The incidence of cutaneous melanoma in the United States has increased in the last 30 years, with the American Cancer Society estimating that 99,780 new melanomas will be diagnosed and 7650 melanoma-related deaths will occur in 2022.1 Patients with melanoma have an increased risk for developing a second primary melanoma or other malignancy, such as salivary gland, small intestine, breast, prostate, renal, or thyroid cancer, but most commonly nonmelanoma skin cancer.2,3 The incidence rate of melanoma among residents of Olmsted County, Minnesota, from 1970 through 2009 has already been described for various age groups4-7; however, the incidence of a second primary malignancy, including melanoma, within these incident cohorts remains unknown.
Mutations in the BRAF oncogene occur in approximately 50% of melanomas.8,9They cause downstream activation of the mitogen-activated protein kinase signaling pathway, stimulating growth in melanoma cell lines.10BRAF mutations also occur in hairy cell leukemia, papillary thyroid cancers, colorectal cancers, liver cancers, gliomas, lung cancers, sarcomas, ovarian cancers, and breast cancers, with incidence rates varying from 2% to 100%.9,11,12 V600E is the most common somatic BRAF mutation (>90%) and is linked to survival in melanoma.13 Targeted therapies with small-molecule BRAF and MEK inhibitors have notably improved survival of patients with advanced or metastatic disease,14 and molecular testing for BRAF mutations is routinely recommended for patients with advanced melanoma.
Although the BRAF mutation event in melanoma is sporadic and should not necessarily affect the development of an unrelated malignancy, we hypothesized that the exposures that may have predisposed a particular individual to a BRAF-mutated melanoma also may have a higher chance of predisposing that individual to the development of another primary malignancy. In this population-based study, we aimed to determine whether the specific melanoma feature of mutant BRAF V600E expression was associated with the development of a second primary malignancy.
Methods
This study was approved by the institutional review boards of the Mayo Clinic and Olmsted Medical Center (both in Rochester, Minnesota). The reporting of this study is compliant with the Strengthening the Reporting of Observational Studies in Epidemiology statement.15
Patient Selection and BRAF Assessment—The Rochester Epidemiology Project (REP) links comprehensive health care records for virtually all residents of Olmsted County, Minnesota, across different medical providers. The REP provides an index of diagnostic and therapeutic procedures, tracks timelines and outcomes of individuals and their medical conditions, and is ideal for population-based studies. Since its inception in 1966, the REP has provided the resource for more than 2000 peer-reviewed publications.16,17
We obtained a list of all residents of Olmsted County aged 18 to 60 years who had a melanoma diagnosed according to the International Classification of Diseases, Ninth Revision, from January 1, 1970, through December 30, 2009; these cohorts have been analyzed previously.4-7 Of the 638 individuals identified, 380 had a melanoma tissue block on file at Mayo Clinic with enough tumor present in available tissue blocks for BRAF assessment. All specimens were reviewed by a board-certified dermatopathologist (J.S.L.) to confirm the diagnosis of melanoma. Tissue blocks were recut, and formalin-fixed, paraffin-embedded tissue sections were stained for BRAF V600E (Spring Bioscience Corporation). BRAF-stained specimens and the associated hematoxylin and eosin−stained slides were reviewed. Melanocyte cytoplasmic staining for BRAF was graded as negative if no staining was evident. BRAF was graded as positive if focal or partial staining was observed (<50% of tumor or low BRAF expression) or if diffuse staining was evident (>50% of tumor or high BRAF expression).
Using resources of the REP, we confirmed patients’ residency status in Olmsted County at the time of diagnosis of the incident melanoma. Patients who denied access to their medical records for research purposes were excluded. We used the complete record of each patient to confirm the date of diagnosis of the incident melanoma. Baseline characteristics of patients and their incident melanomas (eg, anatomic site and pathologic stage according to the American Joint Committee on Cancer classification) were obtained. When only the Clark level was included in the dermatopathology report, the corresponding Breslow thickness was extrapolated from the Clark level,18 and the pathologic stage according to the American Joint Committee on Cancer classification (7th edition) was determined.