Machine-learning driven strategies for adapting immunotherapy in metastatic NSCLC.

Journal: Nature communications
Published Date:

Abstract

Immune checkpoint inhibitors (ICIs), either as monotherapy (ICI-Mono) or combined with chemotherapy (ICI-Chemo), improves survival in advanced non-small cell lung cancer (NSCLC). However, prospective guidance for choosing between these options remains limited, and single-feature biomarkers like PD-L1 prove inadequate. We develop a machine learning model using clinicogenomic data from four cohorts (MD Anderson n = 750; Mayo Clinic n = 80; Dana-Farber n = 1077; Stand Up To Cancer n = 393) to predict individual benefit from adding chemotherapy. Benefit scores are calculated using five distinct functions derived from 28 genomic and 6 clinical features. Our integrated model, A-STEP (Attention-based Scoring for Treatment Effect Prediction), estimates heterogeneous treatment effects and achieves the largest reduction in 3-month progression risk, improving weighted risk reduction by 13-23% over stand-alone models. A-STEP recommends treatment changes for over 50% of patients, most often favoring ICI-Chemo. In simulation on external cohort, patients treated in accordance with A-STEP recommendations show improved 2-year progression-free survival (HR = 0.60 for ICI-Mono treatment arm; HR = 0.58 for ICI-Chemo treatment arm). Predictive features include FBXW7, APC, and PD-L1. In this study, we demonstrate how machine learning can fill critical gaps in immunotherapy selection for NSCLC, by modeling treatment heterogeneity with real-world clinicogenomic data, driving precision medicine beyond conventional biomarker boundaries.

Authors

  • Maliazurina B Saad
    Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Qasem Al-Tashi
    Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Lingzhi Hong
    Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Vivek Verma
    Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Wentao Li
    State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, Hubei, People's Republic of China.
  • Daniel Boiarsky
    Division of Medical Oncology, Yale University School of Medicine, New Haven, CT, USA.
  • Shenduo Li
    Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
  • Milena Petranovic
    Department of Radiology, Massachusetts General Brigham and Harvard Medical School, Boston, MA, USA.
  • Carol C Wu
    University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Brett W Carter
    Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Girish S Shroff
    Department of Thoracic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Tina Cascone
    Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA.
  • Xiuning Le
    Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Yasir Y Elamin
    Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Mehmet Altan
    Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • Simon Heeke
    Laboratoire de pathologie clinique et expérimentale/biobanque (BB 0033-00025), Fédération hospitalo-universitaire OncoAge, CHU de Nice, université Côte-d'Azur, 30, voie Romaine, 06000 Nice, France; Équipe 4, CNRS UMR7284, Inserm U1081, faculté de médecine, institut de recherche sur le cancer et le vieillissement de Nice (Ircan), 28, avenue de Valombrose, 06107 Nice, France.
  • Ajay Sheshadri
    Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Joe Y Chang
    Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Percy P Lee
    Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Radiation Oncology, City of Hope National Medical Center, Los Angeles, CA, USA.
  • Zhongxing Liao
    Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Don L Gibbons
    Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ara A Vaporciyan
    Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • J Jack Lee
    Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Ignacio I Wistuba
    Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX.
  • Cara Haymaker
    Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Seyedali Mirjalili
    Centre for Artificial Intelligence Research and Optimisation, Torrens University Australia, Fortitude Valley, Brisbane, QLD, 4006, Australia; Yonsei Frontier Lab, Yonsei University, Seoul, South Korea; King Abdulaziz University, Jeddah, Saudi Arabia. Electronic address: ali.mirjalili@gmail.com.
  • David Jaffray
    Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada.
  • Justin F Gainor
    Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Yanyan Lou
    Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA.
  • Alessandro Di Federico
    Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Federica Pecci
    Clinica Oncologica, Università Politecnica delle Marche, AOU delle Marche, Ancona, Italy.
  • Mark Awad
    Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Biagio Ricciuti
    Dana-Farber Cancer Institute, Boston, MA, USA.
  • John V Heymach
    Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Natalie I Vokes
    Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • Jianjun Zhang
    Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA.
  • Jia Wu