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Background Image-guided vacuum-assisted breast biopsy (VABB) of the tumour bed, performed after neoadjuvant therapy, is increasingly being used to assess residual cancer and to potentially identify to identify pathological complete response (pCR). In this study, the accuracy of preoperative VABB specimens was assessed and compared with surgical specimens in patients with triple-negative or human epidermal growth factor receptor 2 (HER2)-positive invasive ductal breast cancer after neoadjuvant therapy. As a secondary endpoint, the performance of contrast-enhanced MRI of the breast and PET–CT for response prediction was assessed. Methods This single-institution prospective pilot study enrolled patients from April 2018 to April 2021 with a complete response on imaging (iCR) who subsequently underwent VABB before surgery. Those with a pCR at VABB were included in the primary analysis of the accuracy of VABB. The performance of imaging (MRI and PET–CT) was analysed for prediction of a pCR considering both patients with an iCR and those with residual disease at postneoadjuvant therapy imaging. Results Twenty patients were included in the primary analysis. The median age was 44 (range 35–51) years. At surgery, 18 of 20 patients showed a complete response (accuracy 90 (95 per cent exact c.i. 68 to 99) per cent). Only two patients showed residual ductal intraepithelial neoplasia of grade 2 and 3 respectively. In the secondary analysis, accuracy was similar for MRI and PET–CT (77 versus 78 per cent; P = 0.76). Conclusion VABB in patients with an iCR might be a promising method to select patients for de-escalation of surgical treatment in triple-negative or HER2-positive breast cancer. The present results support such an approach and should inform the design of future trials on de-escalation of surgery.

Recent observations regarding long-term outcomes among patients with early-stage breast cancer (BC) who underwent breast-conserving surgery (BCS) plus whole-breast irradiation (WBI) or mastectomy are from a small number of registry-based studies. Therefore, these findings may overestimate differences in survival between the two groups, compared with randomized controlled trials conducted in the 1980s. The aim of this study is to compare long-term outcomes and clinicopathologic characteristics between patients treated with BCS + WBI or mastectomy for BC.We performed a propensity score-matched analysis in a cohort of 9710 patients aged 70 years who underwent BCS + WBI or mastectomy without external radiotherapy for a first primary BC (pT1-2, N0-3a) at the European Institute of Oncology between 2000 and 2008. Patients were matched by propensity score.Median follow-up was 8.4 years (interquartile range 6.5-10.2). The cumulative incidence of axillary lymph node recurrence at 10 years was lower in the BCS + WBI group [2.4% (95% CI, 1.7-3.3%)] than in the mastectomy group [4.4% (95% CI, 3.5-5.5%)] (P = .0005), and the cumulative incidence of contralateral BC was higher in the BCS + WBI group [3.9% (95% CI, 2.8-5.1%)] than in the mastectomy group [2.5% (95% CI, 1.7-3.4%)] (P = .01). Among the 366 patients with HER2 subtype BC, BCS + WBI was associated with a fivefold higher risk [hazard ratio 4.97 (95% CI, 2.28-10.8)] of ipsilateral breast tumor recurrence (IBTR), compared with mastectomy (P .0001); however, among patients with other BC subtypes, the rates of IBTR were not statistically significantly different.Patients with HER2 subtype BC (T1-2, N0-3) who underwent BCS + WBI had a statistically significantly higher risk of IBTR than patients who underwent mastectomy. Survival was not statistically significantly different between the groups.

To critically review available literature on hypofractionated (≥ 3 Gy/fraction) proton therapy (PT) for breast cancer (BCa).A systematic screening of the literature was performed in April 2021 in compliance with the preferred reporting items for systematic reviews and meta-analyses recommendations. All full-text publication written in English were considered eligible. Acute and late toxicities, oncological outcomes and dosimetric features were considered for the analysis.Twelve publications met the inclusion criteria; all studies but one focused on accelerated partial breast irradiation (APBI). Eleven works considered post-operative patients, one referred to ABPI as a curative-intent modality. The dosimetric profile of PT compared favorably with both photon-based 3D conformal and intensity-modulated techniques, while a more extended follow-up is warranted to fully assess both the long-term toxicities and the non-inferiority of oncological outcomes.Our work shows that results on PT for BCa are currently only available for APBI applications, with dosimetric analyses demonstrating a clear advantage over both 3D conformal and intensity modulated X-rays techniques, especially when ≥ 2 treatment fields were used. However, further evidence is needed to define whether such theoretical benefit translates into clinical improvements, especially in the long-term.

Purpose The purpose of the study was to evaluate the toxicity, local control, overall and disease-free survival of elderly breast cancer (BC) patients treated with adjuvant once-weekly ultra-hypofractionated radiotherapy (RT) either with intensity-modulated RT (IMRT) or 3D conformal RT (3DCRT). Methods From July 2011 to July 2018, BC patients receiving 5.7 Gy once a week for 5 weeks to the whole breast after breast-conserving surgery were considered for the study. Inclusion criteria were: T1–T3 invasive BC, no or limited axillary involvement, age ≥ 65 years or women with commuting difficulties or disabling diseases. Results A total of 271 patients were included in the study. Median age was 76 (46–86) years. Most of BC were T1 (77%), while the remaining were T2 (22.2%) and T3 (0.4%). Axillary status was negative in 68.3% of the patients. The only severe acute toxicity (G3) at the end of RT was erythema (0.4%), registered in the 3DCRT group; no G3 edema or epitheliolysis was recorded. With 18 months of median follow-up, severe early–late toxicity (G3) was reported in terms of fibrosis and breast retraction, both with an incidence of 1.4%, mostly in the 3DCRT group. Oncological outcomes at a median follow-up of 2.9 years reported 249/271 (91.9%) patients alive and free from any event and 5 (1.8%) isolated locoregional recurrences. At 3 years, disease-free survival and overall survival were 94.9% and 97.8%, respectively. Breast volume > 500 cm3 was reported as predictive for moderate–severe (≥ G2) acute toxicity. Conclusions Weekly ultra-hypofractionated whole breast RT seems feasible and effective. Toxicity was mild, local control was acceptable, and overall survival was 97.8% at 3 years. Rates of severe toxicity were reduced with the IMRT technique. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-021-03907-w.

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 Postmastectomy radiotherapy (PMRT) with TomoHelical™ (TH) or TomoDirect™ (TD) allows a uniform target coverage. In this study, we compare treatment plans using TD and TH in the setting of hypofractionated PMRT and immediate breast reconstruction. Material and methods The TD-treatment plans of breast cancer patients treated between May 2016 and August 2019 were retrospectively selected. All the TD plans were re-planned on TH with the same prescription dose (40.05 Gy/15 fractions) and according to our dose/volume constraints. Data about the 2 treatment plans were compared with a focus on PTV coverage and all the organs at risk (OARs) constraints. Results Fifty patients for a total number of 100 treatment plans (50 with TD and 50 re-planned with TH) were analyzed. All the median value in the TD PTV CHEST WALL plans fulfilled the predefined planning objectives, even though TH emerged as best for target coverage with statistically significant difference for V90%. TD provided the lowest V95% for the PTV SVC, but the median value was near to the recommended value of 90% (89.8 % vs 98.6% for TD and TH, respectively). Overall, TD reached the best OARs sparing. The main statistically significant differences with TH were for contralateral breast, ipsilateral and contralateral lung. All the other dose values for TH were higher than TD, but they fulfilled the recommended/acceptable predefined planning objectives. Conclusions In the setting of PMRT, TD compared to TH reached an acceptable target volume coverage, with an optimal sparing of OARs.

Aim To assess the rate of positive non-sentinel lymph nodes (non-SLNs) after neoadjuvant systemic therapy (NAST) in breast cancer (BC) following positive sentinel lymph node biopsy (SLNB). Materials and methods From institutional database, 265 consecutive patients receiving NAST for cT1-3, any N, M0 BC between 2001 and 2018 were identified. Patients presented clinically negative axilla before surgery and were candidate for SLNB. Following metastatic SLNB, completion axillary lymph node dissection (AxLND) was performed. Non-SLNs rate was investigated using multivariate (MV) logistic regression models. The distribution of non-SLNs across the axilla was observed. Results Positive non-SLNs were found in 62.3% of cases and showed no correlation with SLN metastasis size. At MV, statistically significant variables associated with non-SLNs were older age (p = 0.025), clinically positive lymph nodes (p = 0.002), SLN extracapsular extension (ECE, p = 0.001), and higher ratio of positive SLNs/total SLNs (p = 0.016). ECE and higher nodal ratio were independent predictors of III axillary level positivity. By categorizing patients in intermediate- and high-risk groups using the study variables, positive non-SLNs were found in the range of 23–56% across the three axillary levels, rates which did not support radiotherapy volume de-escalation. The III axillary level lower involvement (6.3%) was better identified with the RAPCHEM trial criteria based on the ypN status after AxLND. Conclusions Involved non-SLNs rate following positive SLNB after NAST is nearly double the rate observed after primary surgery, supporting some intervention on the axilla. If AxLND is limited to I and II level, the involvement of the III level up to 31% of the cases seems to require some additional treatment, while the omission in selected cases needs further investigation.

The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial.This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133.Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events.The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR.Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health.

Kahler Ribeiro Fontana S1, Bonetti E2, Bernard L3, Calvello M4, Bonanni B4, Bonizzi G 5, Veronesi P1,6, Mazzarella L 2, Galimberti V1 Introduction Triple-negative breast cancer (TNBC) is frequently associated with germline genetic variants associated with cancer predisposition. Approximately 20% of TNBC carry a germline BRCA1 or BRCA2 mutation. Germline mutations in other genes involved in DNA repair, specifically Homologous Recombination (HRR), including ATM, BARD1, BRIP1, CHEK2, PALB2, RAD50, RAD51C, RAD51D may be associated with TNBC however remain imprecise in several populations as in Italy. In recent years, there has been an increase in multigenic panel testing thanks to better technology and the fact that genetic testing is no longer done just for prevention but they have become relevant in the clinical setting and this is especially true for triple negative disease. At the European Institute of Oncology, we conducted a prospective clinical trial, the PERSONA Breast trial, aimed at providing a more comprehensive picture of the mutational landscape and cancer risk in patients with TNBC by multigene germline genetic testing. Methods PERSONA is a prospective observational trial conducted between June 2018 and January 2022 on 313 patients with a diagnosis of TNBC ≤ 60 years and able to undergo surgery (primary or post-neoadjuvant). Peripheral blood DNA was sequenced with the Illumina TruSight Cancer panel (94 cancer predisposition genes). Genes were classified as germline actionable (n. 15) or non-actionable (n. 79) according to their associated relative risk of cancer. Genetic variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and the databases of genetic variants (ClinVar, LOVD, BRCA-Exchange,). All enrolled patients were followed up six-monthly for 10 years from informed consent or to death or withdrawal of consent. Results We present preliminary germline results from a 94-gene panel testing performed on a cohort of 313 TNBC patients. The clinical data of these patients was considered for a descriptive analysis of the cohort. Data on outcome such as overall survival and disease-free survival were not yet available. Germline multigene testing detected 62 unique (i.e., n. 49 in actionable, n. 13 in non-actionable genes) pathogenic (C5) and likely pathogenic (C4) variants in 25.2% of TNBC patients (79/313). As expected, 53.2% (42/79) of TNBC patients were carriers of a C5/C4 in BRCA1. C4/C5 were identified also in other actionable genes: 13.9% (11/79) in BRCA2, 8.9% (7/79) in MUTYH, 3.8% (3/79) in PALB2, 2.5% (2/79) in MSH2, 1.3% (1/79) in PMS2, and 1.3% (1/79) in TP53. In addition, 12 TNBC patients had C4/C5 variants in non-actionable genes, and 4 were carriers of both C4/C5 variants in actionable and non-actionable genes. Multigene testing resulted in the identification of 655 (i.e., n.82 in actionable, n. 573 in non-actionable genes) variants of uncertain significance (C3 or VUS) in 89.8% (281/313) of patients. Of the 281 C3 carriers, 60 had other variants (C4 and/or C5), of an uncertain result (in whom C3 was the highest class of variant) only in 70.6% (221/313) of TNBC patients. In 13 patients (13/313; 4.1%) only benign (C1) or likely benign (C2) variants were identified. Regarding family history, 67% of BRCA1 carriers versus 30% of BRCA2 carriers were familial. Conclusion Germline multigene testing in TNBC can identify C4/C5 in actionable genes providing information for a more tailored management of TNBC. Our study showed that the rate of VUS remains high using multigene testing. Of note, VUS were mainly identified in non-actionable genes supporting the rationale of the use in the clinical setting of phenotype-specific multigene panels, including a minor, but more appropriate, number of genes. Citation Format: sabrina K. kahler ribeiro fontana, emanuele bonetti, loris bernard, mariarosaria calvello, Bernardo Bonanni, ppina Bonizzi, Paolo Veronesi, Luca Mazzarella, Viviana Galimberti, claudia sangalli. Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-11.

Neoadjuvant chemotherapy (NAC) changed the breast surgery approach and increased indications in recent years. NAC allows to downstage the primary tumor and also may clear the axilla of lymph node metastases in some patients. In fact, NAC allows de-escalation of surgery: not only resulted in an increase in conservative surgery in 40%, which was the initial goal of chemotherapy, but in particular it allows for a reduction in axillary surgery. Furthermore, in relation to the molecular characteristics of the tumors we can have a pathological complete response (pCR) ranging from 20 to 80%. In node-positive patients who converted to cN0 different prospective studies ACOSOG Z1071, SENTINA, SN FNAC and GANEA 2, have demonstrated that the FNR of the SNB was high, more than the acceptable 10%. Therefore, strategies to reduce the FNR treatment in cN+ patients are being investigated: is to remove more than three negative axillary lymph nodes or marking of positive axillary nodes with a tattoo or clip, the so-called target axillary dissection (TAD), to document their removal. But all the effort to reduce the FNR rate do not have clinical prognostic significance. This has already been demonstrated in the literature in different randomized trials with long term follow up. The 10-year follow-up of our study confirmed our preliminary data that the use of standard sentinel node biopsy (SNB) without the use of clip is acceptable in cN1/2 patients who become cN0 after NAT and will not translate into a worse outcome. In fact, the axillary recurrences found were less than 2% in particular in the group that started from a positive axilla were 1.8 %, if we considered that 2 of them had a micrometastatic SN and refused the AD, but if we considered only those with a negative SN the percentage drops to 0.9% Similar positive data with different follow up were also confirmed by other studies that used SNB alone without TAD. All these studies data, with now comforting results on the follow up, confirm that SN surgery alone for selected patients who have an excellent response to NAC is not oncologically inferior to AD during a short- and long-term follow-up. Citation Format: Viviana Galimberti. To clip or not to clip (Part 2) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr CC1-1-2.

This historical surgical retrospection focuses on the temporal de-escalation axillary surgery, focusing on the unceasing efforts of researchers toward new challenges, as documented by extensive studies and trials. Axillary surgery has evolved, aiming to offer the best oncologic treatment and improve the quality of life of women. Axillary lymph-node dissection (ALND) has been replaced by sentinel lymph-node biopsy (SLNB) in women with early clinically node-negative breast cancer, providing adequate axillary nodal staging information with minimal morbidity, and becoming the standard of care in the management of breast cancer. However, this is only the beginning. Strategies in defining systemic and radiotherapeutic treatments have gradually been optimized, offering increasingly refined and targeted breast cancer treatment tools. In recent years, the paradigm of completion ALND after a positive SLNB has been questioned, and several studies have led to revolutionary changes in clinical practice. Moreover, the increasingly pivotal role played by neoadjuvant chemotherapy (NAC) has had a profound effect on the extent of axillary surgery, paving the way to a more finite "targeted" procedure in women with node-positive breast cancer who convert to negative nodes clinically after NAC. The utility of SLNB itself and its subsequent omission in women with negative nodes clinically and breast conservative surgery is also under scientific evaluation. The changes over time in the surgical approach to breast cancer have been numerous and significant. The novel emerging perspective characterized by recent advances in biology and genetics, in dedicated axillary ultrasound imaging and chemotherapy regimens, is the present reality that points to the future of axillary node treatment in breast cancer.

Introduction: During the COVID-19 pandemic, Lombardy (Northern Italy) Regional Health Council created hubs for cancer care, meant to be SARS-CoV-2-free pathways for cancer patients. The workflow of breast cancer (BC) radiotherapy (RT) in one of the hubs is presented here. Methods: Candidates to adjuvant RT during the pandemic peak of March-April 2020 were compared to those treated in the same period of 2019, and patient volume, deferral rate, and type of RT were analyzed. Statistics were calculated with χ2 or Fisher exact tests for categorical variables, and the Wilcoxon rank test for continuous variables. Results: In March-April 2020 the BC patient volume increased by 28% compared to the same period in 2019 (scheduled patients: 175 vs. 137) and amid travel restrictions it was kept high (treated patients: 136 vs. 133), mainly due to an influx from across Lombardy. RT schemes basically did not change, being already centered on hypofractionation. The increase of median time (67 vs. 74.5 days in 2019 and 2020, respectively) to the commencement of RT for low-risk patients was clinically negligible yet statistically significant (p = 0.03), and in line with the pertinent recommendations. No significant difference was found in the time interval between treatments and RT for high-risk patients. Concomitant chemoradiotherapy was avoided throughout the pandemic peak. Twenty-one women (13.6%) delayed either computed tomography simulation or RT commencement mainly because of COVID-19-related concerns and mobility restrictions. Conclusion: The workload for BC was high during the pandemic peak. Hubs allowed the continuation of oncologic treatments, while mitigating the strain on frontline COVID-19 hospitals.

The purpose of this study is the evaluation of clinical and surgical impact of the Z0011 trial criteria on the management of breast cancer (BC) patients undergoing breast conservative surgery (BCS) at the European Institute of Oncology (IEO). We studied 1386 patients who underwent BCS and sentinel lymph node biopsy (SLNB) from July 2016 to July 2018. Clinical evaluation, breast ultrasound, mammogram, and cyto/histological examination were performed for all patients at the time of diagnosis. Frozen sections of the sentinel lymph node (SLN) were not performed for any patient. Patients who underwent neo-adjuvant therapy were excluded. To evaluate the results before and after the introduction of Z0011 criteria, a group of 1425 patients with the same characteristics who underwent BCS and SLNB from July 2013 to July 2015 were analyzed. We studied the characteristics of the patients by nodal status, and we observed that T stage, tumor grade, and lymphovascular invasion were statistically related with the highest rate of positive SLN. Of the 1386 patients who underwent surgery after the introduction of the Z011 trial, 1156 patients (83.4%) had negative SLN, 230 patients (16.6%) had positive SLN. Subsequent axillary lymph node dissection (ALND) was performed in only 7 cases (3.0%). Of the 1425 patients operated before the introduction of the Z0011 trial, 216 patients had subsequent ALND (15%). The reduction in the number of ALND performed after the introduction of Z0011 is statistically significant, and this could result in a remarkable reduction of the comorbidities of our patients.

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.

Introduction: Breast cancer (BC) occurring during gestation or lactation is rare, yet highly challenging under both biological and clinical standpoints. This condition, referred to as pregnancy-associated (PA) BC (PABC), shows enrichment in mismatch repair (MMR) deficiency mutational signature, higher expression of immune-checkpoint genes, and less tumor-infiltrating lymphocytes (TILs) compared to non-PA BCs. Despite these insights, no comprehensive data on MMR protein status, immune checkpoints, and immune microenvironment are currently available for these tumors. The aim of this study was to characterize the MMR status and immunologic milieu of PABC. Methods: Among a multi-Institutional database comprising 142 PABCs, we conducted a comparative analysis of a cohort of PABC (n=29) and a control group of age-matched non-PA BCs (n=74). Distinct areas of each tumor and the corresponding normal breast tissue were incorporated into a tissue microarray (4-6 cores per case, mean 4.5). For all cases, both stromal and intratumoral TILs were quantified according to the International TILs Working Group recommendations. Representative slides were subjected to immunohistochemical (IHC) analysis of the MMR proteins (i.e. MLH1, MSH2, MSH6, and PMS2), programmed death-ligand 1 (PD-L1), CD4, and CD8. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and, when the protein was expressed only in a part of the tumor, MMR-heterogeneous (hMMR). PD-L1 expression was evaluated separately in the tumor cells, stromal TILs, and intratumoral TILs. Finally, the relative proportion of CD4+ and CD8+ cells was assessed in both stromal and intratumoral TILs. Results: The study group included 4 (14%) Luminal A, 10 (35%) Luminal B, 4 (14%) non-luminal HER2+, and 11 (37%) triple-negative (TN) PABCs. Taken together, both the dMMR and hMMR status were more common in PABCs than in non-PA BC (n=3/29, 19% vs. n=6/74, 8% and n=7/29, 24% vs. 14/74, 19%, respectively). Specifically, dMMR was seen in Luminal A (n=2, 50%) and in TN (n=1, 9%) PABCs. Conversely, in non-PA BCs, all Luminal A (n=15, 100%) were pMMR, while 5/45(11%) Luminal B and 1/13 (7%) TNBC were dMMR. Despite no differences were observed in intratumoral TILs, PABCs showed significantly higher levels of stromal TILs (p=0.01). Compared to the control group, PD-L1 expression in PABCs was significantly higher in the tumor cells and in stromal TILs (p Discussion: This study is the first to investigate the immune response alongside the MMR status by IHC in PABCs. Our findings broaden the understanding of the immunobiology underpinning PABC, suggesting that in these tumors i) MMR protein alterations occur at higher frequency than in non-PA BCs; ii) the tumor cells and tumor microenvironment may be capable to suppress the adaptive arm of immune system through the expression of PD-L1; and iii) lymphocytes located at the periphery rather than those inside of the tumor are likely to be implicated in the immune modulation. Conclusion: The MMR system and immune microenvironment may play a consistent role in the natural history of PABCs. An intimate knowledge of the multifaceted interplay between tumor and tumor immune microenvironment is likely to unveil clinically relevant mechanisms that may have a positive net health impact for women with BC during gestation or lactation. Citation Format: Nicola Fusco, Elena Guerini-Rocco, Barbara Buonomo, Roberto Croci, Caterina Fumagalli, Gianluca Lopez, Giorgio A Croci, Letterio Runza, Elham Sajjadi, Concetta Blundo, Luca Despini, Massimo Giroda, Viviana E Galimberti, Paolo Veronesi, Massimo Barberis, Stefano Ferrero, Giovanna Scarfone, Silvano Bosari, Giuseppe Viale, Fedro Peccatori. Integrated analysis of mismatch repair, PD-L1, and immune microenvironment status in pregnancy-associated breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-03.

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 The latest National Comprehensive Cancer Network Breast Cancer Guidelines still discourage repeat sentinel node biopsy (SNB) after mastectomy, and the largest multicentric study available reports only 35 cases in the absence of previous axillary dissection (AD). Methods From January 2003 to November 2018, 89 patients of the European Institute of Oncology with local recurrence of breast cancer after mastectomy, free of distant metastases, with a clinically negative axilla and a negative axillary ultrasound, in absence of AD, underwent lymphatic mapping before wide local excision. Results During surgery, SNB was successful for 99% of the patients, with 14% being metastatic. Additional metastatic nodes removed by AD after a positive sentinel node occurred in 82% of cases. After a medium follow-up period of 3.7 years, the overall survival rate was 96.7%, and the disease-free survival rate was 84.4%. No axillary relapse after AD was recorded. One patient who refused human epidermal growth factor receptor 2 (HER2)-targeted treatment experienced ipsilateral axillary recurrence after a negative repeat SNB. The first axillary level was never directly irradiated because all the patients with positive repeat SNB underwent AD. For invasive luminal-like HER2-negative recurrences, the metastatic sentinel node was significantly associated with the choice to prescribe adjuvant chemotherapy (p = 0.003). Conclusions In specialized centers, repeat axillary SNB for patients with local recurrence after mastectomy in the absence of previous AD can represent a safe option for detection and removal of occult axillary disease that would otherwise not be excised/irradiated to achieve better local control and could possibly influence the choice of adjuvant treatments.

Aims: The clinical significance of nonvisualized sentinel lymph nodes (non-vSLNs) is unknown. The authors sought to determine the incidence of non-vSLNs on lymphoscintigraphy, the identification rate during surgery, factors associated with non-vSLNs and related axillary management. Patients & methods: A total of 30,508 consecutive SLN procedures performed at a single institution from 2000 to 2017 were retrospectively studied. Associations between clinicopathological factors and the identification of SLNs during surgery were assessed. Results: Non-vSLN occurred in 525 of the procedures (1.7%). In 73.3%, at least one SLN was identified intraoperatively. Nodal involvement was only significantly associated with SLN nonidentification (p

Purpose To present an overview of the management of male patients with Ductal Carcinoma In Situ of the breast (male DCIS). Methods We retrospectively studied all male patients with a diagnosis of pure DCIS from January 1999 to December 2018: 20 patients were identified in our cancer referral center. We collected data regarding clinical presentation, age of onset, radiological features, receptor status of the neoplasm, histological type, and the follow-up of those patients. Results The median age was 62 years (range 21–80). All patients underwent surgery, in 15/20 (75%) cases a mastectomy was carried out. Two patients (10%) underwent endocrine treatment and 1/20 (5%) underwent radiotherapy. The receptor status for 15/20 patients was documented: 13/15 patients were ER+/Pr+. In 3 cases the Ki 67% was positive (i.e., > 20%). All cases were negative for Her2. The median follow-up time was 9.0 years (IQR 4.0–13.7). Only one patient had an ipsilateral recurrence with the finding of an infiltrating carcinoma in the same breast after 14 years. The 5-year disease-free survival was 92.9%. Conclusion Pure DCIS in men is an extremely rare disease: proper diagnosis and management allow an excellent prognosis.

Pathologic evaluation of early breast cancer after neoadjuvant therapy is essential to provide prognostic information based on tumor response to treatment (pathologic complete response [pCR] or non-pCR) and to inform therapy decisions after surgery. To harmonize the pathologist’s handling of surgical specimens after neoadjuvant therapy, a panel of experts in breast cancer convened to developed a consensus on six main topics: (1) definition of pCR, (2) required clinical information, (3) gross examination and sampling, (4) microscopic examination, (5) evaluation of lymph node status, and (6) staging of residual breast tumor. The resulting consensus statements reported in this document highlight the role of an accurate evaluation of tumor response and define the minimum requirements to standardize the assessment of breast cancer specimens after neoadjuvant therapy.

BACKGROUND Despite the continued progress of medicine, dealing with breast cancer is becoming a major socio-economic challenge, particularly due to its increasing incidence. The ability to better manage and adapt to the entire care process depends not only on the type of cancer, but also on the patient's socio-demographic and psychological characteristics and on the social environment in which a person lives and interacts. Therefore, it is important to understand which factors may contribute to a successful adaptation to breast cancer. To our knowledge, no studies have been already performed on the combination effect of multiple psychological, biological and functional variables in predicting the patient’s ability to bounce back from the stressful life event, such as a breast cancer diagnosis. OBJECTIVE The aim of the study will be to build a quantitative mathematical model of factors associated with optimal adjustment capacity to cancer and study resilience through the cancer continuum in a population of breast cancer patients. METHODS 660 women with breast cancer will be recruited in five European cancer centers in Italy, Finland, Israel and Portugal. Biomedical and psychosocial variables will be collected using the Noona Healthcare platform. Psychosocial, socio-demographic, lifestyle and clinical variables will be measured every 3 months, starting from pre-surgery assessment (baseline) to 18 months after surgery. RESULTS Temporal data mining, time-series prediction, sequence classification methods, clustering time-series data, and temporal association rules will be used to develop the predictive model. Results will be disseminated during 2022. CONCLUSIONS The present study will provide a predictive model able to describe individual resilience and identify different resilience’s trajectories along the care process. The results will allow the implementation of tailored interventions according to the patient’s need, supported by e-health technologies. CLINICALTRIAL ClinicalTrials.gov Identifier: NCT05095675

Objective To compare robotic mastectomy with open classical technique outcomes in breast cancer patients. Summary Background Data As the use of robotic nipple sparing mastectomy continues to rise, improved understanding of the surgical, oncologic and quality of life outcomes is imperative for appropriate patient selection as well as to better understand indications, limits, advantages and dangers. Methods In a phase III, open label, single center, randomized controlled trial involving 80 women with breast cancer (69) or with BRCA mutation (11), we compared the outcome of robotic and open nipple sparing mastectomy. Primary outcomes were surgical complications and quality of life using specific validated questionnaires. Secondary objective included oncologic outcomes. Results Robotic procedure was 1 hour and 18 minutes longer than open (P < 0.001). No differences in the number or type of complications (P = 0.11) were observed. Breast-Q scores in satisfaction with breasts, psychosocial, physical and sexual well-being were significantly higher after robotic mastectomy vs open procedure. Respect to baseline, physical and sexual well-being domains remained stable after robotic mastectomy while they significantly decreased after open procedure (P

The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state that occurs in various tissues. Whether this tissue-level mechanical transition impact phenotypes during carcinoma progression remains unclear. We show, here that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. Cells react to these protracted mechanical stresses by mounting a mechano-protective response that includes enlarged nuclear size and rigidity, altered heterochromatin distribution, and the remodeling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS/STING-dependent cytosolic DNA response gene program. This mechanically-driven transcriptional rewiring ultimately results in a change in cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemo-resistance in invasive breast carcinoma. One-Sentence Summary: A solid-to-fluid phase transition promotes a pro-inflammatory transcriptional response in invasive breast carcinoma

Background Previous breast surgery does not represent an absolute contraindication for nipple-sparing mastectomy, although it may negatively interfere with surgical outcomes. The aim of the authors' study was to confirm the feasibility of nipple-sparing mastectomy after previous breast surgery, focusing on skin incisions and risk factors, complications, and oncologic outcomes. Methods The authors retrospectively identified 368 patients who underwent 387 nipple-sparing mastectomies and reconstruction after previous surgery (quadrantectomy, breast resection, augmentation and reduction mammaplasty, mastopexy) at the European Institute of Oncology from January of 2003 to November of 2017. Patterns of skin incisions (i.e., radial, hemiperiareolar, periareolar, vertical pattern, inframammary fold, Wise-pattern, and round-block) for primary surgery and for mastectomy, type of reconstruction, and radiotherapy have been recorded. The authors collected data regarding early and late complications and further operations (implant change, fat grafting) performed within 2 years to improve cosmetic outcomes. Oncologic follow-up has been reported for in-breast recurrences. Results Complete and partial nipple-areola complex necrosis occurred, respectively, in 2.8 percent and in 5.4 percent of cases. The authors recorded 5.4 percent failures resulting in implant removal. The analysis of risk factors for complications or for the need for further operations showed no significant association with skin incision for first surgery and mastectomy, use of the same skin incision, previous radiotherapy, or type of primary surgery. Five-year overall survival and disease-free survival were 99.1 and 93.8 percent, respectively. No nipple recurrence was recorded. Conclusions The authors' results confirm that nipple-sparing mastectomy can be a safe surgical procedure after previous breast surgery. Surgical planning should be tailored to each patient. Clinical question/level of evidence Therapeutic, III.

Giant malignant phyllodes tumor of the breast: Insights into optimal management and reconstructive options for a rare and challenging entity

Background: The aim of this work is to evaluate pattern of care and clinical outcome in a large series of patients with in-breast recurrence (IBR), after quadrantectomy and intraoperative radiation therapy with electrons (IOERT) as partial breast irradiation. Patients and Methods: Patients with IBR after IOERT, treated with salvage surgery ± adjuvant reirradiation (re-RT), were selected from a multiinstitution database. Disease-free survival (DFS), overall survival (OS), cumulative incidence of second IBR, and distant metastases (DM) were estimated. Results: A total of 224/267 patients from seven institutions were included. Primary tumors received 21 Gy. Median time to first IBR was 4.3 years (range 2.6–6.1 years). Salvage mastectomy and repeat quadrantectomy were performed in 135 (60.3%) and 89 (39.7%) patients, followed by adjuvant re-RT in 21/135 (15.5%) and 63/89 (70.8%), respectively. Median follow-up after salvage treatment was 4.1 years. Overall, 5- and 8-year outcomes were as follows: cumulative incidence of second IBR: 8.4% and 14.8%; cumulative incidence of DM: 17.1% and 22.5%; DFS: 67.4% and 52.5%; OS: 89.3% and 74.7%. The risk of second IBR was similar in the salvage mastectomy and repeat quadrantectomy + RT groups [hazard ratio (HR) 1.41, p = 0.566], while salvage mastectomy patients had greater risk of DM (HR 3.15, p = 0.019), as well as poorer DFS (HR 2.13, p = 0.016) and a trend towards worse OS (HR 3.27, p = 0.059). Patients who underwent repeat quadrantectomy alone had worse outcomes (second IBR, HR 5.63, p = 0.006; DFS, HR 3.21, p = 0.003; OS, HR 4.38, p = 0.044) than those adding re-RT. Conclusions: Repeat quadrantectomy + RT represents an effective salvage approach and achieved local control comparable to that of salvage mastectomy.

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.

BackgroundMicroinvasive breast cancer is an uncommon pathological entity. Owing to the rarity of this condition, its surgical axillary management and overall prognosis remain controversial.MethodsA database was analysed to identify patients with microinvasive ductal carcinoma in situ (DCIS) who had surgery for invasive breast cancer at the European Institute of Oncology, Milan, between 1998 and 2010. Women who had undergone axillary staging by sentinel lymph node biopsy were included in the study.ResultsOf 257 women with microinvasive breast cancer who underwent sentinel lymph node biopsy (SLNB), 226 (87·9 per cent) had negative sentinel lymph nodes (SLNs) and 31 had metastatic SLNs. Twelve patients had isolated tumour cells (ITCs), 14 had micrometastases and five had macrometastases in sentinel nodes. Axillary lymph node dissection was performed in 16 of the 31 patients with positive SLNs. After a median follow-up of 11 years, only one regional first event was observed in the 15 patients with positive SLNs who did not undergo axillary lymph node dissection. There were no regional first events in the 16 patients with positive SLNs who had axillary dissection.ConclusionGood disease-free and overall survival were found in women with positive SLNs and microinvasive DCIS. This study is in line with studies showing that SLNB in microinvasive DCIS may not be useful, and supports the evidence that less surgery can provide the same level of overall survival with better quality of life.