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We report a case of a 68-year-old man who developed an advanced Triple-Negative Breast Cancer (TNBC) presented as a Carcinoma of Unknown Primary (CUP) at diagnoses. After progressing to first line therapy, the molecular platform EPICUP® was performed and the results suggested breast cancer as origin, although non breast primary tumor was found by imaging techniques; and the patient was treated according to this origin. During the evolution of the disease a nodule appeared in the left breast, and a biopsy confirmed the diagnosis of an infiltrating ductal carcinoma. Male breast cancer (MBC) represents an infrequent and heterogeneous disease, but TNBC in men represents less than 0.02% of total breast cancer cases. Unfortunately, there is no standard of care for MBC, and due to the development of new treatment strategies are focused on women BC, there are less opportunities to participate in clinical trials for MBC.Through the review of a clinical case, we show how the molecular platform could help in finding the origin of the CUP. Moreover, further coordinated multicenter international collaboration is necessary to conduct larger and successful therapeutic clinical trials in MBC, and specifically, male TNBC trials to better understand this rare entity and guide future management strategies.

Chimeric antigen receptor (CAR)-T cell therapy for solid tumors faces significant hurdles, including T-cell inhibition mediated by the PD-1/PD-L1 axis. The effects of disrupting this pathway on T-cells are being actively explored and controversial outcomes have been reported. Here, we hypothesize that CAR-antigen affinity may be a key factor modulating T-cell susceptibility towards the PD-1/PD-L1 axis. We systematically interrogate CAR-T cells targeting HER2 with either low (LA) or high affinity (HA) in various preclinical models. Our results reveal an increased sensitivity of LA CAR-T cells to PD-L1-mediated inhibition when compared to their HA counterparts by using in vitro models of tumor cell lines and supported lipid bilayers modified to display varying PD-L1 densities. CRISPR/Cas9-mediated knockout (KO) of PD-1 enhances LA CAR-T cell cytokine secretion and polyfunctionality in vitro and antitumor effect in vivo and results in the downregulation of gene signatures related to T-cell exhaustion. By contrast, HA CAR-T cell features remain unaffected following PD-1 KO. This behavior holds true for CD28 and ICOS but not 4-1BB co-stimulated CAR-T cells, which are less sensitive to PD-L1 inhibition albeit targeting the antigen with LA. Our findings may inform CAR-T therapies involving disruption of PD-1/PD-L1 pathway tailored in particular for effective treatment of solid tumors., (© 2024. The Author(s).)

Background: Early-stage triple-negative breast cancer (TNBC) displays clinical and biological diversity. From a biological standpoint, immune infiltration plays a crucial role in TNBC prognosis. Currently, there is a lack of genomic tools aiding in treatment decisions for TNBC. This study aims to assess the effectiveness of a B-cell/immunoglobulin signature (IGG) alone, or in combination with tumor burden, in predicting prognosis and treatment response in patients with TNBC., Methods: Genomic and clinical data were retrieved from 7 cohorts: SCAN-B (N = 874), BrighTNess (n = 482), CALGB-40603 (n = 389), METABRIC (n = 267), TCGA (n = 118), GSE58812 (n = 107), GSE21653 (n = 67). IGG and a risk score integrating IGG with tumor/nodal staging (IGG-Clin) were assessed for event-free survival (EFS) and overall survival (OS) in each cohort. Random effects model was used to derive pooled effect sizes. Association of IGG with pathological complete response (pCR) was assessed in CALGB-40603 and BrighTNess. Immune significance of IGG was estimated through CIBERSORTx and EcoTyper., Findings: IGG was associated with improved EFS (pooled HR = 0.77, [95% CI = 0.70-0.85], I 2  = 18%) and OS (pooled HR = 0.79, [0.73-0.85], I 2  = 0%) across cohorts, and was predictive of pCR in CALGB-40603 (OR 1.25, [1.10-1.50]) and BrighTNess (OR 1.57 [1.25-1.98]). IGG-Clin was predictive of recurrence (pooled HR = 2.11, [1.75-2.55], I 2  = 0%) and death (pooled HR = 1.99, 95% [0.84-4.73], I 2  = 79%) across cohorts. IGG was associated with adaptive immune response at CIBERSORTx and EcoTyper analysis., Interpretation: IGG is linked to improved prognosis and pCR in early-stage TNBC. The integration of IGG alongside tumor and nodal staging holds promise as an approach to identify patients benefitting from intensified or de-intensified treatments., Funding: This study received funding from: Associació Beca Marta Santamaria, European Union's Horizon 2020 research and innovation and Marie Skłodowska-Curie Actions programs, Fundación FERO, Fundación CRIS contra el cáncer, Agència de Gestó d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Fundación Contigo, Asociación Cáncer de Mama Metastásico IV, Breast Cancer Research Foundation, RESCUER, Fundación científica AECC and FSEOM., Competing Interests: Declaration of interests B. Conte reports speaker fees from Veracyte and payment for educational events from Medsite and Novartis. A. Prat reports consulting fees from Roche, Pfizer, Novartis, Amgen, BMS, Puma, Oncolytics Biotech, MSD, Guardant Health, Peptomyc and Lilly, lecture fees from Roche, Pfizer, Novartis, Amgen, BMS, Nanostring Technologies and Daiichi Sankyo; patents filed PCT/EP2016/080056, PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369; stockholder and consultant of Reveal Genomics, SL; and institutional financial interests from Boehringer, Novartis, Roche, Nanostring, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas and Pfizer. F. Schettini has declared consulting fees from Pfizer, honoraria for lectures from Novartis, Gilead and Daiichy Sankyo, and travel expenses from Novartis and Daiichy Sankyo. O. Martínez-Sáez has declared institutional grants from Roche; personal consulting fees from Roche and Reveal Genomics; honoraria for presentations by Daiichi Sankyo, Pierre Fabre, and Reveal Genomics; and travel expenses by Gilead, Pierre Fabre, Novartis, and MSD. A. Vivancos has declared institutional grants from Bristol Meyers Squibb, Incyte, and Roche; personal consulting fees from Bayer, Bristol Meyers Squibb (BMS); Guardant, Incyte, and Roche; and personal stock options from Reveal Genomics. F. Brasó-Maristany has patents filed: PCT/EP2022/086493, PCT/EP2023/060810, EP23382703 and EP23383369. J. Parker as declared individual and institutional royalties from Veracyte–Prosigna, consulting fees from Bristol Meyers Squibb, Reveal Genomics, and GeneCentric, and holds a patent for breast cancer subtyping. Additionally, he has an equity interest in Reveal Genomics. M. Vidal has declared honoraria for presentations from Novartis, Roche, Pfizer, and Daichii, and travel expenses from Roche and Pfizer. Additionally, she has participated on a Data Safety Monitoring Board or Advisory Board for Novartis and Roche. C. Perou has declared consulting fees and personal stock options from Reveal Genomics. T. Pascual has declared consulting fees from Novartis; honoraria from Novartis, Astra-zeneca, Veracyte, and Argenetics. I. Garcia-Fructuoso has declared honoraria for presentations from Novartis, Daiichi Sankyo, Esteve, GSK; and travel expenses from Novartis, Gilead, Daiichi Sankyo, Lilly, and BMS. L. Paré has declared contract from Reveal Genomics, a HER2DX patent filed (PCT/EP2022/086493), and the TNBCDX patent filed (EP23382703.9). M. Marín-Aguilera has declared contract from Reveal Genomics. P. Villagrasa has declared contract and personal stock options from Reveal Genomics, the HER2DX patent filed (PCT/EP2022/086493), and the DNADX patent filed (EP22382387.3). G. Villacampa has received a speaker's fee from Merck Sharp & Dohme, Pfizer, GlaxoSmithKline and Pierre Fabrer, and received consultant fees from Reveal Genomics. C. Falato is currently employed in AstraZeneca. The remaining authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The lack of validated surrogate biomarkers is still an unmet clinical need in the management of early breast cancer cases that do not achieve complete pathological response after neoadjuvant chemotherapy (NACT). Here, we describe and validate the use of SAMHD1 expression as a prognostic biomarker in residual disease in vivo and in vitro., Methods: SAMHD1 expression was evaluated in a clinical cohort of early breast cancer patients with stage II-III treated with NACT. Heterotypic 3D cultures including tumor and immune cells were used to investigate the molecular mechanisms responsible of SAMHD1 depletion through whole transcriptomic profiling, immune infiltration capacity and subsequent delineation of dysregulated immune signaling pathways., Results: SAMHD1 expression was associated to increased risk of recurrence and higher Ki67 levels in post-NACT tumor biopsies of breast cancer patients with residual disease. Survival analysis showed that SAMHD1-expressing tumors presented shorter time-to-progression and overall survival than SAMHD1 negative cases, suggesting that SAMHD1 expression is a relevant prognostic factor in breast cancer. Whole-transcriptomic profiling of SAMHD1-depleted tumors identified downregulation of IL-12 signaling pathway as the molecular mechanism determining breast cancer prognosis. The reduced interleukin signaling upon SAMHD1 depletion induced changes in immune cell infiltration capacity in 3D heterotypic in vitro culture models, confirming the role of the SAMHD1 as a regulator of breast cancer prognosis through the induction of changes in immune response and tumor microenvironment., Conclusion: SAMHD1 expression is a novel prognostic biomarker in early breast cancer that impacts immune-mediated signaling and differentially regulates inflammatory intra-tumoral response., (© 2023. The Author(s).)

Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p < 0.001). Immunotherapy-naïve status was independently associated with better PFS (p = 0.005). Time-to-best response (TTBR) and ORR (p < 0.001 both) were associated with better OS at univariate analysis. PFS and DOR were moderately correlated with OS (p < 0.001 both). A PD-L1 10% cut-off detected worse/best responders in terms of ORR (univariate p = 0.011, multivariate p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored., (© 2023. The Author(s).)

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)