Who's More Likely to Develop a Second Primary Melanoma?

Roxanne Nelson, RN, BSN

November 30, 2022

Individuals with a primary melanoma may be more likely to develop a second primary melanoma if they have certain characteristics, a new study suggests.

In a cohort study of more than 38,000 patients, those diagnosed with a second primary melanoma were significantly more likely to have a "nevus-prone" phenotype and a high polygenic risk score for melanoma.

Notably, the researchers also found only limited evidence that elevated levels of sun exposure contributed to second melanoma risk.

Overall, the findings suggest that "within the general population, the presence of many nevi and having a high genetic predisposition to melanoma were associated with the highest risks of developing second primary melanoma," Catherine M. Olsen, PhD, of the University of Queensland, Australia, and colleagues concluded.

The study was published online November 23 in JAMA Dermatology.

People with melanoma are believed to be at high risk for developing subsequent tumors, yet most never do. Population-based studies indicate that only about 8%–18% of patients are diagnosed with a second primary melanoma.

Previous studies using modified case-control design have identified several factors associated with developing multiple primary melanomas, including older age, male sex, a family history of melanoma, high nevus counts or presence of atypical nevi, higher ambient UV radiation and personal sun exposure, as well as certain inherited genetic variants.

However, these studies aren't equipped to assess the magnitude of risk of developing multiple melanomas among those who have not yet had melanoma.

In the current analysis, Olsen and colleagues set out to understand the level of risk using a prospective cohort study design. The cohort comprised participants in the QSkin Sun and Health Study and included 38,845 patients with a baseline median age of 56 years, followed for a median of 7.4 years. Among these participants, 1212 (3.1%) had only one primary melanoma diagnosis, and 245 (0.6%) had two or more primary melanomas. Of those with more primary melanomas, 59 had synchronous primary melanoma, meaning first and second primary melanomas were diagnosed on the same day.

Olsen and colleagues compared the clinical characteristics of patients with first and second melanomas, looking at demographic, phenotypic, sun exposure, and genetic factors. The team found that the median time between first and second melanoma, excluding cases of synchronous primary melanoma, was 18.4 months.

Those who developed second melanomas were older at baseline than those who only developed one (59.3 years vs 58.2 years, respectively; P < .001), and were more likely to have a sun-sensitive phenotype, a self-reported history of excisions for non-melanoma skin cancers, and a high polygenic risk score for melanoma. Among people who developed second primary melanomas, the second melanomas were more likely to be in situ and of the lentigo maligna subtype.

Notably, factors including age, sex, sunburn tendency, and family history of melanoma had similarly elevated effect sizes among those diagnosed with first and second melanomas. The authors also found similar associations with baseline measures for personal sun exposure — including sunburns and cumulative sun exposure; however, the number of past skin cancer excisions was more strongly associated with second primaries (P = .05).

The team did identify two factors associated with a higher risk of developing a second primary melanoma. A nevus phenotype was more strongly associated with developing a second primary melanoma (hazard ratio [HR], 6.36) than the initial one (HR, 3.46). And second primary melanomas had stronger associations with high melanoma polygenic risk scores than first primary melanomas (HR, 3.28 vs HR, 2.06; P = .03).

The authors noted several limitations to the study, including the generalizability of the findings outside of Australia and the relatively small number of people with second primary melanomas.

Still, the investigators note that the data "offer unique insights that differ from earlier efforts." Namely, the "findings showed that many of the classic phenotypic risk factors for melanoma were similarly associated with risk of first and second melanomas; however, high numbers of nevi and high genetic predisposition were more strongly associated with second [rather] than first primary melanomas."

This work was supported by grants from the NHMRC. Olsen reports no relevant financial relationships. Co-author Rachel Neale, PhD, reported grants from Viatris and the National Health and Medical Research Council of Australia (NHMRC)outside the submitted work. Co-author David Whiteman, MBBS, PhD, reported personal fees from Pierre Fabre (speaker fees for conference presentation) outside the submitted work. No other disclosures were reported.

JAMA Dermatol. Published online November 23, 2022. Abstract

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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