Abstract
BackgroundInhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma who carry relevant oncogenic mutations. However, BRAF inhibitors are found to induce cutaneous squamous cell carcinoma (cuSCC). Population-based background rates of cuSCC and non-cutaneous squamous cell carcinoma (non-cuSCC) in the metastatic melanoma population may contextualize safety signals from randomized clinical trials or the clinics. However, these background rates are lacking.MethodsWe conducted a historical cohort study to evaluate the background rates of new-onset non-melanoma skin lesions and non-cuSCC among 2,814 metastatic malignant melanoma patients diagnosed in 1997–2010, identified through the Danish Cancer Registry and the National Pathology Registry. Patients were excluded if they had a history of cancer before the metastatic melanoma diagnosis, other than skin cancers. We determined the incidence of non-melanoma malignant skin lesions and non-cuSCC that occurred post metastatic melanoma diagnosis, censoring patients at death, emigration, or December 31, 2011 (end of study period), whichever came first.ResultsThe median age at metastatic melanoma diagnosis was 64 years. Over 40 % of patients died within one year of metastatic diagnosis and ~70 % died within 5 years. The percentages of patients with prior history or prevalent disease at metastatic melanoma diagnosis included: 8.6 % with cuSCC or basal cell carcinoma (BCC), 3.9 % with actinic keratosis (AK), and 0.7 % with Bowen’s disease. No patients had past or current non-cuSCC per study exclusion criterion. The incidence of non-melanoma skin lesions during the 6 months post-metastatic melanoma diagnosis was as follows: BCC, 1.8 % (42.5 per 1000 person-years [PY]); AK, 0.8 % (18.6 per 1000 PY); cuSCC, 0.1 % (1.7 per 1000 PY); Bowen’s disease, 0.04 % (0.8 per 1000 PY); and keratoacanthoma (KA), 0 %. Non-cuSCC was observed in 3 patients (0.1 %; 2.5 per 1000 PY) at 3 sites: bronchi, heart and lung.ConclusionCuSCC and non-cuSCC were rare events among metastatic melanoma patients.
Highlights
Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma who carry relevant oncogenic mutations
During 1997–2010, 3,669 metastatic melanoma patients were identified from the Danish Cancer Registry (DCR) and National Pathology Registry (NPR), including 855 (23 %) patients with a history of cancer, other than cutaneous melanoma, basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cuSCC), Bowen’s disease, actinic keratosis (AK), and KA, before the metastatic melanoma diagnosis (Table 1)
Compared with most randomized clinical trials, the results obtained from this study are relatively robust, given this sample size, and the metastatic melanoma patients included in this study should be fairly representative of those patients in the clinics, as only minor inclusion and exclusion criteria were applied
Summary
Inhibitors of mutant BRAF are emerging as standard of care in patients with metastatic melanoma who carry relevant oncogenic mutations. Population-based background rates of cuSCC and non-cutaneous squamous cell carcinoma (non-cuSCC) in the metastatic melanoma population may contextualize safety signals from randomized clinical trials or the clinics. The incidence of cutaneous melanoma has been rising during the last four decades in white populations worldwide [1] It is highly curable with surgery if detected in its earliest stages, prognosis for metastatic cutaneous melanoma patients has been historically poor, with a median overall survival in the range of 6–10 months. Non-melanoma skin cancers — welldifferentiated cutaneous squamous-cell carcinomas (cuSCC) and keratoacanthomas (KA) — have developed in approximately 11 % to 30 % of patients treated with type I BRAF inhibitors such as dabrafenib and vemurafenib [3, 8,9,10,11,12]. Most cuSCCs (77 %) appeared between weeks 6 and 24 following commencement of therapy on both sun-damaged and nonsun-damaged skin
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