Data Disparities Cloud Treatment Decisions

Poor representation of minority groups in public genomic databases may have a detrimental effect on decisions about which therapies would benefit people from these groups, according to a study published March 19 in npj Precision Oncology. Tumor mutational burden (TMB) is one of several biomarkers used to ascertain whether immunotherapy is likely to be an effective treatment for a particular patient. TMB is a measure of the number of mutations carried by tumor cells compared to normal cells. The most accurate way to count these mutations involves sequencing both the DNA in a person’s cancer cells and DNA from the same person’s noncancerous cells to filter out variants that are part of the person’s baseline genetic makeup. Sequencing of a person’s normal, noncancerous cells is called germline analysis. However, the study’s authors contend that since it’s uncommon for the patient’s DNA to be collected for germline analysis, public germline databases are often used for filtering. The researchers compared TMBs calculated using individual DNA sequencing data with TMBs calculated using databases and found that the latter technique significantly inflated TMBs in tumors from both Black and white patients. However, the inflation was markedly higher for Black patients. “At the level of an individual patient, our findings suggest that when we sequence tumors, it is also important to sequence paired normal tissues to accurately identify differences,” said Aaron Mansfield, a medical oncologist at Mayo Clinic in Rochester, Minnesota, and an author of the paper, in a press release. “At the level of the research community, we need to continue to improve the representation of patients with diverse ancestral backgrounds in reference genome databases.”

Gene Identified That Helps Melanoma to Metastasize to Lungs

A study published March 23 in Communications Biology investigating the means by which melanoma cells metastasize to the lungs has identified a gene that has not previously been linked with cancer as a key factor. Researchers were looking to find cell-surface proteins that help melanoma cells metastasize to the lungs when upregulated. To do so, they used a weakly metastatic mouse melanoma cell line, employing the molecular tool CRISPR to activate the genes that are able to produce cell-surface proteins. One by one, the expression of these genes was raised to see which, if any, increased metastasis when the cells were injected into mice. A gene called LRRN4CL was observed as significantly enhancing the ability of both mouse and human melanoma cells to colonize the lungs of mice. While the focus of the study was melanoma, the researchers also expressed LRRN4CL in colorectal, bladder and breast cancer cells, and observed the same effect. “Our results suggest that reducing the expression of the LRRN4CL gene could help to prevent metastasis to the lungs, which would already make it a potential drug target,” said study co-author Anneliese Speak, a senior scientific manager at the Wellcome Trust Sanger Institute in the United Kingdom, in a press release. “The added bonus is that this gene is expressed at very low levels elsewhere in the body, so hopefully targeting LRRN4CL wouldn’t have severe side effects for patients.”

Keytruda Approved for Esophageal and Gastroesophageal Junction Cancers

On March 22, the Food and Drug Administration approved the immune checkpoint inhibitor Keytruda (pembrolizumab) in combination with platinum and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal junction (GEJ) cancers. The approval is for patients who are not candidates for surgical resection or definitive chemoradiation. Immune checkpoint inhibitors have been approved before for certain people with advanced esophageal and GEJ cancers, but only for patients who have undergone prior treatments. To evaluate the treatment, 749 patients were randomly assigned to take either Keytruda in combination with cisplatin and fluorouracil or a placebo with cisplatin and fluorouracil. Median overall survival was 12.4 months for the patients receiving Keytruda plus chemotherapy, compared with 9.8 months for the patients receiving the placebo plus chemotherapy.​​​​