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Robotic nipple-sparing mastectomy (RNSM) has been developed to reduce conspicuous scar and increase the quality of life in women. This study aimed to evaluate the surgical and oncologic outcomes of RNSM with immediate breast reconstruction (IBR) compared with conventional nipple-sparing mastectomy (CNSM).This international multicenter, pooled analysis of individual patient-level data enrolled a total of 755 procedures in 659 women (609 had breast cancer and 50 underwent risk-reducing mastectomy) who underwent nipple-sparing mastectomy with IBR. Surgical and oncologic outcomes, including 30-days postoperative (POD 30d) complication rate, nipple necrosis rate, grade of Clavien-Dindo classification, disease-free survival, and overall survival, were evaluated. Propensity score-matched analyses were performed to adjust for confounding factors.The median age of both the RNSM and CNSM groups was 45 years. The RNSM group had lower body mass index (BMI) and a higher proportion of benign disease compared with the CNSM group. POD 30d complications and postoperative complication grade III rates were lower in the RNSM group than in the CNSM group (p0.05). The nipple necrosis rate was 2.2% and 7.8% for RNSM and CNSM, respectively (p = 0.002). After propensity score matching, significantly lower rates of POD 30d complications, nipple necrosis, and postoperative complication grade III occurred in the RNSM group than in the CNSM group (all p0.05). Oncologic outcomes were not significantly different between the two groups.RNSM can provide better cosmetic results with favorable surgical and oncologic outcomes for women with early breast cancer or BRCA mutation.

The objective of this study was to determining the frequency of different sub-types of pathogenic CDH1 germline mutations in healthy and asymptomatic individuals from families with the hereditary diffuse gastric cancer (HDGC) syndrome. Relevant literature dating from 1998 to 2019 was systematically searched for data on CDH1 germline mutations. The collected variants were classified according to their subtype into the following classes: missense, non-sense, splicing, insertions and deletions. The χ2 test was used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was statistically significant. CDH1 genetic screening data were retrieved for 224 patients with GC and 289 healthy individuals. Among the subjects that had tested CDH1 positive, splicing mutations were found in 30.4% of the healthy individuals and in 15.2% of the patients with GC (p=0.0076). Missense mutations were also found to occur in healthy subjects with higher frequency (22.2%) than in GC-affected individuals (18.3%), but the difference was not significant in this case. In families meeting the clinical criteria for the HDGC syndrome, CDH1 splicing and missense germline mutations have been reported to occur with higher frequency in healthy subjects than in patients with cancer. This preliminary observation suggests that not all pathogenic CDH1 germline mutations confer the same risk of developing GC.

Background and objectives The oncological benefit of axillary surgery (AS), with sentinel lymph node biopsy (SLNB) or axillary dissection (ALND), in elderly women affected by breast cancer (BC) is controversial. We evaluated AS trends over a 10-year follow-up period as well as locoregional and survival outcomes in this subset of patients. Methods Patients aged 70 years or older, treated between 1994 and 2008, were selected and divided in two groups, depending on whether or not AS was performed. A (1:1) matched analysis for all relevant clinicopathological features was performed. Outcomes were analyzed using the Kaplan–Meier method and univariate Cox-proportional hazard ratio analysis. Results A total of 1.748 patients were identified and stratified by age (70–74, 75–79, 80–84). A matched analysis was performed for 252 patients: 122 who underwent AS and 122 who did not. At 10-year follow-up, ipsilateral breast tumor recurrence, distant metastasis and contralateral BC were similar, p = 0.83, p = 0.42 and p = 0.28, respectively. In the no-AS group, a significant increased risk of axillary lymph-node recurrence was identified at 5- and confirmed at 10-years (p = 0.038), without impact on overall survival at 5- and 10-years (p = 0.52). In the non-AS group, higher rate of axillary recurrence at 10-years was observed in patients with poorly differentiated (24.1%, 95% CI 7.2–46.2), highly proliferative (Ki67 ≥ 20%: 17.1%, 95% CI 0.6–33.3) and luminal B tumors (16.8%, 95% CI 5.9–35.5). Conclusions Axillary staging in elderly women does not impact long-term survival. Tailoring surgery according to tumor biology and age may improve locoregional outcome.

Multiple synchronous (multifocal or multicentric) ipsilateral breast cancers with heterogeneous histopathology are a rare clinical occurrence, however, their incidence is increasing due to the use of MRI for breast cancer screening and staging. Some studies have demonstrated poorer clinical outcomes for this pattern of breast cancer, but there is no evidence to guide clinical practice. In this multidisciplinary review, we reflect on pathology and molecular characteristics, imaging findings, surgical management including conservation and reconstructive options and approach to the axilla, and the role of chemotherapy and radiotherapy. Multidisciplinary discussions appear decisive in planning an appropriate surgical choice and defining the correct systemic treatment tailored to each clinical condition.

BACKGROUND. Around 7% of women who undergo breast-conserving surgery (BCS) or mastectomy are at risk of developing ipsilateral breast tumor recurrence (IBTR). When assessing risks that, like that of IBTR, depend on multiple clinicopathological variables, nomograms are the predictive tools of choice. In this study, we constructed two independent nomograms to estimate the individualized risk of IBTR after breast surgery. METHODS. 18,717 consecutive patients with primary invasive breast cancer were enrolled in this retrospective study. The training set used for building the nomograms comprised 15,124 patients (11,627 treated with BCS and 3,497 with mastectomy), while the validation set included 3,593 women (2,565 BCS and 1,028 mastectomy). Median follow-up time was 8 years in the training set and 6 years in the validation set. Multivariable Cox proportional Hazards regression was used to identify independent factors for IBTR. Two separated nomograms were constructed on multivariate models for BCS and mastectomy, respectively. RESULTS. We identified the factors that associated with IBTR after either BCS or mastectomy. The two multivariable models were used to build nomograms for the prediction of IBTR 1 year, 5 years, and 10 years after BCS or after mastectomy. 5-year and 10-year IBTR rates in the BCS training set were equal to 3.50% and 7.00%, respectively and to 5.39% and 7.94% in the mastectomy training set. The nomograms were subsequently validated with c-index values of 0.77 and 0.69 respectively in the BCS and mastectomy validation sets. CONCLUSION. The nomograms presented in this study provide clinicians and patients with a valuable decision-making tool for choosing between different treatment options for invasive breast cancer.

Background: To assess the clinical usefulness of serum tumor markers for early detection of distant breast cancer recurrence using FDG-PET/CT. Methods: We retrospectively analyzed 561 consecutive patients who underwent surgery for invasive primary breast cancer and had increased tumor markers (CA 15-3 and CEA) after completion of locoregional therapy. FDG-PET/CT data were reviewed for all cases. CA 15-3 and CEA were evaluated both in a continuous and in a quartile (Q) distribution. The Wilcoxon rank-sum test and logistic regression models were used to evaluate the association between increased tumor marker values and the presence (and type) of distant metastases. Results: The median value of CA 15-3 was 35.0 U/mL (IQR, 29.5–43.0) in cases where no distant metastases were detected, and it was 58.9 U/mL (IQR, 40.0–108.0) in cases where metastases were detected (p < 0.001). The median value of CEA was 6.6 U/mL (IQR, 4.4–10.0) in cases of no metastases and 12.4 U/mL (IQR, 6.9–30.0) in cases of metastases (p < 0.001). Increased levels of both tumor markers (Q3 and Q4) were strongly associated with the presence of distant metastases. The association between CA 15-3 and bone/liver metastases was stronger compared with other types of metastases (p heterogeneity between odds ratios [ORs] = 0.03 for Q3 and Conclusion: Increased tumor marker levels detected in asymptomatic breast cancer patients during adjuvant therapies and follow-up are significantly predictive of distant metastases identified on FDG-PET/CT.

PURPOSE: Robotic nipple-sparing mastectomy (RNSM) may allow for more precise anatomic dissection and improved cosmetic outcomes over conventional open nipple-sparing mastectomy; however data about the feasibility and safety of the procedure is limited. The aim of this study is to present and discuss peri-operative surgical outcomes and early oncologic follow-up data on consecutive patients undergoing RNSM from June 2014 to January 2019. METHODS: Women underwent RNSM and immediate robotic breast reconstruction through an axillary incision at a single institution. Peri-operative data, complications at 3 months postoperatively, pathological data, and adjuvant therapies were recorded. Local recurrence free survival, disease free survival and overall survival were analyzed. RESULTS: Seventy-tree women underwent 94 RNSM procedures. Indications were invasive breast cancer in 39 patients, ductal carcinoma in situ in 17 patients, and BRCA mutation in 17 patients. Mean surgery time was 3 hours and 32 minutes. One-step reconstruction with implant occurred in 89.4% of procedures. The rate of complications requiring re-operation was 4.3%. The rate of flap or nipple necrosis was 1.1% The median follow up was 19 months (range: 3.1–44.8). No local recurrences occurred. The overall survival at 12 months, 24 or 60 months was 98% (95% CI 86–100%). DISCUSSION: We observed low complication rate in 94 consecutive RNSM procedures demonstrating the procedure is technically feasible and safe. We found no early local failures at 19 months follow-up. Long-term follow-up is needed to confirm oncologic safety. Future clinical trials to study the advantages and disadvantages of RNSM are warranted.

To assess outcome of breast cancer (BC) stages pT1-2 N0-1 after mastectomy alone and to identify prognostic factors calling for the need of postmastectomy radiotherapy. Patients who were not eligible for breast conserving surgery (BCS) were operated on with mastectomy between 1998 and 2008. Locoregional (LRR), distant (DM) control and breast cancer specific survival (BCSS) were retrospectively evaluated. Cumulative incidence (CI) of events was estimated according to Kalbfleisch and Prentice while Gray’s test tested difference. Kaplan–Meier method for survival and Cox proportional hazards model for univariable and multivariable analysis were used. A matched pair analysis between mastectomy alone and BCS plus whole breast irradiation (WBI), using the propensity score method, was performed. 1281 pT1-2 N0 and 1081 pT1-2 N1 were identified. Median follow-up was 8.2 years (9.2 years for survival). Overall, LRR rate was low for both N0 and N1 subgroups (10-year CI, 8.8% and 10.9%, respectively). Young age, lymphovascular invasion and Ki-67 ≥ 20% were proved to be statistically significant prognostic factors at multivariable analysis. The combination of ≥ 2 risk factors increased LRR rate to ≥ 15%. Risk factors combination weighed on LRR rate more than nodal status itself. DM rate doubled moving from negative to positive nodal status (10-year CI 10.5% versus 20.3%, respectively). BCSS remained high in both N0 and N1 subgroups (10-year CI 92.4% versus 84.5%, respectively). Remarkably, all the molecular subtypes except Luminal A significantly affected DM and BCSS both in the N0 and N1 subgroups. Nodes number significantly impacted on DM and BCSS but not on locoregional control. In the matched pair analysis, WBI decreased nodal recurrence rate and improved distant control, without affecting survival. Selected patients, namely those with at least two additional risk factors, presented high enough LRR risk to support the use of postmastectomy radiotherapy in both N0 and N1 subgroups. Moreover, the observation that radiotherapy may provide benefits that go beyond local control deserves to be further investigated.

Introduction Metaplastic breast cancer (MBC) is a rare condition of breast tumor with different subtypes, considered a disease with worse prognosis; treatments and survival are often unclear and conflicting. Methods We consecutively collected 153 primary MBCs of different subtypes. Breast surgery, neoadjuvant or adjuvant treatment, clinic-pathological factors, number and type of events during follow-up were considered to evaluate overall survival (OS) and invasive disease-free survival (IDFS). Results The majority of MBC was triple-negative (TN) subtype (88.7%), G3 (95.3%), pN0 (70.6%), and with high levels of Ki-67 (93.5%). For OS and IDFS, no significant associations were seen between the different MBC subtypes. The matched triple-negative MBC (TNMBC) and ductal TNBC cohorts had similar prognosis both in terms of OS (p = .411) and IDFS (p = .981). We observed a positive trend for TNMBC patients treated in the adjuvant setting with the cyclofosfamide, methotrexate, 5-fluorouracil protocol for better OS (p = .090) and IDFS (p = .087). A poor or absent response rate was observed in the neoadjuvant setting. Conclusion Our results demonstrate that metaplastic and ductal breast cancers with TN phenotype are similar in terms of overall and disease-free survival. Metaplastic cancers are poorly responsive to neoadjuvant treatment, and in the absence of novel targeted therapies, surgical treatment remains the first choice.

Objective: The aim of this retrospective study was to assess the risk factors for developing ipsilateral breast tumor reappearance (IBTR) and de novo contralateral breast cancer (BC) after primary BC treatment. Methods: Retrospectively, 15,168 consecutive patients with primary monolateral BC were enrolled in this monocentric study (from June 1994 to December 2006). Clinicopathological features, follow-up, and survival at 15 years were considered for statistical analysis. Results: Significant associations of increased risk for IBTR were verified with metastatic axillary lymph nodes (HR 1.37 [1.15–1.62], p = 0.0004), high tumor grade G2 (HR 1.35 [1.05–1.74], p = 0.02) and G3 (HR 1.35 [1.01–1.79], p = 0.04), luminal B (HR 1.51 [1.25–1.82], p < 0.0001), and HER2-positive (HR1.66 [1.14–2.41], p = 0.008) and triple-negative subtype (HR 1.54 [1.07–2.21], p = 0.02). Older age (HR 1.44 [1.08–1.91], p = 0.01) and positive family history (HR 1.85 [1.47–2.32], p < 0.0001) were risk factors for contralateral BC. Significant protective factors for IBTR were hormonotherapy (HR 0.71 [0.59–0.85], p = 0.0003), chemotherapy (HR 0.72 [0.60–0.87], p = 0.001), and radiotherapy (HR 0.73 [0.61–0.87], p = 0.0005). Hormonotherapy was also confirmed as a protective factor for contralateral second BC (HR 0.43 [0.30–0.60], p < 0.0001). Conclusions: We classified factors for IBTR and contralateral BC in high- and low-risk groups. In the high-risk group, breast surgery still remains more important than in the low-risk group, which seems to benefit more from adjuvant treatments.

Purpose: Around 7% of women who undergo breast-conserving surgery (BCS) or mastectomy are at risk of developing ipsilateral breast tumor recurrence (IBTR). When assessing risks that, like that of IBTR, depend on multiple clinicopathological variables, nomograms are the predictive tools of choice. In this study, we constructed two independent nomograms to estimate the individualized risk of IBTR after breast surgery. Patients and Methods: 18,804 consecutive patients with primary invasive breast cancer were enrolled in this retrospective study. The training set used for building the nomograms comprised 15,168 patients (11,648 treated with BCS and 3520 with mastectomy), while the validation set included 3636 women (2581 BCS and 1055 mastectomy). Median follow-up time was 8 years in the training set and 6 years in the validation set. Multivariable Cox proportional Hazards regression was used to identify independent factors for IBTR. Two separated nomograms were constructed on multivariate models for BCS and mastectomy, respectively. Results: We identified the factors that associated with IBTR after either BCS or mastectomy. The 2 multivariable models were used to build nomograms for the prediction of IBTR 1 year, 5 years, and 10 years after BCS or after mastectomy. The nomograms were validated on the patients in the validation set. A relative score was associated to each variable. The final number predicted the risk of IBTR. Conclusion: The nomograms presented in this study provide clinicians and patients with a valuable decision-making tool for choosing between different treatment options for invasive breast cancer. Funding: The preparation of this study was supported in part by NIH/NCI Cancer Center Support Grant No. P30 CA008748 to Memorial Sloan Kettering Cancer Center. Declaration of Interest: The authors have no conflict of interest disclosures to report. Ethical Approval: This study was approved by the review board/ethics committee of the European Institute of Oncology.

e12004 Background: The aim of this clinical study was to assess a panel of risk factors for ipsilateral breast tumor recurrence (IBTR) and de novo contralateral breast cancer (BC) after primary BC treatment. Methods: Retrospectively, 15,168 consecutive patients with primary monolateral BC were enrolled in this monocentric study (1994-2006). Clinicopathological features, follow-up and survival at 15 years were considered for statistical analysis. Results: Significant increased risk for IBTR were verified with younger age ( < 50 years) [HR = 1.31 (1.15-1.49), p < 0.0001], lobular subtype [HR 1.40 (1.15-1.70), p = 0.0007)], pT3 [HR 1.90 (1.42-2.54), p < 0.0001] or pT4 [HR 2.70 (1.47-4.97), p = 0.001], metastatic axillary lymph nodes [HR 1.50 (1.29-1.73), p < 0.0001], peritumoral vascular invasion (PVI) [HR = 1.27 (1.10-1.46), p = 0.001], luminal B [HR 1.57 (1.33-1.87), p < 0.0001], HER2-positivity [HR 1.85 (1.32-2.59), p = 0.0004] and triple-negative subtype [HR 1.76 (1.28-2.43), p = 0.0005]. Older age ( > 70 years) [HR 1.50 (1.05-2.15), p = 0.03] and positive family history [HR 1.86 (1.48-2.34), p < 0.0001] were risk factors for contralateral BC. Significant protective factors for IBTR were mucinous subtype [HR 0.45 (0.27-0.77), p = 0.003], total mastectomy [HR = 0.37 (0.30-0.46), p < 0.0001], hormonotherapy [HR 0.56 (0.45-0.69), p < 0.0001], chemotherapy [HR 0.77 (0.66-0.90), p = 0.001] and external radiotherapy [HR 0.39 (0.31-0.50), p < 0.0001]. Hormonotherapy was also confirmed as a protective factor for contralateral second BC [HR 0.51 (0.38-0.69), p < 0.0001]. Cumulative incidence for IBTR at 5, 10, and 15 years was higher than for than for contralateral BC. Conversely, overall survival for IBTR was lower than for contralateral BC. Conclusions: We classified factors influencing IBTR and contralateral BC into high- and low-risk groups. The high-risk group for IBTR included: age < 50 years, positive axillary nodes, PVI positivity, luminal B, HER2-positive, lobular and triple-negative subtypes. The low-risk group included: adjuvant treatments (hormone-chemotherapy, external radiotherapy) and mucinous histotype. We hypothesize that in the low-risk group, adjuvant treatments exert a strong impact in the prevention of IBTR risk (HER2-positive and triple negative BC should be considered also for neo-adjuvant therapies); this was not confirmed in the high-risk group, in which a more aggressive surgery is still theoretically justified. The proposed panel represents the basis for a nomogram to predict BC reappearance.

Recent studies have reported germline CDH1 mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for CDH1 screening and results’ interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, CDH1 genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset CDH1 asymptomatic mutant carriers, breast surveillance with clinical examination, yearly mammography, contrast-enhanced breast MRI and breast ultrasonography (US) with 6-month interval between the US and the MRI should be implemented as a first approach. In selected cases with personal history, family history of LBC and CDH1 mutations, prophylactic mastectomy could be discussed with an integrative group of clinical experts. Psychodecisional support also plays a pivotal role in the management of individuals with or without CDH1 germline alterations. Ultimately, the definition of a specific protocol for CDH1 genetic screening and ongoing coordinated management of patients with HLBC is crucial for the effective surveillance and early detection of LBC.