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In this paper we provide a summary of several of the completed and ongoing surgical trials of the National Surgical Adjuvant Breast and Bowel Project, one of the cancer cooperative trials groups supported by the US National Cancer Institute. [ABSTRACT FROM AUTHOR]

Women with ductal carcinoma in situ (DCIS) are at substantially increased risk for a second breast cancer, but few strong predictors for these subsequent tumors have been identified. We used Cox regression modeling to examine the association between mammographic density at diagnosis of DCIS of 504 women from the National Surgical Adjuvant Breast and Bowel Project B-17 trial and risk of subsequent breast cancer events. In this group of patients, mostly 50 years old or older, approximately 6.6% had breasts categorized as highly dense (i.e., > or =75% of the breast occupied by dense tissue). After adjusting for treatment with radiotherapy, age, and body mass index, women with highly dense breasts had 2.8 (95% confidence interval [CI] = 1.3 to 6.1) times the risk of subsequent breast cancer (DCIS or invasive), 3.2 (95% CI = 1.2 to 8.5) times the risk of invasive breast cancer, and 3.0 (95% CI = 1.2 to 7.5) times the risk of any ipsilateral breast cancer, compared with women with less than 25% of the breast occupied by dense tissue. Our results provide initial evidence that the risk of second breast cancers may be increased among DCIS patients with highly dense breasts. [ABSTRACT FROM AUTHOR]

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.)

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: 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.)

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.)

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.)

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.

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.

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.

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.

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.

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.)

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: Electron or photon boost immediately following whole-breast irradiation performed after conservation surgery for early-stage breast cancer is the accepted standard of care. This regimen frequently results in Grade III dermatitis, causing discomfort or treatment interruption. Herein, we compare patients treated with whole-breast irradiation followed by boost compared with a cohort with a planned intercurrent radiation boost., Methods and Materials: The records of 650 consecutive breast cancer patients treated at Allegheny General Hospital (AGH) between 2000 and 2008 were reviewed. Selected for this study were 327 patients with T1 or T2 tumors treated with external beam radiotherapy postlumpectomy. One hundred and sixty-nine patients were treated by whole-breast radiotherapy (WBRT) followed by boost at completion. One hundred fifty-eight were treated with a planned intercurrent boost (delivered following 3,600 cGy WBRT). The mean whole breast radiation dose in the conventionally treated group was 5,032 cGy (range, 4500-5400 cGy), and the mean whole breast dose was 5,097 cGy (range, 4860-5040 cGy) in the group treated with a planned intercurrent boost., Results: The occurrence of Grade III dermatitis was significantly reduced in the WBRT/intercurrent boost group compared with the WBRT/boost group (0.6% vs. 8.9%), as was the incidence of treatment interruption (1.9% vs. 14.2%). With a median follow-up of 32 months and 27 months, respectively, no significant difference in local control was identified., Conclusions: Patients treated with intercurrent boost developed less Grade III dermatitis and unplanned treatment interruptions with similar local control., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background and Objectives: Three year post-surgical morbidity levels were compared between patients with negative sentinel lymph node dissection alone (SLND) and those with negative sentinel node dissection and negative axillary lymph node dissection (ALND) in the NSABP B-32 trial., Methods: A total of 1,975 ALND and 2,008 SLND node negative breast cancer patients had shoulder range of motion and arm volumes assessed along with self reports of arm tingling and numbness. Relative shoulder abduction deficits and relative arm volume differences between ipsilateral and contralateral arms were calculated., Results: Shoulder abduction deficits >or=10% peaked at 1 week for the ALND (75%) and SLND (41%) groups. Arm volume differences >or=10% at 36 months were evident for the ALND (14%) and SLND (8%) groups. Numbness and tingling peaked at 6 months for the ALND (49%, 23%) and SLND (15%, 10%) groups. Logistic regression correlates of residual morbidity included treatment group, age, handedness, tumor size, systemic chemotherapy, and radiation to the axilla., Conclusions: Although residual morbidity for both treatment groups was evident, the results of the NSABP B-32 study indicate the superiority of the SLND compared to the ALND treatment approach relative to post-surgical morbidity outcomes over a 3-year follow-up period., ((c) 2010 Wiley-Liss, Inc.)

Purpose: To present guidance for patients and physicians regarding the use of accelerated partial-breast irradiation (APBI), based on current published evidence complemented by expert opinion., Methods and Materials: A systematic search of the National Library of Medicine's PubMed database yielded 645 candidate original research articles potentially applicable to APBI. Of these, 4 randomized trials and 38 prospective single-arm studies were identified. A Task Force composed of all authors synthesized the published evidence and, through a series of meetings, reached consensus regarding the recommendations contained herein., Results: The Task Force proposed three patient groups: (1) a "suitable" group, for whom APBI outside of a clinical trial is acceptable, (2) a "cautionary" group, for whom caution and concern should be applied when considering APBI outside of a clinical trial, and (3) an "unsuitable" group, for whom APBI outside of a clinical trial is not generally considered warranted. Patients who choose treatment with APBI should be informed that whole-breast irradiation (WBI) is an established treatment with a much longer track record that has documented long-term effectiveness and safety., Conclusion: Accelerated partial-breast irradiation is a new technology that may ultimately demonstrate long-term effectiveness and safety comparable to that of WBI for selected patients with early breast cancer. This consensus statement is intended to provide guidance regarding the use of APBI outside of a clinical trial and to serve as a framework to promote additional clinical investigations into the optimal role of APBI in the treatment of breast cancer.

Sentinel node excision has been widely accepted as the initial surgical step for evaluating the axilla for metastatic breast cancer. When the nodes are positive, the standard of care is to complete the axillary node dissection, a more extended procedure that carries an increased risk for morbidity. This article reviews data from sentinel lymph node trials, case series reports of outcomes when axillary node dissection was not performed in the setting of positive sentinel nodes, models for predicting the status of nonsentinel nodes, and the morbidity associated with axillary operations. Despite an approximate 10% false-negative rate, early results indicate that there is a much lower local recurrence rate after sentinel node excision alone and that systemic therapy may sterilize the axilla. In selected patients, it may be appropriate to forgo an axillary node dissection, although there are no randomized clinical trial data to support or refute this suggestion.

Neo-adjuvant endocrine therapy has opened new alternatives for locally advanced breast cancer. Such therapy, which has permitted us to expand the treatment role of neo-adjuvant therapies, may be of great benefit to patient groups such as the elderly, those not suited for chemotherapy, and those whose response may not be optimal. This therapy also may be able to help us identify agents that could improve outcomes in the adjuvant setting as well as possible biologic predictors for outcome. The latest generation of endocrine therapy for breast cancer, aromatase inhibitors, has proved superior to tamoxifen in terms of toxicity and efficacy in the adjuvant setting and is currently being studied in other clinical trials. Current findings indicate that these agents are less toxic and better tolerated than neo-adjuvant chemotherapy and that third-generation anti-hormonal therapy offers improved tumor response compared with tamoxifen, which has resulted in increased breast conserving surgery. Biomarker findings of improved response in tumors that are both estrogen receptor positive and HER-2 positive as well as progesterone receptor positivity only will be important for planning future selective treatment and clinical trials.

Background: The goals of axillary-lymph-node dissection (ALND) are to maximise survival, provide regional control, and stage the patient. However, this technique has substantial side-effects. The purpose of the B-32 trial is to establish whether sentinel-lymph-node (SLN) resection can achieve the same therapeutic goals as conventional ALND but with decreased side-effects. The aim of this paper is to report the technical success and accuracy of SLN resection plus ALND versus SLN resection alone., Methods: 5611 women with invasive breast cancer were randomly assigned to receive either SLN resection followed by immediate conventional ALND (n=2807; group 1) or SLN resection without ALND if SLNs were negative on intraoperative cytology and histological examination (n=2804; group 2) in the B-32 trial. Patients in group 2 underwent ALND if no SLNs were identified or if one or more SLNs were positive on intraoperative cytology or subsequent histological examination. Primary endpoints, including survival, regional control, and morbidity, will be reported later. Secondary endpoints are accuracy and technical success and are reported here. This trial is registered with the Clinical Trial registry, number NCT00003830., Findings: Data for technical success were available for 5536 of 5611 patients; 75 declined protocol treatment, had no SLNs removed, or had no SLN resection done. SLNs were successfully removed in 97.2% of patients (5379 of 5536) in both groups combined. Identification of a preincision hot spot was associated with greater SLN removal (98.9% [5072 of 5128]). Only 1.4% (189 of 13171) of SLN specimens were outside of axillary levels I and II. 65.1% (8571 of 13 171) of SLN specimens were both radioactive and blue; a small percentage was identified by palpation only (3.9% [515 of 13 171]). The overall accuracy of SLN resection in patients in group 1 was 97.1% (2544 of 2619; 95% CI 96.4-97.7), with a false-negative rate of 9.8% (75 of 766; 95% CI 7.8-12.2). Differences in tumour location, type of biopsy, and number of SLNs removed significantly affected the false-negative rate. Allergic reactions related to blue dye occurred in 0.7% (37 of 5588) of patients with data on toxic effects., Interpretation: The findings reported here indicate excellent balance in clinical patient characteristics between the two randomised groups and that the success of SLN resection was high. These findings are important because the B-32 trial is the only trial of sufficient size to provide definitive information related to the primary outcome measures of survival and regional control. Removal of more than one SLN and avoidance of excisional biopsy are important variables in reducing the false-negative rate.

The incidence of ductal carcinoma in situ (DCIS) has markedly increased as a result of the use of screening mammography. Whether DCIS is a premalignant lesion or a cancer remains a cause of debate, but evidence supports the idea that DCIS evolves into invasive breast cancer based on histologic patterns, similar risk factors, and genetic similarities. Microcalcifications identified during mammography generally raise the suspicion of DCIS, and biopsy, often by core needle, confirms such a diagnosis. The extent of disease can be further delineated by breast magnetic resonance imaging. Radiation therapy in breast-conserving treatment, along with tamoxifen, decreases the overall rate of local recurrence in patients with DCIS. Studies in the treatment of DCIS exploring partial breast radiation and trastuzumab are under way. Ongoing investigations with comparative genomic hybridization suggest that there are independent, evolutionary genetic pathways within DCIS. Genome-wide microarray-based gene expression analyses are now providing new opportunities to discover genes that are specifically activated or inactivated during the course of breast cancer progression.

Background: Occult metastases, by definition, are not detected on initial examination. They may be present on slides but missed during screening or may be present in paraffin embedded tissue blocks and undetected without additional levels. Anticytokeratin immunohistochemistry (CK IHC) enhances detection of occult metastases, particularly micrometastases (> 0.2 mm but not larger than 2.0 mm) or isolated tumor cell clusters (< or = 0.2 mm). This study defines the rate at which pathologists miss metastases on CK IHC of sentinel lymph nodes (SLN)., Methods: CK IHC sections 0.5 and 1.0 mm from the original surface of SLN tissue blocks were screened by pathologists using standard bright field light microscopes (LM) and by supervised computer assisted cell detection (CACD). All blocks were from breast cancer patients, initially classified 'node negative' on review of routinely stained sections from the surface of each block. Cases missed by LM screening but detected by CACD defined false negative screens., Results: Of 236 cases screened, LM detected 34 (14.4%; 95% CI: 9.6-20.2) cases and, in the 202 cases negative by LM, CACD detected an additional 30 (14.9%; 95% CI: 9.6-21.2%) cases with occult metastases. Occult metastases missed by LM screening ranged from 0.01 to 0.1 mm in greatest dimension. The probability of missing an occult metastasis < or = 0.02 mm; < or = 0.05 mm, and < or = 0.10 mm was 75%, 69.2%, and 61.2%, respectively. No occult metastases larger than 0.10 mm were missed by LM screening., Conclusions: Pathologists screening the CK IHC stained slides may frequently miss detecting metastases < 0.10 mm.

Objective: To estimate the added cancer yield of magnetic resonance imaging (MRI) over mammography in the contralateral breast of patients with a recent diagnosis of breast cancer., Methods: We conducted a prospective, international study of mammography and MRI in women with a recent diagnosis of unilateral breast cancer. Each subject received a mammogram, clinical breast exam (CBE), and MRI of the unaffected breast within a 90 day time period. Definitive diagnosis of suspicious findings was determined through biopsy and central pathology review., Results: Of the 103 eligible women included in study analyses, MRI detected 4 cancers in the contralateral breast while mammography detected none. MRI resulted in 12% (95% CI, 6%-20%) of women recommended for biopsy and 10% of women undergoing additional biopsy. The added cancer yield of MRI was 4% (95% CI, 1%-10%) and the positive predictive value of an abnormal MRI was 33% (95% CI, 10%-65%). Forty percent (4/10) of the biopsies performed based on the MRI recommendation were positive for malignancy., Conclusion: In women with a recent breast cancer diagnosis, approximately 4% will have an otherwise occult invasive breast cancer detected in the opposite breast by MRI alone.

The NSABP-32 trial is a randomized, phase III clinical trial to compare sentinel node (SN) resection to conventional axillary dissection in clinically node-negative breast cancer patients. The primary aims of the trial are to determine if removal of only SNs provides survival and regional control equivalent to those of axillary dissection, while diminishing the magnitude of surgically related side effects. In order to ensure consistency of the outcomes for this trial, a standardized method of SN surgery has been utilized for all cases. A secondary aim of the B32 trial is to evaluate whether patients with "occult" metastases in the SNs have worse survival. Accrual is taking place at 73 institutions in North America, and 217 surgeons are enrolling patients.

Background: After neoadjuvant chemotherapy, while results of sentinel node biopsy (SNB) are encouraging, conditions that may affect sentinel node (SN) detection and false negative rates with respect to clinical and pathological tumor response after neoadjuvant therapy require investigation., Methods: Thirty-four patients with clinical stage I, II and IIIA invasive breast cancer underwent neoadjuvant chemotherapy with doxorubicin/cyclophosphamide or doxorubicin/cyclophosphamide and docetaxel/segmental resection, SNB, and axillary node dissection (AND)., Results: SNs were found in 31 of 34 patients (91.2%). SNs were found in 20 of 21 patients (95.2%) with complete clinical tumor response, it was positive in 40% and no false negatives occurred. SNs were found in 11 of 13 patients (84.6%) with partial or no clinical tumor response; in four patients (33%) the SN was positive and no false negative nodes were found. Seven patients had complete pathological tumor response. SNs were found in six of these patients (85.7%). The SN was positive in 1 of 6 patients (16.7%) with no false negative. In 25 of 27 patients (92%) with partial or no pathological tumor response, the SN was identified. Eleven of these patients (44%) had positive nodes with no false negatives., Conclusions: SN identification rate and accuracy after neoadjuvant chemotherapy for breast carcinoma were extremely good however there is potential for inaccuracy after less than complete pathological tumor response. Further evaluation of SNB in larger clinical trial is warranted prior to accepting this approach as a standard care.