Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors.

The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown.

Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors. TMB estimates from tumor-only panels substantially overclassified individuals into the clinically important TMB-high group due to germline contamination, and this bias was particularly pronounced in patients with Asian/African ancestry. Among patients with non-small cell lung cancer treated with ICIs, those misclassified as TMB-high from tumor-only panels did not associate with improved outcomes. TMB-high was significantly associated with improved outcomes only in European ancestries and merits validation in non-European ancestry populations. Ancestry-aware tumor-only TMB calibration and ancestry-diverse biomarker studies are critical to ensure that existing disparities are not exacerbated in precision medicine.

Cancer cell. 2022 Sep 29 [Epub]

Amin H Nassar, Elio Adib, Sarah Abou Alaiwi, Talal El Zarif, Stefan Groha, Elie W Akl, Pier Vitale Nuzzo, Tarek H Mouhieddine, Tomin Perea-Chamblee, Kodi Taraszka, Habib El-Khoury, Muhieddine Labban, Christopher Fong, Kanika S Arora, Chris Labaki, Wenxin Xu, Guru Sonpavde, Robert I Haddad, Kent W Mouw, Marios Giannakis, F Stephen Hodi, Noah Zaitlen, Adam J Schoenfeld, Nikolaus Schultz, Michael F Berger, Laura E MacConaill, Guruprasad Ananda, David J Kwiatkowski, Toni K Choueiri, Deborah Schrag, Jian Carrot-Zhang, Alexander Gusev

Department of Hematology/Oncology, Yale New Haven Hospital, New Haven, CT 06510, USA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA., Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA., Center for Prevention of Progression of Blood Cancers, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Urologic Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Melanoma Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, 1275 York Avenue, New York, NY 10065, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: .

Read an Expert Commentary by Bishoy Faltas, MD

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