ATM Mutations in NSCLC Define Patients with Distinct Clinicopathologic, Genomic, and Immunophenotypic Characteristics

Intact DNA damage repair machinery is critical for maintaining normal cell-cycle function and preventing the development of cancer. Dysregulation of these pathways results in the accumulation of mutations, which increases malignancy potential. In addition, the continued disruption of the DNA repair machinery drives further progression of metastatic disease. Lung cancer is among the most genomically unstable cancers.¹

In non–small-cell lung cancer (NSCLC), ATM is mutated in approximately 10% of patients and thus is the most mutated DNA damage and repair gene. A recent study by Ricciuti and colleagues characterized the clinicopathologic, genomic, and immunophenotypic correlates of ATM mutations in NSCLC and the effect of these mutations on the clinical outcomes with PD-(L)1 inhibition.²

Clinicopathologic and genomic data were collected from 3592 patients with NSCLC at the Dana-Farber Cancer Institute. Genomic profiling of tumor samples was performed using OncoPanel.² Multiplexed immunofluorescence for CD8, PD-1, PD-L1, FOXP3, and CK AE1/AE3 was performed on 416 NSCLC samples to examine tumor-infiltrating immune cells. ATM immunohistochemistry was also performed on 184 ATM mutated (ATM^MUT) NSCLC samples with available tissue. ATM^MUT tumors were defined as harboring loss-of-function mutations (nonsense, frameshift, splice site, known deleterious missense mutations). Tumors lacking ATM mutations or harboring benign ATM alterations were defined as ATM wild-type (ATM^WT).²

The researchers identified 399 deleterious ATM mutations in 10.2% (365/3592) of samples. Of these mutations, 138 (34.6%) were truncating, such as nonsense, frameshift, and splice site mutations. The remaining 261 (65.4%) were missense mutations. They further found that ATM^MUT NSCLC samples were significantly enriched with KRAS, STK11, RBM10, and KDM5C co-mutations (P <.01), whereas co-mutations in EGFR, CDKN2A, and TP53 were nearly mutually exclusive (P <.01).²

Among ATM^MUT NSCLC, those with ATM loss by immunohistochemistry were significantly enriched with KRAS and STK11 co-mutations, whereas those with retained ATM expression were enriched with TP53 co-mutations (P <.01).²

Patients with ATM^MUT NSCLC had similar outcomes with PD-(L)1 inhibition with or without chemotherapy compared with ATM^WT patients and similar immune cell subsets infiltration (P >.05). Patients with deleterious mutations in ATM and TP53 (ATM^MUT/TP53^MUT) had increased response rates to chemoimmunotherapy compared with those with ATM^MUT/TP53^WT, ATM^WT/TP53^MUT, or ATM^WT/TP53^WT genotypes (70% vs 56.2% vs 35.7% vs 27.4%, respectively; P = .01). These patients also had increased tumor–stroma interface CD8+ T-cells (P <.01) and higher PD-L1 expression on tumor (P <.01) and immune (P <.01) cells.²

The investigators concluded that deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features, which could guide treatment selection in the future. In addition, response rates to chemoimmunotherapy were correlated with the presence of deleterious mutations in ATM and TP53 (ATM^MUT/TP53^MUT).

References

1. Burgess JT, Rose M, Boucher D, et al. The therapeutic potential of DNA damage repair pathways and genomic stability in lung cancer. Front Oncol. 2020;10:1256.
2. Ricciuti B, Alessi J, Wang X, et al. Clinicopathologic, genomic and immunophenotypic landscape of ATM mutations in non-small cell lung cancer. Presented at: 2022 American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 2143.