2019 ASCO Annual Meeting!
Session: Lung Cancer—Non-Small Cell Metastatic
Type: Poster Session
Time: Sunday June 2, 8:00 AM to 11:00 AM
Location: Hall A
DNA damage response and repair (DDR) gene mutations and correlation with tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC).
Metastatic Non-Small Cell Lung Cancer
Lung Cancer—Non-Small Cell Metastatic
2019 ASCO Annual Meeting
Poster Board Number:
Poster Session (Board #423)
J Clin Oncol 37, 2019 (suppl; abstr 9100)
Author(s): Hirva Mamdani, Jerry Chen, Seongho Kim, Yahya Ibrahim, Mohammad Fahad Bin Asad, Jorge J. Nieva, Rebecca Feldman, Abdul Rafeh Naqash, Stephen V. Liu, Patrick C. Ma, David Craig Portnoy, Hossein Borghaei, Nagla Fawzy Abdel Karim, Yanis Boumber, Ari M. Vanderwalde, Alexander I. Spira, Shadia Ibrahim Jalal; Karmanos Cancer Institute, Detroit, MI; Wayne State University School of Medicine, Detroit, MI; Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI; Wayne State University, Detroit, MI; University of Southern California, Los Angeles, CA; Caris Life Sciences, Phoenix, AZ; East Carolina University/Vidant Cancer Center, Greenville, NC; Georgetown University Medical Center, Washington, DC; WVU Cancer Institute, West Virginia University, Morgantown, WV; The West Clinic, Memphis, TN; Fox Chase Cancer Center, Philadelphia, PA; Augusta University, Augusta, GA; Division of Hematology/Oncology, The University of Tennessee Health Science Center, West Cancer Center, Germantown, TN; Virginia Cancer Specialists, Fairfax, VA; Indiana University School of Medicine, Indianapolis, IN
Background: Loss of DNA repair fidelity is a common feature of human cancers and can drive genomic instability and tumor evolution. DNA repair deficiency has also emerged as a predictive biomarker of response to PARP inhibition and more recently to immune checkpoint inhibition. Information on relationship between DNA repair defects and TMB in NSCLC is limited. Methods: We analyzed molecular profiles of 5667 NSCLC tumors harboring mutations in DDR genes (ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, ERCC2/3, FANCA/C/D2/E/F/G/L, MLH1, MSH2/6, MRE11, NBN, PALB2, POLE, PTEN, RAD50/51, WRN). Profiles included next-generation sequencing of 592 genes, TMB, and PD-L1 (22c3) by immunohistochemistry. Association of DDR gene mutations with immune biomarkers (TMB and PD-L1) was assessed. Results: Of the 5667 samples, 54% (n = 3060) had high TMB (defined as ≥10 mutations/Mb) with median TMB of 14 (range, 10-168). Among the remaining 46% (n = 2607) with low TMB, median TMB was 7 (range, 1-9). PD-L1 expression was high (≥50%) in 33% (n = 1878), intermediate (1-49%) in 26% (n = 1446), and negative ( < 1%) in 41% (n = 2343). Among all DDR mutated pts, 19% (n = 1058) had both high PD-L1 and high TMB, 35% (n = 2002) had high TMB alone, 15% (n = 820) had high PD-L1 alone. Most commonly mutated genes were RAD50 (52%), WRN (29%), CHEK2 (20%), ATM (19%), MRE11 (19%), and ATR (18%). Genes with a high likelihood of being associated with high TMB were ATM, ATR, BARD1, BRCA1, BRCA2, ERCC2, ERCC3, FANCA, MSH2, PALB2, and POLE. Strongest association was seen with BRCA1 (OR 1.81, 95% CI 1.47-2.22), PALB2 (OR 1.76, 95% CI 1.40-2.21), and POLE (OR 1.71, 95% CI 1.45-2.01). DDR genes mutations were not mutually exclusive - 77.5% (n = 4397) had 2 or more mutated genes. Tumors with ≥3 mutated genes were more likely to be associated with high TMB. No such correlation was observed with PD-L1 expression. Conclusions: The majority of NSCLC pts harboring DDR gene mutations have high TMB. Presence of ≥3 gene mutations and BRCA1, PALB2, and POLE mutations strongly correlate with high TMB. These patients may represent a unique subset that is more likely to benefıt from immune checkpoint blockade and PARP inhibition.