Molecular classification of pulmonary sarcomatoid carcinomas suggests new therapeutic opportunities

Background

Pulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3), or APOBEC enzyme deamination (signatures 2 and 13).

Patients and methods

Whole-exome sequencing was carried out in 15 SC patients and on data from 10 previously published cases. Hierarchical clustering and consensus non-negative matrix factorization were carried out for samples classification based on mutational signatures.

Results

In the two series, SC distributed between two clusters (C): C_sig4 (characterized by signature 4) and C_{sig2–3–13} (signatures 2, 3, and 13). C_sig4 exhibited more frequent MAPK pathway mutations than C_{sig2–3–13} (pooled series: n = 10/14 versus 2/11, P < 0.05, respectively) and stronger PD-L1 expression (our series: n = 6/9 versus 1/6, P = 0.12). MET alterations were only found in C_{sig2–3–13} (pooled series: n = 5/11 versus 0/14, P = 0.009), as well as BRCA1/BRCA2 (n = 3/11 versus 0/15), EGFR (n = 1), and IDH1 (n = 1) mutations. C_{sig2–3–13} patients had better overall survival than C_sig4 patients (median: >45 versus 7 months, respectively, P = 0.001).

Conclusions

Our study suggests that SC presents at least two clusters comprising different mutational processes, gene alterations, and PD-L1 expression. New potential treatment possibilities are immune checkpoint inhibitors in C_sig4 and specific targeted agents in C_{sig2–3–13}. These findings should encourage clinicians to conduct broad molecular and immunological testing in SC patients beyond MET exon 14 alterations.

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