Hong et al. developed a non-invasive, blood-based method to quantify early response of melanoma patients to immune checkpoint blockade. Blood samples were microfluidically enriched for circulating tumor cells (CTCs) by efficient depletion of normal hematopoietic cells, and digital droplet-based PCR was used to detect and quantify a 19-gene melanoma RNA signature (CTC score). A decrease in CTC score within 7 weeks of treatment correlated with improved clinical outcomes, allowing for monitoring of early treatment-based changes.
A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17; P = 0.008] and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.
Author Info: (1) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (2) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Division o
Author Info: (1) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (2) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (3) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (4) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (5) Division of Biostatistics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215. (6) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (7) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (8) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (9) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (10) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (11) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (12) Division of Biostatistics, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215. (13) Center for Bioengineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Harvard Medical School, Boston, MA 02114. (14) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (15) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (16) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (17) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (18) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (19) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (20) Center for Bioengineering in Medicine, Massachusetts General Hospital and Shriners Hospital for Children, Harvard Medical School, Boston, MA 02114. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (21) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114; kisselbacher@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu dhaber@mgh.harvard.edu. (22) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114; kisselbacher@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu dhaber@mgh.harvard.edu. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. (23) Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114; kisselbacher@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu dhaber@mgh.harvard.edu. Howard Hughes Medical Institute, Chevy Chase, MD 20815.
