Search

Elucidating the adaptive mechanisms that prevent host immune response in cancer will help predict efficacy of anti-programmed death-1 (PD1)/L1 therapies. Here, we study the cell-intrinsic response of lung cancer (LC) to interferon-γ (IFNγ), a cytokine that promotes immunoresponse and modulates programmed death-ligand 1 (PD-L1) levels. We report complete refractoriness to IFNγ in a subset of LCs as a result of JAK2 or IFNGR1 inactivation. A submaximal response affects another subset that shows constitutive low levels of IFNγ-stimulated genes (IγSGs) coupled with decreased H3K27ac (histone 3 acetylation at lysine 27) deposition and promoter hypermethylation and reduced IFN regulatory factor 1 (IRF1) recruitment to the DNA on IFNγ stimulation. Most of these are neuroendocrine small cell LCs (SCLCs) with oncogenic MYC/MYCL1/MYCN. The oncogenic activation of MYC in SCLC cells downregulates JAK2 and impairs IγSGs stimulation by IFNγ. MYC amplification tends to associate with a worse response to anti-PD1/L1 therapies. Hence alterations affecting the JAK/STAT pathway and MYC activation prevent stimulation by IFNγ and may predict anti-PD1/L1 efficacy in LC. The authors thank Isabel Bartolessis (Cancer Genetics Group) and Eva Mussolen (Cancer Epigenetics Group) at IJC for technical assistance. This work was supported by Spanish grants from the MINECO (PID2020-114541RB-I00 to M.S.-C.) and from the Fundación Científica Asociación Española Contra el Cáncer (GCB14142170MONT to M.S.-C.). P.L. was supported by a fellowship from the Formación de Personal Investigador program (BES-2015-072204) and J.M.M. from the FI program AGAUR (2022 FI_B1 00085M). M.S. was supported by a Juan Rodes contract from the Instituto de Salud Carlos III (JR20/00015). O.A.R. was supported by an AECC contract (INVES19045ROME). We thank the CERCA Program/Generalitat de Catalunya for institutional support.

Background: With the approval of the vaccines against SARS-CoV-2, oncologic scientific societies have recommended cancer p to be prioritized for vaccination. Since cancer p have not participated in vaccine development studies, these recommendations arise some questions regarding their efficacy, safety and impact on survival. The aim of this prospective study is to evaluate the immune response to the SARS-CoV-2 vaccine in LC p. Secondary objectives include vaccine-related adverse events (AE), cancer treatment AE after vaccination, impact of the vaccine on survival, immune response, toxicity and survival outcomes in p>75 y, (re)infection after vaccination, complications and mortality. Methods: LCp who receive the vaccine against SARS-COV-2 are candidates to participate in this study. A pre-vaccination IgG determination will be performed to identify p with previous infection, but asymptomatic course. After vaccination, IgG will be repeated at 3, 6 and 12 months. Information on short and long term vaccine-related AEs will be collected, as well as, serological results, tumor and treatment-related data, and survival. Results: From March, 31 to April 15, 2021,106p have participated in the study. 58.5% were male, median age was 66 y (46- 83), 90.6% were Non-Small Cell LC, 83% has stage IV at diagnosis, Systemic therapy included EGFR/ALK/ROS1/RET/MET TKI (22.6%), immunotherapy (IT) (39.6%), chemotherapy (CT) (19.4%) and CTIT (14.1%). 4p were not receiving active therapy. 94.3% received Moderna® vaccine on behalf of the Hospital Vaccination Program. AES to 1st dose (1D) included local pain (16%), swelling (0.9%), fever (2.8%) and myalgia (0.9%). 5p had prior known COVID infection. No vaccine-related AE were reported in this group. 6p were admitted after vaccination due to cancer-related symptoms. No deaths were reported. Definitive data on baseline and 3-m serological data, as well as complete 1D and 2D related-AE and potential interactions with cancer therapy will be presented later. Conclusions: 1D of SARS-COV-2 vaccine appears to be safe irrespective of systemic therapy in our cohort of LCp. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: M. Saigi: Financial Interests, Institutional, Funding: Merck;Financial Interests, Personal, Other: BMS;Financial Interests, Personal, Other: Pfizer. E. Carcereny Costa: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Roche, Takeda;Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda, Amgen;Financial Interests, Personal, Other: Bristol-Myers Squibb, Pfizer, Roche, Takeda. M. Domenech: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS. A. Estival: Financial Interests, Personal, Other: Lilly, Pharmamar, Bayer, MSD, BMS, Roche. Honoraria: Roche, MSD, AstraZeneca, Pharmamar. M. Romeo Marin: Non-Financial Interests, Personal, Advisory Board: MSD, GSK;Non-Financial Interests, Personal, Other: AZ. M.T. Moran Bueno: Financial Interests, Personal, Advisory Board: AstraZeneca Boehringer Ingelheim Roche BMS. All other authors have declared no conflicts of interest.

Cancer is a dynamic process of somatic evolution. Distinct cell populations that undergo mutations, result in positive or negative selection depending on whether or not these mutations confer an advantage over other cells. In current clinical practice, predictive biomarkers such as EGFR mutation and ALK rearrangement are used routinely for treatment making decisions in non-small cell lung cancer (NSCLC). However, pressure from targeted therapies increases positive selection of resistant clones, eventually resulting in resistance to the drug. Monitoring the mutation pattern during the disease's course may allow the most suitable therapeutic approach to be selected. Here we report two clinical cases with lung adenocarcinoma demonstrating discordance in oncogene driver mutations between primary site and subsequent metastasis, and how this has contributed to therapeutic decisions.

Aim: New targeted therapeutics approved for mRCC offer multiple options in each line (L) of treatment (tto). Approximately 10-15% of mRCC p are treated with a 3rd L target agent. However, there are few data about which is the most appropriate strategy in the sequential tto in these p. Our aim is to analyze the efficacy of these strategies in terms of overall survival (OS). Methods: P diagnosed with mRCC from January 2005 to December 2013 in 3 multidisciplinary centres of Spain were retrospectively studied. Therapies were classified as: vascular endothelial growth factor receptor inhibitors (VEGFi) or mamaliam target of rapamycin inhibitors (mTORi). P were classified into subgroups depending on which strategy of tto they received: VEGFi-VEGFi-VEGFi, VEGFi-mTOR-VEGFi or VEGFi-VEGFi-mTOR. Analyses OS curve and medians were estimated using Kaplan Meier Method. Results: 279p were diagnosed with mRCC. P characteristics were: mean age 61.07y; 69.5% males, 29% females; Histology: 79.2% Clear Cell (CC), 7.2% Papilar, 3.2% Chromophob, 7.2% others; Prognosis: 13.6% poor, 49.1% Intermediate, 34.1% Good; 76.3% Prior nephrectomy. 97.5% (272p) of p received at least 1L of tto, 40% (109p) 2nd L and 16.5% (45p) 3rd L. 78.37% of p from the group of VEGFi-VEGFi tto recived a 3rd L (27% VEGFi and 51% mTORi) in front of 56% from VEGFi-mTOR (all VEGFi as 3rd L). OS of all p was 25 months (m) 95%CI(17.8-32.23). OS from p who only recived 2nd L were: VEGFi-mTOR 20m 95%CI(4.63-35.38); VEGFi-VEGFi 32m 95%CI(8.67-55.33). OS for 3rd L of tto were: VEGFi-mTOR-VEGFi 35m 95%CI(15.05-54.95); VEGFi-VEGFi-mTOR 30m 95%CI(19.37-40.68); VEGFi-VEGFi-VEGFi not reached. Conclusions: Results suggest that sequence with VEGFi has a trend in better outcomes: median OS has not been reached in VEGFi-VEGFi-VEGFi subgroup at the time of analyses and OS from 3rd L subgroups treated with an mTORi was similar than p receiving only 2nd L with two VEGFi. However, the study is limited by unbalanced factors and small number of p. More details of p characteristics subgroups will be provided. Disclosure: All authors have declared no conflicts of interest.