title: Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set.
abstract: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements.
  
  
  
  We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method.
  
  
  
  PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R2= 0.73 and R2= 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts).
  
  
  
  The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA. jroszik@mdanderson.org.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. jroszik@mdanderson.org.
authors: Jason
authors: J
authors: Roszik
authors: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Lauren E
authors: LE
authors: Haydu
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Kenneth R
authors: KR
authors: Hess
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA.
authors: Junna
authors: J
authors: Oba
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Aron Y
authors: AY
authors: Joon
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Alan E
authors: AE
authors: Siroy
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Tatiana V
authors: TV
authors: Karpinets
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Francesco C
authors: FC
authors: Stingo
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Veera
authors: V
authors: Baladandayuthapani
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Michael T
authors: MT
authors: Tetzlaff
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.|Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Jennifer A
authors: JA
authors: Wargo
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Ken
authors: K
authors: Chen
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA.
authors: Marie-Andrée
authors: MA
authors: Forget
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA.
authors: Cara L
authors: CL
authors: Haymaker
authors: Lion Biotechnologies, Woodland Hills, CA, 91637, USA.
authors: Jie Qing
authors: JQ
authors: Chen
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.|Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 770393, USA.
authors: Funda
authors: F
authors: Meric-Bernstam
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Agda K
authors: AK
authors: Eterovic
authors: Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 770393, USA.
authors: Kenna R
authors: KR
authors: Shaw
authors: Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, 770393, USA.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Gordon B
authors: GB
authors: Mills
authors: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Jeffrey E
authors: JE
authors: Gershenwald
authors: EMD Serono, Rockland, MA, 02370, USA.
authors: Laszlo G
authors: LG
authors: Radvanyi
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA.
authors: Patrick
authors: P
authors: Hwu
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: P Andrew
authors: PA
authors: Futreal
authors: Department of Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Don L
authors: DL
authors: Gibbons
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Alexander J
authors: AJ
authors: Lazar
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA.
authors: Chantale
authors: C
authors: Bernatchez
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors: Michael A
authors: MA
authors: Davies
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 904, Houston, TX, 77030, USA. swoodman@mdanderson.org.|Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. swoodman@mdanderson.org.
authors: Scott E
authors: SE
authors: Woodman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D000465:Algorithms; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D015331:Cohort Studies; D059472:Exome; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016219:Immunotherapy, Adoptive / Q000379:methods; D000074324:Ipilimumab; D008175:Lung Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D009154:Mutation; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D047368:Tumor Burden / Q000235:genetics; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab
keywords: CTLA-4; Immunotherapy; Lung cancer; Melanoma; PD-1; Total mutation load