P1148: multi-site pre-therapeutic biopsies reveals genetic heterogeneity in patients with newly diagnosed diffuse large b-cell lymphoma

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Diffuse large B-cell lymphoma is a heterogeneous disease, both regarding clinical and genetic presentation, response to treatment, and outcome. To enhance personalized treatment and improve patient outcome, research has sought to stratify patients based on clinical features, the International Prognostic Index (IPI), and molecular profiling, the latter showing great diversity among patients’ mutational signatures. However, a requisite for the use of tumour genetics for prognostic and predictive stratification is that the tumour sample which is sequenced is fully representative of the patient’s cancer. Aims: To explore genetic heterogeneity. We present a prospective study of multi-site biopsy sampling in newly diagnosed patients with DLBCL prior to treatment. Methods: By next generation exome sequencing (NGS), two spatially different biopsies from 16 patients were analysed using a clinical 59 gene lymphoma panel. Results: Clinically relevant differences, between the two biopsies were found in 8/16 (50%) of the patients. In six of these 8 patients, an additional mutation emerged in one of the biopsies, including pathogenic TP53 mutation in two patients. In both cases, the patients had biopsies performed from a nodal and an extra-nodal site. The TP53 mutation were found in the extra-nodal sites. Large mutational discrepancies, between the two sites, were observed in the remaining two patients – one patient displaying completely different mutational profiles between the two sites. IgG rearrangement analysis revealed this patient to be harboring two different clones. In the remaining half of the patients, the mutational profile was identical in the two biopsies from spatially different sites Summary/Conclusion: To our knowledge, this is the first study to explore intra-patient heterogeneity in multiple pre-treatment biopsies in patients with de novo DLBCL. Our findings, of mutational discrepancies in 50% of our patients, indicate that multiple biopsies from spatially different involved sites can provide additional information about the biological heterogeneity of DLBCL. This highlights the question of whether classification and/or patient selection for trials and treatment can be made based only on a single biopsy. Future research should examine the potential clinical implications of these findings for patient stratification, treatment, and survival. Keywords: Diffuse large B cell lymphoma, TP53