Checkpoint inhibitors in a marriage: consented or arranged?

There is currently a strong development of therapeutic combinations with checkpoint inhibitors (CPIs). The most promising combinations with CPIs concern anti-angiogenic agents and BRAF/MEK inhibitors. The timing of the initiation of the combination should be particularly well investigated for chemotherapy. Combinations between CPIs raise questions about risk/benefit ratio and overall clinical activity.

Host Polymorphisms May Impact SARS-CoV-2 Infectivity.

Based on a broad public database compilation, we support the hypothesis that germinal polymorphisms may regulate the expression of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular target itself and proteases controlling the process of its shedding or, conversely, its internalization. Consequently, a genetic influence on individual susceptibility to coronavirus disease 2019 (COVID-19) infection is strongly suspected.

Author Correction: Hyperprogression under Immune Checkpoint Inhibitor: a potential role for germinal immunogenetics.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hyperprogression under Immune Checkpoint Inhibitor: a potential role for germinal immunogenetics.

Hyperprogressive disease (HPD), an unexpected acceleration of tumor growth kinetics, is described in cancer patients treated with anti-PD-1/anti-PD-L1 agents. Here, our aim was to take into consideration the host and explore whether single nucleotide polymorphisms (SNPs) in key genes involved in immune response might predispose to HPD. DNA was extracted from blood-samples from 98 patients treated under CPI monotherapy. Four candidate genes (PD-1, PD-L1, IDO1 and VEGFR2) and 15 potential SNPs were selected. The TGKR (ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR≥2. TGKR calculation was feasible for 80 patients (82%). HPD was observed for 11 patients (14%) and was associated with shorter overall survival (P = 0.003). In univariate analysis, HPD was significantly associated with age ≥70 y (P = 0.025), immune-related toxicity (P = 0.016), VEGFR2 rs1870377 A/T or A/A (P = 0.005), PD-L1 rs2282055 G/T or G/G (P = 0.024) and PD-L1 rs2227981 G/A or A/A (P = 0.024). Multivariate analysis confirmed the correlation between HPD and age ≥70 y (P = 0.006), VEGFR2 rs1870377 A/T or A/A (P = 0.007) and PD-L1 rs2282055 G/T or G/G (P = 0.018). Immunogenetics could become integral predictive factors for CPI-based immunotherapy.

Germinal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors.

Background Checkpoint inhibitors bring marked benefits but only in a minority of patients and may also be associated with severe adverse events. Treatment outcome still cannot be faithfully predicted. The following study hypothesized that host genetics could be applied as predictive biomarkers for checkpoint inhibitor response and immune-related adverse events. We conducted a study based on germinal polymorphisms from genes coding for proteins involved in immune regulation. Methods Germinal DNA was obtained from advanced cancer patients treated with anti-PD-1/PD-L1 checkpoint inhibitors. DNA was genotyped using a custom panel of 166 single nucleotide polymorphisms covering 86 preselected immunogenetic-related genes. Computational analysis using a GTEX portal was made to determine potential expression Quantitative Trait Loci in tissues. Results Ninety-four consecutive patients were included. Objective response rate (complete or partial response) was significantly correlated to tumor microenvironment-related SNPs concerning CCL2, NOS3, IL1RN, IL12B, CXCR3 and IL6R genes. Toxicity were linked to target-related gene SNPs including UNG, IFNW1, CTLA4, PD-L1 and IFNL4 genes. The Area Under the ROC curve (AUC) was 0.81 (95% CI: 0.72-0.9) for response and 0.89 (95% CI: 0.76-1.00) for toxicity. In silico functionality exploring pointed rs4845618 (IL6R), rs10964859 (IFNW1) and rs3087243 (CTLA4) as potentially impacting gene expression. Conclusion These results strongly support a role for distinct immunogenetic-related gene SNPs able to predict efficacy and safety of anti-PD1/PD-L1 therapies. The results highlight the existence of patient-specific, germinal biomarkers able predict response to checkpoint inhibitor efficacy and, possibly, to predict treatment-related adverse events.

Germinal immunogenetics as a predictive factor for immunotherapy.

Clinical response to checkpoint inhibitors-based (CPIs) therapies can vary among tumor types and between patients. This led to a significant amount of pre-clinical and clinical research into biomarker identification. Biomarkers have been found to cover both the tumor itself and the tumor microenvironment. Entering host-related parameters into the equation should provide a valuable strategy for identifying not only factors predictive of treatment efficacy but also of treatment-related toxicity. It is clear that germline variants can offer efficient and easily-assessable indicators (blood DNA) to enlarge the spectrum of predictive markers for CPI-based treatment. A major issue concerns the real functional significance of the reported single-nucleotide polymorphisms (SNPs) linked to CPI-treatment outcome. Powered calculations should lead to an optimal trade-off between sample size and allele frequency. New molecular technologies and new analytical methods should provide opportunities to bridge the knowledge gap between SNP-CPI treatment associations and the functional impact of these SNPs.

Extended anti-HER2 therapy in early breast cancer: longer beats shorter?

PURPOSE OF REVIEW: One-year duration of adjuvant trastuzumab is the gold standard since 2005. During the last decade many attempts have been made to both increase and reduce the treatment duration. The purpose of this article is to review the current available evidence regarding alternative anti-HER2 therapy durations in the (neo)adjuvant treatment of HER2-positive localized breast cancer patients. RECENT FINDINGS: According to the majority of published data, shorter trastuzumab schedule has shown a decreased benefit in the overall HER2 population, whereas extending adjuvant trastuzumab, beyond 1 year, does not improve the outcome and is associated with increased cardiac toxicity. However, new challenging questions are raised by the recent results of ExteNet trial, in which sequential introduction of 1 year neratinib after standard trastumab-based therapy improved the outcome, especially in the estrogen receptor-positive subset of patients. SUMMARY: To date the standard duration of adjuvant trastuzumab remains 1 year in the adjuvant setting. It is likely that ongoing trials will clarify which patients could benefit from a shorter or a longer treatment. Taking into account patient's specific risk/benefit ratio and new biomarkers, in future, a 'personalized' treatment duration would be warranted.

Molecular cytogenetics of pediatric adipocytic tumors.

Both epidemiologic and cytogenetic data on pediatric adipose tissue tumors are scarce. Pediatric adipose tumors are mainly represented by lipomas, though only 28 cytogenetic descriptions of pediatric lipoma have been reported to date. Similar to adult cases, most of these pediatric lipomas harbored rearrangements of the chromosomal regions 12q14-q15 and 6p21, involving the HMGA2 and HMGA1 genes. Further cytogenetic studies of pediatric lipoma would be useful to determinate whether some partner genes of HMGA2, such as NFIB, may have a specific role in the early onset of these tumors. Cytogenetically, the best documented pediatric adipose tumor is lipoblastoma, which is the second most frequent adipose tumor in children. Chromosomal alterations in lipoblastoma, observed in 61% of cases studied by conventional cytogenetics, typically involve the 8q11-q12 region. The target gene of this rearrangement is PLAG1. Anomalies of PLAG1 have been observed in 70% of cases of pediatric adipose tumors studied by molecular cytogenetics methods, such as fluorescence in situ hybridization (FISH) or comparative genomic hybridization on array (array-CGH). The rare described cases of malignant pediatric adipose tumors in children are mostly myxoid liposarcomas. In the 27 cases explored at the genetic level, all pediatric myxoid liposarcomas showed the classical rearrangement of the DDIT3 gene at 12q13. In conclusion, the epidemiology and the prevalence of histological types of adipose tissue tumors differ in the pediatric population compared with adults, whereas chromosomal and genic rearrangements are similar to those of adult cases in each histological type.