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A First Look at Genetic and Biomarker Testing in the Disease Journey of RARE Registry Participants

By: Precious Ngnosse & Jessica Scales

One major focus of cancer research is genetics–the study of changes in DNA that can drive the development of cancer. These genetic alterations may be inherited (helping to explain why cancer can run in families) or acquired over an individual’s lifetime. One way that physicians may diagnose and characterize cancer in their patients is by using tests that look at changes in DNA–such as gene mutations–that occur in healthy cells (inherited mutations) and cancer cells (acquired mutations). An understanding of these genetic alterations is important for informing cancer risk, diagnosis, prognosis, and treatment.

Compared to cutaneous (skin) melanoma, much less is known about the genetic risk factors (inherited mutations) or genetic tumor biomarkers (acquired mutations) present in patients with rare melanoma subtypes such as acral and mucosal melanoma. To help advance research in this area, the Melanoma Research Alliance (MRA) sponsored the first direct-to-patient registry called RARE to collect information on the patient perspective and disease journey from participants with cutaneous, acral, or mucosal melanoma. Using patient-reported data from the RARE Registry, we have examined for the first time the use of genetic and biomarker testing in the medical journeys of participants diagnosed with cutaneous, acral, or mucosal melanoma.

Genetic Testing: A Closer Look at Inherited Gene Mutations in Melanoma

Genetic testing is used to identify inherited changes in genes of healthy cells that may increase an individual’s risk for developing specific types of cancer. For a subset of melanomas, inherited changes in genes may increase an individual’s lifetime risk of developing the disease.

Given the importance of genetic testing in assessing melanoma risk and the RARE Registry’s goal of advancing knowledge about hereditary melanoma across all subtypes, we looked at the use of genetic testing by participants enrolled in RARE (Figure 1).

Among participants diagnosed with acral, cutaneous, or mucosal melanoma, between 24% to 32% reported having genetic testing. Of these participants, genetic testing results revealed the presence of inherited gene mutations, including nearly 42% of participants with cutaneous melanoma. Genetic testing showed that inherited mutations in cancer risk genes were overlapping yet distinct across the three melanoma subtypes. For all melanoma subtypes, participants accessed genetic testing most frequently through a hospital laboratory, followed by genetic testing companies like Ambry and Invitae.

Tumor Biomarker Testing: Decoding Your Melanoma

One type of tumor biomarker testing looks at the genetic changes in DNA or genes present in cancer cells (acquired mutations) and helps physicians to understand more about a patient’s specific cancer, including prognosis and personalized treatments. Studies of genetic tumor biomarkers in acral and mucosal melanomas are emerging: these rare subtypes have been found to harbor fewer acquired mutations and have distinct mutational profiles compared to cutaneous melanomas.

RARE Registry participants were asked whether their melanoma tumors had biomarker testing performed that specifically looked for acquired (not inherited) gene mutations in the DNA of melanoma tumor cells. For patients with melanoma, understanding the genetic changes acquired by the tumor cells is important for making treatment decisions.

In the RARE registry, participants with mucosal melanoma were the most likely to have had tumor biomarker testing performed (47%), compared to those with acral or cutaneous melanomas (<30%) (Figure 2). Of these participants, tumor biomarkers were identified in 72% of individuals with cutaneous melanoma, compared to approximately 43% of individuals with either acral or mucosal melanoma. Differences in the specific tumor biomarkers found by testing were observed across all three melanoma subtypes. Hospital-affiliated labs were most commonly used for tumor biomarker testing, followed by clinical diagnostic companies like Tempus, Caris, and others.

Blood Biomarker Testing: Monitoring Your Melanoma

Blood biomarker testing measures specific molecules in blood samples (such as DNA) to monitor the progression of an individual’s cancer and responses to particular treatments. This is a newer type of testing that is starting to be used by physicians to monitor how well a treatment is working in patients with cancer.

For RARE registry participants, blood biomarker testing was the least common type of testing performed relative to genetic and tumor biomarker testing with between 11% to 19% of participants having had testing performed (Figure 3). Participants with cutaneous or mucosal melanoma reported the presence of tumor biomarkers showing acquired mutations in cancer risk genes.

Collectively, this initial look at RARE Registry data indicates that this patient-driven platform is valuable for capturing meaningful data across melanoma subtypes, and can enable collaborative efforts between patients and researchers to advance knowledge and use of genetic and biomarker testing in both common and rare melanoma subtypes.

Additional Resources and Ways to Get Involved

These findings represent the first in a series of insights emerging from MRA’s RARE Registry. Interested in participating in the RARE Registry? Learn more about how to become involved in this initiative by visiting raremelanoma.org.

Visit MRA’s dedicated resource pages to learn more about genetic and biomarker testing. If you are interested in genetic and biomarker testing, speak to your healthcare provider about potential options. It is important to ask what information these types of testing can provide, the limitations of such tests, and how testing can impact your current and future care.

An Opportunity to Donate Tissue: MRA Launches New Melanoma Biorepository to Advance Research

The Melanoma Research Alliance (MRA) is excited to announce the launch of a Melanoma Biorepository, a new initiative poised to accelerate melanoma research and improve health outcomes for patients with melanoma.

Participants enrolled in the RARE Registry can now choose to donate tumor and normal tissue samples to the MRA Melanoma Biorepository, which will give qualified researchers access to high-quality specimens for research studies, especially those focused on acral and mucosal melanoma. Participants will also have an opportunity to connect their RARE Registry data with their donated tissue samples.

“The MRA Melanoma Biorepository solves one of the largest barriers to scientific progress for rare subtypes like acral and mucosal melanomas, which is the scarcity of patient samples. By providing timely access to a larger and more genetically diverse pool of patient samples, this resource will help accelerate scientific breakthroughs,” shared Dr. Jessica Scales (MRA’s Associate Director of Rare Melanoma Research).

To learn more about the MRA Melanoma Biorepository and how to donate, please visit our dedicated site, read MRA’s latest blog, or contact biorepository@curemelanoma.org.

Bringing Patient Experience to the Forefront: The MRA’s RARE Registry at JADPRO Live 2025

The MRA highlighted new work on the RARE Registry in a poster presented called, MRA RARE Registry: Inspired by Patient Advocates Working Closely with MRA, which was presented at the 13^th Annual JADPRO Live Conference—the annual meeting for the Advanced Practitioner Society for Hematology and Oncology (APSHO). APSHO’s mission is to improve outcomes and quality of life for patients with cancer by championing a team-based approach to cancer care.

This year’s conference, held at Maryland’s National Harbor, welcomed over 1,600 attendees and centered on the theme “United in Care” to spotlight the power of collaboration among patients, their caregivers, and multidisciplinary care teams in driving progress in cancer care. Paralleling this mission, MRA showcased its efforts to advance rare melanoma research at the JADPRO Annual Meeting, where Dr. Jessica Scales (MRA’s Associate Director of Rare Melanoma Research) shared new findings from the RARE Registry—a patient-powered effort aimed at addressing key knowledge gaps in rare melanoma research to improve patient care, treatments, and outcomes.

Accompanying charts in Dr. Scales’ poster illustrates early findings from the RARE Registry:

Three years after launch, 625 participants have enrolled in the RARE Registry, including 219 with a history of mucosal melanoma, 180 with acral melanoma, and 226 with cutaneous melanoma. “Participant data is powerful for the growth of the RARE Registry, allowing us to perform more robust analyses to learn about the patient experience, how cancer care can be improved, and for informing better treatment options,” said Dr. Scales.

As MRA is working towards publishing an initial report in early 2026, the completion of surveys will play a vital role in generating a more thorough and impactful analysis.

Please click to open MRA's JADPRO poster as a PDF in a new window.

MRA Meet Ups: Acral Melanoma Research Update

MRA Meet-ups are a series of live webinars designed specifically to educate and empower patients and caregivers. Several with specific application for RARE melanomas are showcased below and full repository of recorded MRA Meet Ups can be found here.

The Melanoma Research Alliance’s (MRA) CEO, Dr. Marc Hurlburt hosted Dr. Boris Bastian, a leading melanoma researcher, from the University of California, San Francisco who presented an in-depth overview of the genomic differences between various types of melanomas, with a focus on acral and mucosal melanoma. He explains how melanoma arises from the accumulation of mutations in cells, often due to environmental exposures such as UV radiation, as seen in cutaneous melanoma, or possibly physical trauma, as in acral melanoma. Dr. Bastian explains that while cutaneous melanoma usually has small DNA changes caused by UV exposure, acral and mucosal melanomas often show much larger and more complex genetic changes—nicknamed “hail storms”—which may result from other environmental factors such as repeated physical stress on weight-bearing areas like the soles of the feet.  

Dr. Bastian further discusses the challenges of treating acral and mucosal melanoma due to their lower mutation burden and genomic complexity, which makes them less responsive to immunotherapy compared to UV-induced melanomas. He emphasizes that these rare melanoma subtypes affect people of all ethnicities equally and are biologically distinct from cutaneous forms. The webinar concludes with a Q&A covering therapy responses, AI in genomics, gender-related mutation differences, long-term survivorship, and future directions for research and treatment.   

Watch the full recording here: Acral Melanoma Research Update with Dr. Boris Bastian

MRA's Latest Research Report: Powering Progress Together

The Melanoma Research Alliance (MRA) convened in February for its 2025 Scientific Retreat and Melanoma Exchange Patient Forum in Washington, D.C., bringing together more than 300 participants from across the melanoma community. One of the focus areas of the Retreat was advancing research and care for rare melanoma subtypes. In addition to several scientific talks on rare melanomas, MRA hosted a cross-sector industry roundtable, “Harnessing Collective Power for Rare Melanomas,” involving 35 representatives across industry, academia, and patient advocacy groups. This roundtable explored key issues for rare melanoma patients, including drug access, clinical trials inclusion, health insurance denials of melanoma therapies, and model development for advancing rare melanoma research. The meeting produced actionable strategies that are detailed in the 2025 MRA Retreat & Patient Forum Report.  

The Melanoma Exchange Patient Forum featured a panel discussion moderated by MRA’s Dr. Joan Levy. Experts, with leading rare melanoma researchers, including Drs. Vito Rebecca, Kasey Couts, and Keiran Smalley. They shared their latest research efforts—from developing new model systems and understanding metastasis patterns, to studying tumor microenvironments and treatment resistance. These efforts underscore the power of collaboration and data sharing in unlocking new treatments for rare melanomas. MRA continues to support these efforts, including the forthcoming MRA Melanoma Biorepository, which will further enable rare melanoma research and collaboration. 

Summaries of the talks and panels at the Retreat and Patient Forum can also be found in the 2025 MRA Retreat & Patient Forum Report.

Tumor Infiltrating Lymphocyte Therapy: Expanding a Patient’s Own Tumor-Fighting Cells to Generate a Long-Term Response in Advanced Melanoma

Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs), has transformed the treatment landscape for patients with advanced melanoma. While many have benefited, a significant portion of patients do not respond or eventually experience disease progression, highlighting the need for new options. One promising approach is tumor-infiltrating lymphocyte (TIL) therapy, a personalized, cell-based immunotherapy that harnesses a patient’s own immune cells to target and destroy melanoma tumors. Some patients treated with TIL therapy have experienced long-lasting or even curative responses. 

Lifileucel (Amtagvi) is currently the only FDA-approved TIL therapy for patients with unresectable or metastatic melanoma whose disease has progressed following ICI and, when appropriate, targeted therapy for BRAF mutations. Ongoing research aims to expand its use, including the Phase 3 TILVANCE-301 clinical trial, which is evaluating TIL therapy in the first-line setting in combination with pembrolizumab (anti–PD-1) for patients with newly diagnosed metastatic melanoma. This trial seeks to assess whether the combination can improve response rates and durability of treatment while maintaining safety. The trial includes cutaneous, mucosal and acral melanoma patients who meet the eligibility criteria. 

In a recent interview with MRA, Dr. Stephanie Goff of the National Cancer Institute emphasized both the promise and complexity of TIL therapy. She highlighted its potential as a one-time, durable treatment—even for patients with tumors in hard-to-reach areas like the brain—but also noted logistical and clinical challenges, including side effect management, treatment delays, and limited accessibility. Dr. Goff encouraged physicians and patients to consider clinical trials involving TIL therapy early in the treatment journey and to stay informed about evolving options. 

Further highlighting this evolving field, MRA hosted a webinar, MRA Meet Ups: Clinical Trials and the Current State of TIL Therapy – TILVANCE-301, which featured insights from Dr. Young Ki Hong of Cooper University Health and melanoma survivor Jamie Goldfarb. Moderated by MRA’s Dana Deighton, the session offered an in-depth look at the science behind TIL therapy, the design and goals of the TILVANCE-301 trial, and the vital role of clinical trials. Jamie’s personal experience underscored the importance of viewing clinical trials as proactive treatment options. Both speakers encouraged patients to stay informed, consult experts, and engage with advocacy and support communities. 

Watch the full recording here: Clinical Trials and the Current State of TIL Therapy: TILVANCE-301

Tumor infiltrating lymphocyte (TIL) therapy, first pioneered by Dr. Stephen Rosenberg from the National Cancer Institute, isolates immune cells called lymphocytes from a patient’s surgically removed tumor that are then grown in large quantities in the lab. The army of grown TILs are then reinfused back into the patient where they recognize and destroy cancer cells in the body. Prior to the reinfusion, the patient is treated with chemotherapy to deplete all existing lymphocytes. After TIL reinfusion, the patient is treated with a therapy that encourages lymphocytes in the body to grow and divide.

Iovance Biotherapeutics has a proprietary TIL manufacturing process that is being used to develop an individualized TIL therapy called Lifileucel. It is being tested in advanced unresectable or metastatic melanoma patients who have progressed on or after treatment with checkpoint immunotherapy and/or BRAF/MEK targeted therapy. Recent data presented at the Society for Immunotherapy of Cancer (SITC) annual conference demonstrated durable efficacy and a 4-year overall survival rate of 21.9% in this advanced and difficult to treat patient population.³

Included in the above study is a small group of patients with mucosal melanoma, a rare melanoma subtype that develops in the mucous membranes of the body. Mucosal melanoma accounts for only 1% of all melanomas diagnosed and represents a difficult to treat subtype of the disease. Preliminary data was presented by Dr. Evido Domingo-Musibay (Masonic Cancer Center) at the 2023 European Society of Medical Oncology Annual Congress and by Dr. Harriet Kluger (Yale Cancer Center) at this year’s Society for Melanoma Research Annual Congress from 12 patients with advanced mucosal melanoma that were refractory to anti-PD1 treatment. These patients had an overall response rate of 50% (6 out of 12 patients) with durable responses in 4 patients from a single infusion of Lifileucel.⁴ Researchers plan to follow these patients for a number of years to look at the true durability of response.

On March 24th, 2023, Iovance submitted a Biologics License Application (BLA) to the FDA for the approval of Lifileucel. The FDA decision is expected by the end of February 2024.

In addition, a large phase 3 clinical trial is now enrolling patients with untreated melanoma in a study testing the efficacy and safety of lifileucel in combination with pembrolizumab compared with pembrolizumab alone (NCT05727904).

Advancing RARE Registry Insights: The Power of Your Data

The Melanoma Research Alliance is excited to share a poster presentation called RARE: A Registry for Patients with Acral and Mucosal Melanoma which was presented last week at the Society for Melanoma Research (SMR)’s 20^th annual Congress. SMR aims to enhance communication among melanoma researchers by organizing annual research congresses, emphasizing new research results to engage both basic and clinical researchers. In addition, SMR works to promote collaboration among organizations focused on prevention, screening, and surveillance, facilitate partnerships among major research groups, and represent the melanoma research community to the public and funding agencies.

This year's conference, hosted in Philadelphia, PA, had over 600 attendees from around the world. Several members from the MRA staff attended and presented recent RARE Registry data, increasing awareness and interest among clinicians, researchers, and participants.

Just over one year since launch, the MRA team shared updates into how your survey data is taking shape as the RARE Registry grows, illustrating how the synergy of individual data points coalesces into a rich tapestry of knowledge. Participant data is a driving force for future advances in acral and mucosal melanoma research and emphasizes the collective strength of our community. Together, we are not only building a comprehensive understanding of these rare melanomas but also paving the way for more appropriate interventions, improved patient outcomes and disease management, and a brighter future for patients and families facing acral and mucosal melanoma.

Click here to open a PDF of the poster in a new window.

During this RARE Registry update, held on August 23 at 12:30 pm ET, de-identified data was shared from the first 100 participants, new participant features were demonstrated, and the MRA team answered questions from participants. Learn more about the RARE Registry at www.raremelanoma.org

 

Despite the tremendous progress made in the last decade in treating melanoma, approximately one third of patients don’t benefit from currently approved therapies. This includes the majority of people with rare forms of melanoma — melanomas that develop in the eye, nailbeds, palms, soles of the feet, and various mucosal membranes. Patients facing these subtypes tend not to respond as well to current treatments as patients with cutaneous melanomas that arise on sun-exposed skin. But as investigators continue to chip away at understanding what causes these melanomas and how they differ from UV-driven cutaneous melanomas, the hope is the better understanding they reap will be sown into improved treatments for these patients. Researchers explored both the challenges and the opportunities for rare melanoma research at the 2021 MRA Scientific Retreat.

New Insights Into the Genetics of Acral Melanoma

Keiran Smalley of H. Lee Moffitt Cancer Center and Research Institute and his MRA-funded team hope to find a genetic ‘smoking gun’ of what causes acral melanoma, a rare subtype of melanoma that develops on the palms, soles of feet, or under finger or toe nails, and comprises about two to three percent of all melanomas. The researchers assumed that, like many cutaneous melanomas, acral melanomas evolve from moles whose growth goes awry due to a series of specific genetic flaws. But this didn’t prove to be so for most of the tissues they analyzed when the researchers genetically compared benign moles from acral sites (feet, hands) to that of acral melanoma tumors. “This surprised us because it suggests it is unlikely that acral nevi [moles] are likely to be the precursors for the majority of acral melanomas,” Smalley said.

Digging deeper, they then mapped out the genetic landscapes of nine acral melanoma samples and found tremendous variability in the genetic material and the ways in which cell functions were altered. Unfortunately, no distinctive genetic signature was found among the samples that could provide a specific target for a drug that might be effective for patients with this rare melanoma. However, the researchers did find a group of genes with altered activity shared among most of the samples. The researchers also noted fewer and less active immune cells in the acral melanoma tumor samples compared to samples from cutaneous melanoma. This suggests that acral melanoma is less likely to spark an immune response and may explain why many patients with this subtype often do not respond to checkpoint immunotherapy, Smalley noted.

Titia de Lange of Rockefeller University, Marcin Imielinski of Weill Cornell, and their research team also found a tremendous amount of variability in the genetic landscape of the acral melanoma samples they studied. Many of these genetic alterations were due to major disruptions in genetic material, akin to typhoons creating piles of genomic wreckage, which break up the chromosomes and reattach the genes on them in new ways. These genetic disruptions are quite different from the smaller number of consistent and more pinpoint genetic changes often seen in cutaneous melanoma on sun-exposed skin. But because of the jumbling and multiplication of genetic material that often occurs after these chromosomal catastrophes, they likely trigger production of new proteins (antigens). The immune system can recognize some of these new tumor antigens and attack the cells that have them when stimulated by checkpoint immunotherapy, the researchers speculate. They suggest that molecular markers for these types of chromosomal disruptions, if present in patients’ tumors, might indicate whether they are likely to respond to such treatments.

UV-Driven Melanomas Extend Beyond the Skin

Richard Marais of the Cancer Research UK Manchester Institute reported on a new discovery that suggests that a subgroup of mucosal melanoma patients could respond to checkpoint immunotherapies or targeted therapies. Most mucosal melanomas arise in areas of the body not exposed to the sun, so lack the telltale genetic changes caused by ultraviolet radiation (UVR) induced DNA damage that are thought to contribute to responsiveness of these melanomas to checkpoint blockade. Mucosal melanomas are also not generally considered to be eligible for BRAF plus MEK inhibitors. However, Marais has found that melanomas arising in the mucosal membrane that covers the eye and lines the inside of eyelids have the distinctive signature common to sun-induced common cutaneous melanoma. These mucosal melanomas also had a high mutation burden and a high incidence of BRAF mutations, suggesting that they are likely to respond to the therapies approved for common cutaneous melanoma. Quoting Nick Hayward’s data, Marais noted that uveal melanomas arising on the iris also bear the telltale genetic signature of sun-induced DNA damage, suggesting that these melanomas may also respond to checkpoint immunotherapies. 

“This makes us start to think about basic concepts in how melanoma is driven,” Marais said, pointing out that the data suggests that melanoma is driven by distinct processes in different parts of the body, but that UVR imprints additional events over the baseline processes to accelerate melanoma development. “We need to apply these findings to develop new treatments for rare melanomas, because responses are driven by the underlying genetics rather than by the tissue of origin” Marais noted, concluding that these findings reinforce public health messages about the importance of protecting the eyes from UVR.