Dusan Bogunovic^a,b, David W. O'Neill^a,b, Ilana Belitskaya-Levy^a, Vladimir Vacic^c, Yi-Lo Yu^a,d, Sylvia Adams^a, Farbod Darvishian^a,b, Russell Berman^a, Richard Shapiro^a, Anna C. Pavlicka, Stefano Lonardi^c, Jiri Zavadil^a,b,e, Iman Osman^a and Nina Bhardwaj<sup>a,b

a</sup>Cancer Institute and ^bDepartment of Pathology, New York University Langone Medical Center, New York, NY 10016;
^cDepartment of Computer Science and Engineering, University of California, Riverside, CA 92507;
^dUniversity of Minnesota Medical School, Minneapolis, MN 55455; and
^eCenter for Health Informatics and Bioinformatics, New York University Langone Medical Center, New York, NY 10016


Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival
Proc Nat Acad Sci U S A 


Melanoma is the deadliest form of skin cancer, and its incidence is on the rise. Treatment options for advanced melanoma are limited and rarely curative. While five-year survival for stage III melanoma patients can reach up to 69 percent depending on the patient sub-category, the reported survival for stage IV disease is rarely longer than a year.  Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis.

The Bhardwaj Lab used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation, and to develop improved methods for predicting patient survival.

In their research, the Bhardwaj Lab has now identified a group of 266 genes associated with post-recurrence survival. Genes positively associated with survival were predominantly immune-response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell-proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24).

Furthermore, any of the four parameters (pre-validated gene expression signature, TILs, CD3 and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict post-recurrence survival. In the Bhardwaj lab's study of metastatic lesions, MI was the strongest indicator of patient survival (HR = 2.13, p = 0.0008) and was the best single factor that improved current staging, significantly improving the separation between stage IIIB and IIIC patients. Dr. Bhardwaj and her team further validated this by expanding patient samples with an additional 52 specimens. Their data supports the use of MI in staging more advanced melanoma as well, following epidemiologic validation of this finding.

In the fight against the tumor, further stimulation of T cells may be possible in patients with an existing immune presence in the tumor lesions. But the biggest benefit from chemotherapy may be seen in the patients whose tumors have high mitotic rates. If so, then sub-categorizing patients based on metastatic lesion immune cell infiltration and mitotic index prior to clinical trial recruitment might yield much more profound results than seen so far.


A related description of the recent research findings from the Bhardwaj Lab can be found in a news announcement by the Office of Communications and Public Affairs.