Using genomic scars to select immunotherapy beneficiaries in advanced non-small cell lung cancer

Abstract

In advanced non-small cell lung cancer (NSCLC), response to immunotherapy is difficult to predict from pre-treatment information. Given the toxicity of immunotherapy and its financial burden on the healthcare system, we set out to identify patients for whom treatment is effective. To this end, we used mutational signatures from DNA mutations in pre-treatment tissue. Single base substitutions, doublet base substitutions, indels, and copy number alteration signatures were analysed in $$m=101$$ m = 101 patients (the discovery set). We found that tobacco smoking signature (SBS4) and thiopurine chemotherapy exposure-associated signature (SBS87) were linked to durable benefit. Combining both signatures in a machine learning model separated patients with a progression-free survival hazard ratio of 0.40$$_{-0.17}^{+0.28}$$ - 0.17 + 0.28 on the cross-validated discovery set and 0.24$$_{-0.14}^{+0.31}$$ - 0.14 + 0.31 on an independent external validation set ($$m=56$$ m = 56 ). This paper demonstrates that the fingerprints of mutagenesis, codified through mutational signatures, select advanced NSCLC patients who may benefit from immunotherapy, thus potentially reducing unnecessary patient burden.

Whole-genome sequencing uncovers the genomic determinants of therapeutic resistance to immune checkpoint blockade

“…Moreover, patients treated with chemotherapy before CPI had reduced overall survival, independent of tumour type. This association contradicts that of thiopurine chemotherapy exposure (SBS87) which was recently shown to be enriched in CPI responders in NSCLC 33 but was absent in our cohort. Platinum chemotherapies such as cisplatin are DNA-damaging agents which could theoretically increase total mutational burden and neoantigen load, however, we did not detect such changes in these tumours.…”

“…This study also found SBS38 and SBS5 to be associated with CPI resistance, which we did not observe 34 . We noted a strong association between SBS4 (tobacco) and outcome after CPI, which was also recently associated with durable clinical bene t in a WGS cohort of lung cancer patients 33 .…”

“…Interestingly, this analysis also identi ed four signatures associated with poor outcomes following CPI including SBS44 (defective DNA mismatch repair and microsatellite instability) 30 , DBS3 (Polymerase epsilon exonuclease domain mutations)) 30 , DBS9 (associated with APOBEC activity) 32 and SBS25 (platinum chemotherapy) 30 . We did not observe any samples with SBS87, a thiopurine chemotherapy exposure-associated signature previously linked to improved CPI response in lung cancer 33 . SBS38, previously described as CPI resistance-associated 34 in WGS-sequenced melanoma, was present in only 6.53% (8/123) of melanoma patients and was not associated with response (HR).…”