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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.

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.

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.

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.

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.

Ductal carcinoma in situ (DCIS) of the breast historically has been a disease detected by physical examination, diagnosed by open surgical biopsy, and treated by mastectomy and axillary dissection. It is now increasingly detected by screening mammography, diagnosed by needle core biopsy, and treated by lumpectomy, with axillary dissection having been abandoned and sentinel node biopsy being used in axillary staging. However, outcomes related to sentinel node biopsy in DCIS have not been validated in well-controlled clinical trials. Current guideline recommendations are to use sentinel node biopsy when needle core biopsy is highly suspicious for invasive cancer or where there is a high-risk DCIS when lumpectomy identifies invasive breast cancer with the DCIS, or when mastectomy is performed for extensive DCIS. Routine use of sentinel node biopsy for DCIS is not supported.

Objective: To evaluate the cosmetic outcome of brachytherapy after lumpectomy in the management of carcinoma of the previously irradiated breast., Materials and Methods: Between January 1998 and April 2008, 26 patients with TIS or T1 breast carcinoma were offered interstitial or intracavitary brachytherapy after lumpectomy in a previously irradiated breast as an alternative to salvage mastectomy. Twenty-five of 26 patients had prior lumpectomy followed by standard postoperative external beam radiotherapy for early stage carcinoma of the breast [dose range 5000-6040 cGy]. One patient developed breast cancer after full mantle irradiation [4500 cGy to the mediastinum and axillae] for Hodgkin Lymphoma 27 years earlier. All tumors were excised with final margins of resection free of disease per National Surgical Adjuvant Breast and Bowel Project definition. After lumpectomy, tumor bed implantation was carried out utilizing a low dose rate interstitial technique in 22 patients, whereas 3 patients were treated with high dose rate brachytherapy using the MammoSite brachytherapy catheter and 1 patient was treated with high dose rate brachytherapy using the Contura catheter. The low dose rate treatment consisted of 4500 to 5000 cGy at 35 to 50 cGy per hour to the tumor bed plus a 1.0 cm margin, whereas the high dose rate treatment consisted of 3400 cGy in twice daily fractions of 340 cGy currently used in National Surgical Adjuvant Breast and Bowel Project B-39. Cosmesis was graded according to the B-39 cosmesis scale for de novo treatments: grade I as excellent, grade II as good, Grade III as fair, and Grade IV as poor., Results: Eighteen patients were scored as grade I, 6 as grade II, and 2 as grade III. No patient received a Grade IV score. All 4 balloon brachytherapy patients were scored as Grade I. Twenty-five of 26 patients remained free of local failure with a median follow-up of 38 months (range 6-75 months). The only patient to develop a second local recurrence was graded as grade I before salvage mastectomy. Two patients developed wound dehiscence after immediate postlumpectomy implantation. Two have succumbed to metastatic breast carcinoma at 17 and 24 months after salvage implant therapy. An additional patient has succumbed to chronic obstructive pulmonary disease. All patients, regardless of cosmesis grade were satisfied with their decision for repeat conservation therapy. Factors affecting cosmesis were distance from the implant to the skin, the type of device used, and the amount of residual breast tissue after repeat lumpectomy., Conclusions: The cosmetic effect of brachytherapy after lumpectomy in the management of recurrent carcinoma of the previously irradiated breast is acceptable in highly selected patients. Intracavitary technique may provide superior cosmetic results for patients retreated with brachytherapy for salvage.

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: We sought to identify the risk of axillary node involvement in patients with ductal carcinoma in situ (DCIS) and to determine whether axillary node assessment is necessary in these patients. Sentinel node biopsy (SNB) is replacing standard axillary lymph node dissection (ALND) for surgical staging of invasive breast cancer. Its use in patients with DCIS versus local excision (LE), observation, and/or breast irradiation remains in question., Methods: We examined the records of 813 patients with localized DCIS and disease-negative margins after LE who were randomly assigned to no further therapy or to breast irradiation in National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-17 and 1799 patients randomized to receive placebo or tamoxifen after LE + radiotherapy in NSABP trial B-24. An ALND was performed in 253 patients in NSABP B-17 and in 162 in NSABP B-24., Results: We found that in NSABP trial B-17, seven patients developed ipsilateral nodal recurrence (INR). Overall INR rate was 0.83/1000 patient-years. In NSABP B-24, overall INR rate was 0.36/1000 patient-years. INR can be considered a surrogate for axillary involvement at the time of DCIS diagnosis., Conclusions: INR in patients with DCIS treated conservatively is extremely rare. Our findings do not support the routine use of SNB in patients with conservatively treated, localized DCIS.

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.