The prognostic and predictive roles of plasma C-reactive protein and PD-L1 in non-small cell lung cancer.

BACKGROUND: Anti-PD-(L)1 agents have revolutionized the treatment paradigms of non-small cell lung cancer (NSCLC), while predictive biomarkers are limited. It has been previously shown that systemic inflammation, indicated by elevated C-reactive protein (CRP) level, is associated with a poor prognosis in anti-PD-(L)1 treated. The aim of the study was to analyze the prognostic and predictive value of CRP in addition to traditional prognostic and predictive markers and tumor PD-L1 score. METHODS: We identified all NSCLC patients (n = 329) who had undergone PD-L1 tumor proportion score (TPS) analysis at Oulu University Hospital 2015-22. CRP levels, treatment history, immune checkpoint inhibitor (ICI) therapy details, and survival were collected. The patients were categorized based on CRP levels (≤10 vs. >10) and PD-L1 TPS scores (<50 vs. ≥50). RESULTS: In the whole cohort (n = 329), CRP level of ≤10 mg/L was associated with improved survival in univariate (HR 0.30, Cl 95% 0.22-0.41) and multivariate analyzes (HR 0.44, CI 95% 0.28-0.68). With ICI treated (n = 70), both CRP of ≤10 and PD-L1 TPS of ≥50 were associated with improved progression-free survival (PFS) in univariate (HR 0.51, CI 95% 0.27-0.96; HR 0.54, CI 95% 0.28-1.02) and multivariate (HR 0.48, CI 95% 0.26-0.90; HR 0.50, CI 95% 0.26-0.95) analyzes. The combination (PD-L1 TPS ≥50 and CRP >10) carried a high negative predictive value with a median PFS of 4.11 months (CI 95% 0.00-9.63), which was similar to patients with low PD-L1 (4.11 months, CI 95% 2.61-5.60). CONCLUSIONS: Adding plasma CRP levels to PD-L1 TPS significantly increased the predictive value of sole PD-L1. Furthermore, patients with high CRP beard little benefit from anti-PD-(L)1 therapies independent of PD-L1 score. The study highlights the combined evaluation of plasma CRP and PD-L1 TPS as a negative predictive marker for ICI therapies.

Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis.

PURPOSE: Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. METHODS: We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. RESULTS: Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004-3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3+ T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1+-immunosuppressive macrophage density in their primary tumours. CONCLUSION: Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.

Treatment discontinuation and re-initiation of anti-PD-(L)1 agents in metastatic cancers.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are approved in multiple indications for cancer care. Most of the clinical trials have not questioned shorter than until disease progression approaches. In this study, we present results from a cohort of multiple advanced cancers treated with restricted anti-PD-(L)1 therapy. METHODS: All patients with advanced cancers treated with anti-PD-(L)1 therapy outside clinical trials at Oulu University Hospital 2014-19 were retrospectively identified from pharmacy records. Clinical variables, treatment history and survival were collected. RESULTS: 106 patients with median age of 66 years with lung cancer (n = 45, 42.5%), melanoma (n = 30, 28.3%), renal and bladder cancers (GU cancers) (n = 26, 24.5%), head and neck (H&N) cancer (n = 4, 3.8%), and colorectal cancer (n = 1, 0.9%) were included in the study. The median (m) OS for the whole population was 14 months (CI 9.7-18.3), 9 months (CI 6.3-11.7) for patients with no IO-free period (n = 64, 62.1%), and 27.0 months (CI 20.6-33.4, p = 0.000001) for patients (n = 39) with IO-free period. The mIO-free survival was 10.0 months (CI 7.1-12.9) for the whole cohort, 8.0 months (CI 1.7-14.3) for lung cancer, 23.0 months (CI 2.6-43.4) for melanoma, and 14.0 months (CI 0.0-20.4) for GU cancer. From the IO-free cohort, 19 patients needed re-treatment during follow-up, of which 8 were re-challenged with anti-PD-(L)1 therapy. The clinical benefit rate of anti-PD-(L)1 re-challenge was 37.5%. CONCLUSIONS: Our study shows that long IO-free periods can be achieved with limited duration of anti-PD-(L)1 therapy with excellent survival outcomes, and that anti-PD-(L)1 re-challenge is feasible in clinical practice.

Prognostic and predictive role of tumour-associated macrophages in HER2 positive breast cancer.

Disease outcomes of HER2+ breast cancers have dramatically improved after targeted therapies, such as trastuzumab became available. The main mechanism of action of trastuzumab depends on immunoactivation, while immunosuppressive tumour phenotype has been linked to adverse outcomes. Current study included metastatic HER2+ breast cancer patients treated with trastuzumab (n = 40). Immunohistochemistry was conducted to detect nitric oxide synthase 2 (iNOS) expressing M1 polarized and CD163+ M2 polarized macrophages, FoxP3+ regulatory T-cells (Tregs), CD47 and indoleamine 2,3-dioxygenase 1 (IDO1). High number of iNOS+ M1-like macrophages, both in the center of the tumour (CT) and invasive margin (IM), was significantly associated with improved survival (p = 0.009) while high expression of IDO1 or CD47 in the malignant cells was associated with worsened prognosis (p = 0.018, p = 0.046). High number of CD163+ M2-like macrophages in the CT, but not in the IM, and high number of FoxP3+ Tregs in both locations showed non-significant tendencies towards poor prognosis. Moreover, high number of iNOS+ M1-like macrophages combined with high number of CD8+ T-cells in the CT was significantly associated with improved survival (p = 0.0003), and this combined marker predicted patient's ability to remain progression-free without trastuzumab after responding to the therapy (p = 0.003). Current study highlights the role of M1 polarized macrophages alone and in combination with CD8+ cells in HER2+ breast cancer.