Clinicopathologic, Genomic, and Immunophenotypic Landscape of ATM Mutations in Non-Small Cell Lung Cancer

Abstract

Purpose: ATM is the most commonly mutated DNA damage and repair gene in non-small cell lung cancer (NSCLC); however, limited characterization has been pursued.

Experimental design: Clinicopathologic, genomic, and treatment data were collected for 5,172 patients with NSCLC tumors which underwent genomic profiling. ATM IHC was performed on 182 NSCLCs with ATM mutations. Multiplexed immunofluorescence was performed on a subset of 535 samples to examine tumor-infiltrating immune cell subsets.

Results: A total of 562 deleterious ATM mutations were identified in 9.7% of NSCLC samples. ATM-mutant (ATMMUT) NSCLC was significantly associated with female sex (P = 0.02), ever smoking status (P < 0.001), non-squamous histology (P = 0.004), and higher tumor mutational burden (DFCI, P < 0.0001; MSK, P < 0.0001) compared with ATM-wild-type (ATMWT) cases. Among 3,687 NSCLCs with comprehensive genomic profiling, co-occurring KRAS, STK11, and ARID2 oncogenic mutations were significantly enriched among ATMMUT NSCLCs (Q < 0.05), while TP53 and EGFR mutations were enriched in ATMWT NSCLCs. Among 182 ATMMUT samples with ATM IHC, tumors with nonsense, insertions/deletions, or splice site mutations were significantly more likely to display ATM loss by IHC (71.4% vs. 28.6%; P < 0.0001) compared with tumors with only predicted pathogenic missense mutations. Clinical outcomes to PD-(L)1 monotherapy (N = 1,522) and chemo-immunotherapy (N = 951) were similar between ATMMUT and ATMWT NSCLCs. Patients with concurrent ATM/TP53 mutations had significantly improved response rate and progression-free survival with PD-(L)1 monotherapy.

Conclusions: Deleterious ATM mutations defined a subset of NSCLC with unique clinicopathologic, genomic, and immunophenotypic features. Our data may serve as resource to guide interpretation of specific ATM mutations in NSCLC.

Figure 1.

A, Lollipop plot showing 485 deleterious ATM mutations identified in the DFCI/MSK cohort. B, Pie chart showing the frequency of deleterious missense, nonsense, insertions/deletions, and splice site mutation in the combined DFCI/MSK cohort (C) TMB distributions in ATM^WT and ATM^MUT NSCLCs in the DFCI and MSK cohorts. D, Distribution of PD-L1 tumor proportion score in ATM^WT and ATM^MUT NSCLCs. E, Volcano plot showing oncogenic gene mutations enriched in ATM^WT and ATM^MUT NSCLCs.

Figure 2.

Oncoprint plot showing the genomic profiles of ATM^MUT NSCLCs in the DFCI genomic cohort. The most frequent 20 genes that are mutated are shown.

Figure 3.

A, Histograms showing the distribution of class I and class II ATM mutations with lost or intact ATM protein expression by IHC. B, Histograms showing the distribution of missense, nonsense, splice site, and ins/del mutations with lost or intact ATM protein expression by IHC. C, Lollipop plot of ATM mutations resulting in complete ATM loss by IHC. D, Lollipop plot of ATM mutations with intact (including heterogeneous loss) ATM expression by IHC. E, H&E low power view of a lung adenocarcinoma (a) that shows heterogeneous expression or ATM (b) including strong expression in a micropapillary component (c) and complete absence in the acinar component with mucinous differentiation (d). F, H&E high power view of a lung adenocarcinoma (a) with multiple intermingled subclones visualized with differing levels of ATM including strong (top left), intermediate/weak (top right), and complete loss (bottom right) (b). Background stromal and inflammatory cells show strong nuclear expression of ATM, as expected.

Figure 4.

A, Oncoprint plot showing the most commonly mutated genes in ATM mutated NSCLCs according to ATM expression by IHC (lost vs. intact). B, Volcano plot showing gene mutations significantly enriched in ATM^MUT NSCLCs with versus without complete ATM loss by IHC.

Figure 5.

A, ORR, (B) PFS, and (C) OS to PD-(L)1 immune checkpoint blockade monotherapy, primarily in the second- or subsequent line setting, among patients with advanced NSCLC, according to ATM mutation status. D, ORR, (E) PFS, and (F) OS to PD-(L)1 immune checkpoint blockade plus platinum doublet chemotherapy, primarily in the first-line setting, among patients with advanced/metastatic NSCLC, according to ATM mutation status.