Comprehensive molecular profiling of sarcomas in adolescent and young adult patients: Results of the EORTC SPECTA-AYA international proof-of-concept study.

BACKGROUND: Adolescent and young adult (AYA) patients with cancer are poorly recruited to molecularly targeted trials and have not witnessed the advances in cancer treatment and survival seen in other age groups. We report here a pan-European proof-of-concept study to identify actionable alterations in some of the worst prognosis AYA cancers: bone and soft tissue sarcomas. DESIGN: Patients aged 12-29 years with newly diagnosed or recurrent, intermediate or high-grade bone and soft tissue sarcomas were recruited from six European countries. Pathological diagnoses were centrally reviewed. Formalin-fixed tissues were analysed by whole exome sequencing, methylation profiling and RNA sequencing and were discussed in a multidisciplinary, international molecular tumour board. RESULTS: Of 71 patients recruited, 48 (median 20 years, range 12-28) met eligibility criteria. Central pathological review confirmed, modified and re-classified the diagnosis in 41, 3, and 4 cases, respectively. Median turnaround time to discussion at molecular tumour board was 8.4 weeks. whole exome sequencing (n = 48), methylation profiling (n = 44, 85%) and RNA sequencing (n = 24, 50%) led to therapeutic recommendations for 81% patients, including 4 with germ line alterations. The most common were for agents targeted towards tyrosine kinases (n = 20 recommendations), DNA repair (n = 18) and the PI3K/mTOR/AKT pathway (n = 15). Recommendations were generally based on weak evidence such as activity in a different tumour type (n = 68, 61%), reflecting the dearth of relevant molecular clinical trial data in the same tumour type. CONCLUSIONS: We demonstrate here that comprehensive molecular profiling of AYA patients' samples is feasible and deliverable in a European programme.

Molecular Characterization of Ovarian Yolk Sac Tumor (OYST).

Most patients with malignant ovarian germ cell tumors (MOGTCs) have a very good prognosis and chemotherapy provides curative treatment; however, patients with yolk sac tumors (OYSTs) have a significantly worse prognosis. OYSTs are rare tumors and promising results are expected with the use of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens. We initiated a project in collaboration with EORTC SPECTA, to explore the molecular characteristics of OYSTs. The pilot project used retrospective samples from ten OYST relapsed and disease-free patients. Each patient had a molecular analysis performed with FoundationOne CDx describing the following variables according to the Foundation Medicine Incorporation (FMI): alteration type (SNV, deletion), actionable gene alteration, therapies approved in EU (for patient's tumor type and other tumor types), tumor mutational burden (TMB), and microsatellite instability (MSI) status. A total of 10 patients with OYST diagnosed between 2007 and 2017 had a molecular analysis. A molecular alteration was identified in four patients (40%). A subset of three patients (33.3% of all patients) harbored targetable oncogenic mutations in KRAS, KIT, ARID1A. Two patients at relapse harbored a targetable mutation. This retrospective study identifies clinically relevant molecular alterations for all relapsed patients with molecular analysis. Dedicated studies are needed to demonstrate the efficacy of specific therapeutic strategies after the failure of platinum-based first-line and salvage regimens and to explore the potential relationship of a molecular alteration and patient outcome.

First results of the EORTC-SPECTA/Arcagen study exploring the genomics of rare cancers in collaboration with the European reference network EURACAN.

PURPOSE: Rare cancers are defined by an incidence of <6 out of 100 000 cases per year. They are under-represented in clinical research including tumour molecular analysis. The aim of Arcagen is to generate a multinational database integrating clinical and molecular information of patients with rare cancers. PATIENTS AND METHODS: We present the retrospective feasibility cohort of patients with rare cancers, with previously collected tumour samples available from any stage. Molecular analysis was performed using FoundationOne CDx for all histologies except for sarcoma where FoundationOne Heme was used. Clinical data including demographic data, medical history, malignant history, treatment and survival data were collected. RESULTS: Eighty-seven patients from three centres were screened; molecular data were obtained for 77 patients (41 sarcomas, 9 yolk sac tumours, 14 rare head and neck cancers, 13 thymomas). The median age at the time of diagnosis was 48 (range 28-85). Most patients had reportable genomic alterations (89%). The most common alterations were linked to cell cycle regulation (TP53, RB1, CDKN2A/B deletions and MDM2 amplification). Multiple activating single-nucleotide variants (SNVs) could be detected in the RAS/RAF family. The tumour mutational burden status was globally low across all samples with a median of 3 Muts/MB (range 0-52). Only 4 cases (ie, 4.7% of tumours) had direct actionable mutations for a treatment approved in Europe within the patient's tumour type. CONCLUSION: The Arcagen project aims to bridge the gap and improve knowledge of the molecular landscape of rare cancers by prospectively recruiting up to 1000 patients.