Now, a new discovery holds promise for people with advanced melanoma skin cancer: inheriting a certain version (or variant) of the apolipoprotein E (APOE) gene may help prevent cancer from spreading (metastasizing) to other parts of the body, and even boost the effects of immunotherapy treatment. The research, published May 25, 2020, in the journal Nature Medicine, is in its early stages, but offers the first evidence that inherited genes are able to drive cancer’s spread. RELATED: Speaking Genetics: A Glossary of Cancer Risk Gene Mutations
The Different APOE Gene Variants and Disease Risk
After discovering that the APOE gene interfered with processes needed for cancer progression, (such as blocking the assault from tumor-fighting immune cells, or the formation of blood vessels to feed the tumor), Rockefeller University researchers began to speculate how different APOE gene variants might explain why cancer progresses in some people versus others. To address this question, lead study investigator Benjamin Ostendorf, MD, PhD, a post-doc fellow at Tavazoie Laboratory in New York City, explains his team first introduced human melanoma cells into mice carrying three APOE gene variants:
APOE2, which is carried by 14 percent of the population and is linked to reduced risk for Alzheimer’s diseaseAPOE3, which is carried by 60 percent of the population and not associated with any disease riskAPOE4, which is carried by 25 percent of the population and is strongly linked with increased Alzheimer’s disease risk
“We discovered that the mice with the APOE4 variant had the best protection against melanoma progression versus mice carrying the APOE2 variant,” says Dr. Ostendorf, adding that these mice also had greater anti-cancer immune responses. To see if these findings would translate to human patients, the team then analyzed genetic data from 365 patients with advanced melanoma, some of whom were also receiving immunotherapy. Not only did patients carrying APOE4 variants have almost fivefold longer survival times compared with patients with the APOE2 variant (approximately 10 versus approximately 2 years), they also responded better to immunotherapy. RELATED: Types of Skin Cancer: Do You Know How to Spot Them?
Differences Most Pronounced in High-Risk Melanoma Patients
Skin cancer is the most common type of cancer affecting Americans, and cases appear to be increasing yearly, according to the American Cancer Society, possibly as a result of better detection, more sun exposure, and the aging population. While most skin cancers are benign, about 1 percent are melanomas and the leading cause of skin cancer deaths. In 2020, an estimated 100,350 new cases of invasive melanoma will be diagnosed and an estimated 6,850 deaths are expected, according to the American Cancer Society’s 2020 statistics. When it comes to APOE4, this high risk for complications and death in late stage melanoma matters. Ostendorf explains that patients with the APOE4 gene variants at low-risk for melanoma progression did not experience the same improved survival rates seen in high-risk peers. While the presence of APOE4 can be detrimental in the general population — due to its predisposition to Alzheimer’s and cardiovascular disease — people with advanced melanoma appear to benefit from the enhanced immune response that APOE4 offers. RELATED: Skin Cancer: Where to Turn for Information and Help
Out of the Lab and Into the Doctor’s Office
Genetic testing is already a component of management in late-stage melanoma, says Eric Whitman, MD, surgical oncologist and founding director of Atlantic Melanoma Center in Morristown, New Jersey. For example, clinicians routinely test for a type of gene mutation called BRAF, that can help determine if and how certain patients will respond to treatments that target it. Dr. Whitman notes that moving forward, genetic testing of both the tumor itself as well as of the patients — as observed in the APOE gene study — are likely to become essential aspects of all types of cancer management and not just melanoma. This contention is already bearing fruit. “We’re interested in looking at how APOE potentially modulates outcomes in breast and other cancers so that we can better understand how different forms of APOE behave,” says Sohail Tavazoie, MD, PhD, Leon Hess Professor at The Rockefeller University and senior attending physician (as well as the study’s coauthor). Dr. Tavazoie explains that an experimental drug called RGX-104 (which has already been shown to increase tumor-fighting activity in mice by increasing levels of APOE) is currently being tested in people with advanced cancers. (Disclosure: Tavazoie is scientific cofounder of Rgenix, the company that developed RGX-104.) “APOE represents a precision medicine genetic predictor of a treatment for metastatic disease associated both with response to a drug, and also survival “ says Tavazoie. Rgenix is conducting genotyping in patients to determine their APOE status and using that to determine who will respond well to RGX-104. Both Rgenix and Tavazoie’s laboratory are also interested in further collaborating with melanoma specialists and dermatologists to learn if genetics can be harnessed at diagnosis to identify patients at highest risk for cancer spread and poor survival. RELATED: What to Know Before You Buy an At-Home Genetic Cancer Risk Test
What Does the Future Hold?
These great strides in cancer genetics are exciting but the researchers caution that genes —inherited or mutated — are not the total solution. Melanoma patients should continue to adhere to recommended lifestyle and behavioral modifications integral to cancer management, such as reducing sun exposure, diet, and exercise. Ostendorf also encourages melanoma patients to donate tissue or blood samples to their clinicians if they are currently participating in clinical research. The American Association of Tissue Banks offers a geographical search engine that enables users to identify tissue banks by state, or people with all types of cancer can check out the Broad Institute’s Count Me In project. Finally, Whitman wants to remind cancer patients that APOE is not yet a clinical reality and the only way to pursue genetic testing for it is within the context of a research study. Still, the future holds a lot of promise for cancers like melanoma and breast — both of which are associated with recurrence many years or decades after remission. For now, researchers finally have an answer as to why melanoma cancer might spread in some patients and not others.
