Mega Doctor News
By University of Texas MD Anderson Cancer Center
Newswise – A new study led by researchers at The University of Texas MD Anderson Cancer Center shows that a specific subset of mutations in the POLE gene is strongly associated with durable responses to immunotherapy in patients with metastatic colorectal cancer (CRC).
This type of mutation, called loss-of-proofreading (LOP) mutations, affects specific functions of the POLE protein. These findings, published in The Journal for ImmunoTherapy of Cancer, may help identify and predict which patients benefit from immune checkpoint therapy, avoiding potentially ineffective treatments for those with non-LOP POLE mutations.
What did the study find and why is this important for patients with colorectal cancer?
Researchers led by John Paul Shen, M.D., assistant professor in Gastrointestinal Medical Oncology, and Giulia Maddalena, M.D., Ph.D., former graduate student and attending physician, wanted to understand why some patients with CRC respond extremely well to immunotherapy while others do not.
POLE mutations have been proposed as a biomarker for immunotherapy responses, but it remained unclear which mutations were associated with benefit. The researchers found that while POLE mutations are relatively rare, patients with the LOP subtype demonstrated high objective response rates and tumor shrinkage.
“Not all POLE mutations behave the same. By refining how we classify POLE subtypes, we can better select patients who will experience the most meaningful benefit from immune checkpoint therapy,” Shen said.
The study retrospectively analyzed 69,223 patients across tumor types using data from cBioPortal and a clinical cohort of 11 patients treated at MD Anderson. They found that while 2.8% of tumors across cancer types carried POLE mutations, just 0.1% harbored LOP variants.
In the clinical cohort, nine CRC patients with LOP POLE mutations responded well to immunotherapy, achieving an 88.9% overall response rate and 100% disease control rate. On the other hand, patients with non-LOP POLEmutations did not experience similar benefits.
What does this mean for colorectal cancer patients considering immunotherapy?
Although rare, patients with CRC benefit from identifying the exact type of POLE mutation they might carry. Those with LOP POLE mutations may have a more favorable response to immunotherapy than other standard-of-care treatments. Similarly, those with other mutations may be able to avoid receiving therapies that will not provide substantial benefit.
These findings reinforce the benefits of tumor sequencing to help guide treatment planning, improve clinical trials, and devise more personalized treatments for patients with CRC.
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Funding was supported by the Col. Daniel Connelly Memorial Fund, the Andrew Sabin Family Fellowship Award, the National Cancer Institute (P30 CA016672), the Cancer Prevention & Research Institute of Texas (RR180035 & RP240392), and a Conquer Cancer Career Development Award (2022CDA-7604125121).
