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Mutations in the estrogen receptor alpha gene (ESR1) can lead to resistance to endocrine therapy (ET) in hormone receptor-positive (HR+)/ HER2- metastatic breast cancer (MBC). ESR1 mutations can be detected in up to 40 % of patients pretreated with ET in circulating tumor DNA (ctDNA). Data from prospective randomized trials highlight those patients with HR+/HER2- MBC with detectable ESR1 mutations experience better outcomes when receiving novel selective estrogen receptor degraders (SERDs). There is a high need for optimizing ESR1 testing strategies on liquid biopsy samples in HR+/HER2- MBC, including a hugh quality workflow implementation and molecular pathology reporting standardization. Our manuscript aims to elucidate the clinical and biological rationale for ESR1 testing in MBC, while critically examining the currently available guidelines and recommendations for this specific type of molecular testing on ctDNA. The objective will extend to the critical aspects of harmonization and standardization, specifically focusing on the pathology laboratory workflow. Finally, we propose a clear and comprehensive model for reporting ESR1 testing results on ctDNA in HR+/HER2- MBC., Competing Interests: Declaration of Competing Interest E.G-R. has relevant relationship (advisory fees, honoraria, travel accommodation and expenses, grants, and non-financial support) with AstraZeneca, Exact Sciences, GlaxoSmithKline (GSK), Novartis, Roche, Thermo Fisher Scientific unrelated to the current work. C.C. reported grants from Gilead, Seagen, personal fees from Pfizer, Lilly, Novartis, MSD, Daiichi Sankyo, and AstraZeneca outside the submitted work. G.C. reports funding from Astra Zeneca, Daichii Sankyo, Merck; consulting fees from BMS, Roche, Pfizer, Novartis, Lilly, Astra Zeneca, Daichii Sankyo, Merck, Seagen, Ellipsis; honoraria from Pfizer, Lilly; support for attending meetings from Roche, Pfizer. C.R. has received speaker honoraria from AstraZeneca, Roche, and MSD; advisory board honoraria from Inivata, Archer, Boston Pharmaceuticals, MD Serono, and Novartis; and institutional research funding for his work as Coordinating Principal Investigator from Pfizer and EMD Serono. U.M. has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientific, Eli Lilly, Diaceutics, GSK, Merck and AstraZeneca, Janssen, Diatech, Novartis and Hedera. N.F. has received honoraria for consulting, advisory role, speaker bureau, travel, and/or research grants from Merck Sharp & Dohme (MSD), Merck, Novartis, AstraZeneca, Roche, Menarini, Daiichi Sankyo, GlaxoSmithKline (GSK), Gilead, Adicet Bio, Sysmex, Reply, Veracyte Inc., Sakura, Leica Biosystems, Lilly. These companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and/or in the decision to publish the results. All other authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pembrolizumab has received approval as a first-line treatment for unresectable/metastatic triple-negative breast cancer (mTNBC) with a PD-L1 combined positive score (CPS) of ≥ 10. However, assessing CPS in mTNBC poses challenges. Firstly, it represents a novel analysis for breast pathologists. Secondly, the heterogeneity of PD-L1 expression in mTNBC further complicates the assessment. Lastly, the lack of standardized assays and staining platforms adds to the complexity. In KEYNOTE trials, PD-L1 expression was evaluated using the IHC 22C3 pharmDx kit as a companion diagnostic test. However, both the 22C3 pharmDx and VENTANA PD-L1 (SP263) assays are validated for CPS assessment. Consequently, assay-platform choice, staining conditions, and scoring methods can significantly impact the testing outcomes. This consensus paper aims to discuss the intricacies of PD-L1 CPS testing in mTNBC and provide practical recommendations for pathologists. Additionally, we present findings from a nationwide Italian survey elucidating the state-of-the-art in PD-L1 CPS testing in mTNBC., Competing Interests: Declaration of Competing Interest Nicola Fusco has received honoraria for consulting, advisory role, speaker bureau, travel, and/or research grants from Merck Sharp & Dohme (MSD), Novartis, AstraZeneca, Roche, Daiichi Sankyo, GlaxoSmithKline (GSK), Gilead, Diaceutics, Adicet Bio, and Sermonix. Mariia Ivanova from Agilent Technologies Denmark ApS. Carmen Criscitiello reports personal fees for consulting, advisory role, and speakers’ bureau from Lilly, Roche, Novartis, MSD, Seagen, Gilead, Daiichi Sankyo, AstraZeneca, and Pfizer. Bruna Cerbelli from MSD and Novartis. Fabio Pagni from MSD, Novartis, Roche, and Amgen. Mauro Mastropasqua from Exact Sciences. Alfredo Santinelli from Roche-Ventana, Novartis, Astrazeneca, Amgen. Giuseppe Curigliano has received honoraria for speaker’s engagement: Roche, Seattle Genetics, Novartis, Lilly, Pfizer, Foundation Medicine, NanoString, Samsung, Celltrion, BMS, MSD; Honoraria for providing consultancy: Roche, Seattle Genetics, NanoString; Honoraria for participating in Advisory Board: Roche, Lilly, Pfizer, Foundation Medicine, Samsung, Celltrion, Mylan; Honoraria for writing engagement: Novartis, BMS; Honoraria for participation in Ellipsis Scientific Affairs Group; Institutional research funding for conducting phase I and II clinical trials: Pfizer, Roche, Novartis, Sanofi, Celgene, Servier, Orion, AstraZeneca, Seattle Genetics, AbbVie, Tesaro, BMS, Merck Serono, Merck Sharp Dome, Janssen-Cilag, Philogen, Bayer, Medivation, Medimmune. Elena Guerini-Rocco from Thermo Fisher Scientific, Novartis, AstraZeneca, Roche, Biocartis, Exact Science, GSK, and Illumina. Paolo Graziano Consulting/Honoraria from Eli-Lilly, Pfizer, Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, MSD, Amgen. Giulia d’Amati from MSD, Roche, Astrazeneca, Daiichi Sankyo. These companies had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and/or in the decision to publish the results. All other authors declare no potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Triple-negative breast cancers (TNBC) comprise biologically and clinically heterogeneous diseases characterized by the lack of hormone receptors (HR) and HER2 expression. This subset of tumors accounts for 15-20% of all breast cancers and pursues an ominous clinical course. However, there is a spectrum of low-risk TNBCs with no/minimal metastatic potential, including the salivary gland-type tumors, those with extensive apocrine differentiation and/or high tumor-infiltrating lymphocytes, and small-sized, early-stage (pT1a/bN0M0) TNBCs. De-escalating the treatment in low-risk TNBC, however, is not trivial because of the substantial lack of dedicated randomized clinical trials and cancer registries. The development of new diagnostic and/or prognostic biomarkers based on clinical and molecular aspects of low-risk TNBCs would lead to improved clinical treatment. Here, we sought to provide a portrait of the clinicopathological and molecular features of low-risk TNBC, with a focus on the diagnostic challenges along with the most important biological characteristics underpinning their favorable clinical course., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Immune checkpoint inhibitors have revolutionized the cancer treatment with an approved efficacy in different solid tumors and hematologic malignancies. These agents are increasing the indication in cancer treatment, but can be associated with serious immune-related adverse effects (IRAEs). Dermatologic and gastrointestinal toxicities are the most common IRAE followed by endocrinopathies with a different time of occurrence. Rarely cases of gastrointestinal toxicities are observed almost 2 years after initiation of the therapy. In this review we focus on liver toxicity related to these immunotherapeutic agents for which the largest amount of safety data is available. The management of drug-induced liver toxicity is very complicated and in same cases may take a long period of time to be resolved. A prompt recognition of liver IRAEs and an appropriate management of this event, requiring close collaboration with other specialist figures, could improve its treatment with evident implication on the efficacy of the therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)