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Background: CDK4/6 inhibitors (CDKi), namely, palbociclib, ribociclib, and abemaciclib, combined with either an aromatase inhibitor (AI) or fulvestrant are the standard first/second line for hormone receptor-positive(HR+)/HER2-negative(neg) metastatic breast cancer (MBC). However, the choice of one specific CDKi is arbitrary and based on the physician's experience with the drug, toxicity profile, and patient's preferences, whereas biomarkers for optimal patient selection have not been established so far. Moreover, upfront chemotherapy is still recommended in case of clinical presentation with visceral crisis, despite no evidence of superior benefit for chemotherapy regimens against CDKi-based regimens. Recent correlative biomarker analyses from pivotal trials of palbociclib and ribociclib showed that HR+/HER2-neg MBC might respond differently according to the molecular intrinsic subtype, with Luminal A and B tumors being sensitive to both CDKi, Basal-like being insensitive to endocrine therapy, irrespective of CDKi, and HER2-enriched tumors showing a benefit only with ribociclib-based therapy., Clinical Case: We hereby present a paradigmatic clinical case of a woman affected by a relapsed HR+/HER2-neg MBC with bone and nodal lesions, presenting with a visceral crisis in the form of lymphangitis carcinomatosis and diagnosed with a molecularly HER2-enriched tumor, successfully treated with upfront ribociclib + fulvestrant. The patient experienced a complete symptomatic and radiologic remission of the lymphangitis with a partial response as best response, according to RECIST 1.1 criteria. The progression-free survival (PFS) was of 20 months, in line with the median PFS observed in the ribociclib + fulvestrant pivotal trial, where, however, patients with visceral crisis had been excluded., Conclusions: This clinical case confirms in the real-world setting that non-luminal subtypes can be found in HR+/HER2-neg disease and may have potential therapeutic implications in the metastatic setting. It also questions the recommendation of upfront chemotherapy in the case of a visceral crisis in the era of CDKi-based regimens. These issues merit further evaluation in prospective and larger studies., Competing Interests: AP declares no competing non-financial interests but reports advisory and 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; and institutional financial interests from Boehringer, Novartis, Roche, NanoString, Sysmex Europa GmbH, Medica Scientia Innovation Research, SL, Celgene, Astellas, and Pfizer and shares ownership and a leadership role in Reveal Genomics, SL. MV declares consulting fees e.g., advisory boards from Roche, Novartis, and Daiichi Sankyo/AstraZeneca; support for attending meetings and/or travel from Roche, Novartis, and Daiichi Sankyo/AstraZeneca; and honoraria for presentations by Roche, Novartis, and Daiichi Sankyo/AstraZeneca FS declares honoraria for presentations/educational materials paid by Novartis.. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schettini, Seguí, Conte, Sanfeliu, Gonzalez-Farre, Jares, Vidal-Sicart, Ganau, Cebrecos, Brasó-Maristany, Muñoz, Prat and Vidal.)

The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune checkpoint inhibitors in TNBC beyond PD-L1 expression and to better select patients that will benefit from immunotherapy., Competing Interests: Potential conflicts of interest are the following: AP reports consulting fees from Nanostring Technologies, Roche, Pfizer, Novartis, AstraZeneca, Foundation Medicine, Guardant Health, and Daiichi Sankyo outside the submitted work. AV reports consulting fees from Sysmex, Novartis, Merck, Bristol Meyers Squibb, Guardant Health, and Incyte; research funding from Bristol Meyers Squibb; and royalties from Ferrer outside the submitted work. VP has received fees as consultant, participated in advisory boards, or received travel grants from Sysmex, Roche, MSD, AstraZeneca, Bayer, and Exact Sciences outside the submitted work. CS has declared personal fees as consultant and advisory board or travel grants of AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann–La Roche Ltd, MediTech, Merck Sharp & Dohme, Novartis, Pfizer, Philips, Piere Fabre, Puma, Roche Farma, Sanofi-Aventis, SeaGen, and Zymeworks and institutional financial interests from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck, Sharp and Dhome España S.A., Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Synthon, and Zenith Pharma. CS and AP are Board Members of SOLTI Cooperative Group and are employed by Institut Oncològic Baselga (IOB), Quironsalud Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Brasó-Maristany, Sansó, Chic, Martínez, González-Farré, Sanfeliu, Ghiglione, Carcelero, Garcia-Corbacho, Sánchez, Soy, Jares, Peg, Saura, Muñoz, Prat and Vivancos.)