Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma Journal Article
| Authors: | Tarantino, G.; Ricker, C. A.; Wang, A.; Ge, W.; Aprati, T. J.; Huang, A. Y.; Madha, S.; Chen, J.; Shi, Y.; Glettig, M.; Feng, C. H.; Frederick, D. T.; Freeman, S.; Holovatska, M. M.; Manos, M. P.; Zimmer, L.; Rösch, A.; Zaremba, A.; Livingstone, E.; Jameson, J. C.; Saghafian, S.; Lee, A.; Zhao, K.; Morris, L. G. T.; Reardon, B.; Park, J.; Elmarakeby, H. A.; Schilling, B.; Giobbie-Hurder, A.; Vokes, N. I.; Buchbinder, E. I.; Flaherty, K. T.; Haq, R.; Wu, C. J.; Boland, G. M.; Hodi, F. S.; Van Allen, E. M.; Schadendorf, D.; Liu, D. |
| Article Title: | Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma |
| Abstract: | The introduction of immune checkpoint blockade (ICB) has markedly improved outcomes for advanced melanoma. However, many patients develop resistance through unknown mechanisms. While combination ICB has improved response rate and progression-free survival, it substantially increases toxicity. Biomarkers to distinguish patients who would benefit from combination therapy versus aPD-1 remain elusive. We analyzed whole-exome sequencing of pretreatment tumors from four cohorts (n = 140) of ICB-naïve patients treated with aPD-1. High genomic heterogeneity and low ploidy robustly identified patients intrinsically resistant to aPD-1. To establish clinically actionable predictions, we optimized and validated a predictive model using ploidy and heterogeneity to confidently identify (90% PPV) patients with intrinsic resistance to and worse survival on aPD-1. We further observed that three of seven (43%) patients predicted to be intrinsically resistant to single-agent PD-1 ICB responded to combination ICB, suggesting that these patients may benefit disproportionately from combination ICB. These findings highlight the importance of heterogeneity and ploidy, nominating an approach toward clinical actionability. © 2024 American Association for the Advancement of Science. All rights reserved. |
| Keywords: | middle aged; genetics; mortality; biomarkers; melanoma; metastasis; progression free survival; drug resistance; pathology; drug resistance, neoplasm; oncology; tumor marker; neoplasm metastasis; genomics; combination therapy; drug therapy; dermatology; diseases; genetic heterogeneity; programmed death 1 receptor; predictive models; metastatic melanoma; procedures; response rate; single-agent; ploidy; ploidies; immune checkpoint inhibitor; humans; human; male; female; exome sequencing; pdcd1 protein, human; programmed cell death 1 receptor; whole exome sequencing; immune checkpoint inhibitors; biomarkers, tumor; actionability; intrinsic resistance; pre-treatments |
| Journal Title: | Science Advances |
| Volume: | 10 |
| Issue: | 48 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2024-11-29 |
| Start Page: | eadp4670 |
| Language: | English |
| DOI: | 10.1126/sciadv.adp4670 |
| PUBMED: | 39602539 |
| PROVIDER: | scopus |
| PMCID: | PMC11601251 |
| DOI/URL: | |
| Notes: | Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work