Abstract 3162: Prognostic value of tumor mutational burden using a 409 gene NGS panel in cancer patients with advanced stage recurrent or treatment refractory disease
Authors: Yang Richard K. , Wang Peng , Jelloul Fatima Z. , Routbort Mark J. , Kopetz Scott , Shaw Kenna R. , Lee Jack J. , Zhang Jiexin , Chen Hui , Patel Keyur P. , Luthra Raja , Broaddus Russell R. 
Published: August 2019

Abstract
Tumor Mutational Burden (TMB) is a promising biomarker for prediction of response to immune checkpoint blockade (ICB). It is uncertain whether ICB has prognostic value outside of ICB therapy. The CMS400 next generation sequencing panel (NGS) is a 409 gene, 15,992 amplicon, and 1.745 Mb panel instituted during 2014-2015 and run for 556 cancer patients who had been consented for participation within a prospective molecular pathology biomarker trial (PA14-0099). All patients had advanced or recurrent solid tumor malignancies that were refractory to at least one line of systemic therapy prior to enrollment. Survival time was calculated from time of NGS-tested tissue collection. TMB was calculated by dividing reported mutations (RM) by 1.745Mb, the genetic footprint of the NGS panel. Subtraction of germline single nucleotide polymorphisms was performed for each patient. GraphPad Prism 7.03 software was used to calculate p values and to plot Kaplan-Meier survival curves. One hundred seven patients (19.2%) received ICB. When stratified by reported mutations (RM: 0, 1, 2, 3, 4-5, 6-7, 8-9, 10-18, and &gt;19), a statistically significant decrement of overall survival was seen with increasing TMB in patients not treated with ICB (Table 1, p&lt;0.0001). Also, in patients treated with ICB, significantly increased overall survival was seen on the extreme ends of the TMB spectrum (Table 1, p=0.0249). In contrast, stratification by the top four histologic diagnoses (Colorectal ADCA [n=94] - 34.2 months, breast ductal ADCA [n=44] - 26.6 months, gynecologic high grade serous [n=39] - 45.6 months, and lung ADCA [n=30] - 31.5 months) did not show difference in overall survival (p=0.332). We report here a novel molecular phenomena showing that high TMB in patients with advanced cancers is associated with worse survival. This negative impact of high TMB can be reversed by treatment with ICB. These effects of ICB were seen across a broad spectrum of cancer types.
Median Survival Stratified by Tumor Mutational Burden and ICB Treatment StatusAll PtsAll PtsICB TreatedICB TreatedNo ICBNo ICBReported Mutations# of PtsMedian Survival (Months)# of PtsMedian Survival (Months)# of PtsMedian Survival (Months)p-value (Log-rank)Hazard Ratio of ICB Therapy95% CI of HR of ICB Therapy0 RM7150.71958.85248.50.3190.7050.368 - 1.341 RM8550.91262.07347.40.3390.6840.345 - 1.362 RM9433.91928.07533.90.8650.9510.535 - 1.693 RM8830.51951.26928.90.1890.7040.428 - 1.164-5 RM9330.81141.08230.40.5390.8150.442 - 1.506-7 RM4928.41127.33828.550.6230.8270.401 - 1.718-18 RM5623.95828.84823.10.5491.2520.553 - 2.84&gt;19 RM2041.38102.31224.20.00230.1800.0599 - 0.543Total55635.810747.944933.40.00490.7070.567 - 0.882p-value (Log-rank)&lt;0.00010.0249&lt;0.0001
Citation Format: Richard K. Yang, Peng Wang, Fatima Z. Jelloul, Mark J. Routbort, Scott Kopetz, Kenna R. Shaw, Jack J. Lee, Jiexin Zhang, Hui Chen, Keyur P. Patel, Raja Luthra, Russell R. Broaddus. Prognostic value of tumor mutational burden using a 409 gene NGS panel in cancer patients with advanced stage recurrent or treatment refractory disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3162.