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Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC)., Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown., Design: A multicenter, retrospective-prospective Italian study., Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables., Results: We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively)., Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i., (© The Author(s), 2023.)

Background: Advanced triple-negative breast cancer (aTNBC) has a poor prognosis; thus, there is a need to identify novel biomarkers to guide future research and improve clinical outcomes., Objectives: We tested the prognostic ability of an emerging, complete blood count (CBC)-based inflammatory biomarker, the pan-immune-inflammation value (PIV), in patients with aTNBC treated with first-line, platinum-based chemotherapy., Design: This was a retrospective, monocentric, observational study., Methods: We included consecutive aTNBC patients treated with platinum-based, first-line chemotherapy at our Institution, and for whom baseline (C1) CBC data were available. We collected CBC data early on-treatment, when available. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) were included in a control, non-TNBC cohort., Results: A total of 78 aTNBC patients were included. When evaluated as a continuous variable, PIV-C1 was associated with worse overall survival (OS; p  < 0.001) and progression-free survival (PFS; p  < 0.001). On the other hand, when PIV-C1 was assessed on the basis of its quantile distribution, patients with 'high PIV-C1' experienced worse OS [adjusted hazard ratio (HR): 4.46, 95% confidence interval (CI): 2.22-8.99; adjusted p  < 0.001] and PFS (adjusted HR: 2.03, 95% CI: 1.08-3.80; adjusted p  = 0.027) when compared to patients with 'low PIV-C1'. Higher PIV-C1 was also associated with primary resistance to chemotherapy. Similarly, a higher PIV calculated from CBC at C2D1 (PIV-C2) was associated with worse survival outcomes. We also created a PIV-based score combining information about both PIV-C1 and PIV-C2 and allowing the stratification of patients at low, intermediate, and high risk of death. No association was observed between PIV-C1 and clinical outcomes of HR+/HER2- aBC patients., Conclusion: PIV has a promising prognostic discrimination ability in aTNBC patients treated with first-line, platinum-based chemotherapy. Both baseline and early on-treatment PIV are associated with clinical outcomes and may be exploited for creating PIV-based risk classifiers if further validated., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Background: Systemic immunosuppression characterizing cancer patients represents a concern regarding the efficacy of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, and real-world evidence is needed to define the efficacy and the dynamics of humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines., Methods: We conducted an observational study that included patients with solid tumors who were candidates for mRNA anti-SARS-CoV-2 vaccination at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. The primary objective was to monitor the immunologic response to the mRNA anti-SARS-CoV-2 vaccination in terms of anti-spike antibody levels. All the patients received two doses of the mRNA-1273 vaccine or the BNT162b2 vaccine. Healthcare workers served as a control group of healthy subjects., Results: Among the 243 patients included in the present analysis, 208 (85.60%) and 238 (97.94%) resulted seroconverted after the first and the second dose of vaccine, respectively. Only five patients (2.06%) had a negative titer after the second dose. No significant differences in the rate of seroconversion after two vaccine doses were observed in patients as compared with the control group of healthy subjects. Age and anticancer treatment class had an independent impact on the antibody titer after the second dose of vaccination. In a subgroup of 171 patients with available data about the third timepoint, patients receiving immunotherapy with immune checkpoint inhibitors seem to have a higher peak of antibodies soon after the second dose (3 weeks after), but a more pronounced decrease at a late timepoint (3 months after)., Conclusions: The systemic immunosuppression characterizing cancer patients did not seem to dramatically affect the humoral response to anti-SARS-CoV-2 mRNA vaccines in our population of patients with solid tumors. Further investigation is needed to dissect the interplay between immunotherapy and longitudinal dynamics of humoral response to mRNA vaccines, as well as to analyze the cellular response to mRNA vaccines in cancer patients., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2022.)

Human Epidermal growth factor Receptor 2 (HER2) overexpression or HER2 gene amplification defines a subset of breast cancers (BCs) characterized by higher biological and clinical aggressiveness. The introduction of anti-HER2 drugs has remarkably improved clinical outcomes in patients with both early-stage and advanced HER2+ BC. However, some HER2+ BC patients still have unfavorable outcomes despite optimal anti-HER2 therapies. Retrospective clinical analyses indicate that overweight and obesity can negatively affect the prognosis of patients with early-stage HER2+ BC. This association could be mediated by the interplay between overweight/obesity, alterations in systemic glucose and lipid metabolism, increased systemic inflammatory status, and the stimulation of proliferation pathways resulting in the stimulation of HER2+ BC cell growth and resistance to anti-HER2 therapies. By contrast, in the context of advanced disease, a few high-quality studies, which were included in a meta-analysis, showed an association between high body mass index (BMI) and better clinical outcomes, possibly reflecting the negative prognostic role of malnourishment and cachexia in this setting. Of note, overweight and obesity are modifiable factors. Therefore, uncovering their prognostic role in patients with early-stage or advanced HER2+ BC could have clinical relevance in terms of defining subsets of patients requiring more or less aggressive pharmacological treatments, as well as of designing clinical trials to investigate the therapeutic impact of lifestyle interventions aimed at modifying body weight and composition. In this review, we summarize and discuss the available preclinical evidence supporting the role of adiposity in modulating HER2+ BC aggressiveness and resistance to therapies, as well as clinical studies reporting on the prognostic role of BMI in patients with early-stage or advanced HER2+ BC., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Filippo de Braud – Consulting Fees: Tiziana Life Sciences, BMS, Celgene, Novartis, Servier, Pharm Research Associates, Daiichi Sankyo, Ignyta, Amgen, Pfizer, Octimet Oncology, Incyte, Pierre Fabre, Eli Lilly, Roche, Astra Zeneca, Gentili, Dephaforum, MSD, Bayer, Fondazione Menarini; Travel/Accommodation/Expenses: BMS, Roche, Celgene, Amgen; Speaker Bureau: BMS, Roche, MSD, Bayer, Ignyta, Dephaforum, Biotechespert Ltd, Prime Oncology, Pfizer; Research Grant/Funding (institution): Novartis, Roche, BMS, Celgene, Incyte, NMS, Merck KGAA, Kymab, Pfizer, Tesaro, MSD. Claudio Vernieri – Consulting Fees: Novartis. All other authors declare no conflict of interest., (© The Author(s), 2022.)

Background: High body mass index (BMI) has been associated with worse clinical outcomes in patients with early-stage breast cancer (BC), and its negative effects could be mediated by hyperglycemia/diabetes. However, the prognostic impact of high BMI in early-stage HER2-positive (HER2+) BC patients remains controversial., Methods: We conducted a retrospective study to investigate the impact of baseline BMI or glycemia on relapse-free survival (RFS) and overall survival (OS) in patients with surgically resected, stage I-III HER2+ BC treated with standard-of-care, trastuzumab-containing adjuvant biochemotherapy. The optimal BMI and glycemia cut-off values for RFS were identified through maximally selected rank statistics. Cox regression models were used to assess the impact of BMI, glycemia and other relevant variables on clinical outcomes., Results: Among 505 patients included in the study, a BMI cut-off of 27.77 kg/m 2 was identified as the best threshold to discriminate between patients with low BMI ( n  = 390; 77.2%) or high BMI ( n  = 115; 22.8%). At multivariable analysis, higher BMI was associated with significantly worse RFS [hazard ratio 2.26; 95% confidence interval (CI): 1.08-4.74, p  = 0.031] and worse OS (hazard ratio 2.25, 95% CI 1.03-4.94, p  = 0.043) in the whole patient population. The negative impact of high BMI was only observed in patients with hormone receptor (HR)-negative/HER2+ BC (hazard ratio 2.29; 95% CI: 1.01-5.20; p  = 0.047), but not in patients with HR-positive (HR+)/HER2+ BC (hazard ratio 1.36; 95% CI: 0.61-3.07, p  = 0.452). By contrast, hyperglycemia (⩾109 mg/dl) at baseline was associated with a trend toward significantly worse RFS at multivariable analysis only in patients with HR+/HER2+ BC (hazard ratio 2.52; 95% CI: 0.89-7.1; p  = 0.080)., Conclusions: High BMI is associated with worse clinical outcomes in early-stage HR-/HER2+ BC patients treated with trastuzumab-containing adjuvant biochemotherapy, while baseline hyperglycemia could be a predictor of worse RFS in HR+/HER2+ BC patients. Prospective studies are needed to investigate if modifying patient BMI/glycemia during treatment can improve clinical outcomes., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Background: Neoadjuvant anthracycline-taxane-based chemotherapy (ChT) is a standard of care treatment option for stage II-III breast cancer (BC) patients. However, the optimal duration of neoadjuvant ChT has been poorly investigated so far., Material and Methods: We retrospectively retrieved clinical data of patients with stage II-III human epidermal growth factor receptor 2-negative (HER2-) BC who were treated between October 2007 and January 2018 with neoadjuvant AT (doxorubicin-paclitaxel) for three cycles followed by CMF (cyclophosphamide-methotrexate-5-fluorouracil) for three cycles (cohort A) or with four AT cycles followed by four CMF cycles (cohort B). The aim of our study was to investigate the impact of neoadjuvant ChT duration (cohort A versus cohort B) on pathological complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS)., Results: Of 209 HER2- BC patients included, 62 had triple-negative breast cancer (TNBC) and 147 had hormone receptor-positive (HR+) BC. Median age was 48 years (range 30-74 years). A total of 111 patients belonged to cohort A and 98 patients belonged to cohort B. pCR was detected in 29 (13.9%) patients, 25 (40.3%) of whom had TNBC and four (2.7%) had HR+ HER2- BC. Patients achieving pCR had significantly longer DFS and OS, with statistical significance reached only in patients with TNBC. We found no differences between cohort A and cohort B in terms of pCR rates (15.3% versus 12.2%; p  = 0.55), DFS ( p  = 0.49) or OS ( p  = 0.94). The incidence of grade 3/4 adverse events was similar in cohort A versus cohort B as well (22.5% versus 19.4%; p  = 0.54)., Conclusion: Shorter duration of neoadjuvant anthracycline-taxane ChT was not associated with worse clinical outcomes in patients with stage II-III BC. Prospective studies are needed to evaluate whether the duration of neoadjuvant anthracycline-taxane-based ChT can be reduced in specific patient subgroups without negatively affecting clinical outcomes., Competing Interests: Conflict of interest: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)