Spare the Nipple: A Systematic Review of Tumor Nipple-Distance and Oncologic Outcomes in Nipple-Sparing Mastectomy.

BACKGROUND: Preserving the nipple-areolar complex (NAC) in breast cancer surgery improves patient satisfaction and quality of life. The oncologic safety of NSM in tumors < 2 cm from the nipple remains in question. We conducted a systematic review to determine whether TND < 2 cm was associated with increased risk of LRR in patients undergoing NSM. METHODS: We included studies of invasive or in situ breast cancer < 2 cm from NAC undergoing NSM which reported LRR rates. LRR rates were stratified by TND and culminated across studies. Cohort study quality was assessed using Newcastle-Ottawa Criteria. Meta-analysis was not possible due to heterogeneity in reporting survival outcomes. RESULTS: We identified seven retrospective cohort studies with 2295 patients and 18 case series with 3507 patients. Direct tumor involvement of NAC was considered an absolute contraindication to NSM in all studies. In cohort studies, median follow-up was 31-112 (range 14-204) months. Cohorts with TND < 2 cm did not have a significantly higher rate of LRR. Amongst case series, 275 patients had TND < 2 cm. Combined LRR in case series was 2.6%, with median follow-up 10.4-71 (range 0-158) months. CONCLUSIONS: Our systematic review did not identify TND < 2 cm as a significant risk factor for LRR. NSM appears oncologically safe in select patients with TND < 2 cm. Given the improved quality of life associated with NSM compared to skin-sparing mastectomy, we suggest NSM as the procedure of choice in appropriately selected patients.

Surgeon Factors Influencing Breast Surgery Outcomes: A Scoping Review to Define the Modern Breast Surgical Oncologist.

BACKGROUND: Modern breast surgical oncology incorporates many aspects of care including preoperative workup, surgical management, and multidisciplinary collaboration to achieve favorable oncologic outcomes and high patient satisfaction. However, there is variability in surgical practice and outcomes. This review aims to identify modifiable surgeon factors influencing breast surgery outcomes and provide a definition of the modern breast surgical oncologist. METHODS: A systematic literature search with additional backward citation searching was conducted. Studies describing modifiable surgeon factors with associated breast surgery outcomes such as rates of breast conservation, sentinel node biopsy, re-excision, complications, acceptable esthetic outcome, and disease-free and overall survival were included. Surgeon factors were categorized for qualitative analysis. RESULTS: A total of 91 studies met inclusion criteria describing both modifiable surgeon factor and outcome data. Four key surgeon factors associated with improved breast surgery outcomes were identified: surgical volume (45 studies), use of oncoplastic techniques (41 studies), sub-specialization in breast surgery or surgical oncology (9 studies), and participation in professional development activities (5 studies). CONCLUSIONS: On the basis of the literature review, the modern breast surgical oncologist has a moderate- to high-volume breast surgery practice, understands the use and application of oncoplastic breast surgery, engages in additional training opportunities, maintains memberships in relevant societies, and remains up to date on key literature. Surgeons practicing in breast surgical oncology can target these modifiable factors for professional development and quality improvement.

Predictors of axillary node response in node-positive patients undergoing neoadjuvant chemotherapy for breast cancer.

BACKGROUND: The ability to accurately predict which patients will achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy could help identify those who could safely be spared the potential morbidity of axillary lymph node dissection. We performed a retrospective analysis of a cohort of clinically node-positive patients managed with neoadjuvant chemotherapy with the goal of identifying predictors of axillary pCR. METHODS: Eligible patients were aged 18 years or older, had clinical T1-T4, N1-N3, M0 breast cancer and received neoadjuvant chemotherapy followed by surgical axillary lymph node staging between 2001 and 2017 at Misericordia Hospital, Edmonton, Alberta. Patient data, including tumour characteristics, details of neoadjuvant chemotherapy, imaging results before and after neoadjuvant chemotherapy, and final pathologic analysis, were collected from the appropriate provincial electronic data repositories. We summarized the data using descriptive statistics. We characterized associations between clinical/tumour characteristics and pCR using univariate and multivariate regression analysis. RESULTS: Of the 323 patients included in the study, 130 (40.2%) achieved axillary pCR. Absence of residual disease in the breast was associated with axillary pCR (odds ratio 6.74, 95% confidence interval 2.89-15.67). HER2-positive, triple-negative and ER-positive/PR-negative/HER2-negative tumours were significantly associated with a pCR on univariate analysis; the association trended toward significance on multivariate analysis. CONCLUSION: Our findings support the routine use of neoadjuvant chemotherapy and sentinel lymph node biopsy in patients with an absence of residual disease in the breast, and potentially in those with HER2-positive or triple-negative subtypes, and highlight the ER-positive/PR-negative biomarker subtype as a potential predictor of nodal response.

Fat Grafting before Delayed Prophylactic Mastectomy and Immediate Implant Reconstruction for Patients at High Risk of Complications.

SUMMARY: The majority of patients undergoing bilateral prophylactic mastectomy request immediate implant-based breast reconstruction. Some patients, especially those with prior radiotherapy, are at increased risk of early cutaneous complications and implant loss. The authors developed the technique of primary fat grafting before delayed prophylactic mastectomy to minimize early complications for selective high-risk patients. They have completed 21 cases in 14 patients, 10 of whom had previous lumpectomy and radiation treatment for breast cancer. A single session of fat grafting, with a median injection volume of 250 ml (interquartile range, 200 to 300 ml), was performed a median period of 19 weeks (interquartile range, 16 to 28 weeks) before prophylactic mastectomy. All cases were direct-to-implant reconstruction using textured silicone implants. The median implant volume was 410 ml (interquartile range, 318 to 450 ml). A minor early complication developed in 14 percent of cases (three of 21), with no early implant loss. At a median follow-up of 9 months (interquartile range, 5 to 27 months), the authors found no cases of implant loss and an excellent or good aesthetic outcome (score of 5 or 4) in 16 of 21 cases (76 percent). Fat grafting before prophylactic mastectomy is a novel strategy to minimize early complications and avoid implant loss in patients at high risk of postoperative complications. . CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Breast-conserving therapy can be offered to women with prior breast augmentation.

INTRODUCTION: Breast cancer in women with cosmetic breast implants is increasingly common. Over the past decade, there has been a push for mastectomy and reconstruction in these patients, based on a fear of poor aesthetic results from small breast volume, and radiation-induced capsular contracture. At the Paris Breast Centre, augmented women routinely undergo lumpectomy with whole-breast irradiation (BCT). MATERIALS AND METHODS: A consecutive cohort of 50 augmented women, who had attempted BCT for early breast cancer at our institution between 2003 and 2018, were retrospectively identified. Post-treatment complications, oncologic outcomes, capsular contracture rates, long-term cosmetic outcomes, and patient-reported outcomes were evaluated. RESULTS: The median follow-up was 51 months. Margins were involved in 7 women (14%); 4 of whom underwent successful re-excision, and 3 had a mastectomy, for an early mastectomy rate of 6%. There were no early complications, nor cases of early implant loss. Long-term aesthetic results were evaluated using our 5-point scale: An excellent (5), or good (4) result was obtained in 68%. Significant capsular contracture (Baker grade 3 or 4) developed in 34%, of which, 5 women underwent capsulotomy and fat grafting; 4 of 5 downstaging their Baker grade. The estimated 5-year local recurrence rate was 2.3%. Ninety-five percent of participants would recommend BCT to augmented women. CONCLUSION: BCT is feasible and safe in augmented women with good long-term aesthetic results, and should be considered to avoid unnecessary mastectomy.

Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer.

Resistance to trastuzumab, a rationally designed HER-2-targeting antibody, remains a major hurdle in the management of HER-2-positive breast cancer. Preclinical studies suggest the mechanisms of trastuzumab resistance are numerous. Unfortunately, the majority of these studies are based around HER-2-positive (HER-2+) luminal cell lines. The role of epithelial to mesenchymal transition (EMT), a genetic program that confers a basal phenotype, may represent a novel mechanism of escape for HER-2+ luminal cells from trastuzumab treatment. Here we investigated this possibility using a model of clonal selection in HER-2+ luminal breast cancer cells. Following a random isolation and expansion of "colony clusters" from SKBR-3 cell lines, several colony clusters underwent a spontaneous EMT in-vitro. In addition to expression of conventional EMT markers, all mesenchymal colony clusters displayed a predominant CD44+/CD24- phenotype with decreased HER-2 expression and elevated levels of a ß1-integrin isoform with a high degree of N-glycosylation. Treatment with a ß1-integrin function-blocking antibody, AIIB2, preferentially decreased the N-glycosylated form of ß1-integrin, impaired mammosphere formation and restored epithelial phenotype in mesenchymal colony clusters. Using this model we provide the first clear evidence that resistance to trastuzumab (and lapatinib) can occur spontaneously as HER-2+ cells shift from a luminal to a basal/mesenchymal phenotype following EMT. While the major determinant of trastuzumab resistance in mesenchymal colony clusters is likely the down regulation of the HER-2 protein, our evidence suggests that multiple factors may contribute, including expression of N-glycosylated ß1-integrin.

Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy.

PURPOSE: To evaluate the risk of locoregional recurrence (LRR) associated with locoregional treatment of women with primary breast cancer tumors negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (triple-negative breast cancer [TNBC]). PATIENTS AND METHODS: Patients diagnosed with TNBC were identified from a cancer registry in a single institution (n=768). LRR-free survival was estimated using Kaplan-Meier analysis. The Cox proportional hazards regression model was used to determine risk of LRR on the basis of locoregional management: breast-conserving therapy (BCT; ie, lumpectomy and adjuvant radiation therapy [RT]) and modified radical mastectomy (MRM) in the TNBC population and T1-2N0 subgroup. RESULTS: At a median follow-up of 7.2 years, 77 patients (10%) with TNBC developed LRR. Five-year LRR-free survival was 94%, 85%, and 87% in the BCT, MRM, and MRM + RT groups, respectively (P < .001). In multivariate analysis, MRM (compared with BCT), lymphovascular invasion and lymph node positivity were associated with increased LRR. Conversely, adjuvant chemotherapy was associated with decreased risk of LRR. For patients with T1-2N0 tumors, 5-year LRR-free survival was 96% and 90% in the BCT and MRM groups, respectively (P = .027), and MRM was the only independent prognostic factor associated with increased LRR compared with BCT (hazard ratio, 2.53; 95% CI, 1.12 to 5.75; P = .0264). CONCLUSION: Women with T1-2N0 TNBC treated with MRM without RT have a significant increased risk of LRR compared with those treated with BCT. Prospective studies are warranted to investigate the benefit of adjuvant RT after MRM in TNBC.

MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib.

Angiogenesis inhibitors, such as sunitinib, represent a promising strategy to improve glioblastoma (GBM) tumor response. In this study, we used the O(6)-methylguanine methyltransferase (MGMT)-negative GBM cell line U87MG stably transfected with MGMT (U87/MGMT) to assess whether MGMT expression affects the response to sunitinib. We showed that the addition of sunitinib to standard therapy (temozolomide [TMZ] and radiation therapy [RT]) significantly improved the response of MGMT-positive but not of MGMT-negative cells. Gene expression profiling revealed alterations in the angiogenic profile, as well as differential expression of several receptor tyrosine kinases targeted by sunitinib. MGMT-positive cells displayed higher levels of vascular endothelial growth factor receptor 1 (VEGFR-1) compared with U87/EV cells, whereas they displayed decreased levels of VEGFR-2. Depleting MGMT using O(6)-benzylguanine suggested that the expression of these receptors was directly related to the MGMT status. Also, we showed that MGMT expression was associated with a dramatic increase in the soluble VEGFR-1/VEGFA ratio, thereby suggesting a decrease in bioactive VEGFA and a shift towards an antiangiogenic profile. The reduced angiogenic potential of MGMT-positive cells is supported by: (i) the decreased ability of their secreted factors to induce endothelial tube formation in vitro and (ii) their low tumorigenicity in vivo compared with the MGMT-negative cells. Our study is the first to show a direct link between MGMT expression and decreased angiogenicity and tumorigenicity of GBM cells and suggests the combination of sunitinib and standard therapy as an alternative strategy for GBM patients with MGMT-positive tumors.

Beta1-integrin circumvents the antiproliferative effects of trastuzumab in human epidermal growth factor receptor-2-positive breast cancer.

Resistance to trastuzumab, the monoclonal antibody targeting human epidermal growth factor receptor 2 (HER-2), is a major concern for HER-2-positive metastatic breast cancer (MBC) patients. To date, HER-2 status is the only available biomarker for selecting patients for trastuzumab-based therapy. Beta(1)-integrin, an adhesion molecule involved in cell survival and drug resistance, shares common downstream signaling elements with HER-2, such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase-1/2 (ERK1/2) pathways. The significance of beta(1)-integrin expression in HER-2-positive breast cancer and its involvement in a patient's response to trastuzumab-based therapy are unknown. We show here that overexpression of beta(1)-integrin is an independent negative prognostic factor for tumor progression of HER-2-positive MBC patients treated with trastuzumab-based chemotherapy. Enforced overexpression of beta(1)-integrin, its small interfering RNA-induced knockdown or treatment with a beta(1)-integrin-blocking antibody in HER-2-positive breast cancer cells, identified a strong inverse relationship between expression level of beta(1)-integrin and in vitro sensitivity to trastuzumab. Notably, beta(1)-integrin overexpression increased the phosphorylation of Akt-Ser473 and ERK1/2, thereby promoting survival and mitogenic signals to bypass the antiproliferative effects of trastuzumab. Our findings show that beta(1)-integrin provides a novel independent prognostic biomarker of trastuzumab response in HER-2-positive MBC patients and suggest a new target to augment the antiproliferative effects of trastuzumab.