Lung Cancer

PD 16 - Lung 4 - Poster Discussion

1142 - Pathogenic Mutations in ATM As Determinants of Local Control in Non-Small Cell Lung Cancers Treated with Radiation Therapy

Wednesday, October 24
11:42 AM - 11:48 AM
Location: Room 217 C/D

Pathogenic Mutations in ATM As Determinants of Local Control in Non-Small Cell Lung Cancers Treated with Radiation Therapy
K. L. Pitter1, D. L. Casey1, J. Setton1, C. Lu1, A. Rimner1, J. Reis-Filho1, S. N. Powell1, N. Lee2, T. A. Chan1, and N. Riaz2; 1Memorial Sloan Kettering Cancer Center, New York, NY, 2Memorial Sloan Kettering Cancer Center, Department of Radiation Oncology, New York, NY

Purpose/Objective(s): The Ataxia-Telangiectasia-Mutated (ATM) gene, is a key signaling protein in the double-stranded break DNA repair process and has recently been described as recurrently altered in non-small cell lung cancer (NSCLC). Radiation therapy (RT) causes double strand breaks and is frequently used in both definitive and palliative NSCLC treatment. Here, we sought to determine the relationship between ATM mutation and local control after RT in NSCLC patients.

Materials/Methods: The study cohort was identified from an institutional database of patients who underwent genomic testing using a capture-based next-generation sequencing assay targeting all coding exons and select introns of 486 key cancer genes with target coverage of 500-1000x. Among 21,675 patients with available genomic data, we identified 5339 NSCLC patients, 226 (4.2%) of whom harbored an ATM mutation. Of these, 95 patients received RT at any point during their treatment course to a total of 201 unique sites representing both thoracic and extrathoracic lesions which were subsequently analyzed for local control. Forty-two patients treated to 95 sites had a pathogenic ATM mutation predicted to impair protein function (frame shift, truncating, splicing, or fusion) while 53 patients treated to 106 sites had missense ATM mutations of unclear significance. The cumulative incidence of local failure (LF) after RT was compared in patients with pathogenic ATM mutations versus those with missense mutations using Gray’s method.

Results: The median age was 66 years old at time of diagnosis with a median follow up of 8.5 months from RT. Eighty-seven percent of the treated sites were in patients with metastatic disease and 84% of sites were treated with palliative intent. The cumulative incidence of LF at any irradiated site at the median follow-up time and at 2 years was 4.8% and 6.3% among patients with pathogenic mutations versus 7.3% and 18.7% in patients with missense mutations (p=0.02). The cumulative incidence of LF at the same time points for palliatively treated sites (N=169) was 5.3% and 6.7% for pathogenic ATM sites compared to 8.5% and 19.9% for missense ATM sites (p=0.01). For sites treated definitively (N=32), LF was 12.5% and 12.5% versus 6.7% and 30.1%, respectively (p=0.39). The median BED­10 was 72 Gy (range 60-150 Gy) for definitive sites and 50.4 Gy (range 14-97 Gy) for palliative sites, and there was no statistical difference in dose between the pathogenic and missense groups.

Conclusion: NSCLC tumors harboring a pathogenic ATM mutation were more likely to be locally controlled after RT than tumors harboring missense mutations of unclear significance. These findings suggest that genetic inactivation of ATM is a powerful predictor of local response to RT. Further studies are warranted to validate these findings and determine how to incorporate this information to guide personalized treatment decisions of NSCLC patients.

Author Disclosure: K.L. Pitter: None. D.L. Casey: None. J. Setton: None. C. Lu: None. A. Rimner: Research Grant; Varian Medical Systems, Boehringer Ingelheim, Pfizer, Astra Zeneca. Advisory Board; Astra Zeneca, Merck. J. Reis-Filho: None. N. Lee: Consultant; Lily. Advisory Board; Pfizer, Vertex, Merck. T.A. Chan: Vice Chair; Memorial Sloan Kettering. N. Riaz: None.

Kenneth Pitter, MD, PhD

Disclosure:
No relationships to disclose.

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