‘Warm’ Autopsy Suggests Metastatic Melanoma Has Different DNA Landscape Than Early-Stage Disease

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Findings may offer insight into new strategies to tackle skin cancer in patients already treated with a prior line of therapy.

Investigators discovered underlying mechanisms that allow some cancers to evade or become resistant to immunotherapies, according to the results of a translational study of metastatic cutaneous melanoma from the University of California-Los Angeles (UCLA) Jonsson Comprehensive Cancer Center and published in Nature Medicine.

Credit: Evgeniy Kalinovskiy - stock.adobe.com

Credit: Evgeniy Kalinovskiy - stock.adobe.com

“We are taking a much-needed approach to understand cancer-related death, which usually results after the cancer has spread to distant sites, even after treatment with multiple systemic therapies,” said Roger Lo, a UCLA investigator and professor of medicine and molecular and medical pharmacology at the David Geffen School of Medicine at UCLA, in the press release.

Although precision immunotherapies can be an effective treatment against cancer, they are not foolproof. Once-effective immunotherapies can lose efficacy over time in a process called “acquired therapy resistance,” which leads to metastatic disease and patient mortality.

In the current study, investigators performed “rapid” or “warm” autopsies on recently deceased patients with metastatic and terminal cancer to learn more about cancer-related mortality in patients already treated with immunotherapies. Warm autopsies are a type of biopsy performed shortly after death (with patient consent) that is not ethical for a living patient.

The UCLA team collaborated on the study with investigators at Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, and the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, to analyze the DNA and RNA of patients who received an autopsy, focusing on those with melanoma that was caused by mutations of the proto-oncogene B-Raf (BRAF) or NRAS Proto-Oncogene, GTPase (NRAS) gene.

Following the autopsy, the team singled out the traits that distinguished terminal melanoma from early-stage or untreated melanoma, according to lead author Sixue Liu, PhD, a post-doctoral fellow. Some cancers also escape precision treatments by taking advantage of an organ’s environment.

“We need to know how many ways, even within the same patient, the cancer evades these powerful therapies, what underlying processes create ‘new species’ capable of escaping therapies, whether the cancer co-opts different organs to help it spread and resist therapies,” Lo said in the press release.

Traditionally, patients with a BRAF mutation will receive BRAF-targeted therapy or immune checkpoint blockade, whereas patients with NRAS-mutated cancer will receive immunotherapy. However, BRAF-targeted therapy was found to change the mutational profile of melanoma, Liu said. This mutational change suggests that the immunotherapy created defective DNA damage repair processes that can have diagnostic or therapeutic implications, according to the study.

“Warm autopsies represent a unique, precious, and humbling opportunity that allows for our deceased patients to ‘talk’ and guide next generations of treatments, such that future patients suffer less and live longer,” said Stergios Moschos, associate professor of medicine and leading figure of the rapid autopsy program at the University of North Carolina at Chapel Hill, in a recent press release. “This study puts a sharp focus on alternative strategies to make the cancer visible to our body’s anti-tumor immune system.”

Reference

University of California—Los Angeles Health Sciences. In a ‘rapid autopsy’ study, UCLA researchers identify lethal molecular alterations after present-day therapies fail patients with metastatic melanoma. News Release. April 27, 2023. Accessed on May 8, 2023. https://www.eurekalert.org/news-releases/987128

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