Abstract 4610: Prognostic impact of KRAS driver mutations and GSTT1 expression in colorectal cancer to FOLFOX treatment

Abstract

Abstract Colorectal cancer (CRC) is one of the most common cancer and the leading causes of cancer-related death worldwide. CRCs are neoplasms which have high propensity for metastasis, especially spreading to liver and lung. Liver metastasis accounts for around 50% of CRC patients, usually associated with cancer relapse and worse prognosis of the patient. The combination chemotherapy FOLFOX including 5-flurouracil, oxaliplatin and leucovorin is one of the most common and standard first-line chemotherapy utilized for adjuvant and/or neoadjuvant treatment of patients with CRC, which can reduce the risk of cancer relapse. However, a number of studies reported that chemotherapy alone cannot completely eradicate all the cancer cells, especially metastatic cells. Moreover, the mutations of oncogenes such as KRAS, existed in more than 40% of CRC patients, are often associated with poor response of anti-EGFR therapy either as single agent or in combination with FOLFOX. There is still no direct evidence on the association of KRAS or other oncogenic drivers with the resistance to FOLFOX. To understand if any of the potential biomarkers have the predictive value of FOLFOX treatment for CRC patients, especially later stage diseases, we have selected 16 CRC PDX models derived from patients who are in stage II or later where most of patients’ tumors present invasion and metastatic features. We have evaluated the drug efficacy of FOLFOX treatment in vivo for these 16 CRC PDX models and found that 6 of them were sensitive to FOLFOX and 10 models have poor responses. To study the potential biomarkers which affect the efficacy of FOLFOX in CRC PDX models, we analyzed the correlation of tumor growth inhibition (TGI) with the genomic background of these PDX models and identified the genes with significant correlation. Through filtering the genes by their functional relevance to FOLFOX treatment, we found that low expression of GSTT1 was highly related to FOLFOX resistance in these CRC PDX models. GSTT1 deletions was found to enhance the resistance to chemotherapy and a shorter survival in AML patients, which is consistent with our observation. Furthermore, we have also run the driver mutation analysis for these 16 PDX models, and found that models without KRAS driver mutations are more sensitive to FOLFOX treatment. Interestingly, in 32 CRC patients treated with FOLFOX, we found the sensitivity of FOLFOX is correlated with wild type KRAS and high expression of GSTT1, similar to our findings in PDX studies. In conclusion, our studies demonstrated that KRAS driver mutations or low expression of GSTT1 gene may render higher chances of resistance to FOLFOX treatment, these biomarkers may be beneficial for clinicians to choose effective therapies for advance CRC patients. Citation Format: Jessie Jingjing Wang, Binchen Mao, Sheng Guo, Davy Xuesong Ouyang, Henry Qixiang Li. Prognostic impact of KRAS driver mutations and GSTT1 expression in colorectal cancer to FOLFOX treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4610.