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Genomic-oriented oncology has improved tumor classification, treatment options, and patient outcomes. However, genetic heterogeneity, tumor cell plasticity, and the ability of cancer cells to hijack the tumor microenvironment (TME) represent a major roadblock for cancer eradication. Recent biotechnological advances in organotypic cell cultures have revolutionized biomedical research, opening new avenues to explore the use of cancer organoids in functional precision oncology, especially when genomics alone is not a determinant. Here, we outline the potential and the limitations of tumor organoids in preclinical and translational studies with a particular focus on lung cancer pathogenesis, highlighting their relevance in predicting therapy response, evaluating treatment toxicity, and designing novel anticancer strategies. Furthermore, we describe innovative organotypic coculture systems to dissect the crosstalk with the TME and to test the efficacy of different immunotherapy approaches, including adoptive cell therapy. Finally, we discuss the potential clinical relevance of microfluidic mini-organ technology, capable of reproducing tumor vasculature and the dynamics of tumor initiation and progression, as well as immunomodulatory interactions among tumor organoids, cancer-associated fibroblasts (CAFs) and immune cells, paving the way for next-generation immune precision oncology.

Background: MET-driven acquired resistance is emerging with unanticipated frequency in patients relapsing upon molecular therapy treatments. However, the determination of MET amplification remains challenging using both standard and next-generation sequencing-based methodologies. Liquid biopsy is an effective, non-invasive approach to define cancer genomic profiles, track tumor evolution over time, monitor treatment response and detect molecular resistance in advance. Circular RNAs (circRNAs), a family of RNA molecules that originate from a process of back-splicing, are attracting growing interest as potential novel biomarkers for their stability in body fluids., Methods: We identified a circRNA encoded by the MET gene (circMET) and exploited blood-derived cell-free RNA (cfRNA) and matched tumor tissues to identify, stratify and monitor advanced cancer patients molecularly characterized by high MET activity, generally associated with genomic amplification., Results: Using publicly available bioinformatic tools, we discovered that the MET locus transcribes several circRNA molecules, but only one candidate, circMET, was particularly abundant. Deeper molecular analysis revealed that circMET levels positively correlated with MET expression and activity, especially in MET-amplified cells. We developed a circMET-detection strategy and, in parallel, we performed standard FISH and IHC analyses in the same specimens to assess whether circMET quantification could identify patients displaying high MET activity. Longitudinal monitoring of circMET levels in the plasma of selected patients revealed the early emergence of MET amplification as a mechanism of acquired resistance to molecular therapies., Conclusions: We found that measurement of circMET levels allows identification and tracking of patients characterized by high MET activity. Circulating circMET (ccMET) detection and analysis could be a simple, cost-effective, non-invasive approach to better implement patient stratification based on MET expression, as well as to dynamically monitor over time both therapy response and clonal evolution during treatment., (© 2023. The Author(s).)

Purpose: COVID-19 cancer patients (C19-CP) represent a population at high risk for mortality, whose clinical characteristics are still unknown in the second SARS-CoV-2 wave. The aim of this retrospective study was to compare epidemiology and clinical presentation of C19-CP referring to the emergency department (ED) of our institution (San Luigi Gonzaga University Hospital, Orbassano, Turin, Italy), in a 3-week observation period of the first and second COVID-19 waves, starting from the introduction of the corresponding national lockdowns., Methods: We retrieved ED admissions from March 9 to 29, 2020, for the first wave, and from October 24 to November 13, 2020, for the second wave. We collected clinical characteristics of consecutive patients with molecularly confirmed SARS-CoV-2 infection. We also considered untested or SARS-CoV-2-negative cancer patients referring to the ED in the reference time frames., Results: C19-CP in the second wave exceeded those in the first wave despite the nonsignificant difference (39 of 576 v 8 of 163; P = .5). Compared with nononcological patients, C19-CP were older (median age 70 years [interquartile range 61-77] v 60 years [interquartile range 45-73]; P = .02) and presented more often with ≥ 2 comorbidities (40.4% v 24.3%; P = .02). Compared with nononcological patients, in C19-CP, respiratory failure (29 of 47 v 321 of 692; P = .049) and hospitalization (37 of 47 v 363 of 692; P = .0004) were higher, with comparable frequencies across the waves. Five of 24 and 10 of 27 hospitalized cancer patients in the first and second waves developed SARS-CoV-2 infection during hospitalization., Conclusion: C19-CP were a vulnerable population, irrespective of the COVID-19 waves. This highlights the need to prioritize vaccinations in oncological patients to safeguard and guarantee optimal anticancer care., Competing Interests: Paolo BironzoHonoraria: AstraZeneca, Bristol Myers Squibb, MSD Oncology, BeiGene, Roche, TakedaSpeakers' Bureau: AstraZeneca, RocheResearch Funding: RocheTravel, Accommodations, Expenses: Amgen Enrica CapellettoConsulting or Advisory Role: AstraZeneca, MSD, Boehringer Ingelheim Francesco PassigliaConsulting or Advisory Role: AstraZeneca, MSD Oncology, AmgenTravel, Accommodations, Expenses: MSD Oncology, Roche Massimo Di MaioHonoraria: Pfizer, Takeda, AstraZeneca, Janssen, Eisai, Novartis, Roche, Astellas PharmaConsulting or Advisory Role: AstraZeneca, Pfizer, Takeda, Janssen, Eisai, Novartis, RocheResearch Funding: Tesaro Silvia NovelloConsulting or Advisory Role: SanofiSpeakers' Bureau: AstraZeneca, MSD, Bristol Myers Squibb, Roche, Pfizer, Lilly, Takeda, AbbVie, Boehringer Ingelheim, Bayer, Amgen, BeigeneNo other potential conflicts of interest were reported.

The immune surveillance system is complex and regulated by different actors. Programmed death protein-ligand 1 (PD-L1), the only approved biomarker in clinical practice, has proven to be imperfect in selecting patients to immune checkpoint inhibitors treatment. Therefore, new biomarkers, and new therapeutic targets, are needed to maximise the efficacy of immunotherapy. V-domain Ig Suppressor of T-cell Activation (VISTA) is a programmed death protein-1 (PD-1) homolog expressed on T cells and on antigen-presenting cells, which regulates processes of activation and repression of the immune system with not yet completely clarified mechanisms. Its blockage has demonstrated in vitro and in vivo antitumour activity. The clinical research of VISTA antagonists is ongoing. Particularly, CA-170, an orally delivered dual inhibitor of VISTA and PD-L1, has shown to have clinical efficacy in phase I and II clinical trials in different advanced solid tumour types. Further data are needed to define whether this drug class can become a new therapeutic option for patients with VISTA expressing cancers., Competing Interests: Competing interests: MT: travel, accommodations, expenses: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda. Activity as Medical Writer supported by Novartis. PB: AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche. Speaker’s Bureau: Boehringer Ingelheim. SN: Advisor/Speaker’s Bureau: AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim, Eli Lilly, Roche, Takeda, Pfizer, AbbVie, Bristol-Myers Squibb., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Aim: Reporting toxicities of targeted therapies (TTs) and immunotherapy in oncology requires special attention. Materials & methods: We identified TTs and immunotherapies approved by the US FDA for solid malignancies in the adult population. Publications were reviewed according to a 24-point score based on the Consolidated Standards of Reporting Trials guidance. Results: We identified 81 trials (>45,000 patients). The experimental drug was studied as single agent in 51% of the cases; setting of disease was mainly (95%) advanced/metastatic. Lowest scores in adverse event (AE) description regarded: reporting recurrent/late toxicities and duration of the AEs (>90%), time of occurrence and indication of all-grade AEs (>75%). Conclusion: Suboptimal reporting of AEs in trials leading to approval of TTs and immunotherapy was shown. Improving AE descriptions should be a priority in ongoing trials.

Quality of life (QoL) is a relevant end point and a topic of growing interest by both scientific community and regulatory authorities. Our aim was to review QoL prevalence as an end point in cancer phase III trials published in major journals and to evaluate QoL reporting deficiencies in terms of under-reporting and delay of publication. All issues published between 2012 and 2016 by 11 major journals were hand-searched for primary publications of phase III trials in adult patients with solid tumors. Information about end points was derived from paper and study protocol, when available. Secondary QoL publications were searched in PubMed. In total, 446 publications were eligible. In 210 (47.1%), QoL was not included among end points. QoL was not an end point in 40.1% of trials in the advanced/metastatic setting, 39.7% of profit trials and 53.6% of non-profit trials. Out of 231 primary publications of trials with QoL as secondary or exploratory end point, QoL results were available in 143 (61.9%). QoL results were absent in 37.6% of publications in the advanced/metastatic setting, in 37.1% of profit trials and 39.3% of non-profit trials. Proportion of trials not including QoL as end point or with missing QoL results was relevant in all tumor types and for all treatment types. Overall, 70 secondary QoL publications were found: for trials without QoL results in the primary publication, probability of secondary publication was 12.5%, 30.9% and 40.3% at 1, 2 and 3 years, respectively. Proportion of trials not reporting QoL results was similar in trials with positive results (36.5%) and with negative results (39.4%), but the probability of secondary publication was higher in positive trials. QoL is not included among end points in a relevant proportion of recently published phase III trials in solid tumors. In addition, QoL results are subject to significant under-reporting and delay in publication.

Immune checkpoint inhibitors have emerged as an effective treatment for several tumor types and their use in clinical practice is expected to further increase in the immediate future. Although these agents are well tolerated, they are associated with a peculiar spectrum of toxicity, which is immune mediated and may potentially affect every organ. However, immune-related adverse events are mostly reversible if promptly diagnosed and adequately treated. Therefore, it is crucial that medical oncologists know how to diagnose and treat immune-related adverse events. This review focuses on the pathogenesis, clinical manifestations and management of immune-related toxicity of anti-CTLA-4 and anti-PD-1 antibodies.