Dr. Elli Papaemmanuil is part of a team studying the link between clonal hematopoiesis and worse cancer outcomes.
Doctors and scientists have known for nearly a decade that a precancerous blood condition called clonal hematopoiesis (CH) is present in one in three patients with solid tumors and is associated with poor cancer outcomes. People with CH are less likely to respond to treatment and are more likely to develop a secondary leukemia related to chemotherapy. But it was not known whether CH actually caused patients to do worse or whether it was just more likely to be present in patients who have worse outcomes.
Now for the first time, a collaborative team including researchers from Memorial Sloan Kettering Cancer Center (MSK) and the Francis Crick Institute in London has shown that there may be a direct link between CH and cancer outcomes. The study shows that in some patients, CH-derived blood cells migrate to the tumor, a phenomenon called tumor-infiltrating clonal hematopoiesis (TI-CH).
The study found that patients with TI-CH — but not those with CH alone — are the ones who have worse outcomes. This discovery offers a new perspective for understanding the biology of tumors, including how they grow, spread, and respond to treatment. The findings were published April 24 in the New England Journal of Medicine (NEJM).
“This is important not only because we now have a new biomarker that helps us identify which cancer patients are at most risk, but it also opens up a whole new field of research that so far has been underappreciated,” says MSK molecular geneticist Elli Papaemmanuil, PhD, co-senior author of the NEJM paper. “We know that cancer behavior is influenced by a number of different factors. Our new data suggest that an age-associated phenomenon in the blood has a direct effect on how tumors develop and likely how they respond to treatment.”
The findings are especially significant for patients with lung cancer, but are relevant for all cancer types.
What Is Clonal Hematopoiesis and Why Is It Important?
CH occurs when a subset of hematopoietic stem cells (the cells that give rise to all types of blood cells) acquire genetic mutations that give them a growth advantage. These mutated cells expand over time and enter the bloodstream. CH becomes more common with age, affecting about 10% of people over 65.
In addition to being linked to poor prognosis and secondary leukemias in people with cancer, CH is associated with an increased risk of cardiovascular disease, heart attacks, and strokes.
How Common Is Tumor-Infiltrating Clonal Hematopoiesis in Patients?
In the new study, the researchers used data from the tumor genomic test MSK-IMPACT® to evaluate 49,351 MSK patients with more than 75 types of cancer. They found that about one in four patients with CH also had TI-CH. This means that TI-CH affects more than 6% of all cancer patients.
The study also revealed that TI-CH is especially common in people with lung cancer. “About one in eight lung cancer patients have TI-CH,” Dr. Papaemmanuil says. “Lung cancer patients with TI-CH are much less likely to respond to treatment and are more likely to have aggressive disease.”
Why Tumor-Infiltrating Clonal Hematopoiesis Makes Tumors More Aggressive
This study shows for the first time that CH may have a direct role in how lung and other cancers progress and respond to treatment.
Dr. Elsa Bernard is a former postdoc in the Papaemmanuil lab.
The discoveries came about when Elsa Bernard, PhD, then a postdoctoral fellow studying blood cancers in the Papaemmanuil lab, was conducting research as a visiting fellow in the lab of Charles Swanton, MD, PhD, at the Crick Institute. Dr. Bernard, now a scientist at the Gustave Roussy Institute in France, is co-first author of the NEJM paper alongside Oriol Pich, MD, PhD, and Maria Zagorulya, PhD, both postdoctoral fellows in Dr. Swanton’s lab. Dr. Swanton is co-senior author of the study.
In this study, research in the Swanton lab showed that lung cancer tumors in patients with CH were enriched with a specific type of blood cells known as myeloid cells. Follow-up experiments confirmed that these myeloid cells originated from CH blood cells, providing clear evidence of TI-CH. The presence of TI-CH was a strong predictor of how aggressive a cancer would be.
Then, using data from MSK-IMPACT, Dr. Bernard, Dr. Papaemmanuil, and their team found that 26% of cancer patients with CH had TI-CH. Further, they showed that mutations in a specific gene called TET2 strongly predicted the likelihood of TI-CH. The TET2 protein plays a crucial role in regulating the function of immune cells and controlling inflammation.
“Given the prevalence of this age-associated phenomenon and its link to poor patient outcomes, it is fundamental to understand how CH-derived immune cells influence tumor initiation and progression,” Dr. Bernard says.
Additional research in collaboration with Dominique Bonnet, PhD, at the Crick Institute showed that when lung cancer organoids were cultured with myeloid cells that contained the TET2 mutation, the lung tumor cells grew faster. Organoids are mini models of lung tumors grown in a dish.
What Is MSK Doing to Help People With Clonal Hematopoiesis?
Based on findings about the risks of CH, MSK launched a clonal hematopoiesis clinic in 2018 to follow patients with CH. It was the first such program in the country.
The clinic offers people previously treated for cancer at MSK regular monitoring and tests to check for blood disorders, including early signs of blood cancer. CH clinic patients also meet with a cardiologist to be screened for cardiovascular disease risk.
“As we learn more about the link between CH and cancer, we hope to eventually develop new treatments that are more effective against the interplay of TI-CH, tumor progression, and treatment response,” Dr. Papaemmanuil says.
