A High Proliferative Index of Recurrent Melanoma Is Associated with Worse Survival

Abstract

Objective: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. Methods: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. Results: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24–3.54), p = 0.006]. Conclusions: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care.

Physiologically Relevant Oxygen Concentration (6% O2) as an Important Component of the Microenvironment Impacting Melanoma Phenotype and Melanoma Response to Targeted Therapeutics In Vitro

“…Whether in this setting MITF downregulation in physiological normoxia provided direct advantage is unclear, however, it was concomitant with limited effects of drugs on the frequency of Ki-67-positive cells in normoxia (6% O 2 ) when compared with drug effects in the atmospheric oxygen concentration (21%). Clinically, high proliferative index of recurrent melanomas, displayed as high Ki-67 expression, is an independent predictor of worse overall survival [72,73]. Our study indicates that the response of melanoma cells to treatment can be greatly altered by artificial levels of oxygen in cell culture.…”

Pathophysiological Characteristics of Melanoma In-Transit Metastasis in a Lymphedema Mouse Model

“…Compared with mitotic rate, the expression level of nuclear antigen Ki-67 may be a better assessment of proliferation, as Ki-67 is expressed in mitosis as well as during the G1, S, and G2 phases of the cell cycle in proliferating cells (Gerdes et al, 1983). Ki-67 expression has also been shown to have prognostic value in melanoma (Tu et al, 2011) and other cancers (most notably in breast cancer; Gerdes et al, 1983;Railo et al, 1993;Keshgegian and Cnaan, 1995;Bettencourt et al, 1996;Fitzgibbons et al, 2000;Mucci et al, 2000). Given that the tumor cells and the animals used in this study were genetically identical, high expression of Ki-67 in ITM may have been caused by the environment surrounding the tumor or the selection of a highly proliferative tumor variant.…”

Classification and Grading of Melanocytic Lesions in a Mouse Model of NRAS-driven Melanomagenesis

“…60,61 Nevertheless, as demonstrated by a growing number of clinical studies across different species, increased expression of Ki-67 in melanocytic proliferations is significantly associated with features of malignancy and poor prognosis, including worse survival, metastatic progression, high recurrence rate, and therapeutic resistance. 62–67…”