Identification and Validation the Predictive Biomarkers Based on Risk-adjusted Control Chart in Gemcitabine with or Without Erlotinib for Pancreatic Cancer Therapy

Overview

Journal Front Genet

Date 2025 Jan 1

PMID 39741907

Authors

Aijun Zhao

Dongsheng Tu

Ye He

Liu Liu

Bin Wu

Yixing Ren

Affiliations

Soon will be listed here.

Abstract

Background: In a randomized clinical controlled trial (PA.3) conducted by the Canadian Cancer Trials Group, the effects of gemcitabine combined with the targeted drug erlotinib (GEM-E) gemcitabine alone (GEM) on patients with unresectable, locally advanced, or metastatic pancreatic cancer were studied. This trial statistically demonstrated that the GEM-E combination therapy moderately improves overall survival (OS) of patients. However, real-world analysis suggested that GEM-E for pancreatic cancer was not more effective than GEM. The heterogeneity in outcomes or treatment effect exist. Thus, we tried to find predictive biomarkers to identifying the heterogeneous patients.

Methods: Of the 569 eligible patients, 480 patients had plasma samples. Univariate and multivariate Cox proportional hazards model were used to identify baseline characteristics related to OS, and a risk adjusted Exponentially Weighted Moving Average (EWMA) control chart based on a weighted score test from the Cox model was constructed to monitor patients' survival risk. Maximally selected rank statistics were constructed to identifying the predictive biomarkers, in addition, a risk adjusted control chart based on a weighted score test from the Cox model was constructed to validating the predictive biomarkers, discover the patients who sensitive to the GEM-E or GEM.

Results: Three baseline characteristics (ECOG performance status, extent of disease, and pain intensity) were identified related to prognosis. A risk-adjusted EWMA control chart was constructed and showed that GEM-E did improve OS in a few patients. Three biomarkers (BMP2, CXCL6, and HER2) were identified as predictive biomarkers based on maximum selected rank test, and using the risk-adjusted EWMA control chart to validate the reality and discover some patients who are sensitive to the GEM-E therapy.

Conclusion: In reality, GEM-E has not shown a significant advantage over GEM in the treatment of pancreatic cancer. However, we discovered some patients who are sensitive to the GEM-E therapy based on the predictive biomarkers, which suggest that the predictive biomarkers provide ideas for personalized medicine in pancreatic cancer.

References

Fredriksson S, Dixon W, Ji H, Koong A, Mindrinos M, Davis R . Multiplexed protein detection by proximity ligation for cancer biomarker validation. Nat Methods. 2007; 4(4):327-9. DOI: 10.1038/nmeth1020. View

Berlin J, Catalano P, Thomas J, Kugler J, Haller D, Benson 3rd A . Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002; 20(15):3270-5. DOI: 10.1200/JCO.2002.11.149. View

Moore M, Goldstein D, Hamm J, Figer A, Hecht J, Gallinger S . Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007; 25(15):1960-6. DOI: 10.1200/JCO.2006.07.9525. View

Steinberg W . The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990; 85(4):350-5. View

Li T, Lai Y, Han X, Niu X, Zhang P . BMP2 as a promising anticancer approach: functions and molecular mechanisms. Invest New Drugs. 2022; 40(6):1322-1332. DOI: 10.1007/s10637-022-01298-4. View

Neoptolemos J, Stocken D, Friess H, Bassi C, Dunn J, Hickey H . A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004; 350(12):1200-10. DOI: 10.1056/NEJMoa032295. View

Cooper W, Tan P . Predictive and prognostic biomarkers in solid tumours. Pathology. 2024; 56(2):145-146. DOI: 10.1016/j.pathol.2023.12.002. View

Kung H, Yu J . Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study. MedComm (2020). 2023; 4(2):e216. PMC: 9939368. DOI: 10.1002/mco2.216. View

Fernandez-Avila L, Castro-Amaya A, Molina-Pineda A, Hernandez-Gutierrez R, Jave-Suarez L, Aguilar-Lemarroy A . The Value of CXCL1, CXCL2, CXCL3, and CXCL8 as Potential Prognosis Markers in Cervical Cancer: Evidence of E6/E7 from HPV16 and 18 in Chemokines Regulation. Biomedicines. 2023; 11(10). PMC: 10604789. DOI: 10.3390/biomedicines11102655. View

10.

Stefanoudakis D, Frountzas M, Schizas D, Michalopoulos N, Drakaki A, Toutouzas K . Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer. Curr Issues Mol Biol. 2024; 46(4):2827-2844. PMC: 11049225. DOI: 10.3390/cimb46040177. View

11.

Shultz D, Pai J, Chiu W, Ng K, Hellendag M, Heestand G . A Novel Biomarker Panel Examining Response to Gemcitabine with or without Erlotinib for Pancreatic Cancer Therapy in NCIC Clinical Trials Group PA.3. PLoS One. 2016; 11(1):e0147995. PMC: 4725948. DOI: 10.1371/journal.pone.0147995. View

12.

Fjallskog M, Lejonklou M, Oberg K, Eriksson B, Janson E . Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumors. Clin Cancer Res. 2003; 9(4):1469-73. View

13.

Halbrook C, Lyssiotis C, Pasca di Magliano M, Maitra A . Pancreatic cancer: Advances and challenges. Cell. 2023; 186(8):1729-1754. PMC: 10182830. DOI: 10.1016/j.cell.2023.02.014. View

14.

Shin S, Park C, Kwon H, Lee K . Erlotinib plus gemcitabine versus gemcitabine for pancreatic cancer: real-world analysis of Korean national database. BMC Cancer. 2016; 16:443. PMC: 4940912. DOI: 10.1186/s12885-016-2482-z. View

15.

Gennari A, Andre F, Barrios C, Cortes J, de Azambuja E, DeMichele A . ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021; 32(12):1475-1495. DOI: 10.1016/j.annonc.2021.09.019. View

16.

He Y, Lin H, Tu D . A single-index threshold Cox proportional hazard model for identifying a treatment-sensitive subset based on multiple biomarkers. Stat Med. 2018; 37(23):3267-3279. DOI: 10.1002/sim.7837. View

17.

Kato H, Kishiwada M, Hayasaki A, Chipaila J, Maeda K, Noguchi D . Role of Serum Carcinoma Embryonic Antigen (CEA) Level in Localized Pancreatic Adenocarcinoma: CEA Level Before Operation is a Significant Prognostic Indicator in Patients With Locally Advanced Pancreatic Cancer Treated With Neoadjuvant Therapy.... Ann Surg. 2020; 275(5):e698-e707. DOI: 10.1097/SLA.0000000000004148. View

18.

Reinholz M, Kitzmann K, Tenner K, Hillman D, Dueck A, Hobday T . Cytokeratin-19 and mammaglobin gene expression in circulating tumor cells from metastatic breast cancer patients enrolled in North Central Cancer Treatment Group trials, N0234/336/436/437. Clin Cancer Res. 2011; 17(22):7183-93. PMC: 5723083. DOI: 10.1158/1078-0432.CCR-11-0981. View

19.

Mitra D, Brumlik M, Okamgba S, Zhu Y, Duplessis T, Parvani J . An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol Cancer Ther. 2009; 8(8):2152-62. DOI: 10.1158/1535-7163.MCT-09-0295. View

20.

Riely G, Pao W, Pham D, Li A, Rizvi N, Venkatraman E . Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006; 12(3 Pt 1):839-44. DOI: 10.1158/1078-0432.CCR-05-1846. View