Background: Breast cancer (BC) is a global health concern with significant outcome variation across different subtypes and populations. Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) for early BC (eBC) is a prognostic factor for relapse-free survival (RFS) and overall survival (OS). Despite recent therapeutic developments for eBC, a significant proportion of patients still does not achieve pCR, and the emergence of "HER2-low" BC as a new disease subtype may provide additional opportunities to improve treatment outcomes. In this study we evaluated the correlation of HER2-low status with pathological complete response (pCR) and prognosis.

547 Background: Estrogen Receptor (ER)-positive (+)/Human Epidermal Growth Factor Receptor 2 (HER2)-negative (-) breast cancers (BCs) express variable protein levels of both ER and HER2, which can influence prognosis. Methods: We evaluated all invasive ER+/HER2- BCs (n = 3633) that were diagnosed and systematically collected by the Parma Province Cancer Registry, Italy, from 2004 to 2018. Tumors were classified by HER2 (IHC score of 0, 1+ or 2+ with negative FISH) and ER status (ER-low [1-9%], ER-moderate [10-79%] or ER-high [80-100%]). Comparisons of clinicopathologic characteristics and disease outcome were performed. Results: BCs with late-stage diagnosis ( P = 0.04), high histologic grade ( P < 0.0001), or high proliferative rate ( P < 0.0001) were more likely HER2 2+/FISH-. The rate of ER-high BCs did not change from 2675 of 2938 (91%) HER2 0 tumors to 508 of 560 (90.7%) HER2 1+, and 124 of 135 (91.9%) HER2 2+/FISH- tumors. Correspondingly, ER-low BCs were not enriched among HER2 0 tumors compared to the other tumors with different HER2 expression ( P = 0.6). The 5-year overall survival (OS) for HER2 2+/FISH- BCs was lower than that for HER2 0 or 1+ tumors ( P = 0.03). ER-low/moderate tumors were associated with poorer OS in comparison with ER-high BCs ( P < 0.0001). HER2 2+/FISH- status was detrimental to OS among patients (pts) with ER-high tumors ( P = 0.04), while this finding was not observed among ER-low/moderate BCs ( P = 0.21). An interaction between HER2 2+/FISH- expression and ER-high status was found for poorer OS after adjusting for prognostic variables (HR = 1.7; 95% CI: 1.1-2.9). Conclusions: The prognostic role of HER2 expression in pts with ER-positive/HER2-negative BCs seems to be restricted to ER-high tumors, while the worse prognosis of tumors with lower ER expression is not associated with HER2 status. These findings may help identify optimal patient inclusion criteria for clinical trials with novel anti-HER2 therapies in ER-positive/HER2-negative disease.

The groundbreaking results of Immune Checkpoint Inhibitors (ICIs) in NSCLC still involve a limited subset of cases, thus imposing an optimization of patient selection. With the aim to non-invasively intercept tumor-host events implicated in cancer immune surveillance and response to immunotherapy, we explored the dynamic of blood immune-inflammatory markers in a cohort of advanced NSCLC treated with first-line ICIs. Peripheral blood was prospectively collected at baseline (T0) and at first radiological disease assessment (T1) from 47 consecutive NSCLC patients undergoing first-line ICI-based therapy. We performed a flow-cytometric analysis of circulating CD3+, CD8+, CD4+, NK, NKT and Tregs as their expression of functional molecules (PD-1, Granzyme B [GnzB], Perforin [Perf]) and proliferative index (Ki67). Soluble PD-L1 (sPD-L1) was determined by immunoassay together with Lung Immune Prognostic Index (LIPI: LDH + derived Neutrophil-to-Lymphocyte Ratio). All these parameters were correlated to objective response rate (ORR) according to RECIST v1.1 criteria. From October 2020 to August 2021, 47 advanced NSCLC patients candidate to receive first-line ICI-based therapy were enrolled. Median age was 67.8 years (range 41-82), 66% were males and 81% underwent chemo-immunotherapy. ORR resulted 51%. Among baseline parameters, number of metastatic sites, bone lesions and poor LIPI negatively correlated with ORR (p<0.05), while a trend towards favorable response was apparent in tissue PD-L1high cases (ORR=67% vs 28% in PD-L1neg). A significant proliferative burst of CD8+PD-1+ lymphocytes carrying cytotoxic molecules (GnzB+, Perf+) coupled with sPD-L1 decline characterized responders. Conversely, CD8+ GnzB+/Perf+ and NK cells dramatically dropped in non-responders (χ2 test, p<0.01). Furthermore, the kinetic and extent of Treg counteraction, likely triggered by the expanding (Ki67+) pool of effector lymphocytes, appeared to be a distinctive feature of responsive patients. Our results suggest that tracking the evolution of blood immune-inflammatory profiles may provide valuable predictors of ICI efficacy in NSCLC patients.