Faculty Bibliography

Purpose: We have shown that the aged microenvironment increases melanoma metastasis, and decreases response to targeted therapy, and here we queried response to anti-PD1.Experimental Design: We analyzed the relationship between age, response to anti-PD1, and prior therapy in 538 patients. We used mouse models of melanoma, to analyze the intratumoral immune microenvironment in young versus aged mice and confirmed our findings in human melanoma biopsies.Results: Patients over the age of 60 responded more efficiently to anti-PD-1, and likelihood of response to anti-PD-1 increased with age, even when we controlled for prior MAPKi therapy. Placing genetically identical tumors in aged mice (52 weeks) significantly increased their response to anti-PD1 as compared with the same tumors in young mice (8 weeks). These data suggest that this increased response in aged patients occurs even in the absence of a more complex mutational landscape. Next, we found that young mice had a significantly higher population of regulatory T cells (Tregs), skewing the CD8⁺:Treg ratio. FOXP3 staining of human melanoma biopsies revealed similar increases in Tregs in young patients. Depletion of Tregs using anti-CD25 increased the response to anti-PD1 in young mice.Conclusions: While there are obvious limitations to our study, including our inability to conduct a meta-analysis due to a lack of available data, and our inability to control for mutational burden, there is a remarkable consistency in these data from over 500 patients across 8 different institutes worldwide. These results stress the importance of considering age as a factor for immunotherapy response. Clin Cancer Res; 1-10. ©2018 AACR.

Myxoid lesions of the breast can be diagnostically challenging entities. We report 4 cases of CD34+ fibromyxoid lesion that have been previously diagnosed as "benign myxoid lesion," "nodular mucinosis," or "mammary myofibroblastoma, myxoid type" on the basis of CD34-positivity. The lesions were microscopically well circumscribed and composed of a paucicellular spindle cell proliferation in a background of myxoid stroma. No epithelial component was identified. The spindle cells showed immunohistochemical reactivity for CD34 and smooth muscle actin. Based on morphologic and immunohistochemical similarities between these cases and myxoid myofibroblastoma, we compared 4 myxoid lesions with cases of typical myofibroblastoma, utilizing retinoblastoma (Rb) antibody and fluorescent in situ hybridization for 13q14 gene rearrangement (encoding the Rb gene). The myxoid lesions showed retention of Rb protein by immunohistochemistry, whereas Rb expression was lost in cases of myofibroblastoma. We identified loss of 13q14 in 3 of 4 cases of myofibroblastoma. Notably, 13q14 gene rearrangement was not observed in any of the myxoid lesions. Our data show that there is at least a subset of CD34+ fibromyxoid lesions that, despite overlapping morphologic and immunohistochemical phenotype and proposed common histogenesis with myofibroblastomas, is genetically distinct from the latter based on Rb analysis.

BACKGROUND:Patients with thick primary melanomas (≥4 mm) have highly variable survival outcomes. Cell proliferation marker Ki-67 has been identified as promising biomarker in thick melanoma but has not been evaluated since the wide spread adoption of sentinel lymph node biopsy. We revisit its prognostic relevance in the sentinel node era. METHODS:We studied patients with thick (≥4 mm) primary melanoma prospectively enrolled in a clinicopathological biospecimen database from 2002 to 2015, and evaluated the prognostic value of Ki-67 expression while controlling for features included in the existing staging criteria. RESULTS:We analyzed 68 patients who underwent lymph node sampling and who had an available tumor for Ki-67 immunohistochemical (IHC) staining. The median tumor thickness was 6.0 mm; the median follow-up was 2.6 years. In multivariable analysis including nodal status and primary tumor ulceration, Ki-67 expression was an independent predictor of worse recurrence-free survival (HR 2.19, P = 0.024) and overall survival (HR 2.49, P = 0.028). Natural log-transformed tumor thickness (ln [thickness]) was also significantly associated with worse OS (HR 2.39, P = 0.010). CONCLUSION/CONCLUSIONS:We identify Ki-67 and ln (thickness) as potential biomarkers for patients with thick melanoma who have undergone nodal staging. If validated in additional studies, these biomarkers could be integrated into the staging criteria to improve risk-stratification.