From the Journals

Systemic therapies are impacting melanoma’s prognostic factors

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The new paradigm of melanoma disease kinetics

Effective systemic treatments have forever altered the kinetics of events in advanced melanoma, with the natural history outcome curves of this cancer now highly dependent on treatment response. The relapse-free survival (RFS) curves of patients with stage IIC/III melanoma with and without adjuvant dabrafenib/trametinib demonstrate the contemporary natural history of frequent early recurrences with few late events in the placebo groups and of fewer and later recurrences, with an as yet unknown frequency of late events, in the treated groups.

The three reported studies examine melanoma disease kinetics and speak to this new paradigm.

The first study, conducted by von Schuckmann and colleagues, looked for factors associated with disease recurrence within 2 years of treatment for localized, T1b to T4b melanoma.

Factors were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and location on the head and neck. Also, the study had two major limitations. First, the patient population was a heterogenous one – 442 patients with clinical T1b to T4b did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b had a negative SLNB result, and 38 patients had at least stage IIIa disease after a positive SLNB finding. Second, as the 8th edition of the AJCC [American Joint Committee on Cancer] Staging Manual notes, most events in this cohort of patients are expected to occur after the 2-year threshold described in this prospective study and the disease can recur as much as 10 years after effective treatment.

The second study, conducted by Vallet and colleagues, analyzed data from patients with unresectable stage IV melanoma to determine if time to distant recurrence after excision of antecedent primary melanoma was associated with survival.

Time to first distant metastasis was not related to Breslow thickness or to tumor stage at the start of therapy; however, the data analysis did not include multiple patient variables that might have shed more light on predictive factors.

As systemic therapy increasingly leads to stabilization of previously progressive disease as well as durable complete remissions in melanoma patients, best response to immunotherapy or targeted therapy is likely to emerge as a much more important predictor than the time it took for stage IV melanoma to become apparent. There has been some thoughtful interest in exploring the prognostic value of establishing the kinetics of stage IV melanoma as a prognostic factor prior to initiating therapy, but there has been limited uptake of this approach by the melanoma oncology community.

In the third study, Calomarde-Rees and colleagues explored associations between melanoma disease characteristics and hematogenous or lymphatic metastases.

The anticipated findings include the observed association between tumor thickness and risk of recurrence, either lymphatic or hematogenous. As satellitosis is already considered a criterion for stage III in AJCC8, these two observations serve as internal controls that validate the credibility of the data set.

The researchers’ most intriguing finding is the strong potential association of the combination of both MAPK (either BRAF or NRAS) and TERT promoter mutations with poor survival, as demonstrated in their second prognostic model (hazard ratio, 5.7). This finding warrants cautious interpretation as the authors clearly acknowledge that a minority of the study population underwent detailed assessments of the mutation status of each gene.

While the biologic behavior of melanoma is likely to be much more complex than the mutation of one or two genes, the potential interaction of the mutated TERT promoter gene is provocative, especially in the context of a recent article suggesting a role for monitoring BRAF and TERT circulating free DNA as an indicator of response to systemic therapy and outcome.

Multigene panels are being developed, but it remains to be demonstrated whether any of these highly discrepant gene profiles will outperform optimized contemporary multivariable individual patient risk prediction models across the prognostic spectrum of melanoma.

Daniel G. Coit, MD is a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York. He made his remarks in an editorial in JAMA Dermatology (2019 May 1. doi: 10.1001/jamadermatol.2019.0200). Dr. Coit disclosed that he has no relevant financial conflicts of interest.



As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.

Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.

The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.

“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).

They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.

Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm2, thickness, ulceration, and primary tumor location on the head or neck.

Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.

“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”

The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.

“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”

To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.

“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.

The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.

“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).

The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.

The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).

Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).

“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”

Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.

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