Male breast cancer: a multicenter study to provide a guide for proper management.

INTRODUCTION: To offer an extensive retrospective experience on the management of male breast cancer. METHODS: A multicenter retrospective observational cohort study was conducted, including male patients diagnosed with breast cancer (invasive or in situ) in 12 Italian breast units from January 1975 to December 2019. Patients aged 18 years or older were assessed for eligibility. Exclusion criteria were metastatic cancer at diagnosis, previous cancer(s), received neoadjuvant treatment, incomplete data on (neo) adjuvant treatment(s), and/or follow-up data. Data on radiological examinations, demographic characteristics, risk factors, histological features, receptor status, treatments, and follow-up were collected. RESULTS: In a series of 671 male patients with breast cancer assessed for eligibility, 403 (28 in situ and 375 invasive neoplasms) were included in the study. All included patients underwent surgery. The median age at surgery was 63.8 years (IQR 56.1-72.1). In 68% of cases, patients underwent echography, and in 55.1%, a mammography. Most patients were ER and PR positive (63.8%), HER2 negative (80.4%), with high (≥ 20%) Ki67 values (61.3%), and luminal B subtype (51.1%). The 10-year overall survival was 73.6% (95% CI 67.0-79.1) for invasive breast cancer and 90% (95% CI 65.6-97.4) for in situ breast cancer. In patients with invasive breast cancer, at univariable analysis, having a G3 tumor (vs. G1), pT2/3/4 (vs. pT1), pN2/3 (vs. pN0), luminal B subtype with Ki67 ≥ 20% (vs. Luminal A), were significantly associated with a higher risk of death. In multivariable analyses, pT2/3/4 (vs. pT1) remained significantly associated with a higher risk of death (HR 3.14, 95% CI 1.83-5.39), and having a HER2 positive or a triple-negative subtype (vs. Luminal A) was also significantly associated with a higher risk of mortality (HR 4.76, 95% CI 1.26-18.1). CONCLUSION: Male breast cancer is a rare disease, the better understanding of which is necessary for a more effective diagnostic and therapeutic approach.

Occurrence of breast-cancer-related lymphedema after reverse lymphatic mapping and selective axillary dissection versus standard surgical treatment of axilla: A two-arm randomized clinical trial.

BACKGROUND: The need for axillary dissection (AD) is declining, but it is still essential for many patients with nodal involvement who risk developing breast-cancer-related lymphedema (BCRL) with lifelong consequences. Previous nonrandomized studies found axillary reverse mapping and selective axillary dissection (ARM-SAD) a safe and feasible way to preserve the arm's lymphatic drainage. METHODS: The present two-arm prospective randomized clinical trial was held at a single comprehensive cancer center to ascertain whether ARM-SAD can reduce the risk of BCRL, compared with standard AD, in patients with node-positive breast cancer. Whatever the type of breast surgery or adjuvant treatments planned, 130 patients with nodal involvement met our inclusion criteria: 65 were randomized for AD and 65 for ARM-SAD. Twelve months after surgery, a physiatrist assessed patients for BCRL and calculated the excess volume of the operated arm. Lymphoscintigraphy was used to assess drainage impairment. Self-reports of any impairment were also recorded. RESULTS: The difference in the incidence of BCRL between the two groups was 21% (95% CI, 3-37; p = .03). A significantly lower rate of BCRL after ARM-SAD was confirmed by a multimodal analysis that included the physiatrist's findings, excess arm volume, and lymphoscintigraphic findings, but this was not matched by a significant difference in patients' self-reports. CONCLUSIONS: Our findings encourage a change of surgical approach when AD is still warranted. ARM-SAD may be an alternative to standard AD to reduce the treatment-related morbidity.

Sentinel Node Biopsy Alone or With Axillary Dissection in Breast Cancer Patients After Primary Chemotherapy: Long-Term Results of a Prospective Interventional Study.

OBJECTIVE: To ascertain, in cN0/1 breast cancer patients given primary chemotherapy followed by sentinel node biopsy (SNB), whether SNB alone is adequate axillary treatment if the sentinel nodes (SNs) are clear (pN0). SUMMARY BACKGROUND DATA: 2020 guidelines do not recommend SNB in most cN1 patients with clear SNs after primary chemotherapy because the high SNB false negative rate might lead to poorer outcomes. METHODS: We prospectively assigned SNB after primary chemotherapy to 353 consecutive cT2 cN0/1 patients, median age 47 years (range 22-76) treated from 2007 to 2015. If the SNs were pN0, patients generally received no further axillary treatment (SNB only); if the SNs were pN1, completion axillary dissection (AD) (SNB + AD) was usually performed. Primary outcomes were overall (OS) and disease-free (DFS) survival in SNB only versus SNB + AD patients, assessed by Kaplan-Meier and compared using log-rank test, with use of propensity scores to account for bias due to nonrandom assignment to SNB versus SNB + AD. RESULTS: Median follow-up was 108 months, interquartile range 66 to 136. OS and DFS did not differ significantly between the groups by propensity score- weighted comparison: 10-year OS 89% [95% confidence interval (CI): 81%- 99%] in SNB only patients versus 86% (95%CI: 78%-95%) in SNB + AD patients; 10-year DFS 79% (95%CI: 68%-92%) versus 69% (95%CI: 58%-81%). No SNB-only patient developed axillary failure. CONCLUSIONS: cT2 cN0/1 patients whose SNs are disease-free (pN0) after primary chemotherapy can be offered SNB (with no further axillary treatment if the SNs are negative), irrespective of axillary status beforehand, without affecting OS or DFS.

¹8F-FLT PET/CT as an imaging tool for early prediction of pathological response in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy: a pilot study.

PURPOSE: We evaluated whether (18)F-3'-deoxy-3'-fluorothymidine positron emission tomography (FLT PET) can predict the final postoperative histopathological response in primary breast cancer after the first cycle of neoadjuvant chemotherapy (NCT). METHODS: In this prospective cohort study of 15 patients with locally advanced operable breast cancer, FLT PET evaluations were performed before NCT, after the first cycle of NCT, and at the end of NCT. All patients subsequently underwent surgery. Variables from FLT PET examinations were correlated with postoperative histopathological results. RESULTS: At baseline, median of maximum standardized uptake values (SUVmax) in the groups showing a complete pathological response (pCR) + residual cancer burden (RCB) I, RCB II or RCB III did not differ significantly for the primary tumour (5.0 vs. 2.9 vs. 8.9, p = 0.293) or for axillary nodes (7.9 vs. 1.6 vs. 7.0, p = 0.363), whereas the Spearman correlation between SUVmax and Ki67 proliferation rate index was significant (r = 0.69, p < 0.001). Analysis of the relative percentage change of SUVmaxin the primary tumour (∆SUVTmax(t1)) and axillary nodes (∆SUVNmax(t1)) after the first NCT cycle showed that the power of ∆SUVTmax(t 1) to predict pCR + RCB I responses (AUC = 0.91, p < 0.001) was statistically significant, whereas ∆SUVNmax(t1) had a moderate ability (AUC = 0.77, p = 0.119) to separate subjects with ΔSUVTmax(t1) > -52.9 % into two groups: RCB III patients and a heterogeneous group that included RCB I and RCB II patients. A predictive score µ based on ΔSUVTmax(t1) and ΔSUVNmax(t1) parameters is proposed. CONCLUSION: The preliminary findings of the present study suggest the potential utility of FLT PET scans for early monitoring of response to NCT and to formulate a therapeutic strategy consistent with the estimated efficacy of NCT. However, these results in a small patient population need to be validated in a larger independent cohort.

Axillary lymph node dissection versus no dissection in patients with T1N0 breast cancer: a randomized clinical trial (INT09/98).

BACKGROUND: Although axillary surgery is still considered to be a fundamental part of the management of early breast cancer, it may no longer be necessary either as treatment or as a guide to adjuvant treatment. The authors conducted a single-center randomized trial (INT09/98) to determine the impact of avoiding axillary surgery in patients with T1N0 breast cancer and planning chemotherapy based on biological factors of the primary tumor on long-term disease control. METHODS: From June 1998 to June 2003, 565 patients aged 30 years to 65 years with T1N0 breast cancer were randomized to either quadrantectomy with (QUAD) or without (QU) axillary lymph node dissection; a total of 517 patients finally were evaluated. All patients received radiotherapy to the residual breast only. Chemotherapy for patients in the QUAD treatment arm was determined based on lymph node status, estrogen receptor status, and tumor grade. Chemotherapy for patients in the QU treatment arm was based on estrogen receptor status, tumor grade, and human epidermal growth factor receptor 2 and laminin receptor status. Overall survival (OS) was the primary endpoint. Disease-free survival (DFS) and rate and time of axillary lymph node recurrence in the QU treatment arm were the secondary endpoints. RESULTS: After a median follow-up of >10 years, the estimated adjusted hazards ratio of the QUAD versus QU treatment arms for OS was 1.09 (95% confidence interval, 0.59-2.00; P = .783) and was 1.04 (95% confidence interval, 0.56-1.94; P = .898) for DFS. Of the 245 patients in the QU treatment arm, 22 (9.0%) experienced axillary lymph node recurrence. The median time to axillary lymph node recurrence from breast surgery was 30.0 months (interquartile range, 24.2 months-73.4 months). CONCLUSIONS: Patients with T1N0 breast cancer did not appear to benefit in terms of DFS and OS from immediate axillary lymph node dissection in the current randomized trial. The biological characteristics of the primary tumor appear adequate for guiding adjuvant treatment.

Ex vivo MRI evaluation of breast tumors: a novel tool for verifying resection of nonpalpable only MRI detected lesions.

A fundamental question in surgery of only magnetic resonance imaging (MRI)-detected breast lesions is to ensure their removal when they are not palpable by clinical examination and surgical exploration. This is especially relevant in the case of small tumors, carcinoma in situ or lobular carcinoma. Thirty-nine patients were enrolled in the study, 21 patients with breast lesions detected by both conventional imaging and breast MRI (bMRI) and 18 patients with bMRI findings only. Preoperative bMRI allowed staging the disease and localizing the lesion. In the operating theater, contrast medium was injected 1 minute before skin incision. After removal, surgical specimens were submitted to ex vivo MRI, performed using a dedicated surface coil and Spair inversion recovery sequences for suppression of fat signal intensity. All MRI enhancing lesions were completely included within the surgical specimen and visualized by ex vivo MRI. In the first 21 patients, bMRI was able to visualize branching margins or satellite nodules around the core lesion, and allowed for better staging of the surrounding in situ carcinoma; in the last 18 patients, eight of whom were breast cancer type 1 susceptibility protein (BRCA) mutation carriers, bMRI identified 12 malignant tumors, otherwise undetectable, that were all visualized by ex vivo MRI. This is the first description of a procedure that re-enhances breast lesions within a surgical specimen, demonstrating the surgical removal of nonpalpable breast lesions diagnosed only with bMRI. This new strategy reproduces the morphology and the entire extension of the primary lesion on the specimen, with potentially better local surgical control, reducing additional unplanned surgery.

Magnetic Localization of Breast Lesions: A Large-Scale European Evaluation in a National Cancer Institute.

INTRODUCTION: For decades the standard for preoperative breast lesions' localization has been wire localization. In recent years the options for nonwired localization have significantly expanded and include radioactive seeds, radar reflectors, radiofrequency identification tags and magnetic seeds. The aim of our study is to evaluate on a large scale the performance of preoperative magnetic seed localization of nonpalpable breast lesions. MATERIAL AND METHODS: We prospectively collected data on all patients undergoing image-guided magnetic seed localization from September 2019 to December 2022. We analyzed imaging findings, histological results, and type of surgery. The primary outcome was the successful localization rate. Secondary outcomes were the successful placement rate, the ease of percutaneous positioning, the procedural complications, and the reintervention rate. RESULTS: A total of 1123 magnetic seeds were placed in 1084 patients by 4 radiologists under ultrasound (1053) or stereotactic (70) guidance. All seeds were detectable transcutaneously in all breasts sizes and at all depths by 7 surgeons with a success rate of 100%. A total of 97.5% seeds were correctly placed into the target lesions (only 2.5% were dislocated). All radiologists have shown good compliance during the procedure, and there were no complications or safety issues. The reoperation rate was 5.1%. CONCLUSIONS: Image-guided localization with magnetic seeds is an easy, safe, reliable, and effective method for localizing nonpalpable breast lesions. Both radiologists and surgeons agreed that the technology was intuitive to use and that it can be widely applied in preoperative localization in breast units.

Oncological safety of selective axillary dissection after axillary reverse mapping in node-positive breast cancer.

INTRODUCTION: Although the need for axillary lymph node dissection (AD) is decreasing in breast cancer patients, it remains necessary in some cases. Axillary reverse mapping (ARM) enables the detection of upper extremity lymphatic drainage that may be spared during selective axillary dissection (SAD) so as to reduce the risk of lymphedema. The ability of the ARM-SAD procedure to reduce the incidence of lymphedema is being tested in an ongoing randomized trial. Crossover between arm drainage and breast drainage is well documented in the axilla, however, and whether the procedure is oncologically safe remains controversial. We aim to assess the axillary failure rate when a few nodes draining the upper arm are being spared by the ARM-SAD. METHODS: We report oncological outcomes, and axillary failure in particular, in the first 100 consecutive axillary node-positive patients treated with ARM-SAD as part of a pilot study and a randomized trial. RESULTS: A median of 18 (IQR 14-22) axillary nodes were excised per patient. During the follow-up (median 51 months, IQR 34-91), 11 patients experienced a treatment failure, but only one - treated with neoadjuvant chemotherapy - developed overt axillary disease as a first (and isolated) event. The crude rate of axillary failure was 1.36% (95% CI: 0.19-9.63) with an estimated 5-year crude cumulative incidence of 1.85% (95% CI: 0-5.47%). CONCLUSIONS: The axillary failure rate was low in our patients and did not exceed rates reported in the literature after standard AD, thus indicating that the ARM-SAD procedure is oncologically safe.

Partial breast irradiation with CyberKnife after breast conserving surgery: a pilot study in early breast cancer.

BACKGROUND: Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer. METHODS: This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result. RESULTS: Mean pathological tumor size was 10.5 mm (±4.3, range 3-18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched. Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107-213; range:56-325) with a median PTV isodose prescription of 86.0% (IQR 85.0-88.5; range:82-94). The median PTV was 88.1 cm3 (IQR 63.8-108.6; range:32.3-238.8). The median breast V100 and V50 was 0.6 (IQR 0.1-1.5; range:0-13) and 18.6 (IQR 13.1-21.7; range:7.5-37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7-27.6; range 22.3-29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients' evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer. CONCLUSIONS: These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results. TRIAL REGISTRATION: The present study is registered at Clinicaltrial.gov ( NCT02896322 ). Retrospectively egistered August 4, 2016.

Evaluation of Local Oncologic Safety in Nipple-Areola Complex-sparing Mastectomy After Primary Chemotherapy: A Propensity Score-matched Study.

BACKGROUND: Nipple-areola complex-sparing mastectomy (NSM), extending the concept of skin-sparing mastectomy, allows for the provision of a better cosmetic result. Large operable T2-T3 breast cancer might theoretically appear suitable for this surgical option as an alternative to conventional mastectomy or breast-conserving surgery, when a good response to primary chemotherapy has been achieved. PATIENTS AND METHODS: From January 2009 to May 2013, 422 patients with invasive breast cancer were progressively accrued to NSM. Of the 422 patients, 361 underwent NSM as first-line treatment (NSM group), and 61 underwent surgery after primary chemotherapy (NSM-PC group). A total of 151 breast cancer patients, who had undergone PC and conventional total mastectomy (TM-PC group) from 2004 to 2009 were evaluated as comparative group with respect to the NSM-PC group. Using propensity score matching, local disease-free survival (LDFS) was evaluated comparatively. RESULTS: The rate of nipple-areola involvement in the NSM and NSM-PC groups was 13.3% and 9.8%, respectively (P = .539). The nipple-areola involvement in the NSM and NSM-PC groups was significantly associated with the tumor size (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.13-1.95; P = .004), plurifocal or pluricentric tumor (OR, 3.18; 95% CI, 1.72-5.89; P < .001), and the presence of an intraductal component (OR, 2.38; 95% CI, 1.22-4.64; P = .011). The LDFS in the NSM-PC and TM-PC matched cohorts did not show a significant difference, with a 4-year LDFS of 0.89 (95% CI, 0.77-0.95) and 0.93 (95% CI, 0.83-0.97), respectively (hazard ratio [HR], 1.31; 95% CI, 0.40-4.35; P = .655). The NSM-PC cohort was also compared with the NSM cohort in terms of LDFS using 2 different matching criteria, with the tumor size before and after neoadjuvant chemotherapy as the balancing covariate. In the first of the 2 comparisons, the hazards of local relapse were comparable between the 2 matched groups (HR, 1.23; 95% CI, 0.37-4.04; P = .739). In the second comparison, the NSM-PC patients showed a significant greater hazard of local relapse than did the NSM patients (HR, 3.60; 95% CI, 1.10-11.80; P = .035). CONCLUSION: NSM might be a valuable option for large breast cancer treated by primary chemotherapy. The rate of local relapse seemed to be related to the disease stage, and no significant association with the type of surgery was detected.

Different biological and prognostic breast cancer populations identified by FDG-PET in sentinel node-positive patients: results and clinical implications after eight-years follow-up.

BACKGROUND: Sentinel node (SN) biopsy is the standard method to evaluate axillary node involvement in breast cancer (BC). Positron emission tomography with 2-(fluorine-18)-fluoro-2-deoxy-D-glucose (FDG-PET) provides a non-invasive tool to evaluate regional nodes in BC in a metabolic-dependent, biomolecular-related way. In 1999, we initiated a prospective non-randomized study to compare these two methods and to test the hypothesis that FDG-PET results reflect biomolecular characteristics of the primary tumor, thereby yielding valuable prognostic information. PATIENTS AND METHODS: A total of 145 cT1N0 BC patients, aged 24-70 years, underwent FDG-PET and lymphoscintigraphy before surgery. SN biopsy was followed in all cases by complete axillary dissection. Pathologic evaluation in tissue sections for involvement of the SN and other non-SN nodes served as the basis of the comparison between FDG-PET imaging and SN biopsy. RESULTS: FDG-PET and SN biopsy sensitivity was 72.6% and 88.7%, respectively, and negative predictive values were 80.5% and 92.2%, respectively. A subgroup of more aggressive tumors (ER-GIII, Her2+) was found mainly in the FDG-PET true-positive (FDG-PET+) patients, whereas LuminalA, Mib1 low-rate BCs were significantly undetected (p = 0.009) in FDG-PET false-negative (FDG-PET-) patients. Kaplan-Meier survival estimates after a median follow-up of more than 8 years showed significantly worse overall survival for FDG-PET+ patients in node-positive (N+) patients (p = 0.035) as compared to N+/FDG-PET- patients, which overlapped with survival curves of N- and FDG-PET+ or - patients. CONCLUSIONS: Our findings suggest that FDG-PET results reflect intrinsic biologic features of primary BC tumors and have prognostic value with respect to nodal metastases. FDG-PET false negative cases appear to identify less aggressive indolent metastases. The possibility to identify a subgroup of N+ BC patients with an outcome comparable with N- BC patients could reduce the surgical and adjuvant therapeutic intervention.