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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. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 amnionderived 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 (cNO) 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 TO through T4, N1 through N2, MO 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 cNO 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 1SLN 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. [ABSTRACT FROM AUTHOR]

The role of breast conservation in patients expressing BRCA1 and BRCA2 genetic mutations is controversial. A patient who was found to have bilateral synchronous breast cancers and expressed a BRCA genetic mutation was recently evaluated. The patient had a strong desire for breast preservation. This case and a review of the pertinent literature are presented to discuss the role of breast conservation and radiation in patients with BRCA1 or BRCA2 genetic mutations. [ABSTRACT FROM AUTHOR]

The article presents debate on axillary dissection versus no axillary dissection in women who is suffering with invasive breast cancer and sentinel node metastasis. It discusses evidence-based medicine and skills which clinicians need for practicing it. It informs on Evidence Based Reviews in Surgery (EBRS) which is a program meant to help practicing surgeons improve their critical appraisal skills. It discusses utility of methodological article and how it helps in appraisal of clinical article.

The increased use of sentinel lymph node (SLN) excision for staging the axilla in women with breast cancer has benefited women by lowering morbidity and at the same time has raised issues related to the extent of treatment needed to the nodal basin. This is of particular concern when micrometastases or isolated tumor cells are found in the sentinel nodes on the final pathology. The probability of finding metastatic disease in non-sentinel lymph nodes (NSLN) ranges from 0 to 20% with only micrometastatic deposits in the SLN. Very low rates (0-3.7%) of axillary recurrence have been reported in selected patients with micrometastases tumor in sentinel nodes who have not had a completion axillary node dissection (ALND). Risk factors for additional positive NSLN include primary tumor size, the presence of lymphovascular invasion and the size of the SN metastatic deposit. Currently, the decision to not complete the ALND when micrometastic disease is found in the SLN should be made on a case-by-case basis. One should consider the tumor characteristics, findings within the SLN, and a multidisciplinary treatment plan. Clinical trial results may help to resolve the dilemma. There appears to be a low risk for axillary recurrence. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Background: The National Surgical Adjuvant Breast and Bowel Project B-32 trial was designed to determine whether sentinel lymph node resection can achieve the same therapeutic outcomes as axillary lymph node resection but with fewer side effects and is one of the most carefully controlled and monitored randomized trials in the field of surgical oncology. We evaluated the relationship of surgeon trial preparation, protocol compliance audit, and technical outcomes. [ABSTRACT FROM PUBLISHER]

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-hormomal 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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]

This study reports the preliminary results of a new totally stapled end-to-end colonic anastomosis in 11 dogs. This “triple-stapled” end-to-end anastomosis was performed with one circular staple line and two linear staple lines, eliminating the need for a colotomy or purse-string suture. The fact that the anvil and anvil stem of a new circular stapling device (Premium EEA™) can be detached from the frame of the instrument allows the anvil stem to be brought out through the proximal linear stapled colon. The trocar mounted on the main stem of the circular stapler allows the stem of the main device to be brought out through the distal staple line. Thus, a totally stapled colonic anastomosis is created after mating the anvil stem and main stem of the instrument. The new anastomosis was evaluated radiographically and at necropsy. The use of this technique resulted in no clinically detectable leaks, suggesting that it may facilitate the performance of anterior resections in humans. [ABSTRACT FROM AUTHOR]

The tour de force of this paper lies in the review of clinical presentation of occluded Greenfield filters in a group of patients contraindicated for postopera tive anticoagulation. Nine of 59 patients (15.3%) had occluded filters. Eight of these 9 patients (88.8%) had primary brain tumors. This study, for the first time, to the authors' knowledge, reports a high incidence of caval thrombosis in brain tumor patients (8/31:25.8%) and of an association between caval throm bosis and recurrent deep vein thrombosis. Deep vein thrombosis (DVT) was seen in 88.8% of patients with caval thrombosis in this service. It is the authors' contention that recurrent DVT, at least in brain tumor patients, should alert the physician to evaluate caval patency. Caval thrombosis was noticed even sixty weeks after the placement of Greenfield filter. The authors conclude, therefore, that brain tumor patients had a high incidence of occluded filters; lower extrem ity morbidity provided a clue to such an event, and such a scenario should raise concerns regarding caval patency, even in long-term follow-up. [ABSTRACT FROM PUBLISHER]

The microcirculatory evolution of healing wounds has not been well documented. The authors tested the generally accepted hypothesis that an end-to-end, stapled anastomosis (EEA) causes less microcirculatory compromises to the wound edge than an end-on, single-layer, hand-sewn anastomosis (HSA) does. The quanti tative measurement of the microcir culation associated with hand-sewn and stapled colonic anastomoses was carried out in two groups of dogs, each containing 28 animals. The mi crocirculatory evolution with use of either technique was similar, and the data in this study failed to support the common belief that the "B" shape of the staples results in mini mal trauma to the microcirculation and thus allows capillary growth through the tissue enclosed by the staple. In contrast to other studies, however, the authors noticed cross- circulation as early as the third post operative day in either technique. Moreover, by this angiographic method, they noted a gradual in crease in the extent of cross-circula tion from days 3 to 13 in both types of anastomoses. To their knowledge this study represents the first report of a comparison of trauma caused to the microcirculation by mechanical su tures and single-layer, hand-sewn technique. [ABSTRACT FROM PUBLISHER]

The tour de force of this paper lies in the review of clinical presentation of occluded Greenfield filters in a group of patients contraindicated for postoperative anticoagulation. Nine of 59 patients (15.3%) had occluded filters. Eight of these 9 patients (88.8%) had primary brain tumors. This study, for the first time, to the authors' knowledge, reports a high incidence of cavai thrombosis in brain tumor patients (8/31:25.8%) and of an association between cavai thrombosis and recurrent deep vein thrombosis. Deep vein thrombosis (DVT) was seen in 88.8% of patients with cavai thrombosis in this service. It is the authors' contention that recurrent DVT, at least in brain tumor patients, should alert the physician to evaluate cavai patency. Cavai thrombosis was noticed even sixty weeks after the placement of Greenfield filter. The authors conclude, therefore, that brain tumor patients had a high incidence of occluded filters; lower extremity morbidity provided a clue to such an event, and such a scenario should raise concerns regarding cavai patency, even in long-term follow-up. [ABSTRACT FROM AUTHOR]

The microcirculatory evolution of healing wounds has not been well documented. The authors tested the generally accepted hypothesis that an end-to-end, stapled anastomosis (EEA) causes less microcirculatory compromises to the wound edge than an end-on, single-layer, hand-sewn anastomosis (HSA) does. The quantitative measurement of the microcirculation associated with hand-sewn and stapled colonic anastomoses was carried out in two groups of dogs, each containing 28 animals. The microcirculatory evolution with use of either technique was similar, and the data in this study failed to support the common belief that the "B" shape of the staples results in minimal trauma to the microcirculation and thus allows capillary growth through the tissue enclosed by the staple. In contrast to other studies, however, the authors noticed cross-circulation as early as the third postoperative day in either technique. Moreover, by this angiographic method, they noted a gradual increase in the extent of cross-circulation from days 3 to 13 in both types of anastomoses. To their knowledge this study represents the first report of a comparison of trauma caused to the microcirculation by mechanical sutures and single-layer, hand-sewn technique. [ABSTRACT FROM AUTHOR]

The article discusses the effectiveness of a multigene expression assay in predicting the local recurrence risk for ductal carcinoma in situ (DCIS). Based on the results of four randomized clinical studies, breast-conserving surgery (BCS) emerged as the accepted alternative approach to mastectomy for the treatment of DCIS. Some studies identified the genetic similarities of DCIS with an ipsilateral breast event (IBE).

The article examines the efficiency of the Allegheny General Modification of the Harvard/NSABP/RTOG scoring scale in analyzing the outcome of the breast cancer treatment. It states that the modified scoring scale aims to reestablish a baseline in the previously treated breast and allow a meaningful and equivalent assessment of potential therapeutic change following retreatment.

The article discusses research being done on ductal carcinoma in situ (DCIS). It references the study "Treatment of Ductal Carcinoma in Situ After Exciation: Would a Prophylactic Paradigm Be More Appropriate?," by R. Punglia, S. Schnittand J. Weeks published in a 2013 issue of the "Journal of National Cancer Institute." It is recommended that further studies into the molecular biology and genetics of breast cancer should be undertaken given the controversy of classifying DCIS.

The authors explore the questions about the role of axillary node dissection in the setting of a positive sentinel node biopsy in line with the paper "International Multicenter Tool to Predict the Risk of Nonsentinel Node Metastases in Breast Cancer," published in a previous issue of the "Journal of the National Cancer Institute." An overview of the outcomes of the primary endpoint analysis of the B-32 trial and the Oxford overview analysis.

A review of the article "Irradiation in Early-Stage Breast Cancer: Conventional Whole-Breast, Accelerated Partial-Breast, and Accelerated Whole-Breast Strategies Compared" by Mouw K. and Harris, which appeared in the periodical "Oncology" in a previous issue is presented.

Editorial. Comments on an article analyzing trends of modern practice patterns for the surgical management of breast cancer patients, published in the October 15, 2003 issue of the 'Journal of the National Cancer Institute.' Data indicating that sentinel node biopsy alone and omission of axillary node dissection was more frequently performed in patients with earlier stage breast cancer.

The article presents report of the working groups on breast magnetic resonance imaging (MRI). Breast MRI may be employed before, after, and during the course of chemotherapy to evaluate chemotherapeutic response and the extent of residual disease prior to surgical treatment. Localization tissue markers prior to neo-adjuvant chemotherapy may be helpful in the event of complete response and no definable tumor for resection. Accurate post-treatment size determinations may be problematic since tumors do not typically reduce concentrically in size and often islands of tumor are intermixed with non-enhancing fibrosis and necrosis. Automated tumor volume calculations would be helpful in quantitating tumor response and aid in the generation of data for chemotherapeutic trials.

The ability to accurately perform Magnetic resonance imaging (MRI)-guided breast localization and biopsy procedures is essential to the further development of breast MRI procedures, and ultimately to clinical use. Real-time and accurate surrogate markers are critical for the development of MRI as a diagnostic tool, but they are even more imperative for the development of percutaneous minimally invasive procedures. Development of MRI biopsy and localization techniques also impacts on the development of breast cancer staging and high-risk screening trials. Collaboration between industry and researchers in the development of magnets, coils, contrast agents, biopsy devices and techniques and surrogate and real-time markers will expedite the development of improved products and techniques.