Age, Cancer Type May Determine Tumor Mutation Load

A new study has found that high tumor mutation load is associated with older age, absence of oncogenic mutations, and presence of tumor suppressor gene mutations.

Measuring tumor mutation load (TML) may improve clinical outcomes by helping clinicians better identify those patients who would benefit most from immunotherapy. A new study has found that high TML is associated with older age, absence of oncogenic mutations, and presence of tumor suppressor gene mutations.

Researchers at Georgetown Lombardi Comprehensive Cancer Center assessed 8,020 tumors from 14 different cancers using somatic nonsynonymous missense mutations sequenced with a 592-gene panel. By employing this type of advanced gene sequencing technique, the investigators were able to determine the TML for each tissue sample and catalogue which genes were most frequently mutated in the samples.

They found that TML was highest in melanoma, non–small-cell lung cancer (NSCLC), and bladder cancer. The lowest levels were found in prostate cancer, pancreatic adenocarcinoma, and renal cell carcinoma. The numbers were significantly varied with melanoma (36%) far surpassing NSCLC (15%), bladder cancer (15%), and anal cancer (9%). The levels were vastly lower in prostate cancer (1.6%) and RCC (0.5%).

“One of our more interesting findings was the fact that mutation load increased with age in many cancers,” said principal study investigator, Mohamed Salem, MD, who is an assistant professor of medicine at Georgetown Lombardi, Washington, DC. “Older age correlated closely with TML in most of the cancers we examined, but in some cancers, such as bladder cancer, there was no correlation by age, which also makes for an important observation in a difficult to treat type of cancer.”

In this new era of ever expanding numbers of immunotherapies, there is a growing need for biomarkers to better identify which patients may benefit the most from individual immunotherapies. TML is proposed as a potential predictive biomarker due to its association with tumor immunogenicity.

This current investigation found that primary NSCLC carried lower levels of TML than its brain metastases (11 vs 16). In addition, older age was found to be associated with higher TML in melanoma, colorectal cancer, breast cancer, and NSCLC. The researchers also found that higher TML was seen in males when compared to females for melanoma and NSCLC.

Salem said the observation that melanoma had the highest TML may help explain why melanoma responds well to immunotherapy. It was also shown that high TML often occurs in tumors lacking well-known cancer-related genes, such as BRAF or NRAS genes in melanoma, and EGFR or ALK genes in NCLC. He said this suggests that immune checkpoint inhibitors may be particularly effective in patients who are not candidates for common targeted therapies in these types of cancer.

Salem said the next steps will be to validate and correlate TML levels with outcomes in patients who have received immunotherapy. He said TML levels may be something that can be measured at baseline and throughout therapy. This could be very useful in designing clinical trials for many types of cancer.   

The study findings were released on May 17, 2017, and additional details will be presented at the upcoming American Society of Clinical Oncology (ASCO) annual meeting in Chicago.