Abstract GS1-10: Clinical utility of molecular tumor profiling: Results from the randomized trial SAFIR02-BREAST
Authors: André Fabrice , Gonçalves Anthony , Filleron Thomas , Dalenc Florence , Lusque Amélie , Campone Mario , Sablin Marie-Paule , Bonnefoi Hervé , Bieche Ivan , Lacroix Ludovic , Tran-Dien Alicia , Jimenez Marta , Jacquet Alexandra , Wang Qing , Rouleau Etienne , Gentien David , Soubeyran Isabelle , Morel Alain , Arnedos Monica , Bachelot Thomas 
Published: March 2022

Background: While studies have shown feasibility and reported preliminary evidence of utility, there is no evidence that multigene sequencing improves outcome in patients with metastatic cancer. The aim of the present study was to assess the clinical utility of multigene sequencing and DNA copy number analyses.. Methods: In SAFIR02-BREAST (NCT: 02299999) and SAFIR-PI3K (NCT: 03386162), open-label multicentric phase II randomized trials, patients were selected if they had a Her2-negative metastatic breast cancer eligible to 1st or 2nd line chemotherapy. Patients underwent a pre-treatment biopsy of metastatic disease when feasible, followed by genomic analysis by next generation sequencing and SNParray. After 6 to 8 cycles of induction chemotherapy, patients without progressive disease and presenting an actionable genomic alteration, were randomized between targeted therapies matched to genomic alterations or maintenance chemotherapy. The primary objective was to evaluate whether targeted therapies guided by genomics improves progression-free survival (PFS) as compared to maintenance chemotherapy, in a pooled analyses of SAFIR02-BREAST and SAFIR-PI3K populations. A hierarchical testing was applied. The efficacy of targeted therapies matched to genomic alterations was first tested in patients presenting an ESCAT I/II alteration (ESMO Scale of Actionability of Molecular Targets). If a p value &lt;0.1 was observed in the first step, analyses were then performed in the Intent-to-treat population. Results: Out of the 1462 patients included, 238 (16%) were subsequently randomized between maintenance chemotherapy (n=81) and targeted therapy (n=157). In 115 patients presenting an ESCAT I/II genomic alteration, the median PFS was 9.1 months (90%CI: 7.1-9.8) and 2.8 (90%CI: 2.1-4.8) in matched targeted therapy and maintenance chemotherapy arms respectively (adjusted HR for stratification factors =0.41;90%CI: 0.27-0.61, p&lt;0.001). In the overall population, there was no significant difference in the duration of PFS between the two arms (adjusted HR: 0.77 (95%CI: 0.56- 1.06, p=0.109). ESCAT classification was highly predictive for the benefit of targeted therapies matched to genomic alterations (interaction test, p= 0.004). Targeted therapies matched to genomic alterations were not effective in patients without ESCAT I/II alteration (HR: 1.15, 95%CI: 0.76-1.75). The SNP array analyses (n=926) identified 21 genes altered more frequently in metastases as compared to primary tumors (TCGA+ METABRIC). Of these, focal TERT amplifications were associated with a poor outcome. Focal CDK4 amplifications were observed after resistance to CDK4 inhibitors. Finally, high HRD was associated with longer PFS in patients with BRCA mutation treated with olaparib (HR: 0.32 [95%CI: 0.12;0.83], p=0.013).. Conclusion: SAFIR02/PI3K trials report that the clinical use of multigene sequencing must be driven by a framework of actionability, and identifies new genomic alterations associated with metastatic evolution and drug resistance or sensitivity.

Citation Format: Fabrice André, Anthony Gonçalves, Thomas Filleron, Florence Dalenc, Amélie Lusque, Mario Campone, Marie-Paule Sablin, Hervé Bonnefoi, Ivan Bieche, Ludovic Lacroix, Alicia Tran-Dien, Marta Jimenez, Alexandra Jacquet, Qing Wang, Etienne Rouleau, David Gentien, Isabelle Soubeyran, Alain Morel, Monica Arnedos, Thomas Bachelot. Clinical utility of molecular tumor profiling: Results from the randomized trial SAFIR02-BREAST [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-10.