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Background: Malignant mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification and characterization of germline variants in malignant mesothelioma is relevant for identifying potential actionable targets and genetic counseling of family members. Methods: Patients referred to the Phase I Unit at Rigshospitalet were prospectively enrolled into the Copenhagen Prospective Personalized Oncology trial and underwent whole exome sequencing for somatic and germline variants. Between January 2014 and September 2021, 45 patients with MM were identified and 40 patients underwent whole exome sequencing. Germline variants were selected according to association to inherited cancer using a 168-gene panel and variants were classified according to ACMG/AMP classification as pathological (class 5) or likely pathogenic (class 4). Results: 34 males (85%) and 6 females (15%) with a median age of 64 years (range: 43-77) were available for analysis. The majority (85%) had malignant pleural mesothelioma whilst the rest (15%) had malignant peritoneal mesothelioma. Histological subtypes were distributed between epithelioid type (N=24, 60%), biphasic type (N=12, 30%) and the sarcomatoid type (N=4, 10%). A pathogenic or likely pathogenic variant was found in 16 patients (40%). In total 13 different germline variants were identified (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The variants included five frameshifts (33%), four missenses (25%), four nonsenses (25%), one splice site (6%), one start loss (6%) and one synonymous (6%). The pathogenic germline variants were found in DNA repair pathways, including homologous recombination repair (69%), nucleotide excision repair (13%), cell cycle regulatory (6%), DNA damage checkpoint control (6%) and hypoxic pathway (6%). Three (19%) of the patients with a germline variant had a second cancer. A previously undiagnosed BRCA2 germline mutation was found in 2 patients. A potential treatment target based on the pathogenic germline variant could be suggested in four patients (10%). Conclusion: The current analysis revealed a high frequency of pathogenic germline variants in patients with malignant mesothelioma. These data support germline testing in these patients and provide a rationale for additional investigation of the homologous recombination pathway as a potential target for precision medicine. Citation Format: Laila Belcaid, Birgitte Bertelsen, Karin A. Wadt, Ida V. Tuxen, Iben Spanggaard, Martin Højgaard, Jens B. Sørensen, Ulrik Lassen, Finn C. Nielsen, Kristoffer Rohrberg, Christina W. Yde. High frequency of pathogenic germline variants in patients with malignant mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2276.

Background: Circulating tumor DNA (ctDNA) sequencing is a promising approach for testing gene alterations and tailoring therapy in cancer patients given, its limited invasiveness, high sensitivity and potential to comprehensively represent tumor heterogeneity. Here, we report the results from a single-center study conducted at Gustave Roussy (Villejuif, France) where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors. Methods: Genomic analysis was performed using the Foundation One Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB) dedicated to precision medicine, attended by experts in clinical oncology, molecular biology, and clinical genetics. Actionable targets were defined by the MTB according to the existing level of evidence (classified by ESCAT tier), and molecular-based treatment suggestions were proposed where possible. Results: Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 theragnostic alterations including : high blood TMB (> 16 mutations/Mb) (N= 243, 13%), alteration of the DNA damage repair response pathway (N=336, 18%), PIK3CA mutations (N=150, 8%), FGFR alterations (N= 67, 4%), MET activations (N=13, 0.7%), ERBB family pathway alterations (N=127, 7%) and PTEN mutations (N=95, 5%). Overall, the MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (N= 639, 78%), off label/compassionate use (N=81, 10%), drug with a market authorization (N=51, 6%) and drug within an early access program (N=48, 6%). MTB did not recommend treatment for 462 patients (44%) with targetable molecular alterations for the following reasons: no clinical trial (N=421, 65%), matched treatment was already received (N=169, 26%), worsening of performance status (N= 49, 8%). Conclusions: This large-scale study demonstrates that liquid biopsy with a large NGS ctDNA panel is an efficient approach to match patients to genomically directed clinical trials/targeted therapies. Outcomes of patients treated with matched therapy will be presented at the meeting. Citation Format: Arnaud Bayle, Laila Belcaid, Miha Aldea, Florent Peyraud, Patricia Martin Romano, Félix Blanc-Durand, Rebecca Clodion, Santiago Ponce, Claudio Nicotra, Antoine Hollebecque, Yohann Loriot, Benjamin Besse, Damien Vasseur, Ludovic Lacroix, Etienne Rouleau, Jean-Charles Soria, Fabrice Barlesi, Geoffrey R. Oxnard, Fabrice Andre, Antoine Italiano. Clinical utility of circulating tumor DNA sequencing with a large panel: The experience of Gustave Roussy/National Center for Precision Medicine (PRISM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3413.

Background: Genomic profiling with tissue sequencing is still considered as the gold standard despite several limitations including screening failures due to limited tissue availability, and inability to capture intratumor spatial and temporal heterogeneity, which may impair accurate treatment selection. Several studies have demonstrated the potential of circulating tumor DNA (ctDNA) to detect genomic alterations at high accuracy compared with tissue analysis. However, no studies have comprehensively evaluated differences between tissue and ctDNA by using a large panel in the same cohort. Methods: Genomic analysis was performed for each patient by using the Foundation One Liquid CDx Assay and the Foundation One CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability). Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were defined by the MTB according to the existing level of evidence (ESCAT tiers) and molecular-based treatment suggestions were proposed where possible. Results: Between Dec 2020 and Nov 2021, 1021 patients (median age: 62 years) with advanced cancer underwent both tissue and ctDNA NGS. Five most frequent tumor types were colorectal (N=137,13%), NSCLC (N=130,13%), breast (N=120, 12%), prostate (N=82, 8%) and pancreas (N=65, 6%). Median time elapsed between request and assay results was 12 days for ctDNA and 46 days for tissue. Testing failure was 15% for tissue and 3.9% for ctDNA. Overall, 824 (81%) patients had evaluable results for both tissue and liquid. Total number of cancer-related alterations and variants of unknown significance were 4704 and 11673 vs 4645 and 7481 for ctDNA and tissue, respectively. Proportion of patients with a higher number of cancer alterations identified in ctDNA compared with tissue increased in parallel with the time elapsed between the tissue and ctDNA sampling (45% vs 33% for a delay > 26 months or < 8 months). MSI and TMB status were concordant for 71% and 64% of patients, respectively. MSI status was evaluable for 97% of patients through ctDNA vs 90% through tissue. Number of actionable alterations was similar in 346 (42%) of cases, whereas it was higher in tissue for 289 (35%) and in liquid for 189 (23%) patients. ctDNA profiling allowed the identification of an ESCAT I/II or III or IV alteration not present in tissue for 74 (9%), 113 (14%) and 52 (6%) patients, respectively. Overall, MTB recommended a matched therapy for 430 patients (52%). Such a recommendation would not have been made without the results of ctDNA for 120 patients (15%). Conclusion: This systematic comparison of ctDNA vs tissue sequencing demonstrates the capacity of ctDNA for capturing clinically relevant alterations to guide therapy in cancer patients with high accuracy and rapid turnover results. Citation Format: Arnaud Bayle, Florent Peyraud, Laila Belcaid, Maxime Brunet, Miha Aldea, Rebecca Clodion, Paul Dubos, Damien Vasseur, Claudio Nicottra, Santiago Ponce, Isabelle Soubeyran, Emmanuel Khalifa, Yohann Loriot, Benjamin Besse, Ludovic Lacroix, Etienne Rouleau, Geoffrey Oxnard, Fabrice Barlesi, Fabrice Andre, Antoine Italiano. Systematic comparison of ctDNA vs tissue sequencing with a large panel to guide therapy in patients with advanced cancer: A study from the French National Center for Precision Medicine (PRISM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3414.

3016 Background: Despite the effectiveness of the various targeted therapies currently approved in solid tumors, acquired resistance remains a persistent problem that limits the ultimate effectiveness of these treatments. Polyclonal resistance to targeted therapy has been described in multiple solid tumors through high throughput analysis of multiple tumor tissue samples from a single patient. However, biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. We used here sequencing of circulating tumor DNA (ctDNA) to characterize the landscape of secondary resistance mechanisms in a large cohort of patients with solid tumors. Methods: This study enrolled patients with advanced cancer from two institutional molecular profiling program STING (NCT04932525, sponsor: Gustave Roussy) or BIP (NCT02534649sponsor: Institut Bergonié). Genomic analysis was performed for each patient by using the Foundation One Liquid CDx Assay (324 genes, tumor mutational burden [TMB], microsatellite instability status). Results: 3435 patients with metastatic disease entered the study. Among them 992 patients (29%) received a targeted therapy matched to a specific molecular alteration before ctDNA. The main tumor types were: prostate cancer (349, 35%), luminal breast cancer (236, 24%), oncogene-addicted non-small cell lung cancer (129, 13%), KRAS-wild type colorectal cancer (126, 13 %). The most frequent class of targeted agents were androgen receptor pathway inhibitor (n = 350, 35%), aromatase inhibitor (236, 24%), anti- EGFR monoclonal antibodies (166, 17%), anti- EGFR tyrosine kinase inhibitors (83, 8%). ctDNA sequencing revealed DNA aberrations involved in secondary resistance in 308 patients (31%). The most frequent aberrations were AR mutations/amplifications, ESR1 point mutations, KRAS point mutations, EGFR point mutations. Among patients with resistance mutation, polyclonal aberrations were identified in 123 patients (40%). The median number of polyclonal aberrations per patient was 2 (range: 2-16). Polyclonal aberrations involved at least 2 different genes in 32 patients (10%). Preliminary results suggest that patients with polyclonal aberrations had worse outcome in comparison with patients with one or no detected aberration and final data will be presented at the time of the congress. Conclusions: We report here the first comprehensive landscape of genomic aberrations in ctDNA involved in resistance to targeted therapies in cancer patients. Polyclonal secondary genomic aberrations represent a frequent clinical resistance mechanism that may explain the poor rate of sustained complete remission observed with targeted therapies and must guide the development of future combinatorial strategies.

Background: Immunotherapy in the form of immune checkpoint inhibition (ICI) is now well established as acornerstone for treating many advanced malignancies. Nevertheless, as the number of indications for checkpoint inhibitors increases, so does the risk of immune-related adverse events (irAEs). Methods: We report two patient cases who, after being treated by an anti-programmed cell death 1 (PD-1), presented with grade III dyspnea due to pneumonitis. Discussion: Immunotherapy was discontinued and the patients required treatment with systemic corticosteroids. At the time of writing, both patients are still in complete response (CR), more than 1year beyond immunotherapy discontinuation. We discuss our cases with regard to recent literature reports on immune-related pneumonitis and persistence of response beyond discontinuation.

BACKGROUND/AIMS In patients with obesity, there is increased inflammation with attendant oxidative stress in perivascular adipose tissue. This has functional consequences with loss of vasodilator adipokine bioavailability. Part of the inflammatory response is mediated by increased activation of the renin-angiotensin-aldosterone axis. Therefore, this study was designed to investigate whether angiotensin-converting enzyme inhibitors or angiotensin receptor blockers can improve the anticontractile function of perivascular adipose tissue. METHODS Segments of rat mesenteric small artery were dissected and mounted in a wire myograph and contracted to incremental doses of norepinephrine in the presence and absence of perivascular adipose tissue and in conditions of normal oxygenation or after hypoxia and incubated with captopril or telmisartan. RESULTS Vessels with perivascular adipose tissue contracted significantly less than arteries with perivascular adipose tissue removed under normal oxygenation conditions, indicating that perivascular adipose tissue exerts an anticontractile effect. Hypoxia induced a loss of this anticontractile effect which could be completely prevented with captopril or telmisartan. CONCLUSION The in-vitro creation of a hypoxic environment can simulate the loss of anticontractile perivascular adipose tissue function seen in vivo in obese patients, and this can be prevented using inhibitors of the renin-angiotensin cascade.