To the editor Soft-tissue sarcomas (STS) represent a very heterogeneous group of rare tumors including more than 100 different subtypes [1]. Surgery and neo/adjuvant radiation therapy represent the cornerstone of treatment for STS. However, despite an optimal resection of the tumor, up to 40% of patients will develop metastatic relapse and will die from the disease [1]. Doxorubicin represents the first-line standard of care for patients with advanced disease since the 1970s, despite several attempts to identify better regimens. The median overall survival (OS) of patients with metastatic disease is < 18 months and has only modestly improved over the past 20 years [2].We and others have previously reported that nextgeneration sequencing (NGS) of tumor tissues allows the identification of genomic aberrations with the potential to influence and personalize therapy in up to 50% of patients with advanced STS [3,4].Genomic profiling of circulating tumor DNA (ctDNA) is increasingly used to tailor therapy in cancer patients. Indeed, such liquid biopsy has several advantages: noninvasiveness, reduced turnaround times for faster results, and the ability to fully capture the landscape of tumor heterogeneity [5].The aims of the present study were to investigate the impact of ctDNA profiling in a large cohort of patients with advanced STS included in two prospective precision medicine studies and to decipher the ctDNA molecular landscape of sarcoma.

3005 Background: Typical entry criteria in early phase studies include expected life expectancy greater than 3 months. However, this evaluation is quite subjective and more objective and reproducible tools are needed to improve patients (pts) selection. The quantification of ctDNA shed by measuring tumor fraction (TF) has been associated with prognosis in solid tumors pts. However, prognostic implications of TF quantification have been evaluated primarily in retrospective studies and in a limited number of cancer types. We report here the first prospective evaluation of the prognostic impact of TF in 2 independent precision medicine studies enrolling pts referred to consider their eligibility to early phase trials. Methods: All consecutive adult pts with an advanced solid tumor included between December 2020 and December 2021 in 2 precision medicine studies: BIP (NCT02534649, sponsor: Institut Bergonié, Bordeaux, France) and STING (NCT04932525, sponsor: Institut Gustave Roussy, Villejuif, France). All pts underwent comprehensive genomic profiling with the 324-gene FoundationOne. TF was analyzed as a binary variable, indicating whether a specimen had TF ≥10% or TF <10%. Multivariate analysis included previously validated prognostic scores: the Royal Marsden Hospital (albumin, LDH, number of metastatic sites) and the GRIm (LDH, neutrophil/lymphocyte ratio (NLR), albumin) scores as well as their individual components. Results: 1912 pts: N=965 in BIP and N=947 in STING were included. Their characteristics are described. High TF was associated with significantly worse overall survival (OS) in both BIP and STING studies. On multivariate analysis, TF was associated with worse OS (HR:2.49 [CI95%: 2.11 - 2.95, p<0.001] and HR:2.52 [CI95%: 2.06 - 3.08, p<0.001] in BIP and STING studies respectively) independently of the RMH and GRIM scores as well as their individual components. Conclusions: This is the first prospective analysis confirming that TF is a strong prognostic factor in pts with advanced solid tumors and represent an helpful tool in the process of patient selection for phase I trial entry. [Table: see text]

Imaging can capture phenotypic intra- and inter-tumoral heterogeneities. Radiomics provides a radiophenotypic quantification but has mostly focused on single tumors, letting apart metastatic patients. Our aim was to develop inter-site heterogeneity indices (ISHIs) using radiomics and to investigate their predictive value regarding treatment response and overall survival (OS) in lung adenocarcinoma patients. All measurable target lesions per RECIST with volume&gt;1cm3 from consecutive adult patients with newly-diagnosed metastatic lung adenocarcinoma were segmented on contrast-enhanced CT-scan to extract 121 3D-radiomics features (RFs). Four methods were developed to quantify the dissimilarity (Ds) between the lesion profiles from a same patient in the radiomics space, namely: Centroid-to-Lesion (CL), Lesion-to-Lesion (LL), Primitive-to-Lesion (PL) - followed by mean, range and standard deviation (SD) of those distances -, and using clustering to define lesion groupings and calculating grouping diversity with Shannon Entropy (SE). Associations between the 10 resulting ISHIs and disease control rate (DCR), objective response rate (ORR) to first-line treatment and OS were investigated in univariate and stepwise multivariate analyses including cofounding variables (performance status, sex, age, staging, number of metastatic sites, liver and bone metastases). 167 patients (62 women, median age: 62.3 years) were included between 2016 and 2019, and randomly separated into one experimental (N=117 [70%], 546 lesions) and one validation (N=50 [30%], 232 lesions) cohorts. Higher ISHIs were systematically found in patients without disease control, without objective response and with worse OS. Range(Ds-PL) was independently associated with DCR in both cohorts (odds ratio [OR]=1.30, P=0.02 and OR=1.50, P=0.02, respectively). Range(Ds-PL) was independently associated with ORR in the validation cohort (OR=1.46, P=0.049 versus OR=1.23, P=0.055 in the experimental cohort). SE was independently correlated with OS in the experimental cohort (hazard ratio [HR]=2.39, P=0.005) whereas Range(Ds-PL) was selected in the last regression step in the validation cohort (HR=1.16, P=0.08). None of the ISHIs was associated with PD-L1 status; however, trend towards lower ISHI values were observed in EGFR, ALK and ROS1 altered tumors versus the others. Radiomics-based ISHIs were associated with ORR, DCR and OS and appeared as promising metrics to deepen our understanding of the clinical implication of intra-patient inter-tumor heterogeneity. Correlation assessment between radiomics-based ISHIs and tumor heterogeneity evaluated by a baseline ctDNA profiling (FondationOne® Liquid CDx) before treatment in metastatic lung adenocarcinoma patients is ongoing and will be presented. Citation Format: Mathilde Lafon, Sophie Cousin, Mélissa Alamé, Michèle Kind, Antoine italiano, Amandine Crombé. Predictive value of baseline inter-sites heterogeneity measured by radiomics in metastatic lung adenocarcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 863.

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.

11550 Background: Preliminary studies have suggested that the detection, quantification, and profiling of ctDNA in patients with sarcoma is feasible and may improve prognostication, measure treatment response, and detect relapse. However, data related to impact of ctDNA profiling to tailor therapy in patients with advanced disease are lacking. Methods: Patients with advanced soft-tissue sarcomas (STS) have been included in two ongoing institutional molecular profiling studies (BIP: NCT02534649, STING: NCT04932525). Genomic analysis (ctDNA in all cases and tissue when available) was performed by 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 tumour board 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 (ESCAT), and molecular-based treatment suggestions were proposed where possible. Results: Between December 2020 and August 2021, 98 patients with metastatic STS underwent ctDNA profiling. Median time to assay results was 12 days. Results were contributive for 86 patients (88%). At least one actionable target (range 1-4) was detected in 35 patients (36%) including high tumor mutational burden (> 16 mutations/Mb) for 1 patient (1%) and alteration of the DNA repair response pathway for 12 patients (12%). Overall, the MTB recommended a matched therapy for 27 patients (28%). 40 patients underwent also NGS of tissue besides ctDNA profiling. The number of actionable alterations was similar in 26 (65%), whereas it was higher in tissue for 10 (25%) and in liquid for 4 (10%) patients. 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 in patients with advanced STS. Outcomes of patients treated with matched therapy will be presented at the meeting.