Molecular Landscape and Prognostic Biomarker Analysis of Advanced Pancreatic Cancer and Predictors of Treatment Efficacy of AG Chemotherapy

Juan Du; Xin Qiu; Changchang Lu; Yahui Zhu; Weiwei Kong; Mian Xu; Xin Zhang; Min Tang; Jun Chen; Qi Li; Aimei Li; Jian He; Qing Gu; Lei Wang; Yudong Qiu; Baorui Liu

doi:10.3389/fonc.2022.844527

Molecular Landscape and Prognostic Biomarker Analysis of Advanced Pancreatic Cancer and Predictors of Treatment Efficacy of AG Chemotherapy

Front Oncol. 2022 May 18:12:844527. doi: 10.3389/fonc.2022.844527. eCollection 2022.

Authors

Juan Du¹, Xin Qiu², Changchang Lu², Yahui Zhu¹, Weiwei Kong¹, Mian Xu³, Xin Zhang³, Min Tang⁴, Jun Chen⁵, Qi Li⁵, Aimei Li⁶, Jian He⁶, Qing Gu⁷, Lei Wang⁸, Yudong Qiu⁹, Baorui Liu¹

Affiliations

¹ The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.
² The Comprehensive Cancer Center of Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
³ Shanghai OrigiMed Co, Ltd, Shanghai, China.
⁴ Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
⁵ Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
⁶ Department of Nuclear Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
⁷ State Key Lab of Novel Software Technology, Nanjing University, Nanjing, China.
⁸ Department of Gastroenterology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
⁹ Department of Hepatopancreatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Abstract

Purpose: Although mutational analysis of pancreatic cancer has provided valuable clinical information, it has not significantly changed treatment prospects. The purpose of this study is to further investigate molecular alterations in locally advanced pancreatic cancer and identify predictors of the efficacy of nab-paclitaxel plus gemcitabine (AG) chemotherapy.

Experimental design: Tumor samples from 118 pancreatic cancer patients who received AG chemotherapy as first-line treatment were sequenced and genomic profile was generated. Molecular alterations and the involved signaling pathways were analyzed. Genes with a significant difference in mutation frequency between primary and metastatic tumors were identified, and prognostic-related mutant genes were screened using SPSS version 22.0.

Results: The most common altered genes in the patients were KRAS (94.9%), TP53 (81.4%), CDKN2A (36.4%), and SMAD4 (22.9%). The mutational frequencies of CDKN2B (14.8% vs. 0%, p = 0.001), FAT3 (7.4% vs. 0%, p = 0.041), MTAP (13% vs. 1.6%, p = 0.023), and SMAD4 (31.4% vs. 15.6%, p = 0.049) in metastatic tumors were significantly higher than that in primary tumors. TP35 and KRAS mutations were significantly correlated with objective response rate, while EPHA7, RNF43, and HMGA2 mutations were significantly correlated with disease control rate. Additionally, patients with TGFR2B, FGF23, EPHA7, SMARCA4, CARD11, ADGRA2, CCNE1, and ACVR2A alterations had a worse overall survival. Further, EPHA7, CARD11, NOTCH1, GATA6, ACVR2A, and HMGA2 mutations indicated undesirable progression-free survival.

Conclusions: CDKN2B, FAT3, MTAP, and SMAD4 may be biomarkers that distinguish primary tumors from metastases. EPHA7 mutation may serve as a prognostic biomarker to predict the treatment efficacy of AG chemotherapy in locally advanced pancreatic cancer.

Keywords: AG chemotherapy; advanced pancreatic cancer; metastasis; mutational analysis; prognostic biomarker.