Tissue TMB Outperforms Blood-Based Testing for Predicting Immunotherapy Response, Cleveland Clinic Study Confirms
Key Insights
A Cleveland Clinic study of 221 solid tumor patients found tissue TMB (tTMB) is a more reliable predictor of immunotherapy response than blood TMB (bTMB), which runs a median 2.3 times higher.
Patients with high tTMB but low bTMB had the best outcomes with a median time-to-treatment failure of 21.3 months, while those with high bTMB but low tTMB had only 7 months.
Researchers caution that relying solely on bTMB may mislead clinical decisions, even when the bTMB threshold is raised from 10 to 16 mut/Mb.
A new study from Cleveland Clinic researchers confirms that tissue-derived tumor mutational burden (search) (tTMB) remains the more reliable predictor of immunotherapy response in patients with solid tumors, challenging the growing reliance on less invasive blood-based testing. Results were presented at the 2026 ASCO Annual Meeting (Abstract 2580).
"This is really a cautionary tale," said Suneel Kamath, MD, staff oncologist in the Department of Hematology and Medical Oncology at Cleveland Clinic Cancer Institute and senior author of the abstract. "The bottom line is that if you have a tumor-agnostic indication for high TMB, you should rely on tissue TMB to guide immunotherapy decisions—even if you're tempted to use blood TMB as a last resort."
The Growing Role of TMB as a Biomarker
TMB measures the total number of somatic mutations present in tumor DNA. Tumors with high mutation counts are considered more recognizable to the immune system, making them more likely to respond to immune checkpoint inhibitors such as pembrolizumab. The U.S. Food and Drug Administration has approved a tTMB threshold of 10 or more mutations per megabase (mut/Mb) as a tumor-agnostic biomarker for pembrolizumab.
Blood-based TMB (bTMB), derived from circulating tumor DNA through liquid biopsy, has been proposed as a less invasive alternative, particularly for patients who cannot easily undergo repeat tissue biopsies. However, current ASCO guidelines recommend against using bTMB alone, in part because the two measurements do not always agree.
Study Design and Key Findings
Researchers analyzed 221 patients with solid tumors from the Cleveland Clinic genomics repository who had at least one tTMB and one bTMB result between July 2019 and July 2025. Among those patients, 80 received immune checkpoint inhibitors and were included in the outcomes analysis.
The study confirmed that bTMB runs consistently higher than tTMB—a median of 2.3 times higher in matched samples, consistent with prior reports. Despite that gap, the two measurements showed a strong positive correlation across both the full cohort and the immunotherapy-treated subgroup (R² = 0.82 and 0.85, respectively).
"The more clinically significant finding was what we saw when the two tests disagreed," noted Dr. Kamath. Patients with high tTMB but low bTMB had a median time-to-treatment failure of 21.3 months, which was the best outcome of any subgroup. Patients with high bTMB but low tTMB fared considerably worse, with a median of just 7 months, even after raising the bTMB threshold from 10 to 16 mut/Mb.
"A high tissue TMB is what truly matters for predicting a positive outcome with immunotherapy," Dr. Kamath explained. "When we looked at people with high tissue TMB but low blood TMB, they had better outcomes than even the group with both high blood and high tissue TMB. That was unexpected."
Raising the bTMB threshold from 10 to 16 mut/Mb did improve median time-to-treatment failure from 3.5 to 7 months among patients with low tTMB, but those results still lagged significantly behind outcomes in high tTMB patients.
Clinical Implications and Cautions
Dr. Kamath noted that liquid biopsies are often ordered late in a patient's treatment journey, when standard options have been exhausted and the original tissue sample may be several years old. That clinical scenario can make bTMB appealing as a decision-making shortcut. The study's findings, however, suggest that shortcut may mislead more than it guides.
"Relying solely on a high blood TMB without a high tissue TMB does not yield a significant benefit," he said. "Even when you raise the cutoff for blood TMB, you're still not capturing the patients who truly respond well."
Ultra-High TMB in Breast Cancer (search): A Parallel Finding
A separate real-world study examining TMB in breast cancer (search) provides complementary insights. Among 2,049 patients with clinically advanced breast cancer who underwent comprehensive genomic profiling, only 2.2% (45 patients) had ultra-high TMB, defined as at least 20 mutations per megabase. The median TMB in this ultra-high group was 26.3 mut/Mb, compared with 2.5 mut/Mb in tumors below the 20 mut/Mb threshold.
Ultra-high TMB breast cancers were more likely to be estrogen receptor-positive (86.6% versus 68.2%), invasive lobular carcinoma (40.0% versus 14.5%), and enriched for PIK3CA mutations (81.8% versus 37.9%) and CDH1 alterations (45.5% versus 12.3%).
Among patients with hormone receptor-positive/HER2-negative advanced breast cancer (search) receiving single-agent immunotherapy, those with ultra-high TMB demonstrated longer median time to next treatment (4.9 months versus 2.6 months), progression-free survival (3.5 months versus 1.7 months), and real-world overall survival (14.1 months versus 3.2 months). The real-world overall survival difference yielded a hazard ratio of 0.37 for ultra-high TMB compared with TMB below 10 mut/Mb.
Notably, this survival advantage was not observed in patients treated with chemotherapy, suggesting ultra-high TMB may be predictive of immunotherapy benefit rather than simply a marker of better prognosis.
Next Steps and Future Research
Dr. Kamath and his team plan to expand their study by partnering with larger next-generation sequencing companies to analyze paired blood and tissue TMB data across a significantly larger patient population. The next phase will examine results by individual tumor type rather than across multiple solid tumor types.
"These findings may not be a monolithic tale that applies to every cancer," Dr. Kamath said. "The vision in precision oncology is to treat tumors based on their mutations regardless of where they originate. But the evidence, including these differential TMB cutoffs, tells us we're not quite there yet."
Until larger, tumor-specific studies are completed, the clinical message is straightforward: when tTMB is available, use it.