B3 Breast Lesions: Positive Predictive Value and Follow-Up on a Large Single-Institution Series.

INTRODUCTION: Lesions of uncertain malignant potential (B3) represent 10% of core needle biopsies (CNBs) or vacuum-assisted breast biopsies (VABBs). Traditionally, B3 lesions are operated on. This study investigated the association between B3 subtypes and malignancy to determine the best management. METHODS: Pre- and postoperative histological reports from 226 patients, who had undergone excisional surgery for B3 lesions, following CNB or VABB, were retrospectively analyzed. The correlation between the CNB/VABB diagnosis and the final pathology was investigated, along with the correlation between malignancy upgrade and the type of mammographic lesion. The positive predictive value (PPV) of malignancy of B3 lesions was calculated by simple logistic regression. Patients without cancer diagnosis underwent a 7-y follow-up. RESULTS: Pathology showed 171 (75.6%) benign and 55 (24.3%) malignant lesions. The PPV was 24.3% (P = 0.043), including 31 (13.7%) ductal carcinomas in situ and 24 (10.6%) invasive carcinomas. The most frequently upgraded lesions were atypical ductal hyperplasia, 34.2% (P = 0.004), followed by lobular intraepithelial neoplasia, 27.5% (P = 0.025). The median diameter of mammographic lesions was 1.5 [0.9-2.5] cm, while for surgical specimens, it was 5 [4-7] cm (P < 0.0001). Mammographic findings and histology showed a significant correlation (P = 0.038). After a 7-y follow-up, 15 (8.9%) patients developed carcinoma, and 7 patients (4%) developed a new B3 lesion. CONCLUSIONS: We can conclude that atypical ductal hyperplasia and lobular intraepithelial neoplasia still require surgery for a significant PPV. Other types that lacked significance or confidence intervals were too wide to draw any conclusion.

Management of the axilla in breast cancer patients: critical review, regional modified Delphi consensus and implementation in the Tuscan breast network.

PURPOSE: Data from recently trials have provided practice-changing recommendations in management of the axilla in early breast cancer (eBC). However, further controversies have been raised, resulting in heterogeneous diffusion of these recommendations. Our purpose was to obtain a better homogeneity. MATERIAL AND METHODS: In 2021, the Tuscan Breast Network (TBN) established a consensus with the aim to update recommendations in this area. We performed a literature review on axillary management in eBC patients which led to an expert Delphi consensus aiming to explore the gray areas, build consensus and propose evidence-based suggestions for an appropriate management. Thereafter, we investigate their implementation in clinical practice. RESULTS: (1) DCIS patients should have SLN biopsy only in case of mastectomy or in conservative surgery if tumor is in a location that would preclude future nodal sampling or in case of a mass; (2) ALND may be omitted for 1-2 positive SLN patients undergoing BCS in T1-2 tumors with 1-2 SLN positive, eligible for whole-breast irradiation and adjuvant systemic therapies; (3) consider the option of RNI in patients with 1-3 positive lymph nodes and one or more high-risk characteristics; (4) the population identified in 2) should NOT undergo lymph node irradiation as an alternative to axillary surgery and (5) patients with clinically (pre-operatively) positive axilla, or undergoing primary systemic therapy, or outside the criteria reported in 2) must receive additional ALND and/or RT as per local policy. CONCLUSION: This consensus provided a practical tool to stimulate local and national breast surgical and radiotherapy protocols.

Anatomical assessment of local recurrence site in breast cancer patients after breast reconstruction and post-mastectomy radiotherapy: implications for radiation volumes and techniques.

INTRODUCTION: Post-mastectomy radiotherapy (PMRT) improves local control rates and survival in patients with adverse prognostic features. The dose coverage to target volumes is critical to yield maximum benefit to treated patients, increasing local control and reducing risk of toxicity. This study aims to assess patterns of breast cancer relapse in patients treated with mastectomy, breast reconstruction and PMRT. METHODS: Breast cancer patients treated with PMRT between 1992 and 2017 were retrospectively reviewed. Clinical and pathological characteristics of patients were collected. Recurrences were defined as "in field," "marginal" or "out of field." Survival analyses were performed in relation to progression-free survival (PFS) and overall survival (OS). Correlation between baseline features was explored. RESULTS: Data of 140 patients are collected. After a median follow-up time of 72 months, median PFS and OS of 63 and 74 months were detected, respectively. Neoadjuvant chemotherapy, lympho-vascular space invasion (LVI) and size of primary tumor were all significantly associated with worst PFS and OS. Ten patients developed local recurrence: 30% "in field," 30% marginal recurrences, 20% "out of field" and 20% both "in field" and "out of field." No recurrence was detected under the expander, 80% above the device and 20% patients relapsed on IMN chain. The mean distant relapse-free survival was 39 months. Overall, 39 of 140 patients developed distant metastases. CONCLUSIONS: The onset of local-regional relapses occurred mainly above the expander/prosthesis, underlying the importance of inclusion of the subcutaneous tissues within the target volume. In order to refine new contouring recommendations for PMRT and breast reconstruction, future prospective studies are needed.

Pre-pectoral breast reconstruction with tissue expander entirely covered by acellular dermal matrix: feasibility, safety and histological features resulting from the first 64 procedures.

Background: Reconstructive options that can be used following conservative mastectomy, skin-, nipple-sparing and skin-reducing mastectomies, allow a remarkable variety of safe methods to restore the natural shape and aesthetics of the breast mound. In case of two-stage breast reconstruction, tissue expanders (TEs) are usually placed in a subpectoral position. The purpose of this retrospective cohort study is to evaluate the feasibility and safety of two-step reconstruction with TE in pre-pectoral position covered by acellular dermal matrix (ADM). Methods: Between March 2021 and May 2023, at the Azienda Ospedaliero Universitaria Careggi, University of Florence, 55 patients with BRCA 1/2 mutations or early breast cancer underwent conservative mastectomy with immediate pre-pectoral reconstruction using TE covered with ADM, followed by a second surgery with replacement of the expander with definitive prosthesis. Demographic, oncological, and histological data along with surgical complications were recorded. Results: A total of 64 conservative mastectomies were performed. In 2 patients (3.1%) complications were found that required reintervention and, in both cases, the TE had to be removed. Two patients developed hematoma and one patient developed seroma. Two patients showed wound dehiscence, both healed after conservative treatment and without implant exposure. No case of necrosis of the skin or nipple-areola complex has been observed, neither of capsular contracture. Capsule formed around TE was populated with cells and blood vessels and showed a thin area of synovial metaplasia. Conclusions: In selected cases it may be more cautious to perform a two-stage breast reconstruction after radical breast surgery by means of TEs. The placement of TEs in pre-pectoral position combines the excellent aesthetic and functional results of the pre-pectoral philosophy with a quite safer and more prudent two-step approach. Our experience reports optimistic results: the ADM covering the TE is seen successfully integrating during tissue expansion and becoming a vascularised new self-tissue. Complications rates are low and such ADM-assisted two-stage pre-pectoral reconstructive technique is a safe, practical, and reproducible method.

Upgrade rate to malignancy of uncertain malignant potential breast lesions (B3 lesions) diagnosed on vacuum-assisted biopsy (VAB) in screen detected microcalcifications: Analysis of 366 cases from a single institution.

PURPOSE: We retrospectively investigated clinical, radiological, and pathological features of B3 lesions associated with the risk of subsequent upgrade to malignancy. METHODS: We included consecutive vacuum-assisted biopsies (VABs) performed during 2011-2020 on suspicious microcalcifications not associated with other radiological signs diagnosed as B3 lesions and followed by surgical excision (SE) with definitive histological examination. Multiple logistic regression models were fitted to identify independent predictors of malignancy. RESULTS: Out of the 366 B3 lesions included, 56 (15.3 %, 95 % CI 11.8-19.4 %) had upgraded to malignancy at SE: of these, 42/366 (11.5 %, 95 % CI 8.4-15.2 %) and 14/366 (3.8 %, 95 % CI 2.1-6.3 %) were in situ and invasive carcinoma, respectively. At univariate analysis, variables positively associated with upgrade to malignancy were age ≥ 60 years (p = 0.008), mixed morphology (p = 0.018), scattered distribution (p = 0,001), extension of microcalcifications > 10 mm (p = 0.001), and mixed B3 lesion (p = 0.017). Among B3 subtypes, the highest rates of upgrade were observed for AIDEP, LCIS/LIN2, FEA + AIDEP, FEA + LCIS/LIN2, and FEA + AIDEP + LCIS/LIN2 (24.6 %, 21.4 %, 25.3 %, 20.0 % and 40.0 % respectively), while FEA and ALH/LIN1 had a lower rates of upgrade (7.5 % and 3.7 %, respectively). Multiple logistic regression analysis confirmed as risk factors older age (p = 0.029), larger extension (p = 0.001) and mixed morphology (p = 0.007) of microcalcifications, AIDEP (p = 0.011) among pure B3 lesions, and FEA + AIDEP (p = 0.001) and FEA + AIDEP + LCIS/LIN2 (p = 0.037) among mixed B3 lesions. CONCLUSIONS: Based on our findings, vacuum-assisted excision is reasonable as definitive management for FEA and ALH/LIN1, while SE should remain the mainstay of treatment for AIDEP and LCIS/LIN2, whose upgrade rates are too high to safely recommend VAE.

Breast Lesions of Uncertain Malignant Potential (B3) and the Risk of Breast Cancer Development: A Long-Term Follow-Up Study.

Breast lesions of uncertain malignant potential (B3) are frequently diagnosed in the era of breast cancer (BC) screening and their management is controversial. They are generally removed surgically, but some international organizations and guidelines for breast research suggest follow-up care alone or, more recently, propose vacuum-assisted excision (VAE). The risk of upgrade to BC is known, but very little data exist on its role as risk factor for future BC development. We analyzed 966 B3 lesions diagnosed at our institution, 731 of which had long-term follow-up available. Surgical removal was performed in 91%, VAE in 3.8%, and follow-up in 5.2% of cases. The B3 lesions included flat epithelial atypia (FEA), atypical ductal hyperplasia (ADH), lobular intraepithelial neoplasia (LIN), atypical papillary lesions (PLs), radial scars (RSs), and others. Overall, immediate upgrade to BC (invasive or in situ) was 22.7%. After long-term follow-up, 9.2% of the patients were diagnosed with BC in the same or contralateral breast. The highest risk was associated with ADH diagnosis, with 39.8% of patients upgraded and 13.6% with a future BC diagnosis (p < 0.0001). These data support the idea that B3 lesions should be removed and provide evidence to suggest annual screening mammography for women after a B3 diagnosis because their BC risk is considerably increased.

Breast cancer: the first comparative evaluation of oncobiome composition between males and females.

BACKGROUND: Emerging evidence suggests that breast microbiota dysbiosis contributes to cancer initiation, progression, prognosis and treatment efficacy. Anyway, available data are referred only to female patients, and studies on males are completely missing. Male breast cancer (MBC) is 70-100 times less frequent, but the mortality rate adjusted to incidence is higher in men than in females. Currently, MBC diagnostic approaches and treatments have generally been extrapolated from the clinical experience gained in women, while few studies focus on characterizing male cancer biology. Taking into account the rising importance of the oncobiome field and the need of MBC targeted studies, we explored the breast cancer oncobiome of male and female patients. METHODS: 16S rRNA gene sequencing was performed in 20 tumor and 20 non-pathological adjacent FFPE breast tissues from male and female patients. RESULTS: We documented, for the first time, the presence of a sexually dimorphic breast-associated microbiota, here defined as "breast microgenderome". Moreover, the paired analysis of tumor and non-pathological adjacent tissues suggests the presence of a cancer-associated dysbiosis in male patients, with surrounding tissue conserving a healthier microbiome, whereas in female patients, the entire breast tissue is predisposed to cancer development. Finally, the phylum Tenericutes, especially the genera Mesoplasma and Mycobacterium, could to be involved in breast carcinogenesis, in both sexes, deserving further investigation, not only for its role in cancer development but even as potential prognostic biomarker. CONCLUSIONS: Breast microbiota characterization can enhance the understanding of male breast cancer pathogenesis, being useful for detection of new prognostic biomarkers and development of innovative personalized therapies, remarking the relevant gender differences.

Breast tissue can become inhabited by microbes through different pathways, and an uneven distribution of these microorganisms could potentially contribute to the development, prognosis, and treatment response of breast cancer. However, the current available data primarily focus on female patients, with a significant dearth of studies on males. To address this gap, the present study investigates the microbiota composition of both tumorous and healthy breast tissue samples from both male and female patients.The findings of this research highlight a disparity in the types of bacteria present in male and female breast tissue. Specifically, it shows that male patients with breast cancer have a higher imbalance of bacteria in the cancerous area compared to the surrounding healthy tissue. In contrast, in females the dysbiosis extend to the whole breast tissue.Moreover, the study identifies specific strains of bacteria that might potentially be involved in the development of breast cancer in both males and females.In conclusion, this study underscores the significance of microbial colonization in breast tissue and its potential influence on breast cancer in both males and females. By expanding our understanding of the microbial composition in breast cancer, we can pave the way for innovative diagnostic methods and treatment approaches for male breast cancer, while simultaneously advancing our knowledge of this complex disease.

Percutaneous vacuum-assisted excision (VAE) of breast lesions of uncertain malignant potential (B3 lesions): a preliminary single-centre Italian experience.

PURPOSE: In recent years vacuum-assisted excision (VAE) has been described as an alternative treatment for some B3 lesions. This study aims to assess the effectiveness of using VAE to manage selected B3 lesions by quantifying the number of B3 lesions undergoing VAE, the malignant upgrade rate, and the complications encountered. MATERIALS AND METHODS: Our department evaluated all B3 lesions diagnosed between January 2019 and October 2021 and treated them with VAE. The data were collected during the initial biopsy and final histology based on VAE image guidance, also considering initial lesions and complications. The exclusion criteria were: B3 lesion of size > 20 mm, presence of a concomitant malignant lesion, lesion < 5.0 mm distant from the skin, nipple or pectoral muscle, phyllodes tumours or indeterminate B3 lesions. Lesions that upgraded to malignancy underwent surgical excision, while benign lesions performed radiological follow-ups. RESULTS: From 416 B3 lesions diagnosed, 67 (16.1%) underwent VAE. VAE was performed under X-ray (50/67) or ultrasound guidance (17/67). Five cases (7.5%) upgraded to a malignant lesion, 2 ADH, 2 LIN and one papillary lesion that underwent surgery. No malignancy or new lesions has occurred at the site of the VAE, with an average radiological follow-up of 14.9 months. CONCLUSIONS: VAE could be a safe and effective pathway for managing selected B3 lesions. Lesions initially subjected to CNB with ADH and LN outcome, before undergoing VAE, should perform a VAB for better tissue characterization and management.

Reducing the Use of Frozen Section for Sentinel Node Biopsy in Breast Carcinoma: Feasibility and Outcome.

BACKGROUND/AIM: Sentinel lymph node biopsy (SLNB) is a standard practice for staging the axilla in breast cancer. Initially, intraoperative frozen section (FS) examination was used but was time-consuming and often provided false-negative results. Delayed permanent section (PS) analysis is currently performed; FS-SLNB is maintained for selected high-risk cases. The aim of this study was to evaluate the feasibility of this approach. PATIENTS AND METHODS: All patients with breast cancer with clinically negative lymph nodes undergoing SLNB at our institution from 2004 to 2020 were analyzed, comparing operative time, re-operation rate and clinical outcome in terms of regional lymphatic recurrence-free and overall survival by type of SLNB (FS vs. PS). RESULTS: FS-SLNB comprised 100% of the procedures in 2004 and 18.2% at the end of the study period. The use of PS-SLNB instead of FS-SLNB was associated with a significantly reduced rate of axillary dissection (AD): 4.4% vs. 27.2, respectively (p<0.001). There was no significant difference in re-operation rate for AD: 3.9% vs. 6.9%, respectively (p=0.20). The use of PS-SLNB significantly reduced the operative time (mean=51 minutes) (p<0.001). After a mean follow-up of 70.9 months (range=16-180 months) there were no differences in regional lymphatic recurrence free or overall survival. CONCLUSION: The reduced use of FS-SLNB resulted in a significantly lower rate of AD, and significant operative time and costs savings, without any increase in the reoperation rate and lymphatic recurrences. Therefore, this approach is feasible, safe and beneficial, both for patients and healthcare services.

ONEST (Observers Needed to Evaluate Subjective Tests) Analysis of Stromal Tumour-Infiltrating Lymphocytes (sTILs) in Breast Cancer and Its Limitations.

Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopathology specimens is influenced by several factors and is subject to issues of reproducibility. ONEST (Observers Needed to Evaluate Subjective Tests) helps in determining the number of observers that would be sufficient for the reliable estimation of inter-observer agreement of TIL categorisation. This has not been explored previously in relation to TILs. ONEST analyses, using an open-source software developed by the first author, were performed on TIL quantification in breast cancers taken from two previous studies. These were one reproducibility study involving 49 breast cancers, 23 in the first circulation and 14 pathologists in the second circulation, and one study involving 100 cases and 9 pathologists. In addition to the estimates of the number of observers required, other factors influencing the results of ONEST were examined. The analyses reveal that between six and nine observers (range 2-11) are most commonly needed to give a robust estimate of reproducibility. In addition, the number and experience of observers, the distribution of values around or away from the extremes, and outliers in the classification also influence the results. Due to the simplicity and the potentially relevant information it may give, we propose ONEST to be a part of new reproducibility analyses.

Safety of CDK4/6 inhibitors and concomitant radiation therapy in patients affected by metastatic breast cancer.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) currently represent the standard of care for the initial treatment of patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The aim of our study is to evaluate the safety of the use of concomitant radiation therapy (RT) in a consecutive series of HR+/HER2- patients treated in two academic institutions with CDK4/6i in the metastatic setting. METHODS AND MATERIALS: From September 2017 to February 2020, we retrospectively collected and analysed data on a sequential series of patients treated with CDK4/6i, receiving RT or not, at two European institutions. Primary outcome of the study was the association between RT and any adverse events (AEs) ≥ G3. Secondary outcomes were the association between RT and any AEs (any grade), CDK4/6i dose reduction rate, and CDK4/6i treatment discontinuation rate. RESULTS: We analysed a total of 132 consecutive women; RT was prescribed in 57 (43.2%) patients (70 irradiated lesions). The median age of the series was 52.1 years (range 32.3-78.2). Concomitant RT administration was not significantly related to higher AEs ≥ G3 (p = 0.19) and any grade AEs (p = 1.0); there was no association with RT and CDK4/6i dose reduction (p = 0.49) and discontinuation rates (p = 0.14). At a median follow-up of 18.8 months, the progression-free survival (PFS) rate was 35% and the overall survival (OS) rate was 38.7% in the whole group. The use of concomitant RT did not affect both PFS (p = 0.71) and OS rates (p = 0.55). CONCLUSIONS: Our data are encouraging regarding the safety of this combination, showing that concurrent RT did not increase severe toxicity and did not have an impact on systemic treatment conduction.

Preoperative robotic radiosurgery for early breast cancer: Results of the phase II ROCK trial (NCT03520894).

Background and purpose: Preoperative partial breast irradiation (PBI) has got the advantage of treating a well-defined target. We report the results of the phase II ROCK trial (NCT03520894), enrolling early breast cancer (BC) patients treated with preoperative robotic radiosurgery (prRS), in terms of acute and early late toxicity, disease control, and cosmesis. Material and methods: The study recruited between 2018 and 2021 at our Radiation Oncology Unit. Eligible patients were 50 + years old BC, hormonal receptors positive/human epidermal growth factor receptor 2 negative (HR+/HER2-), sized up to 25 mm. The study aimed to prospectively assess the toxicity and feasibility of a robotic single 21 Gy-fraction prRS in preoperative setting. Results: A total of 70 patients were recruited and 22 patients were successfully treated with pRS. Overall, three G1 adverse events (13.6 %) were recorded within 7 days from prRS. Three events (13.6 %) were recorded between 7 and 30 days, one G2 breast oedema and two G1 breast pain. No acute toxicity greater than G2 was recorded. Five patients experienced early late G1 toxicity. One patient reported G2 breast induration. No early late toxicity greater than G2 was observed. At a median follow up of 18 months (range 6-29.8), cosmetic results were scored excellent/good and fair in 14 and 5 patients, respectively, while 3 patients experienced a poor cosmetic outcome. Conclusions: ROCK trial showed that a single 21 Gy dose prRS represents a feasible technique for selected patients affected by early BC, showing an acceptable preliminary toxicity profile.

Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties.

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops. Previous data have linked NAMPT over-expression to the acquisition of BRAF resistance, paving the way for therapeutic strategies targeting the two pathways. METHODS: Exploiting the TCGA database and a collection of MM and THCA tissue microarrays we studied the association between BRAF mutations and NAMPT expression. BRAF wild-type (wt) cell lines were genetically engineered to over-express the BRAF V600E construct to demonstrate a direct relationship between over-activation of the BRAF pathway and NAMPT expression. Responses of different cell line models to NAMPT (i)nhibitors were studied using dose-response proliferation assays. Analysis of NAMPT copy number variation was performed in the TCGA dataset. Lastly, growth and colony forming assays were used to study the tumorigenic functions of NAMPT itself. RESULTS: The first finding of this work is that tumor samples carrying BRAF-mutations over-express NAMPT, as demonstrated by analyzing the TCGA dataset, and MM and THC tissue microarrays. Importantly, BRAF wt MM and THCA cell lines modified to over-express the BRAF V600E construct up-regulated NAMPT, confirming a transcriptional regulation of NAMPT following BRAF oncogenic signaling activation. Treatment of BRAF-mutated cell lines with two different NAMPTi was followed by significant reduction of tumor growth, indicating NAMPT addiction in these cells. Lastly, we found that several tumors over-expressing the enzyme, display NAMPT gene amplification. Over-expression of NAMPT in BRAF wt MM cell line and in fibroblasts resulted in increased growth capacity, arguing in favor of oncogenic properties of NAMPT. CONCLUSIONS: Overall, the association between BRAF mutations and NAMPT expression identifies a subset of tumors more sensitive to NAMPT inhibition opening the way for novel combination therapies including NAMPTi with BRAFi/MEKi, to postpone and/or overcome drug resistance. Lastly, the over-expression of NAMPT in several tumors could be a key and broad event in tumorigenesis, substantiated by the finding of NAMPT gene amplification.

Sentinel lymph node assessment in breast cancer-an update on current recommendations.

Sentinel lymph node biopsy (SLNB) has become the preferred method of surgical pathological nodal staging of early breast cancer by the end of the nineties. As the most likely sites of metastasis, the SLNs allow a more precise staging, and indeed gross sectioning, step sectioning, immunohistochemistry, and molecular staging methods have been used to disclose metastatic involvement of these lymph nodes. This review summarizes the backgrounds of SLNB, trends in related surgery and pathology. It also gives an insight into European National recommendations related to SLN and divergent daily practices in European pathology departments, on the basis of replies to questionnaires from 84 pathologists from 38 European countries. The questionnaires revealed the post-neoadjuvant setting as an area where a significant minority of pathologists report less confidence in classifying residual nodal involvement into TNM categories. The review also summarizes the neoadjuvant therapy-related aspects of SLNB.

Pre-pectoral breast reconstruction: early and long-term safety evaluation of 146 unselected cases of the early pre-pectoral era of a single-institution, including cases with previous breast irradiation and post-mastectomy radiation therapy.

We re-evaluated acute and early-late toxicity-related factors among pre-pectoral immediate tissue expander/implant (TE/I) breast reconstruction (BR) unselected, first-era, cases, including previous breast radiation treatment and post-mastectomy radiation therapy (PMRT). A retrospective analysis of 146 (117 therapeutic and 29 prophylactic) pre-pectoral reconstructions, between 2012 and 2016, considered patient-related (age, body mass index [BMI], smoke-history, comorbidity, BRCA mutation), and treatment-related characteristics (previous irradiation, axillary surgery, PMRT, pre- and postoperative chemotherapy, endocrine therapy, and target-therapy). Safety was evaluated as acute and early-late complications, and TE/I failures. At multivariate analysis of the 146 cases (117 patients submitted to BR) a significant factor related to acute toxicity was: BMI ≥ 25 (31.3% [≥ 25] vs 8.8% [< 25]; OR 4.44, 95% CI 1.56-12.6; p = 0.003), while previous breast surgery on ipsilateral side presented a borderline significance (31.6% [previous surgery] vs 7.4% [no previous surgery]; OR 3.74, 95% CI 0.97-14.40; p = 0.055). Factors significantly related to TE/I failure were: current or previous smoking exposition (13.8% [smokers] vs 2.6% [non-smokers]; OR 7.32, 95% CI 1.37-39.08; p = 0.02) and preoperative chemotherapy (18.8% [yes] vs 3.5% [no]; OR 8.16, 95% CI 1.29-51.63; p = 0.026). At 4-year median follow-up, 3 deaths, 5 locoregional recurrences, and 14 distant metastases occurred. Immediate pre-pectoral BR is safe and effective, with low rates of acute and early-late complications. BMI and previous breast surgery were related to higher complications but not failure; smoking and preoperative chemotherapy were related to TE/I explant. Previous RT and PMRT were related neither to early-late toxicity nor failure.

Triple-Negative Breast Cancer Histological Subtypes with a Favourable Prognosis.

Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent course. This review on behalf of the European Working Group for Breast Screening Pathology reviews the literature on the special histological types of BC that are reported to have a triple negative phenotype and indolent behaviour. These include adenoid cystic carcinoma of classical type, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade mucoepidermoid carcinoma, secretory carcinoma, acinic cell carcinoma, and tall cell carcinoma with reversed polarity. The pathological and known molecular features as well as clinical data including treatment and prognosis of these special TNBC subtypes are summarised and it is concluded that many patients with these rare TNBC pure subtypes are unlikely to benefit from systemic chemotherapy. A consensus statement of the working group relating to the multidisciplinary approach and treatment of these rare tumour types concludes the review.

Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance.

Male breast cancer (MBC) is a rare and understudied disease compared with female BC. About 15% of MBCs are associated with germline mutation in BC susceptibility genes, mainly BRCA1/2 and PALB2. Hereditary MBCs are likely to represent a subgroup of tumors with a peculiar phenotype. Here, we performed a whole transcriptome analysis of MBCs characterized for germline mutations in the most relevant BC susceptibility genes in order to identify molecular subtypes with clinical relevance. A series of 63 MBCs, including 16 BRCA2, 6 BRCA1, 2 PALB2, 1 RAD50, and 1 RAD51D germline-mutated cases, was analyzed by RNA-sequencing. Differential expression and hierarchical clustering analyses were performed. Module signatures associated with central biological processes involved in breast cancer pathogenesis were also examined. Different transcriptome profiles for genes mainly involved in the cell cycle, DNA damage, and DNA repair pathways emerged between MBCs with and without germline mutations. Unsupervised clustering analysis revealed two distinct subgroups, one of which was characterized by a higher expression of immune response genes, high scores of gene-expression signatures suggestive of aggressive behavior, and worse overall survival. Our results suggest that transcriptome matched with germline profiling may be a valuable approach for the identification and characterization of MBC subtypes with possible relevance in the clinical setting.

Intra-Tumour Heterogeneity Is One of the Main Sources of Inter-Observer Variation in Scoring Stromal Tumour Infiltrating Lymphocytes in Triple Negative Breast Cancer.

Stromal tumour infiltrating lymphocytes (sTILs) are a strong prognostic marker in triple negative breast cancer (TNBC). Consistency scoring sTILs is good and was excellent when an internet-based scoring aid developed by the TIL-WG was used to score cases in a reproducibility study. This study aimed to evaluate the reproducibility of sTILs assessment using this scoring aid in cases from routine practice and to explore the potential of the tool to overcome variability in scoring. Twenty-three breast pathologists scored sTILs in digitized slides of 49 TNBC biopsies using the scoring aid. Subsequently, fields of view (FOV) from each case were selected by one pathologist and scored by the group using the tool. Inter-observer agreement was good for absolute sTILs (ICC 0.634, 95% CI 0.539-0.735, p < 0.001) but was poor to fair using binary cutpoints. sTILs heterogeneity was the main contributor to disagreement. When pathologists scored the same FOV from each case, inter-observer agreement was excellent for absolute sTILs (ICC 0.798, 95% CI 0.727-0.864, p < 0.001) and good for the 20% (ICC 0.657, 95% CI 0.561-0.756, p < 0.001) and 40% (ICC 0.644, 95% CI 0.546-0.745, p < 0.001) cutpoints. However, there was a wide range of scores for many cases. Reproducibility scoring sTILs is good when the scoring aid is used. Heterogeneity is the main contributor to variance and will need to be overcome for analytic validity to be achieved.

Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial.

IMPORTANCE: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. OBJECTIVE: To determine whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with anthracycline-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at 8 oncology departments in Italy. It was a prespecified interim analysis on the first 174 patients who had completed cardiac assessment at 12 months. The study recruitment was conducted between July 2015 and June 2020. The interim analysis was performed in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded. INTERVENTIONS: Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5 mg, once daily), ramipril (5 mg, once daily), and placebo, if tolerated. MAIN OUTCOMES AND MEASURES: The primary end point was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). RESULTS: The analysis was performed on 174 women (median age, 48 years; range, 24-75 years) who had completed a cardiological assessment at 12 months and reached the end of treatment. At 12 months, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in the ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .01). Global longitudinal strain worsened by 6.0% in placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm (P < .001). The number of patients showing a reduction of 10% or greater in 3D-LVEF was 8 (19%) in the placebo arm, 5 (11.5%) in the ramipril arm, 5 (11.4%) in the bisoprolol, arm and 3 (6.8%) in the ramipril plus bisoprolol arm; 15 patients (35.7%) who received placebo showed a 10% or greater worsening of GLS compared with 7 (15.9; ramipril), 6 (13.6%; bisoprolol), and 6 (13.6%; ramipril plus bisoprolol) (P = .03). CONCLUSIONS AND RELEVANCE: The interim analysis of this randomized clinical trials suggested that cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodeling. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT2236806.

Immunohistochemical Evaluation of FGD3 Expression: A New Strong Prognostic Factor in Invasive Breast Cancer.

Among new prognostic factors for breast cancer, the most promising one seems to be FGD3 (Facio-Genital Dysplasia 3) gene, whose expression improves outcome by inhibiting cell migration. The aim of the study was to evaluate the prognostic role of FGD3 in invasive breast cancer in a series of 401 women, treated at our unit, by evaluating the expression of this gene by immunohistochemistry. Patients with high FGD3 expression showed a significantly better disease-free survival (DFS) (p < 0.001) and overall survival (OS) (p < 0.001). The prognostic value of FGD3 expression was stronger than that of classical pathologic parameters such as histological grade of differentiation, Ki-67 index and molecular subtype. By multivariate Cox analysis, FGD3 expression was confirmed as significant and independent prognostic factor, ranking second after age at diagnosis (≤40 years) for DFS (p = 0.003) and the second strongest predictor of OS, after AJCC Stage (p < 0.001). Our data suggest that inclusion of FGD3 evaluation in the routine workup of breast cancer patients may result in a more accurate stratification of the individual risk. The possibility to assess FGD3 expression by a simple and cheap technique such as immunohistochemistry may enhance the spread of its use in the clinical practice.