Dr Fakih on Navigating Pitfalls With Liquid vs Tissue Biopsy in CRC

“One of the things that we cautioned about is [using] liquid TMB to give a patient pembrolizumab. Pembrolizumab has an approval for any TMB of more than 10 [mutations per megabase] based on tissue TMB…and across the board, liquid TMB is typically higher than tissue TMB.”

Marwan G. Fakih, MD, a professor in the Department of Medical Oncology & Therapeutics Research, associate director of Clinical Sciences, and division chief of GI Medical Oncology at City of Hope, discussed the critical importance of understanding the concordance—and the potential for conflict—between liquid and tissue biopsies in colorectal cancer (CRC).

At the 11th Annual School of Gastrointestinal Oncology®, an event held by Physicians’ Education Resource, LCC, Fakih delivered a presentation on concordance of liquid and tissue biopsy in CRC and detailed several case studies to illustrate the advantages vs limitations of using either method.

A central focus of the discussion was the risk of misinterpreting tumor mutational burden (TMB). Fakih issued a specific caution against utilizing liquid-based TMB results to determine eligibility for pembrolizumab (Keytruda). He reiterated that the FDA approval for pembrolizumab in TMB-high malignancies—defined as 10 mutations per megabase or higher—was specifically predicated on tissue TMB data from the phase 2 KEYNOTE-158 trial (NCT02628067)

Fakih highlighted that liquid TMB values are typically higher than tissue-based counts, often due to the development of subclonality. When patients undergo long-term systemic chemotherapy or targeted therapies, the resulting selective pressure can create diverse tumor subpopulations that artificially drive up the liquid TMB, he explained. Fakih also noted instances where patients presented with a liquid TMB of 30, although a concurrent tissue biopsy revealed a TMB of only 5. These patients generally do not respond to immunotherapy and should not be treated with such agents based solely on liquid TMB. Ultimately, Fakih emphasized that recognizing these pitfalls is essential for ensuring that biomarker-driven treatment decisions remain accurate and effective for patients with CRC.