Disruptions in hematopoiesis, such as monoclonal gammopathy of unknown significance, often herald the onset of hematologic malignancies. With rapidly growing evidence of the role of the immune system in surveillance for oncogenesis in tissues, we now appreciate that hematopoietic disruption could be prognostic in solid tumors. Age-related clonal hematopoiesis of indeterminate potential (CHIP), a condition that involves the expansion of blood cells derived from a somatically mutated hematopoietic stem cell, correlates not only with hematologic cancers and chronic inflammatory diseases, but also with lung cancer incidence. CHIP has also been associated with reduced survival in patients with other solid tumors. The potential relationship between cancer outcomes and the presence of CHIP mutations with high variant allele frequencies (VAFs) within tumors, termed tumor-infiltrating clonal hematopoiesis (TI-CH), was evaluated in a study published earlier this year in the New England Journal of Medicine.
The study included an initial cohort of 421 patients with previously untreated stage IA through IIIA non-small cell lung cancer (NSCLC) from the TRAcking Non-small Cell Lung Cancer Evolution Through Therapy (TRACERx) study. The results were then validated in patient data from the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) pan-cancer cohort of nearly 50,000 patients across 75 cancer types. Among the patients with NSCLC from TRACERx, 34% were found to have CHIP mutations, with a median VAF of 5%. Recurrence-free and overall survival were shorter among patients with CHIP mutations compared with those without. Interrogation of the MSK-IMPACT database found that in patients with CHIP, the respective CHIP mutation was also detected in tumor samples in 96% of cases. Moreover, samples from their primary tumors had higher proportions of myeloid cells than those from patients without CHIP mutations. NSCLC was enriched for CHIP overall compared with other tumor types, with equal prevalence among patients with adenocarcinoma and squamous cell carcinoma. In contrast, patients with colorectal cancer or renal cell carcinoma had a reduced likelihood of CHIP.
In the MSK-IMPACT database, TI-CH was detected in 26% of patients with CHIP and was most common in NSCLC, head and neck cancer, pancreatic cancer, and mesothelioma. In contrast, prostate, endometrial, ovarian cancer, and SCLC were associated with reduced likelihood of TI-CH. There was a higher prevalence of TI-CH among patients with lung cancer who had squamous cell carcinomas vs adenocarcinoma, suggesting potential histology-specific differences in the tumor immune microenvironments. In all lung cancer types evaluated, TI-CH was an independent predictor of shorter recurrence-free and overall survival, risk of death from any cause, lung-cancer-related death, and tumor recurrence or new primary lung cancer. A subsequent Letter to the Editor in New England Journal of Medicine on 3,255 patients with late-stage cancer with matched blood and tissue next-generation sequencing results from a large pan-cancer biorepository confirmed the correlation between TI-CH and poor prognosis in a broad range of late-stage tumors.
High level
This study observed that TI-CH independently predicted higher risk of death or recurrence in NSCLC, as well as increased mortality in patients with solid tumors. Further, TI-CH correlated with higher proportions of myeloid cells, suggesting remodeling of the tumor microenvironment through alterations in myeloid responses. While further studies are needed to better understand the clinical utility and predictive potential of TI-CH, these data support the role that age-related clonal hematopoiesis plays in lung cancer development, progression, and prognosis. This parameter could be integrated into further clinical studies, especially those enrolling elderly patients with lung cancer.
Ground level
This study confirmed the prognostic value of TI-CH relative to blood-only CHIP, suggesting that the effect of TI-CH on outcomes is not merely due to clonal expansions in the blood. The potential for the degree of CHIP-derived tumor infiltration to influence disease outcomes will likely be the topic of much additional study in the next few years. Given the aging population, this age-associated condition may have implications for how we communicate patient outcome expectations. If further research supports the correlation, CHIP and TI-CH may be incorporated into cancer diagnostics, especially for patients with lung cancer.
