3431 - Impact of Radioresistance and Radiosensitivity Gene Alterations on Locoregional Control after Proton Radiotherapy for NSCLC
Presenter(s)
D. T. Bergman1, M. I. Parker1, H. Lin2, A. F. Shepherd3, D. Mah4, J. Willmann5, D. Y. Gelblum1, A. J. Wu1, M. T. McMillan1, T. L. Chaunzwa1, D. Billing1, J. Ma1, P. Iyengar1, N. Y. Lee1, M. M. Awad6, D. Jones7, J. Chaft8, C. B. Simone II2,9, and N. Shaverdian1; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2New York Proton Center, New York, NY, 3Division of Radiation Oncology, University of Washington School of Medicine, Seattle, WA, 4ProCure Proton Therapy Center, Somerset, NJ, 5Department of Radiation Oncology, University Hospital Zurich, University of Zurich, Zurich, Switzerland, 6Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 7Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 9Memorial Sloan Kettering Cancer Center, New York, NY
Purpose/Objective(s):
Genomic drivers of photon radioresistance (RR) in NSCLC (e.g., KEAP1, STK11) are associated with inferior outcomes after conventional radiotherapy. Proton therapy produces distinct DNA damage patterns and may modify the prognostic impact of these genomic predictors, particularly in tumors with impaired DNA damage response (DDR). We evaluated whether established genomic predictors of photon RR retain prognostic value with proton RT in NSCLC.
Materials/Methods:
We conducted a retrospective cohort study of consecutive NSCLC patients treated with proton RT with matched tumor sequencing. Treatment intent included definitive and adjuvant radiotherapy for primary NSCLC, salvage RT of locoregional recurrences, local ablative RT for oligoprogression, and palliative RT for symptom relief. Cases retreated in-field for the same malignancy were considered reirradiation (reRT). Locoregional failure (LRF) and overall survival (OS) were measured from proton RT start. LRF was analyzed using cumulative incidence with death as a competing event and compared by Gray's test. The DDR gene set comprised 43 genes across homologous recombination, mismatch repair, and related pathways; the RR set included KEAP1, NFE2L2, STK11, and PIK3CA. Included alterations were OncoKB oncogenic drivers.
Results:
Among 82 patients, median age was 72 years; 53% were female and 75% were ever smokers. Histology was adenocarcinoma (61%) and squamous (31%); 30% had metastatic disease prior to proton RT. Treatment intent included salvage (39%), definitive (28%), oligoprogression (17%), adjuvant (13%), and palliative (4%); 71% were reRT. Median OS was 30.9 months; 1- and 2-year LRF was 33% and 49%, respectively. Frequent drivers included TP53 (58%), KRAS (23%), EGFR (18%), STK11 (17%), and KEAP1 (8%). RR alterations were present in 30% and DDR alterations in 24%.
In the full cohort, RR status was not associated with LRF (12-mo LRF 24% WT vs. 38% mutated; p=0.96). DDR status showed a trend toward lower LRF (12-mo 30% DDR-WT vs. 21% DDR-mutant; p=0.10). TMB was not associated with LRF (12-mo 33% TMB>10 vs. 26% TMB<10; p=0.93).
In salvage reRT courses (n=31, mean EQD2 61.3 GyE ± 13.0), DDR status significantly stratified outcomes: 12-mo LRF 53% for DDR-WT (n=19) versus 25% for DDR-mutant (n=12), widening at 24 mo to 82% versus 25% (p=0.01). RR alterations were not associated with LRF in salvage or non-salvage settings.
Conclusion:
In 82 proton-treated NSCLC patients (71% reRT), established genomic predictors of photon radioresistance were not associated with LRF. DDR alterations were associated with lower LRF in salvage reRT with a trend toward lower LRF overall, suggesting that DDR deficiency may be a more generalizable predictor of radiosensitivity across treatment platforms. Prospective validation in larger proton cohorts is warranted.