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Approximately 6% of metastatic breast cancers arise de novo . While systemic therapy (ST) remains the treatment backbone as for patients with metachronous metastases, locoregional treatment (LRT) of the primary tumor remains a controversial method. The removal of the primary has an established role for palliative purposes, but it is unclear if it could also determine a survival benefit. Retrospective evidence and pre-clinical studies seem to support the removal of the primary as an effective approach to improve survival. On the other hand, most randomized evidence suggests avoiding LRT. Both retrospective and prospective studies suffer several limitations, ranging from selection bias and outdated ST to a small sample of patients. In this review we discuss available data and try to identify subgroups of patients which could benefit the most from LRT of the primary, to facilitate clinical practice decisions, and to hypothesize future studies design on this topic., Competing Interests: UD received honoraria for advisory boards or speaker fees for Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Roche, Novartis, Clovis, GSK, AstraZeneca, Institutional research grants from AstraZeneca, Sanofi and Roche. MP has received advisory board fees from Novartis. All other authors confirm 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 © 2023 Merloni, Palleschi, Gianni, Casadei, Curcio, Romeo, Rocchi, Cima, Sirico, Sarti, Cecconetto, Mariotti, Di Menna and De Giorgi.)

Adaptive and innate immune cells play a crucial role as regulators of cancer development. Inflammatory cells in blood flow seem to be involved in pro-tumor activities and contribute to breast cancer progression. Circulating lymphocyte ratios such as the platelet-lymphocytes ratio (PLR), the monocyte-lymphocyte ratio (MLR) and the neutrophil-lymphocyte ratio (NLR) are new reproducible, routinely feasible and cheap biomarkers of immune response. These indexes have been correlated to prognosis in many solid tumors and there is growing evidence on their clinical applicability as independent prognostic markers also for breast cancer. In this review we give an overview of the possible value of lymphocytic indexes in advanced breast cancer prognosis and prediction of outcome. Furthermore, targeting the immune system appear to be a promising therapeutic strategy for breast cancer, especially macrophage-targeted therapies. Herein we present an overview of the ongoing clinical trials testing systemic inflammatory cells as therapeutic targets in breast cancer., Competing Interests: This research received no external funding. MP has received advisory board fees from Novartis. UD has received advisory board or consultant fees from Merck Sharp and Dohme, Bristol Myers Squibb, Janssen, Astellas, Sanofi, Bayer, Pfizer, Ipsen, Novartis, and Pharmamar and institutional research grants from Astrazeneca, Sanofi, and Roche. 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 Gianni, Palleschi, Schepisi, Casadei, Bleve, Merloni, Sirico, Sarti, Cecconetto, Di Menna, Schettini and De Giorgi.)

Introduction: Olaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (g BRCA -mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in g BRCA -wild-type (wt) TNBC and, as proof-of-concept in g BRCA -mut HER2-negative BC., Methods: Patients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG 18 -PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria., Results: 27 patients with g BRCA -wt TNBC and 8 with g BRCA -mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non- BRCA 1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% g BRCA -wt patients. g BRCA -mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p<0.001) and CD4/CD8 ratio (p=0.02). Ki67% and TILs did not vary significantly (p=0.67 and p=0.77). A numerical increase in PD-L1 positive cases after olaparib was observed, though non-significant (p=0.134). No differences were observed according to g BRCA status and type of response., Conclusions: Early-stage TNBC might be a target population for olaparib, irrespective of g BRCA mutations. Future trials should combine TILs, PD-L1 and g BRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib., Competing Interests: EM, AB, LX, EZ and DC were employed by Personal Genomics Ltd. GW and ML are employed at Oncologica UK Ltd., which has received project funding from AstraZeneca outside of the submitted work. DG has declared consulting fees from Novartis, Lilly and Pfizer, research funding from LILT, Novartis, Astra-Zeneca and University of Trieste outside of the submitted work. IP has declared consulting fees from Roche, Novartis, Lilly, Pfizer, Astra-Zeneca, Pierre Fabre and Ipsen outside of the submitted work. GS has declared Grant/Research Support from MSD Italia S.r.l., consulting role for TESARO Bio Italy S.r.l. Johnson & Johnson and Clovis Oncology Italy S.r.l., outside of the submitted work. 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 Schettini, Corona, Giudici, Strina, Sirico, Bernocchi, Milani, Ziglioli, Aguggini, Azzini, Barbieri, Cervoni, Cappelletti, Molteni, Lazzari, Ferrero, Ungari, Marasco, Bruson, Xumerle, Zago, Cerra, Loddo, Williams, Paris, Scambia and Generali.)