Clinical outcome and proportion of hereditary cancer genes gPV in TNBC: the HEaRTBeat study Martina Rotolo, Claudia Piombino, Marta Venturelli, Elena Tenedini, Angela Toss, Elena Barbieri, Elisa Gasparini, Isabella Marchi, Federica Domati, Monica Civallero, Luigi Marcheselli, Elisabetta Razzaboni, Enrico Tagliafico, Massimo Dominici, Laura Cortesi Npj Breast Cancer, 2026 We aimed to study the proportion of germline pathogenic variants (gPV) in hereditary cancer genes and the clinical-pathological characteristics, local and systemic treatments, pathological complete response (pCR) rate to neoadjuvant therapy, invasive breast cancer-free survival (IBCFS), and overall survival (OS) in triple-negative breast cancer (TNBC) patients, consecutively tested between 2017 and 2024 at Modena and Reggio Emilia University Hospital, Italy. A total of 387 early-stage patients were included in the study. Eighty-seven patients (22%) showed gPV in hereditary predisposing genes, mostly BRCA1/2 (11%), PALB2 (5%), RAD51C/D (2%), MUTYH (2%), ATM (1%), and others (1%). The proliferation index was high in all, whereas the most frequent stage was stage I/II, except in MUTYH gPV carriers. More mastectomies, also contralateral, were performed in gPV than in non-carriers. Finally, 64% gPV achieved pCR compared to 39% non-carriers (p < 0.001), although no differences were observed between the two groups in IBCFS or OS.
HER2-low breast cancer is immune-cold: insights into tumor-infiltrating immune cells and implications for immunotherapy S. Pizzamiglio, A. Blanda, V. Appierto, P. Minicozzi, M. G. Carnevale, M. C. De Santis, B. Re, L. Cortesi, E. Gasparini, G. Arpino, M. Giuliano, V. Molinaro, M. V. Iorio, L. De Cecco, A. Bertolotti, S. Brich, Andrea Vingiani, C. De Marco, G. Pruneri, P. Verderio, S. Di Cosimo Npj Breast Cancer, 2026 This study investigated, for the first time, the association between HER2 expression, immune infiltration inferred by CIBERSORTx, and immunotherapy response in HER2-negative early breast cancer (EBC). Gene expression was analyzed in prospective discovery ( n = 104), confirmatory ( n = 81), and independent (ABiM, n = 318) cohorts. HER2 expression was measured using a 20-gene signature yielding progressively higher scores from HER2-0 to HER2-low, as routinely defined. Increased HER2 expression was consistently associated with reduced immune-infiltration, especially cytotoxic (CD8 + ) T cells and M1 macrophages; and hormone receptor (HR)-specific depletions with significant interactions for mast cells resting and neutrophils. In analysis of covariance, HER2 expression independently predicted low B-naïve and plasma cell abundance. In a neoadjuvant immunotherapy real-world cohort ( n = 111), HER2-low primary tumors had numerically lower midcourse (28% vs. 44%) and pathological complete response (64% vs. 72%) compared to HER2-0. These findings show that HER2 expression defines immune-cold HER2-negative EBC, hindering immunotherapy and supporting HER2-targeted combination in HER2-low EBC patients.
Transcriptomic deconvolution reveals prognostic immune signatures and immunotherapy-responsive subtypes in male breast cancer Valentina Silvestri, Virginia Valentini, Agostino Bucalo, Virginia Porzio, Giorgia Scafetta, Bruna Cerbelli, Ines Zanna, Simonetta Bianchi, Maria Grazia Tibiletti, Ileana Carnevali, Daniele Calistri, Valentina Arcangeli, Valentina Zampiga, Elisa Gasparini, Laura Cortesi, Giuseppe Giannini, Carlo Capalbo, Stephen B. Fox, Giovanna Masala, Silvia Mezi, Giulia d’Amati, Laura Ottini Breast Cancer Research, 2026 BACKGROUND: Male breast cancer (MBC) is a rare malignancy with distinct biological and clinical features compared to its female counterpart. Emerging evidence suggests that a subset of MBCs may exhibit an immunogenic tumor microenvironment; however, the lack of sex-specific data on immune biomarkers has limited the inclusion of male patients in immunotherapy trials. METHODS: We performed transcriptomic profiling of 123 MBCs, including 41 with germline pathogenic variants (PVs) in BRCA2 (n = 26), BRCA1 (n = 12), and PALB2 (n = 3). Immune characterization included PD-1 and PD-L1 expression, immune scores, and immune cell infiltration using deconvolution tools. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was applied to predict potential response to immune checkpoint inhibitors. RESULTS: A distinct subset of MBCs showed high PD-L1 expression and high immune scores. Immune deconvolution revealed that CD4 + memory resting T cells (24.5%), M2 macrophages (14.4%), and M0 macrophages (13.8%) were the most abundant infiltrating immune populations within the tumor microenvironment. Notably, 37.4% of tumors were predicted to respond to immunotherapy, primarily within the Luminal B subtype. These tumors demonstrated significantly higher PD-1/PD-L1 expression, higher immune scores, and enriched immune cell infiltration, compared to non-responders. Unsupervised clustering identified two transcriptionally distinct molecular subgroups. Cluster 1 was enriched for immune-related pathways and comprised the majority of predicted responders. Immune infiltration patterns varied significantly according to germline mutation status, intrinsic subtype, histological grade, androgen receptor expression, and Ki-67 proliferation index. CONCLUSIONS: This study identifies a transcriptionally defined, immunogenic subset of MBCs with potential sensitivity to immune checkpoint inhibitors. These findings highlight the need for sex-specific immune profiling and provide a rationale for incorporating immunotherapy into precision treatment strategies for men with breast cancer.
Adjuvant endocrine therapy choices in premenopausal patients with hormone receptor-positive early breast cancer: Insights from the prospective GIM23-POSTER study Luca Arecco, Maria Maddalena Latocca, Eva Blondeaux, Ferdinando Riccardi, Carmela Mocerino, Valentina Guarneri, Eleonora Mioranza, Giancarlo Bisagni, Elisa Gasparini, Fabio Puglisi, Alexandro Membrino, Antonella Ferro, Vincenzo Adamo, Filippo Giovanardi, Stefano Tamberi, Sara Donati, Elisabetta Landucci, Laura Biganzoli, Sara Piccinini, Simona Pastorino, Evandro de Azambuja, Francesca Poggio, Matteo Lambertini, Lucia Del Mastro Breast, 2024 BACKGROUND: Most premenopausal patients with early breast cancer (eBC) are diagnosed with hormone receptor-positive disease and therefore candidate for adjuvant endocrine therapy (ET). PATIENTS AND METHODS: The Gruppo Italiano Mammella (GIM) 23-POSTER (GIM23) is a multicenter, prospective, observational study conducted in 26 Italian institutions, aiming to evaluate ET choices for premenopausal patients affected by hormone receptor-positive eBC in a real-world setting. Here we report also the results in terms of type of ET prescribed according to the definition of high-risk patients by monarchE and NATALEE trials. RESULTS: Between October 2019 and June 2022, 600 premenopausal patients were included, with a median age of 46 years. Almost half (271, 45.2 %) of the patients had stage I disease, while 254 (42.3 %) and 60 (10.0 %) patients had stage II and III, respectively. Overall, 149 (25.1 %) patients received tamoxifen alone, 83 (14.0 %) tamoxifen with ovarian function suppression (OFS), while 361 (60.9 %) received aromatase inhibitor (AI) with OFS. Patients treated with AI and OFS had higher number of metastatic axillary nodes, higher grade and more often received chemotherapy (all p < 0.001). According to the inclusion criteria of the monarchE and NATALEE trials, 81 patients (15.6 %) were considered high-risk for the monarchE and received AI with OFS in 88.9 % of the cases, while 231 patients (44.4 %) were considered high-risk for the NATALEE trial and received AI with OFS in 74.5 % of cases. CONCLUSIONS: AI with OFS is the most prescribed adjuvant ET among premenopausal patients, especially in the presence of high-risk features.
Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella and Mammella Intergruppo trials Eva Blondeaux, Wanling Xie, Luca Carmisciano, Silvia Mura, Valeria Sanna, Michelino De Laurentiis, Roberta Caputo, Anna Turletti, Antonio Durando, Sabino De Placido, Carmine De Angelis, Giancarlo Bisagni, Elisa Gasparini, Anita Rimanti, Fabio Puglisi, Mauro Mansutti, Elisabetta Landucci, Alessandra Fabi, Luca Arecco, Marta Perachino, Marco Bruzzone, Luca Boni, Matteo Lambertini, Lucia Del Mastro, Meredith M. Regan Eclinicalmedicine, 2024 Background Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials. Methods Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer–free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R 2 ≥ 0.70 were considered as indicators of a clinically relevant surrogacy. Findings Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49–65). After a median follow-up of 10.3 years (IQR 6.4–14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI. Interpretation Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials. Funding This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health–5 × 1000 funds (years 2021–2022).
Spatial Distribution of Immune Cells Drives Resistance to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Benedetta Donati, Francesca Reggiani, Federica Torricelli, Giacomo Santandrea, Teresa Rossi, Alessandra Bisagni, Elisa Gasparini, Antonino Neri, Laura Cortesi, Guglielmo Ferrari, Giancarlo Bisagni, Moira Ragazzi, Alessia Ciarrocchi Cancer Immunology Research, 2024 Neoadjuvant chemotherapy (NAC) alone or combined with target therapies represents the standard of care for localized triple-negative breast cancer (TNBC). However, only a fraction of patients have a response, necessitating better understanding of the complex elements in the TNBC ecosystem that establish continuous and multidimensional interactions. Resolving such complexity requires new spatially-defined approaches. Here, we used spatial transcriptomics to investigate the multidimensional organization of TNBC at diagnosis and explore the contribution of each cell component to response to NAC. Starting from a consecutive retrospective series of TNBC cases, we designed a case–control study including 24 patients with TNBC of which 12 experienced a pathologic complete response (pCR) and 12 no-response or progression (pNR) after NAC. Over 200 regions of interest (ROI) were profiled. Our computational approaches described a model that recapitulates clinical response to therapy. The data were validated in an independent cohort of patients. Differences in the transcriptional program were detected in the tumor, stroma, and immune infiltrate comparing patients with a pCR with those with pNR. In pCR, spatial contamination between the tumor mass and the infiltrating lymphocytes was observed, sustained by a massive activation of IFN-signaling. Conversely, pNR lesions displayed increased pro-angiogenetic signaling and oxygen-based metabolism. Only modest differences were observed in the stroma, revealing a topology-based functional heterogeneity of the immune infiltrate. Thus, spatial transcriptomics provides fundamental information on the multidimensionality of TNBC and allows an effective prediction of tumor behavior. These results open new perspectives for the improvement and personalization of therapeutic approaches to TNBCs.
Impact of 2 years of COVID-19 pandemic on ovarian cancer treatment in IRCCS-AUSL of Reggio Emilia Vincenzo Dario Mandato, Federica Torricelli, Valentina Mastrofilippo, Carlotta Pellegri, Loredana Cerullo, Gianluca Annunziata, Gino Ciarlini, Debora Pirillo, Matteo Generali, Giovanni D'Ippolito, Chiara Leone, Alessandra Bologna, Elisa Gasparini, Andrea Palicelli, Maria Carolina Gelli, Monica Silvotti, Lorenzo Aguzzoli International Journal of Gynecology and Obstetrics, 2023 ObjectiveTo assess compliance with the 2019 regional recommendation to centralize epithelial ovarian cancer (EOC) patients and to assess whether the COVID‐19 pandemic has affected the quality of care for EOC patients.MethodsWe compared data from EOC patients treated before the introduction of the 2019 regional recommendation (2018‐2019) with data obtained from EOC patients treated after the regional recommendation was adopted during the first 2 years of the COVID‐19 pandemic (2020‐2021). Data were retrieved from the Optimal Ovarian Cancer Pathway records. R software version 4.1.2 (the R Foundation for Statistical Computing, Vienna, Austria) was used for the statistical analysis.Results251 EOC patients were centralized. The number of EOC patients centralized increased from 2% to 49% despite the COVID‐19 pandemic. During the COVID‐19 pandemic, there was an increase in the use of neoadjuvant chemotherapy and interval debulking surgery. There was an improvement in the percentage of Stage III patients without gross residual disease following both primary and interval debulking surgery. The percentage of EOC cases discussed by the multidisciplinary tumor board (MTB) increased from 66% to 89% of cases.ConclusionDespite the COVID‐19 pandemic, centralization has increased and the quality of care has been preserved thanks to the MTB.
Characterization of Gut Microbiome Composition in Patients with Triple-Negative Breast Cancer Treated with Neoadjuvant Chemotherapy Grazia Vernaci, Edoardo Vincenzo Savarino, Ilaria Patuzzi, Sonia Facchin, Fabiana Zingone, Davide Massa, Giovanni Faggioni, Tommaso Giarratano, Federica Miglietta, Gaia Griguolo, Matteo Fassan, Marcello Lo Mele, Elisa Gasparini, Giancarlo Bisagni, Valentina Guarneri, Maria Vittoria Dieci Oncologist, 2023 Introduction Patients with triple-negative breast cancer (TNBC) achieving a pathological complete response (pCR) after neoadjuvant chemotherapy have a better event-free survival. The role of gut microbiome in early TNBC is underexplored. Methods Microbiome was analyzed by 16SrRNA sequencing. Results Twenty-five patients with TNBC treated with neoadjuvant anthracycline/taxane-based chemotherapy were included. Fifty-six percent achieved a pCR. Fecal samples were collected before (t0), at 1 (t1), and 8 weeks (t2) from chemotherapy. Overall, 68/75 samples (90.7%) were suitable for microbiome analysis. At t0, pCR group showed a significantly higher α-diversity as compared with no-pCR, (P = .049). The PERMANOVA test on β-diversity highlighted a significant difference in terms of BMI (P = 0.039). Among patients with available matched samples at t0 and t1, no significant variation in microbiome composition was reported over time. Conclusions Fecal microbiome analysis in early TNBC is feasible and deserves further investigation in order to unravel its complex correlation with immunity and cancer.
Prognostic and clinical impact of the endocrine resistance/sensitivity classification according to international consensus guidelines for advanced breast cancer: an individual patient-level analysis from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) studies Matteo Lambertini, Eva Blondeaux, Giancarlo Bisagni, Silvia Mura, Sabino De Placido, Michelino De Laurentiis, Alessandra Fabi, Anita Rimanti, Andrea Michelotti, Mauro Mansutti, Antonio Russo, Filippo Montemurro, Antonio Frassoldati, Antonio Durando, Stefania Gori, Anna Turletti, Stefano Tamberi, Ylenia Urracci, Piero Fregatti, Maria Grazia Razeti, Roberta Caputo, Carmine De Angelis, Valeria Sanna, Elisa Gasparini, Elisa Agostinetto, Evandro de Azambuja, Francesca Poggio, Luca Boni, Lucia Del Mastro Eclinicalmedicine, 2023 Background: Prior exposure to adjuvant endocrine therapy (ET) and timing to recurrence are crucial factors for first-line treatment choices in patients with hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) and in clinical trial eligibility, classifying metastatic HR+/HER2- BC as endocrine sensitive (ES) or primary (1ER)/secondary (2ER) resistant. However, this classification is largely based on expert opinion and no proper evidence exists to date to support its possible prognostic and clinical impact. Methods: This analysis included individual patient-level data from 4 adjuvant phase III randomized trials by the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) study groups. The impact of endocrine resistance/sensitivity classification on overall survival (mOS, defined as time between date of distant relapse and death) was assessed in both univariate and multivariate Cox proportional hazards models. Findings: Between November 1992 and July 2012, 9058 patients were randomized in 4 trials, of whom 6612 had HR+/HER2- BC. Median follow-up was 9.1 years (interquartile range [IQR] 5.6-15.0). In the whole cohort, disease-free survival and OS were 90.4% and 96.6% at 5 years, and 79.1% and 89.4% at 10 years, respectively. The estimated hazard of recurrence raised constantly during the first 15 years from diagnosis, being more pronounced during the first 2 years and less pronounced after year 7. Among the 493 patients with a distant relapse as first disease-free survival event and available date on ET completion, 72 (14.6%), 207 (42.0%) and 214 (43.4%) were classified as having 1ER, 2ER and ES, respectively. Median follow-up from diagnosis of a distant relapse was 3.8 years (IQR 1.6-7.5). Patients with 1ER were significantly more likely to be younger, to have N2/N3 nodal status, grade 3 tumours and to develop visceral metastases. Site of first distant relapse was significantly different between the 3 groups (p = 0.005). In patients with 1ER, 2ER and ES breast cancer, median mOS was 27.2, 38.4 and 43.2 months, respectively (p = 0.03). As compared to patients with ES disease, a higher risk of death was observed in those with 1 ER (adjusted Hazard Ratio [aHR] 1.54; 95% CI 1.03-2.30) and 2ER (aHR 1.17; 95% CI 0.87-1.56) (p = 0.11). Interpretation: This large analysis with long-term follow-up provides evidence on the prognostic and clinical impact of the currently adopted endocrine resistance/sensitivity classification in patients with HR+/HER2- advanced BC. This classification may be considered a valid tool to guide clinical decision-making and to design future ET trials in the metastatic setting. Funding: AIRC.
Constitutional Mosaicism: A Critical Issue in the Definition of BRCA-Inherited Cancer Risk Elena Tenedini, Simonetta Piana, Angela Toss, Marco Marino, Elena Barbieri, Lucia Artuso, Marta Venturelli, Elisa Gasparini, Vincenzo Dario Mandato, Isabella Marchi, Sara Castellano, Mario Luppi, Tommaso Trenti, Laura Cortesi, Enrico Tagliafico JCO Precision Oncology, 2022
Clinicopathologic profile of breast cancer in germline ATM and CHEK2 mutation carriers Angela Toss, Elena Tenedini, Claudia Piombino, Marta Venturelli, Isabella Marchi, Elisa Gasparini, Elena Barbieri, Elisabetta Razzaboni, Federica Domati, Federica Caggia, Giovanni Grandi, Francesca Combi, Giovanni Tazzioli, Massimo Dominici, Enrico Tagliafico, Laura Cortesi Genes, 2021
The prognostic and predictive role of somatic brca mutations in ovarian cancer: Results from a multicenter cohort study Angela Toss, Claudia Piombino, Elena Tenedini, Alessandra Bologna, Elisa Gasparini, Vittoria Tarantino, Maria Elisabetta Filieri, Luca Cottafavi, Filippo Giovanardi, Stefano Madrigali, Monica Civallero, Luigi Marcheselli, Isabella Marchi, Federica Domati, Marta Venturelli, Elena Barbieri, Giovanni Grandi, Enrico Tagliafico, Laura Cortesi Diagnostics, 2021
