Abstract LB-297: Metabolic alterations in plasma associated with survival in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive histological subset of lung cancer accounting for ~15% of diagnosed lung cancers (more than 230,000 patients in the US in 2018). Five-year survival rates for advanced SCLC are below 10% with a 2% 5-year survival rate for distant metastatic disease. The dismal survival rates are governed by a lack of targetable oncogenic mutations, a lack of therapeutic avenues, diagnosis at advanced (metastatic) stage, and expected therapeutic resistance to standard-of-care therapies. There is an unmet clinical need to identify new therapeutic avenues for SCLC and develop factors that would impact prognosis and predict therapeutic response. Circulating metabolites are functional surrogates for cellular phenotypes, making them ideal to study in cellular transformation and tumor progression. We hypothesize that alterations in cellular metabolism will correlate with patient prognosis and therapeutic response/resistance in SCLC. The clinical cohort was comprised of 27 SCLC patients treated at Samsung Medical Center, Seoul, South Korea. Of these, 15 patients were diagnosed with extensive disease, while 10 patients were detected with limited and 2 patients with intermediate disease. All of the patients were treated with platinum-based cytotoxic chemotherapy regimens. The plasma samples were collected at three stages, before treatment (baseline), six-weeks post treatment, and at clinical relapse. We employed targeted, quantitative metabolomics to query the plasma metabolome of the SCLC patients. The results describe comparisons of baseline and six-week post treatment samples with clinical outcomes. In this SCLC cohort the mutational profile (prevalent mutations in RB1 and TP53) was consistent with other SCLC datasets, although this set tended to have higher incidence of BRCA1/2 mutations. At the baseline measurement, plasma concentrations of 5 acylcarnitines including C14:2, C10:1, C12, C12:1, C14:1-OH and a lysoglycerophosphocholine (lysoPC a C16:1) were significantly associated with progression-free survival (PFS); while proline and acyl carnitine C10:1 were significantly associated with overall survival (OS) across the cohort. When comparing those patients who progressed rapidly on platinum-based therapy (< 93 days) to those that progressed more slowly (> 236 days), two sphingolipids (SM C24:1, SM C20:2) and asymmetric dimethylarginine (ADMA) were significantly increased in those patients progressing more rapidly. In looking at the metabolic alterations across 6-weeks of therapeutic exposure, we saw 5 glycerophospholipids were significantly lower (FDR adjusted p < 0.05). In exploratory analyses (unadjusted p < 0.05), plasma levels of 43 lipids including 31 glycerophospholipids, 7 sphingolipids, 5 acylcarnitines were increased. Overall, exposure to chemotherapy was associated with altered plasma lipid levels. The higher circulating acylcarnitines may indicate modulation of carnitine palmitoyltransferase and suppression of the beta-oxidation process. Thus, changes in the plasma metabolome may be associated with OS and PFS in SCLC, and indicative of rapid recurrence on standard therapies. A larger investigation of the plasma metabolome in SCLC may identify biomarkers of patient prognosis and/or therapeutic response/resistance, necessary advancements towards abating the dismal patient survival rates in this disease.

Citation Format: Khyatiben V. Pathak, Se-Hoon Lee, Marissa McGilvrey, Krystine Mansfield, Derek Cridebring, Denise J. Roe, Timothy G. Whitsett, Keunchil Park, Patrick Pirrotte. Metabolic alterations in plasma associated with survival in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-297.