We examined characteristics trends in early breast cancer patients receiving neoadjuvant chemotherapy (NAC) over a 16-year period. Our primary objective was to analyze variations in tumor stage and subtype over time. Secondary objectives included analyses of type of surgery and pathological response, from January 2005 to May 2021, 1623 patients receiving NAC were identified. Three periods were determined: 2005-2009 (P1), 2010-2014 (P2), 2015-2021 (P3). Correlations between periods and patient features with cT stage, pathological breast and axillary node response, pathological complete response (pCR), and type of surgery were assessed in univariate and multivariate analyses. We observed a significant increase in cT0-1 and N0 stages with periods (from 6.8% at P1 to 21.2% at P3, and from 43.2% at P1 to 55.9% at P3, respectively) and in the proportion of HER2+ and triple negative (TN) subtypes. In a multivariate analysis, a decrease of cT2-3-4 tumors during P3 was observed for HER2+ (OR:0.174; p=0.004) and TN tumors (OR:0.287; p=0.042). In-breast pCR and pCR were observed in 40.8% and 34.4% of all patients, respectively, with strong association with tumor subtypes, but not with tumor size in multivariate analysis (37.0% pCR for cT0-1 tumors, 36.4% for cT2 tumors, 29.1% for cT3 tumors (cT0-1 versus cT≥2; p=0.222)). pCR was negatively associated with cN1 stage (OR:1.499; p<0.001 for cN1 patients compared to cN0). We observed an increase in the proportion of small cT0-1 and N0 stages treated with NAC, especially in HER2+ and TN subtypes. No significant impact of tumor size on pCR rates was found.
Background
Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far.
Methods
We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features.
Results
CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients’ age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42–57) 5-year DFS versus 61% (95% CI 56–68) in patients with low expression (p = 3.17E−03), representing a 49% increased risk of event in the “CSPG4-high” group (HR = 1.49, 95% CI 1.14–1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between “CSPG4-high” and “CSPG4-low” tumors. The "CSPG4-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "CSPG4-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts.
Conclusions
Patients with “CSPG4-high” STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, “CSPG4-low” STS are better candidates for immune therapy involving ICI.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.