Abstract
Background: The immunosuppressive cytokine interleukin- 8 (IL-8), produced by tumor cells and some myeloid cells, promotes inflammation, angiogenesis, and metastasis. In our discovery work, elevated serum IL-8 at androgen deprivation therapy (ADT) initiation portended worse overall survival (OS). Leveraging serum samples from the phase 3 CHAARTED trial of patients treated with ADT +/− docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), we validated these findings. Methods: Two hundred and thirty-three patients had serum samples drawn within 28 days of ADT initiation. The samples were assayed using the same Mesoscale Multiplex ELISA platform employed in the discovery cohort. After adjusting for performance status, disease volume, and de novo/metachronous metastases, multivariable Cox proportional hazards models assessed associations between IL-8 as continuous and binary variables on OS and time to castration-resistant prostate cancer (CRPC). The median IL-8 level (9.3 pg/ml) was the a priori binary cutpoint. Fixed-effects meta-analyses of the discovery and validation sets were performed. Results: Higher IL-8 levels were prognostic for shorter OS (continuous: hazard ratio [HR] 2.2, 95% confidence interval [CI]: 1.4–3.6, p =.001; binary >9.3: HR 1.7, 95% CI: 1.2–2.4, p =.007) and time to CRPC (continuous: HR 2.3, 95% CI: 1.6–3.3, p <.001; binary: HR 1.8, 95% CI: 1.3–2.5, p <.001) and independent of docetaxel use, disease burden, and time of metastases. Meta-analysis including the discovery cohort, also showed that binary IL-8 levels >9.3 pg/ml from patients treated with ADT alone was prognostic for poorer OS (HR 1.8, 95% CI: 1.2–2.7, p =.007) and shorter time to CRPC (HR 1.4, 95% CI: 0.99–1.9, p =.057). Conclusions: In the phase 3 CHAARTED study of men with mHSPC at ADT initiation, elevated IL-8 portended worse survival and shorter time to castration-resistant prostate cancer independent of docetaxel administration, metastatic burden, and metachronous versus de novo metastatic presentation. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.
| Original language | English |
|---|---|
| Pages (from-to) | 1429-1437 |
| Number of pages | 9 |
| Journal | Prostate |
| Volume | 80 |
| Issue number | 16 |
| DOIs | |
| State | Published - Dec 1 2020 |
Bibliographical note
Publisher Copyright:© 2020 Wiley Periodicals LLC
Funding
We appreciate the patients and their families who contributed to this study as well as the many EA3805 co-investigators. This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health (NIH) under the following award numbers: U10CA180820, U10CA180794, UG1CA233180, UG1CA233196, R01CA208254-01, and Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. All authors, ECOG-ACRIN, and Sanofi provide consent for publication. Lauren C. Harshman reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, and Ology Medical Education; research funding from Bayer, Sotio, Bristol‐Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis), and support for research travel from Bayer and Genentech. Currently employed by Surface Oncology. Anis A. Hamid reports consulting fees from Merck Sharp & Dohme; honoraria from Bayer. Charles G. Drake reports this role as a coinventor on patents licensed from JHU to BMS and Janssen, has served as a paid consultant to AZ Medimmune, BMS, Pfizer, Roche, Sanofi Aventis, Genentech, Merck, and Janssen, and has received sponsored research funding to his institution from the Bristol‐Myers Squibb International Immuno‐Oncology Network. Michael A. Carducci reports consulting fees from Pfizer, Roche‐Genentech, Astellas; Research funding: EMD Serrano, Pfizer, Merck, Bristol‐Myers Squibb. Christopher J. Sweeney reports consulting or advisory role: Sanofi, Janssen, Astellas Pharma, Bayer, Genentech, AstraZeneca, Pfizer, Celgene Research Funding: Janssen Biotech (Inst), Astellas Pharma (Inst), Sanofi (Inst), Bayer (Inst), Sotio (Inst), Dendreon (Inst); patents, royalties, other intellectual property: Parthenolide (Indiana University): dimethylaminoparthenolide (Leuchemix); Exelixis: Abiraterone plus cabozantinib combination. Stock or other ownership: Leuchemix. The remaining authors declare that there are no conflict of interests. We appreciate the patients and their families who contributed to this study as well as the many EA3805 co‐investigators. This study was coordinated by the ECOG‐ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co‐Chairs) and supported by the National Cancer Institute of the National Institutes of Health (NIH) under the following award numbers: U10CA180820, U10CA180794, UG1CA233180, UG1CA233196, R01CA208254‐01, and Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. All authors, ECOG‐ACRIN, and Sanofi provide consent for publication.
| Funders | Funder number |
|---|---|
| Ology Medical Education | |
| U.S. Government | |
| National Institutes of Health (NIH) | R01CA208254‐01 |
| National Childhood Cancer Registry – National Cancer Institute | U10CA180820, U10CA180794, UG1CA233180, UG1CA233196 |
| Pfizer | |
| Genentech Incorporated | |
| Novartis | |
| Sanofi | |
| Exelixis Inc. | |
| Bayer Fund |
Keywords
- ADT
- IL-8
- MCP
- TNF-α
- cytokines
- hormone sensitive prostate cancer
ASJC Scopus subject areas
- Oncology
- Urology
