6%; median, 15.2%). After vacuum port use, the median SF:PTV ratio was 1.6% for a median reduction of 91.5%. In addition, the percentage of the prescribed dose covering greater than or equal to 90% of the PTV&#95;EVAL proportionally increased a median of 8% (range, 3-10%) in eligible patients., Conclusion: Use of the Contura MLB vacuum port significantly improved the conformity of the target tissue to the balloon surface, leading to reproducible dose delivery and increased target volume coverage. In addition, application of the vacuum allowed the safe treatment of unacceptable patients with APBI., (Copyright © 2011 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background: Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS., Methods: In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer-specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients)., Results: Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio [HR] of risk of I-IBTR = 0.48, 95% confidence interval [CI] = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM., Conclusions: Although I-IBTR increased the risk for breast cancer-related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.

Background: Retrospective and observational analyses suggest that occult lymph-node metastases are an important prognostic factor for disease recurrence or survival among patients with breast cancer. Prospective data on clinical outcomes from randomized trials according to sentinel-node involvement have been lacking., Methods: We randomly assigned women with breast cancer to sentinel-lymph-node biopsy plus axillary dissection or sentinel-lymph-node biopsy alone. Paraffin-embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. Both routine staining and immunohistochemical staining for cytokeratin were used at two widely spaced additional tissue levels. Treating physicians were unaware of the findings, which were not used for clinical treatment decisions. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in the greatest dimension., Results: Occult metastases were detected in 15.9% (95% confidence interval [CI], 14.7 to 17.1) of 3887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P=0.03), disease-free survival (P=0.02), and distant-disease-free interval (P=0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95% CI, 1.05 to 1.86), 1.31 (95% CI, 1.07 to 1.60), and 1.30 (95% CI, 1.02 to 1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively., Conclusions: Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points). These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003830.).

The need for completion axillary dissection after a positive sentinel node biopsy continues to be challenged. In the 2 years since we last reviewed this subject, a number of authors have shared their experiences about micrometastatic disease and isolated tumor cells, opining both for and against axillary treatment. Data from the ACOSOG Z0011 trial and other small studies do not appear to support the use of completion axillary dissection even for macro-metastatic disease in patients with clinically node-negative (N0) disease. While existing guidelines still recommend axillary dissection for patients with clinically positive nodes, even when conversion to clinically negative disease following neoadjuvant chemotherapy has occurred, this concept is being questioned in ACOSOG Z1071 and in several other recent small trials. The surgical approach to the treatment of breast cancer continues to move away from the traditional Halstedian concept.

Breast-conserving therapy (BCT) for sporadic breast cancer has been widely accepted by surgeons and patients alike. While BCT is associated with a higher risk of ipsilateral breast tumor recurrence (IBTR), it has not been shown to decrease overall survival (OS) in comparison with mastectomy. Many women with a BRCA1/2 mutation opt for mastectomy instead of breast-conserving measures at the time of a breast cancer diagnosis. In some cases, this is due to fear of aggressive disease, but to date, there have been no studies offering strong evidence that breast conservation should not be offered to these women. BRCA1/2-associated breast cancer has not been found to be more aggressive or resistant to treatment than comparable sporadic tumors, and no study has shown an actual survival advantage for mastectomy in appropriately treated affected mutation carriers. This paper reviews the available literature for breast conservation and surgical decision making in BRCA1/2 mutation carriers.

Purpose: To compare brachytherapy and three-dimensional (3-D) conformal external beam radiotherapy for breast cancer presenting in the previously irradiated breast., Methods and Materials: Thirty-six patients with TIS-T2 breast carcinomas received brachytherapy or 3-D conformal radiotherapy (3-D CRT) after lumpectomy in a previously irradiated breast as an alternative to salvage mastectomy. Brachytherapy consisted of low-dose-rate (LDR) interstitial technique in 21 patients, whereas 11 patients were treated using high-dose-rate (HDR) balloon technique. Four patients received 3-D CRT. Cosmesis was graded according to the Harvard criteria and the Allegheny General Modification of the Harvard criteria. Acute sequelae were graded according to the Common Terminology Criteria for Adverse Events (version 3.0)., Results: Thirty-five of 36 patients remained free of local failure, with a mean followup of 37 months. Five patients treated with LDR developed Grade II and two developed Grade III acute side effects. No patient treated with balloon brachytherapy or 3-D CRT developed a Grade II or higher acute effect. Cosmetically, 12 LDR interstitial patients were scored as Grade I, six as Grade II, and three as Grade III. Nine of the HDR patients were scored as Grade I, one as Grade II, and one as Grade III. Two 3-D CRT patients were scored as Grade II and two as Grade III. The Allegheny Modification of the Harvard criteria more accurately reflected the cosmetic effects of re-treatment., Conclusion: Brachytherapy is feasible for patients who desire breast preservation in a previously irradiated breast. All techniques demonstrated similar local control rates. Acute side effects were less, and cosmesis was superior in HDR balloon brachytherapy., (Copyright © 2011 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Dosimetric findings in patients treated with the Contura multilumen balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) on a multi-institutional Phase IV registry trial are presented., Methods and Materials: Computed tomography-based three-dimensional planning with dose optimization was performed. For the trial, new ideal dosimetric goals included (1) ≥95% of the prescribed dose (PD) covering ≥90% of the target volume, (2) a maximum skin dose ≤125% of the PD, (3) maximum rib dose ≤145% of the PD, and (4) the V150 ≤50 cc and V200 ≤10 cc. The ability to concurrently achieve these dosimetric goals using the Contura MLB was analyzed., Results: 144 cases were available for review. Using the MLB, all dosimetric criteria were met in 76% of cases. Evaluating dosimetric criteria individually, 92% and 89% of cases met skin and rib dose criteria, respectively. In 93% of cases, ideal target volume coverage goals were met, and in 99%, dose homogeneity criteria (V150 and V200) were satisfied. When skin thickness was ≥5 mm to <7 mm, the median skin dose was limited to 120.1% of the PD, and when skin thickness was <5 mm, the median skin dose was 124.2%. When rib distance was <5 mm, median rib dose was reduced to 136.5% of the PD. When skin thickness was <7 mm and distance to rib was <5 mm, median skin and rib doses were jointly limited to 120.6% and 142.1% of the PD, respectively., Conclusion: The Contura MLB catheter provided the means of achieving the imposed higher standard of dosimetric goals in the majority of clinical scenarios encountered., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Fat necrosis is a well-described and relatively common complication arising from post-lumpectomy irradiation of the breast, most commonly breast brachytherapy. We wish to assess the clinical significance of fat necrosis resulting from post-lumpectomy breast irradiation., Methods: We reviewed the literature to determine the overall incidence and significance of fat necrosis to determine whether or not fat necrosis poses a significant clinical problem., Results: Fat necrosis occurs in up to one-quarter of patients following post-lumpectomy breast irradiation. Only rarely is invasive intervention required however, it does significantly degrade the quality of all modalities of breast imaging., Conclusions: Fat necrosis is a common complication of radiotherapy which rarely requires therapeutic intervention. However, post-therapeutic clinical imaging such as mammography, ultrasound and magnetic resonance imaging are affected which may result in additional diagnostic procedures up to and including biopsy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Sentinel-lymph-node (SLN) surgery was designed to minimise the side-effects of lymph-node surgery but still offer outcomes equivalent to axillary-lymph-node dissection (ALND). The aims of National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 were to establish whether SLN resection in patients with breast cancer achieves the same survival and regional control as ALND, but with fewer side-effects., Methods: NSABP B-32 was a randomised controlled phase 3 trial done at 80 centres in Canada and the USA between May 1, 1999, and Feb 29, 2004. Women with invasive breast cancer were randomly assigned to either SLN resection plus ALND (group 1) or to SLN resection alone with ALND only if the SLNs were positive (group 2). Random assignment was done at the NSABP Biostatistical Center (Pittsburgh, PA, USA) with a biased coin minimisation approach in an allocation ratio of 1:1. Stratification variables were age at entry (≤ 49 years, ≥ 50 years), clinical tumour size (≤ 2·0 cm, 2·1-4·0 cm, ≥ 4·1 cm), and surgical plan (lumpectomy, mastectomy). SLN resection was done with a blue dye and radioactive tracer. Outcome analyses were done in patients who were assessed as having pathologically negative sentinel nodes and for whom follow-up data were available. The primary endpoint was overall survival. Analyses were done on an intention-to-treat basis. All deaths, irrespective of cause, were included. The mean time on study for the SLN-negative patients with follow-up information was 95·6 months (range 70·1-126·7). This study is registered with ClinicalTrials.gov, number NCT00003830., Findings: 5611 women were randomly assigned to the treatment groups, 3989 had pathologically negative SLN. 309 deaths were reported in the 3986 SLN-negative patients with follow-up information: 140 of 1975 patients in group 1 and 169 of 2011 in group 2. Log-rank comparison of overall survival in groups 1 and 2 yielded an unadjusted hazard ratio (HR) of 1·20 (95% CI 0·96-1·50; p=0·12). 8-year Kaplan-Meier estimates for overall survival were 91·8% (95% CI 90·4-93·3) in group 1 and 90·3% (88·8-91·8) in group 2. Treatment comparisons for disease-free survival yielded an unadjusted HR of 1·05 (95% CI 0·90-1·22; p=0·54). 8-year Kaplan-Meier estimates for disease-free survival were 82·4% (80·5-84·4) in group 1 and 81·5% (79·6-83·4) in group 2. There were eight regional-node recurrences as first events in group 1 and 14 in group 2 (p=0·22). Patients are continuing follow-up for longer-term assessment of survival and regional control. The most common adverse events were allergic reactions, mostly related to the administration of the blue dye., Interpretation: Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes., Funding: US Public Health Service, National Cancer Institute, and Department of Health and Human Services., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: Sentinel lymph node resection (SNR) may reduce morbidity while providing the same clinical utility as conventional axillary dissection (AD). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 is a randomized phase III trial comparing SNR immediately followed by AD (SNAD) to SNR and subsequent AD if SN is positive. We report the definitive patient-reported outcomes (PRO) comparisons., Patients and Methods: Eligible patients had clinically node-negative, operable invasive breast cancer. The PRO substudy included all SN-negative participants enrolled May 2001 to February 2004 at community institutions in the United States (n = 749; 78% age > or = 50; 87% clinical tumor size < or = 2.0 cm; 84% lumpectomy; 87% white). They completed questionnaires presurgery, 1 and 2 to 3 weeks postoperatively, and every 6 months through year 3. Arm symptoms, arm use avoidance, activity limitations, and quality of life (QOL) were compared with intent-to-treat two-sample t-tests and repeated measures analyses., Results: Arm symptoms were significantly more bothersome for SNAD compared with SNR patients at 6 months (mean, 4.8 v 3.0; P < .001) and at 12 months (3.6 v 2.5; P = .006). Longitudinally, SNAD patients were more likely to experience ipsilateral arm and breast symptoms, restricted work and social activity, and impaired QOL (P < or = .002 all items). From 12 to 36 months, fewer than 15% of either SNAD or SNR patients reported moderate or greater severity of any given symptom or activity limitation., Conclusion: Arm morbidity was greater with SNAD than with SNR. Despite considerable fears about complications from AD for breast cancer, this study demonstrates that initial problems with either surgery resolve over time.