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Introduction: Axillary lymph node dissection (ALND) has always been part of breast cancer (BC) treatment. However, during the past 25 years, the surgical management of the axilla has shifted towards a more conservative approach. Until now, ALND has remained the standard surgical technique when the sentinel lymph node (SLN) is macrometastatic. However, ALND may now be considered overtreatment for early-stage BC. The SINODAR-ONE trial is a prospective non-inferiority multicenter randomized study aimed at assessing the role of ALND in patients undergoing either breast-conserving surgery (BCS) or mastectomy for T1-2 BC presenting 1-2 macrometastatic SLNs. Objectives: The primary endpoint was to evaluate whether sentinel lymph node biopsy (SLNB) only was associated with clinically relevant worsening of the prognosis compared with ALND in terms of overall survival (OS). The secondary endpoint was to evaluate whether there was increased regional (lymph node recurrence) or distant recurrence in terms of recurrence-free survival (RFS) in patients with macrometastatic SLN who did not undergo ALND. Methods: Patients were randomly assigned (1:1 ratio) to either removal of ≥10 axillary level I/II non-SLNs followed by adjuvant therapy (standard arm) or no further axillary treatment (experimental arm). Results: The trial started in April 2015 and ceased in April 2020, involving 889 patients. The majority of the patients (75.2%) underwent BCS; 328 of 439 patients (74.7%) in the standard treatment arm, and 333 of 440 patients (75.7%) in the experimental treatment arm. 218 patients (24.8%) underwent mastectomy. SLN status at randomization was comparable between the two groups of treatment, with a median number of two SLNs removed and a median number of one positive SLN in both arms. The median number of non-SLNs identified at definitive histopathological evaluation was 16 (interquartile range [IQR] 12–21) in the ALND group. Overall, 193 of 439 patients (44.0%) in the standard treatment arm had additional macrometastases in the removed axillary lymph nodes. However, the median number of positive non SLNs was 0 (IQR 0–1) in the ALND group. Median follow-up was 34.0 months. There were eight deaths (ALND, 4; SNLB only, 4), with a 5-year cumulative mortality of 5.8% and 2.1% in the standard and experimental arm, respectively (p = 0.984). There were 26 recurrences (ALND 11; SNLB only, 15), with a 5-year cumulative incidence of recurrence of 6.9% and 3.3% in the standard and experimental arm, respectively (p = 0.444). Only one axillary lymph node recurrence was observed in each arm. The 5-year OS rates were 98.9% and 98.8%, in the ALND and SNLB only arm, respectively (p = 0.936). Conclusion: The 3-year survival and relapse rates of T1-2 BC patients with 1-2 macrometastatic SLNs treated with SLNB only, and adjuvant therapy, were not inferior to those of patients treated with ALND. These results do not support the use of routine ALND in patients undergoing BCS. However, given the low number of patients treated with mastectomy, there is no certainty that ALND omission can be extended also to this sub-group. In order to collect further evidence regarding the safety of the experimental treatment in patients candidates for mastectomy, the reopening of the enrollment of these patients as part of a single-arm experimental study started in June 2022. Citation Format: Damiano Gentile, Wolfgang Gatzemeier, Andrea Sagona, Erika Barbieri, Alberto Testori, Valentina Errico, Alberto Bottini, Simone Di Maria Grimaldi, Giulia Caraceni, Luca Boni, Paolo Bruzzi, Bethania Fernandes, Davide Franceschini, Ruggero Spoto, Rosalba Torrisi, Marta Scorsetti, Armando Santoro, Giuseppe Canavese, Corrado Tinterri. Preservation of axillary lymph nodes in breast cancer patients undergoing mastectomy with 1-2 metastatic sentinel lymph nodes: The current status and future perspectives of the multicenter randomized clinical trial SINODAR-ONE [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 OT1-06-01.

Introduction: Patients with triple-negative (TN) or HER2-enriched ipsilateral breast cancer recurrence (IBCR) seem to be excluded from a second breast-conserving surgery (BCS) under the assumption that salvage mastectomy would provide better oncological outcomes. Objectives: The objective of this study was to describe the clinical features of these patients, to compare the two surgical alternatives (salvage mastectomy versus second BCS) in terms of oncological results, and to identify independent factors influencing prognosis and surgical treatment. Methods: We retrospectively reviewed all the consecutive patients with histologically confirmed TN or HER2-enriched IBCR. Disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed and compared between the two groups. Results: Eighty-five patients were affected by TN or HER2-enriched IBCR, with a median age of 60 years (range, 32-87 years). The majority of patients (72.9%) were treated with salvage mastectomy. There was no significant difference in terms of DFS between patients receiving a second BCS or mastectomy (p=0.596). However, patients undergoing a second BCS had significantly better DDFS, OS, and BCSS compared to mastectomy (p=0.009; p=0.002; p=0.001, respectively). Tumor dimension < 16 mm (78.3% versus 38.7%, hazard ratio (HR)=3.602, 95% confidence interval (95% CI)=1.534-8.459, p=0.003) was found to significantly increase the probability of receiving a second BCS and positively affects recurrence and survival outcomes (DFS: HR=8.065, 95% CI=2.320-28.034, p=0.001; DDFS: HR=17.011, 95% CI=3.853-75.099, p=0.001; OS: HR: 13.881, 95% CI=2.730-70.579, p=0.002; BCSS: HR=36.773, 95% CI=4.579-295.322, p=0.001). Second BCS represents an independent protective factor for OS and BCSS (OS: HR=0.246, 95% CI=0.027-0.697, p=0.002; BCSS: HR=0.313, 95% CI=0.092-0.511, p=0.002). Conclusion: Salvage mastectomy is not always necessary and it does not seem to increase survival compared to a second BCS. This reinforces the concept that the prognosis of TN and HER2-enriched BC recurrence is mainly driven by the biology of the disease, rather than by the extent of surgery. In patients with small (< 16 mm) aggressive subtypes of IBCR, a second conservative approach can still be evaluated and offered, presenting acceptable loco-regional control and survival. Citation Format: Damiano Gentile, Andrea Sagona, Erika Barbieri, Simone Di Maria Grimaldi, Ruggero Spoto, Davide Franceschini, Stefano Vaccari, Valeriano Vinci, Ersilia Biondi, Lorenzo Scardina, Corrado Tinterri. Salvage mastectomy is not always necessary for aggressive subtypes of ipsilateral breast cancer recurrence: A single-institution retrospective study [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 P1-09-09.

BackgroundBRCA-mutation carriers have a lifetime risk of breast cancer (BC) that ranges from 36 to 70%. For patients (pts) without mutation, breast conserving surgery (BCS) (followed by radiation therapy) is the treatment of choice since it offers similar survival to that of unilateral mastectomy. However, the optimal local management in BRCA-mutation carriers remains a matter of debate and the role of bilateral salpingo-oophorectomy (BSO) in reducing BC risk might be influenced by age and medical BC treatments (such as GnRH analogues). Patients and methodsWe retrieved clinical pathologic characteristics of 124 BRCA-mutated BC pts, consecutively tested at our Institution from 2008 to 2018. Primary end-point was recurrence-free survival (RFS) evaluation in terms of disease-free survival (DFS), distant DFS (DDFS) and overall survival (OS). Secondary end-point was identification of independent predictive factors for BCS. Clinical pathologic characteristics were evaluated and compared using univariate and multivariate analysis. Kaplan-Mayer curves were used to describe DFS, DDFS and OS. ResultsMedian age at BC surgery was 41 years (range 24-74), most of the pts (79%) were pre-menopausal and presented with ductal invasive carcinoma (91.9%). As per biological subtype, 63 (50.8%) pts had luminal-like BC, 52 (41.9%) triple negative (TN) BC and 9 (7.3%) HER2 enriched-like BC. More than half pts (62.9%) presented with G3 tumors and median Ki-67 was 40% (range 5-95). 17 (13.7%) and 80 (64.5%) pts underwent neo-adjuvant and adjuvant chemotherapy, respectively; 64 (51.6%) pts received adjuvant endocrine therapy, 39 (31.5%) with the addition of GnRH analogue. When comparing BCS to mastectomy, regardless of BSO, we could not observe any statistically significant difference in all the RFS end-points. 10-year DFS rate was 56.4% and 79.5%, respectively (p=0.187); 10-year DDFS rate was 83.7% and 82.3%, respectively (p=0.689); 10-year OS rate was 87.7% and 85.1%, respectively (p=0.947). At a multivariate analysis, age ≤41 years (p=0.008; OR 0.309; 95% CI 0.190-0.513) and primary tumor dimension ≤21 mm (p=0.008; OR 0.320; 95% CI 0.114-0.426), were the only predictors of breast surgery type (BCS compared to any other surgical treatment). ConclusionsOur data suggest that young pre-menopausal BRCA-mutated pts with small tumors may not need up-front mastectomy and BSO might be postponed, when ovarian cancer risk epidemiologically rises and potential reproductive desire is fulfilled. Citation Format: Agnese Losurdo, Damiano Gentile, Monica Zuradelli, Andrea Sagona, Erika Barbieri, Monica Barile, Paolo Bianchi, Rosalba Torrisi, Wolfgang Gatzemeier, Marta Scorsetti, Corrado Tinterri, Armando Santoro. Breast conserving surgery in BRCA-mutation carriers. A single Institution experience [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-16.

Background A small proportion of patients with primary breast cancer who receive breast conserving surgery (BCS) will develop an ipsilateral breast cancer recurrence (IBCR). In these patients, mastectomy is still considered the treatment of first choice, even if a second conservative surgical approach is technically feasible. The aims of our study are to analyze the characteristics of patients with IBCR after BCS, evaluate and compare the different treatment modalities (repeat BCS vs. mastectomy) in terms of patients and tumor characteristics, disease-free interval (DFI), disease-free survival (DFS), and overall survival (OS).MethodsOur prospectively maintained institutional database was queried, and 309 patients with IBCR after BCS who underwent either repeat BCS or mastectomy, between January 2008 and December 2018, were identified. Ipsilateral breast cancer recurrence was defined as a local tumor reappearance in the same breast or in the surgical scar. Exclusion criteria were: age Citation Format: Damiano Gentile, Andrea Sagona, Chiara Annunziata Pasqualina Anghelone, Erika Barbieri, Emilia Marrazzo, Wolfgang Gatzemeier, Giuseppe Canavese, Valentina Errico, Alberto Testori, Corrado Tinterri. Ipsilateral breast cancer recurrence: Treatment and long-term oncological results at a high volume center [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-16.

Background: Sentinel lymph node biopsy (SLNB) has emerged as the standard procedure to replace axillary lymph node dissection (ALND) in breast cancer (BC) patients undergoing neo-adjuvant chemotherapy (NAC). SLNB is accepted in clinically node-negative (cN0) patients; however, its role in clinically node-positive (cN+) patients is debatable. Methods: We performed a retrospective analysis of BC patients undergoing NAC and SLNB. Our aim was to evaluate the clinical significance of SLNB in the setting of NAC. This was accomplished by comparing the characteristics and oncological outcomes between cN0 and cN+ patients prior to NAC and type of axillary surgery. Results: A total of 291 patients were included in the analysis: 131 were cN0 and 160 were cN+ who became ycN0 after NAC. At a median follow-up of 43 months, axillary recurrence occurred in three cN0 (2.3%) and two cN+ (1.3%) patients. However, there were no statistically significant differences in oncological outcomes (disease-free survival, distant disease-free survival, overall survival, and breast-cancer-specific survival) between cN0 and cN+ patients nor between patients treated with SLNB only or ALND. Conclusions: SLNB in the setting of NAC is an acceptable procedure with a general good prognosis and low axillary failure rates for both cN0 and cN+ patients.

Introduction: Treatment of early-stage beast cancer (BC) has changed since recent evidence showed that neoadjuvant chemotherapy (NAC) can reduce residual tumor cellularity (RTC) and improve patient outcomes. Achieving a pathologic complete response (pCR) has been associated with significantly improved disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). However, among patients treated with NAC, few experience pCR, while approximately 60-80% of them achieve a pathologic partial response (pPR). In previous studies, BC patients with different grades of pPR have been usually grouped and analyzed together, with inconsistent results and unclear prognostic significance. Objectives: The primary aims of this study were to describe the clinical and treatment characteristics of BC patients treated with NAC, to identify independent predictive factors of pCR, and to compare the oncologic outcomes between patients achieving pCR or pPR. The secondary aim of this study was to measure the RTC of BC patients with pPR and to compare the outcomes of patients with different RTC in order to improve prognostic information. Methods: All the consecutive BC patients undergoing NAC at the Breast Unit of IRCCS Humanitas Research Hospital (Milan, Italy) between October 2006 and April 2020 and their corresponding post-operative pathology slides were reviewed. The following exclusion criteria were used: excisional biopsy or debulking surgery as first BC operation, patients with a previous BC diagnosis or other prior or synchronous malignancies, male patients, unknown NAC regimen, disease progression during NAC, and follow-up ≤12 months. Results: A total of 495 BC patients received NAC. Overall, 148 (29.9%) patients achieved pCR, while 347 (70.1%) had pPR, and median RTC was 40%. At multivariable analysis, 3 independent factors predicting pCR were identified. Tumor stage pre-NAC (cT1-2 84.5% versus cT3-4 15.5%, odds ratio (OR)=0.119, 95% confidence interval (95%CI)=0.048-0.189, p=0.001), BC sub-type (HER2-enriched 54.7% versus triple-negative 29.8% versus luminal-like 15.5%, OR=2.178, 95%CI=2.055-2.301, p=0.001), and vascular invasion (absence 98.0% versus presence 2.0%, OR=0.022, 95%CI=0.004-0.090, p=0.001). Patients with BC undergoing NAC and achieving pCR presented statistically significant longer DFS, DDFS, and OS (p = < 0.001). Patients with RTC < 40% presented statistically significant better DFS and DDFS (p = 0.033, p = 0.015, respectively). However, no statistically significant difference in terms of OS was observed between RTC < 40% and RTC ≥40% groups (p = 0.148). Conclusions: Tumor stage pre-NAC, BC sub-type, and vascular invasion are significantly and independently associated with pCR. Patients with pCR present a better prognosis compared to patients with pPR in terms of DFS, DDFS, and OS. Measurement of RTC in BC patients with pPR improves the prognostic information that can be obtained from the assessment of the pathologic response. Different patterns of residual disease play an important role in predicting the risk of subsequent loco-regional and distant recurrence, and patients with RTC < 40% present significantly better DFS and DDFS. Citation Format: Damiano Gentile, Andrea Sagona, Camilla De Carlo, Bethania Fernandes, Simone Di Maria Grimaldi, Erika Barbieri, Wolfgang Gatzemeier, Lorenzo Scardina, Ersilia Biondi, Flavia Jacobs, Giulia Vatteroni, Corrado Tinterri. Evaluation of pathologic response and residual tumor cellularity following neo-adjuvant chemotherapy predict prognosis in breast cancer patients [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 P6-01-32.

Background: Loco-regional therapy (LRT) in de novo metastatic breast cancer (MBC) has been investigated in several clinical trials, with heterogeneous and conflicting results. Methods: We conducted a retrospective study of de novo MBC patients treated with front-line chemotherapy (FLC) followed by LRT of the primary tumor. Our aims were to evaluate the characteristics, treatment, and oncological outcomes in terms of progression-free survival (PFS), distant progression-free survival (DPFS), and overall survival (OS) of de novo MBC. We also investigated possible subgroups of patients with better outcomes according to menopausal status, biological sub-type, location, number of metastases, and radiologic complete response after FLC. Results: We included 61 patients in the study. After a median follow-up of 55 months, disease progression occurred in 60.7% of patients and 49.2% died. There were no significant differences in PFS, DPFS, and OS between different subgroups of de novo MBC patients. A trend toward better PFS and DPFS was observed in triple-positive tumors, without a statistically significant difference in OS. Conclusions: No specific subgroup of de novo MBC patients showed a statistically significant survival advantage after FLC followed by LRT of the primary tumor.

Introduction: Neuroendocrine neoplasm of the breast (bNENs) are considered a rare disease, even if in WHO data they represent about 2-5 % of all breast cancer. The last WHO classification includes: welldifferentiated neuroendocrine tumor (bNET), neuroendocrine carcinoma (NEC) and invasive carcinoma with neuroendocrine differentiation. The current knowledge on clinical management of bNENs is poor and patients are usually treated according to non-endocrine tumor components guidelines. Materials and Methods: We presented our experience of six cases of bNENs. Moreover, we conducted a systematic review of published data on diagnosis, treatment and outcome of this kind of tumors. Results: bNENS usually presented as palpable breast masses, classically appearing as irregular hypoechoic lesions at US examination and as hyperdense masses at mammography. Usually pre-operative tumor biopsy is not able to recognize the neuroendocrine components and the final diagnosis is performed only on definitive histopathological assessment. The most frequent subtype seems to be neuroendocrine carcinoma and synaptophysin is positive in most specimens. Treatment strategies, including surgical treatment, radiotherapy and medical treatment are nowadays based on current non-endocrine breast cancer guidelines, independently from neuroendocrine components, even if some studies have proposed the use of somatostatin analogues for bNET and cisplatin-etoposide for NEC. Prognosis of all bNENs, especially of poorly differentiated neoplasia, seems worse compared to non-neuroendocrine breast cancer and stage and morphology seem the best predictor of tumor outcome. Conclusions: We provide an algorithm for clinical management of bNETs, basing on available data. More studies are necessary for confirming the best treatment strategy for these patients, in order to improve clinical outcome

Mucinous carcinoma (MC) is a rare breast cancer characterized by the presence of large extracellular mucin amount. Two main subtypes can be distinguished: pure (PMC) and mixed (MMC). We conducted a retrospective MC analysis in our prospective maintained database, calculating disease-free survival (DFS) and 5-year overall survival (OS). We found a global 92.1% OS (higher in MMC group and statistically significative) and a DFS of 95.3% (higher in MMC group but not statistically significative)., Highlights • Mucinous carcinoma (MC) is a rare breast cancer characterized by the presence of large extracellular mucin amount. • We conducted a literature review and conducted a retrospective analysis in our database, finding 157 cases of MC. • Our findings are consistent with those published in literature, showing fundamental differences between PMC and MMC management and outcomes., We reviewed literature and our data to find out mucinous breast cancer's overall survival (OS), disease free survival (DFS) and if there are differences between pure mucinous breast cancer and mixed mucinous breast cancer in terms of OS and DFS.

Introduction: Sentinel lymph node (SLN) staging is currently used to avoid complete axillary lymph node dissection (ALND) in breast cancer (BC) patients. The SLN is the only site of axillary metastasis (MTS) in ≥60% of cases. Recently, a randomized controlled trial (Z0011) comparing SLN biopsy (SLNB) alone with SLNB followed by ALND in patients with 1-2 SLNs+ demonstrated no significant statistical difference in relapse and overall survival (OS) rates among the two different groups. However, this study had some limitations: small tumor size (≤2cm in 70% of cases), frequent presence of only microMTS in SLN (40%), prevalent use of “whole breast” adjuvant radiotherapy (>90%). Given these considerations, the SINODAR-ONE study started in April 2015. Objectives: The aims are to assess whether ALND omission in BC patients with 1-2 SLNs+ is associated with worse survival and/or increased rate of regional/distant relapse. Thus evaluating whether SLNB is or is not inferior to ALND. Primary endpoint is OS. Secondary endpoints are disease-free survival (DFS) referring to distant MTS and loco-regional recurrence. Methods: Patients received either mastectomy or conservative surgery plus radiotherapy. They all underwent SLNB and were randomly divided into two arms of treatment: standard (SLNB plus ALND) or experimental treatment (only SLNB). According to multidisciplinary evaluation, patients could undergo additional adjuvant radiotherapy, chemo- and/or hormonal therapy, or no further therapy. Eligibility criteria: age 40-75 years; primary invasive T1-T2 tumor; axillary nodes cN0; no more than 2 macro-metastatic SLNs; no distant MTS; no neo-adjuvant therapy; no previous invasive BC. Exclusion criteria: in situ, inflammatory, contralateral BC; micro-metastatic SLNs; pregnancy or breast feeding; comorbidity impeding adjuvant therapy. All analyses were performed both on all patients according to the Intention-To-Treat principle and excluding those patients who did not receive the axillary treatment randomly assigned. Statistical analysis: OS and DFS were calculated using the Kaplan-Meier Product Limit Estimator and differences between arms were assessed with the log-rank test. Results: The enrollment of patients ended in April 2020 with a total of 889 cases (443: standard arm; 446: experimental arm). In April 2021, we conducted a preliminary analysis on 889 patients. We found the two groups homogeneous for epidemiologic characteristics (age and menopausal status), tumor characteristics (tumor size, pTNM, immunohistochemistry, histology, grading, vascular and lymphatic invasion), and adjuvant therapies. The majority of patients (77.2%) received breast conserving surgery, while 22.8% of patients underwent mastectomy. A median of 2 SLNs were removed in both arms. Overall, only 3 micro-metastatic SNLs were found (1 in the standard arm and 2 in the experimental arm). Conclusion: In sum, OS rate is 99.1% and 99.3% in the standard and experimental arm, respectively; DFS rate is 96.8% and 95.9% in the standard and experimental arm, respectively. After a median follow-up of 36 months, there has been only one axillary recurrence in the experimental arm. Additionally, we found seven distant relapses in both arms; four and three deaths in the standard and experimental arm, respectively. Citation Format: Damiano Gentile, Wolfgang Gatzemeier, Erika Barbieri, Andrea Sagona, Alberto Bottini, Valentina Errico, Alberto Testori, Marta Scorsetti, Giuseppe Canavese, Corrado Tinterri. Preservation of axillary lymph nodes compared to complete dissection in T1-T2 breast cancer patients presenting 1-2 metastatic sentinel lymph nodes. A multicenter randomized clinical trial. Sinodar One [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-05.

OBJECTIVE: Neo-adjuvant chemotherapy (NAC) is the treatment of choice for patients with locally advanced breast cancer (BC). In luminal-like BC, the decision to administer NAC remains controversial. The purpose of this study was to describe the clinical characteristics, treatment, and oncological outcomes of luminal-like, node positive, BC patients treated with NAC, and to identify independent predictive factors for treatment. MATERIALS AND METHODS: All consecutive patients with luminal-like, node positive BC who underwent NAC were retrospectively reviewed. Pathologic complete response (pCR) was defined as no invasive or in situ residual tumor in both breast and axillary nodes (ypT0N0). RESULTS: A total of 205 luminal-like, node positive BC patients underwent NAC. Overall, 34 (16.6%) patients showed pCR, 86 (42.0%) patients underwent breast-conserving surgery (BCS), 119 (58.0%) patients underwent mastectomy, 130 (63.4%) patients underwent axillary lymph node dissection (ALND) without prior sentinel lymph node biopsy (SLNB), and 75 (36.6%) patients underwent breast surgery plus SLNB. Pathologic CR to NAC (29.1% vs 7.6% if no pCR, odds ratio = 2.866, 95% confidence interval = 1.296-6.341, p = 0.009) was found to significantly increase the probability to receive BCS. There was no significant difference in terms of disease-free and overall survival between patients with luminal-like, node positive BC receiving BCS or mastectomy (p = 0.596, p = 0.134, respectively), and ALND or SLNB only (p = 0.661, p = 0.856, respectively). CONCLUSION: Luminal-like, node positive BC presents low pCR rates after NAC. Pre-operative chemotherapy increases the rate of BCS. Pathologic CR has emerged as an independent predictive factor for BCS. In patients with axillary pCR, SLNB is an acceptable procedure not associated with worse oncological outcomes.

Salvage mastectomy is regarded as the treatment of first choice for ipsilateral breast cancer recurrence (IBCR), even if a second breast conserving surgery (BCS) is feasible. The purpose of this study was to compare the long-term oncological outcomes of IBCR patients who had undergone either mastectomy or second BCS, performing a propensity score matching (PSM) analysis to reduce the selection bias. All the consecutive patients with IBCR were retrospectively reviewed and divided into two different groups of treatment: repeat BCS versus salvage mastectomy. The propensity score predicting the probability of surgical treatment was determined for each patient and a 1:1 matching was performed. Disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed and compared between the two groups. A total of 309 patients underwent surgical treatment for IBCR. After PSM, 108 patients treated with repeat BCS and 108 patients treated with salvage mastectomy were included in the analysis. There was no significant difference in terms of DFS between patients with IBCR receiving repeat BCS or salvage mastectomy (p = 0.167). However, patients with IBCR undergoing second BCS had significantly better DDFS, OS, and BCSS compared to salvage mastectomy (p

Introduction: Sentinel lymph node (SLN) staging is currently used to avoid complete axillary lymph node dissection (ALND) in breast cancer (BC) patients. The SLN is the only site of axillary metastasis (MTS) in ≤60% of cases. Recently, a randomized controlled trial (Z0011) comparing SLN biopsy (SLNB) alone with SLNB followed by ALND in patients with 1-2 SLNs+ demonstrated no significant statistical difference in relapse and overall survival rates among the two different groups. However, this study had some limitations: small tumor size (≤2cm in 70% of cases), frequent presence of only microMTS in SLN (40%), prevalent use of “whole breast” adjuvant radiotherapy (>90%). Given these considerations, the SINODAR-ONE study started in April 2015.Objectives: The aims are to assess whether ALND omission in BC patients with 1-2 SLNs+ is associated with worse survival and/or increased rate of regional/distant relapse. Thus evaluating whether SLNB is or is not inferior to ALND. Primary endpoint is overall survival (OS). Secondary endpoints are disease-free survival (DFS) referring to distant MTS and loco-regional recurrence. Methods: Patients receive either mastectomy or conservative surgery plus radiotherapy. They all undergo SLNB and are randomly divided into two arms of treatment: standard (SLNB plus ALND) or experimental treatment (only SLNB). According to multidisciplinary evaluation, patients may undergo additional adjuvant radiotherapy, chemo- and/or hormonal therapy , or no further therapy. Eligibility criteria: age 40-75 years; primary invasive T1-T2 tumor; axillary nodes clinically N0; no more than 2 macro-metastatic SLNs; no distant MTS; no neo-adjuvant therapy; no previous invasive BC; signed informed consent. Exclusion criteria: in situ, inflammatory, contralateral BC; micro-metastic SLNs; pregnancy or breast feeding; comorbidity impeding adjuvant therapy. All analyses are performed both on all patients according to the Intention-To-Treat principle and excluding those patients who did not receive the axillary treatment randomly assigned. Statistical analysis: OS and DFS are calculated using the Kaplan-Meier Product Limit Estimator and differences between arms are assessed with the log-rank test. Results: The enrollment of patients ended in April 2020 with a total of 889 cases (443: standard arm; 446: experimental arm). In June 2020, we conducted an ad interim analysis on 889 patients. We found the two groups homogeneous for epidemiologic characteristics (age and menopausal status), tumor characteristics (tumor size, pTNM, immunohistochemistry, histology, grading, vascular and lymphatic invasion), adjuvant therapies and surgery on T. In particular we have performed a 23,1% of mastectomies in the standard arm and 20,1% in the experimental arm. We found a median of 2 sentinel lymph nodes removed in both arms and 1 non-sentinel positive lymph node in the experimental arm, and only 3 micro-metastases (1 in the standard arm and 2 in the experimental arm). Conclusion: In sum, with a median follow-up of 30 months, there have been no axillary recurrence in both arms. In the standard arm we found 8 total events (2 deaths and 6 distant relapses) and in in the experimental arm 6 events (1 death and 5 distant relapses), with a projected 5-years cumulative incidence of 6,5% in standard arm and 4,85% in the experimental arm. Citation Format: Corrado Tinterri, Emilia Marrazzo, Chiara Anghelone, Erika Barbieri, Andrea Sagona, Alberto Bottini, Arianna Rubino, Damiano Gentile, Wolfgang Gatzemeier, Valentina Errico, Alberto Testori, Giuseppe Canavese. Preservation of axillary lymph nodes compared to complete dissection in T1-T2 breast cancer patients presenting 1-2 metastatic sentinel lymph nodes : A multicenter randomized clinical trial. Sinodar One. [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD4-01.

OBJECTIVE: Hypofractionated radiotherapy in early stage breast cancer is an effective adjuvant treatment, but there is a lack of randomized data for patients with ductal carcinoma in situ (DCIS). The aim of this study is the evaluation of skin toxicity and cosmesis, and early clinical outcome of DCIS patients enrolled in an institutional Phase II trial of hypofractionated breast irradiation. METHODS: 137 DCIS patients were enrolled in the trial. All patients underwent volumetric modulated arc therapy (VMAT) to the whole breast with a total dose of 40.5 Gy in 15 fractions over 3 weeks, without tumour bed boost. Acute and late skin toxicities were recorded. Cosmetic outcomes were assessed as excellent/good or fair/poor. Early clinical outcome was reported. RESULTS: Median age was 58 y.o. (range 30–86). The median follow-up time was 22 months (range 6–45). At the end of the radiotherapy, skin toxicity was grade G1 in 56% of the patients, G2 in 15%, no patients presented G3 toxicity. In the range of 3–9 months of follow-up, the skin toxicity was G1 in 28% of patients, no G2–G3 cases; cosmetic outcome was good/excellent in 95% of patients. In the follow-up interval of 9–24 months, the skin toxicity was G1 in 12% of patients, no G2-G3 toxicity; cosmetic outcome was good/excellent in 96% of patients. After an early evaluation of clinical outcomes, 5 patients (3.6%) presented an in-breast recurrence. CONCLUSION: Hypofractionated radiotherapy using VMAT is a viable option for DCIS. A longer follow-up is needed to assess clinical outcomes and late toxicity. ADVANCES IN KNOWLEDGE: The use of hypofractionated VMAT is dosimetrically feasible for treating breast DCIS.

Introduction Sentinel lymph node (SLN) staging is currently used to avoid complete axillary lymph node dissection (ALND) in breast cancer (BC) patients with negative SLNs without jeopardizing survival or regional control. International guidelines keep recommending ALND in the presence of positive (+) SLNs. However SLN is the only site of axillary metastasis (MTS) in many cases (60%). Retrospective studies have also shown a low risk of locoregional relapse in patients with SLNs+ not receiving ALND.This latter finding was recently confirmed in a randomized trial comparing SLN biopsy (SLNB) alone with SLNB followed by ALND in patients with 1-2 SLNs+. However the observation of both similar relapse rate and survival in the 2 arms and the conclusion of a non-inferiority of SLNB compared to ALND require cautiousness because of some study limitations: premature enrollment cessation due to death rate lower than expected, short follow-up (6 years), small tumor size (≤2cm in 70% of cases), frequent presence of only microMTS in SLN (40%), prevalent use of “whole breast” adjuvant radiotherapy (>90%) which irradiates the breast but also the I° axillary level, thereby contributing to the low rate of regional relapse in the SLNB arm due to lymph node sterilization. Consequently further randomized trials with more precise selection criteria based on homogeneous clinico-pathological features and with longer follow-up are needed to confirm that performing only SLNB does not affect survival or relapse risk in patients with 1-2 SLNs+. Materials and Methods Primary and secondary aims of the present 2-arm randomized trial are to assess whether ALND omission in BC patients with 1-2 SLNs+ is associated with worse survival and/or increased rate of regional/distant relapse, respectively, thus evaluating whether SLNB is or is not inferior to ALND. Patients receive either conservative surgery or mastectomy and radiotherapy. They all undergo intraoperative SLNB and SLN evaluation, and are randomly assigned to either further dissection of level I-II axillary lymph nodes (standard ALND arm) or absence of any axillary surgery (experimental SLNB arm). According to International Guidelines post-surgery treatments. Eligibility criteria are: age 40-75 years; primary invasive T1-T2 tumor; axillary nodes clinically N0; no more than 2 SLNs presenting macroMTS at intraoperative or definitive histological evaluation; no distant MTS; no neoadjuvant therapy; no previous invasive BC, signed informed consent. Exclusion criteria are: in situ, inflammatory, contralateral BC; presence of only microMTS in the SLN+; pregnancy or breast feeding; comorbidity impeding adjuvant therapy. Follow-up controls foresee: clinical examination every 6 months for 5 years and yearly thereafter; annual mammography and breast echography; annual axillary echography for patients in the SLNB arm; additional laboratory and instrumental surveys in case of suspected onset of distant MTS. The primary endpoint is overall survival (OS). Secondary endpoints are disease-free survival (DFS) referring to distant MTS and to locoregional (ipsilateral breast or axillary, internal mammary or sopraclaveolar lymph nodes) disease recurrence. All analyses are performed both on all patients according to the Intention-To-Treat principle and excluding those patients who did not receive the axillary treatment randomly assigned. Citation Format: Corrado Tinterri, Emilia Marrazzo, Federico Frusone, Wolfgang Gatzemeier, Erika Barbieri, Andrea Sagona, Alberto Bottini, Valentina Errico, Alberto Testori, Giuseppe Canavese. Preservation of axillary lymph nodes compared to complete dissection in T1-T2 breast cancer patients presenting 1-2 metastatic sentinel lymph nodes: A multicenter randomized clinical trial. Sinodar One Study [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 OT3-01-02.

Background Despite the well-known association between extensive lymphocytic infiltration in breast cancer (BC), good prognosis, and high response rates to neoadjuvant chemotherapy (CT), pathologic evaluation of tumor infiltrating lymphocytes (TILs) is currently not routine and a deep understanding of the properties of TILs, remain largely unfilled. So far, only in triple-negative (TN), PD-L1 positive BCs it has been possible to demonstrate a survival benefit with immunotherapy plus CT, thereby making the definition of possible immunotherapeutic targets across all biological subtypes a fundamental requirement. Material and methods Single-cell RNA-sequencing (scRNAseq) data from 8 BCs were downloaded from Gene Expression Omnibus dataset (GSE114725), obtaining CD45+ single cells only from the tumoral compartment. scRNAseq-guided high-dimensional profiling by 27-parameter FACS was then applied to a large cohort (n=54, including luminal-like, TN and HER2+ BCs) of early BC patients surgically treated at our Institution. We simultaneously profiled the peripheral blood, the normal and tumoral tissue from each patient and acquired using FACS Symphony A5 flow cytometer (BD Biosciences). Flow Cytometry Standard (FCS) 3.0 files were imported into FlowJo software v9, and analyzed by standard gating to remove aggregates and dead cells, and subsequently imported in FlowJo v10, biexponentially transformed, and exported for further analysis in R by a custom-made script, using an ad-hoc pipeline. Data were analyzed using the Phenograph unbiased algorithm coded in the cytofkit package. Data were further analyzed in FlowJo to determine the frequency of positive cells for each marker and the corresponding median fluorescence intensity (MFI). These values were multiplied to derive the integrated MFI; hierarchical metaclustering of all samples, based on the frequency of Phenograph clusters, was performed in R based on the Euclidean distance and Ward-linkage. Pearson correlation analysis was used to investigate the relationship between CD8+ and CD4+ clusters. Results Our scRNA-guided informative 27-colors flow cytometry panel included antibodies to define not only different lymphocyte subpopulations, but also different stages of T lymphocytes: differentiation and memory maturation (CCR7, CD45RA), activation status (HLA-DR), cytotoxicity (GZMK, GZMB), exhaustion (PD-1, TIGIT) and tissue residency (CD69, CD103). Focusing on CD8+ T cells, we observed, as expected, bona fide naïve T cells to be virtually absent at the tumor site and enriched in peripheral blood, while cytotoxic and effector memory cells were enriched in the tumor compartment. Of note, we identified a population of tissue resident memory T cells (Trm) CD69+ CD103+, CD39+, specifically enriched in the tumor, that could be further subdivided into a HLA-DR+ CD127- and a HLA-DR- CD127+ subpopulation. Interestingly, the HLA-DR+ subset exhibited more exhaustion markers (PD-1hi, TIGIT+, NKG2A+) and was significantly positively correlated with CD4+ regulatory T cells. We speculated, and deeply investigated by bulk RNA-seq, that these two subsets of Trm might represent different maturation states and that they could be reinvigorated targeting highly expressed inhibitory molecules using approved (e.g., PD-1) together with newly identified (e.g., NKG2A) immunotherapeutics. Moreover, as no difference was observed in the relative distribution of Phenograph clusters, our data may be applied to revert acquired immune escape mechanisms in all different BC biological subtypes. Conclusions We identified, among Trm CD69+ CD103+, tumor-specific CD39+, PD1+ exhausted population, novel dysfunctional NKG2A+ T cells previously not characterized in BC. This population is of extreme interest to characterize a novel potential immunotherapeutic target. Citation Format: Agnese Losurdo, Caterina Scirgolea, Emilia Mazza, Valentina Errico, Bethania Fernandes, Luca Di Tommaso, Andrea Sagona, Karolina Pilipow, Rosalba Torrisi, Giovanna Masci, Rita De Sanctis, Elisa Agostinetto, Alberto Testori, Corrado Tinterri, Massimo Roncalli, Armando Santoro, Enrico Lugli. Defining T cell dysfunctionality in breast cancer by single cell analysis: Implications for immunotherapy [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 P5-04-07.

The 'regional nodal mapping', is a fundamental step to stage breast carcinoma. In addition to the axillary nodes status, the involvement of internal mammary nodes is an important prognostic factor. Six hundred and sixty-three patients with breast carcinoma, mainly in the inner quadrants, underwent a biopsy of internal mammary nodes. Positive internal mammary nodes were found in 68 out of 663 cases (10.3%) representing 27.2% of all cases with regional node metastases (250). When histologically proven metastases were detected, radiotherapy was administered to the internal mammary nodes chain. In 254 cases, the surgeon's exploration was guided by a gamma probe. Out of these cases, 28 (11.0%) showed metastatic involvement. Out of the other 409 cases, not radioguided, 40 showed positive nodes (9.8%). Patients with internal mammary metastases treated with radiotherapy and appropriate systemic treatment showed an excellent survival (95% at 5 years), a result which is in opposition to the previous experience, which stated that invasion of internal mammary nodes is an ominous prognostic sign. We assume that this excellent result is due to radiotherapy to internal mammary nodes and we propose that exploration of internal mammary nodes should be part of the staging process of carcinomas of the medial part of the breast.

Background To report results in terms of feasibility and early toxicity of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery. Methods Between September 2010 and May 2011, 50 consecutive patients presenting early-stage breast cancer were submitted to adjuvant radiotherapy with SIB-VMAT approach using RapidArc in our Institution (Istituto Clinico Humanitas ICH). Three out of 50 patients were irradiated bilaterally (53 tumours in 50 patients). All patients were enrolled in a phase I-II trial approved by the ICH ethical committee. All 50 patients enrolled in the study underwent VMAT-SIB technique to irradiate the whole breast with concomitant boost irradiation of the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy respectively, delivered in 15 fractions over 3 weeks. Skin toxicities were recorded during and after treatment according to RTOG acute radiation morbidity scoring criteria with a median follow-up of 12 months (range 8–16). Cosmetic outcomes were assessed as excellent/good or fair/poor. Results The median age of the population was 68 years (range 36–88). According to AJCC staging system, 38 breast lesions were classified as pT1, and 15 as pT2; 49 cases were assessed as N0 and 4 as N1. The maximum acute skin toxicity by the end of treatment was Grade 0 in 20/50 patients, Grade 1 in 32/50, Grade 2 in 0 and Grade 3 in 1/50 (one of the 3 cases of bilateral breast irradiation). No Grade 4 toxicities were observed. All Grade 1 toxicities had resolved within 3 weeks. No significant differences in cosmetic scores on baseline assessment vs. 3 months and 6 months after the treatment were observed: all patients were scored as excellent/good (50/50) compared with baseline; no fair/poor judgment was recorded. No other toxicities or local failures were recorded during follow-up. Conclusions The 3-week course of postoperative radiation using VMAT with SIB showed to be feasible and was associated with acceptable acute skin toxicity profile. Long-term follow-up data are needed to assess late toxicity and clinical outcomes.

Background: In the case of ipsilateral breast tumour recurrence (IBTR) after breast-conserving surgery (BCS), a second conservative surgical approach maybe considered in some motivated patients whereas in others mastectomy is unavoidable. Patients and methods: From 1997 to 2004, 282 patients presented at the European Institute of Oncology with an operable invasive IBTR after BCS. One hundred and sixty-one (57%) underwent a second conservative surgery, whereas 121 patients (43%) were given a mastectomy and represent the study population. We investigated the prognosis and determined predictive factors of outcome. Results: Median time from primary breast cancer to IBTR was 41 months (range 5–213). Recurrences were T2–T4 and/or multifocal in 83 cases (68.6%). With a median follow-up of 5 years after mastectomy, 5-year overall survival (OS) and disease-free survival (DFS) were 73.3% [95% confidence interval (CI) 65.0% to 81.6%] and 50.4% (95% CI 40.9% to 59.8%), respectively. At the multivariate analysis, early onset of IBTR, presence of vascular invasion and Ki67 ≥20 of the recurrent tumour were found to significantly affect both DFS and OS. Conclusions: In women who need mastectomy for IBTR, early onset of the relapse, high proliferation index and presence of vascular invasion represent the worst prognostic factors.