Abstract 3137: DNA damage response and repair pathway alteration and its association with tumor mutation burden and platinum-based chemotherapy in small cell lung cancer
Authors: Park Sehhoon , Lee Hayoon , Lee Boram , Sun Jong-Mu , Park Woong-Yang , Ahn Jin Seok , Ahn Myung-Ju , Lee Se-Hoon , Park Keunchil 
Published: August 2019

Background: Impairment in DNA damage response and repair (DDR) pathway is known as a predictive biomarker of platinum sensitivity in many cancer types. In the era of cancer immunotherapy, DDR alteration is re-emphasized as a predictive biomarker of immune-checkpoint inhibitor due to its positive correlation to tumor mutation burden (TMB).

Patients and methods: Target gene sequencing (381 genes) was conducted from 100 extensive disease (ED) and 66 limited disease (LD) small cell lung cancer (SCLC) patients. DDR-related genes were pre-defined by literature review, and mutations were classified as double-strand breaks (DSB, n=82): homologous recombination (n=54), non-homologous end joining (NHEJ, n=19), and Fanconi anemia (FA, n=32); or single-strand breaks (SSB, n=31): mismatch repair (MMR, n=19), base excision repair (BER, n=7), and nucleotide excision repair (NER, n=6). Based on the mutation profile, correlation of TMB and survival outcomes were analyzed.

Results: Compared to patients with an intact DDR pathway (n=70), a higher TMB was observed in patients with homologous recombination (P&lt;0.001), NHEJ (P=0.026), MMR (P&lt;0.001), BER (P=0.046), NER (P=0.017), DSB (P&lt;0.001) and SSB (P&lt;0.001). Survival analyses based on TMB level showed no predictive or prognostic values in ED patients. In LD patients, prolonged progression-free survival (PFS, hazard ratio [HR] 0.497, P=0.015) to platinum compound and overall survival (HR 0.383, P=0.010) were observed in those with TMB above median. Individual DDR pathway alteration showed no survival benefit in ED patients receiving platinum-based chemotherapy. In LD patients, those with mutations in the FA pathway had shorter PFS (HR 2.048, P=0.036) to initial treatment.

Conclusions: DDR pathway alterations, both DSB and SSB, in SCLC have a positive correlation with high TMB. However, it has demonstrated limited value in prediction of platinum efficacy.

Tumor mutation burden and its correlation with DNA damage related gene setsFAHR(-) n=131(+) n=32P(-) n=112(+) n=54PLow TMB69 (52.7%)14 (43.8%)0.47965 (58.0%)20 (37.0%)0.018High TMB62 (47.3%)18 (56.2%)47 (42.0%)34 (63.0%)NHEJBER(-) n=147(+) n=19P(-) n=156(+) n=7P*Low TMB78 (53.1%)7 (36.8%)0.27780 (51.3%)3 (42.9%)0.716High TMB69 (46.9%)12 (63.2%)76 (48.7%)4 (57.1%)MMRNER(-) n=147(+) n=19P*(-) n=157(+) n=6P*Low TMB81 (55.1%)4 (21.1%)0.00781 (51.6%)2 (33.3%)0.437High TMB66 (44.9%)15 (78.9%)76 (48.4%)4 (66.7%)DSBSSB(-) n=84(+) n=82P(-) n=135(+) n=31PLow TMB50 (59.5%)35 (42.7%)0.04476 (56.3%)9 (29.0%)0.006High TMB34 (40.5%)47 (57.3%)59 (43.7%)22 (71.0%)

Citation Format: Sehhoon Park, Hayoon Lee, Boram Lee, Jong-Mu Sun, Woong-Yang Park, Jin Seok Ahn, Myung-Ju Ahn, Se-Hoon Lee, Keunchil Park. DNA damage response and repair pathway alteration and its association with tumor mutation burden and platinum-based chemotherapy 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 3137.