Cite this article as: Zhong C, Fang X, Zhu L, Li D, Tang J, Yuan Y. Report of two cases and a systematic review of breast cancer with gastrointestinal metastasis. Turk J Gastroenterol 2019; 30(11): 997-1000.

Predictive biomarkers of response to chemotherapy in patients with metastatic colorectal cancer (mCRC) are needed to better characterize tumors and enable more tailored therapies. Here we used serum proteomics to screen for chemotherapy predictive markers. We found that higher baseline serum inter-α-trypsin inhibitor Heavy Chain 4 (ITIH4) expression in newly diagnosed mCRC patients was associated with poorer response to standard first-line chemotherapy. In addition, the higher expression of ITIH4 in CRC tissue also suggested poorer prognosis mCRC patients. Moreover, the overexpression of ITIH4 could promote the proliferation of CRC cells and reduce the sensitivity of CRC cells to 5-fluorouracil (5-FU) by inhibiting apoptosis in vivo and vitro. Through RNA-seq combined with bioinformatics analysis, we speculated that ITIH4 may activate phosphatidyl 3-kinase-protein kinase B (PI3K-AKT) pathway to inhibit apoptosis, thereby reducing the sensitivity of CRC cells to 5-FU. In conclusion, our findings unveil that ITIH4 is associated with CRC resistance to 5-FU, and may serve as a potential predictive biomarker for the sensitivity of advanced CRC patients to standard first-line chemotherapy regimens, and also provide a potential therapeutic target to render 5-FU resistance in CRC patients.

Background and Objective: Colorectal cancer (CRC) bone metastasis (BM), particularly synchronous metastasis, is infrequent and has a poor prognosis. Radical surgery for CRC with BM is challenging, and chemotherapy is the standard treatment. However, it is unclear whether combining chemotherapy with primary tumor resection (PTR) yields greater survival benefits than chemotherapy alone, as no relevant reports exist. Material and Methods: The Surveillance, Epidemiology, and End Results (SEER) database provided data on 1662 CRC patients with bone metastasis between 2010 and 2018, who were divided into two groups: chemotherapy combined with PTR and chemotherapy alone. Survival distributions were compared using the log-rank test, and survival estimates were obtained using the Kaplan–Meier method. A Cox proportional multivariate regression analysis was conducted to estimate the survival benefit of chemotherapy combined with PTR while controlling for additional prognostic factors. Results: The chemotherapy only group consisted of 1277 patients (76.8%), while the chemotherapy combined with PTR group contained 385 patients (23.2%). Patients who received chemotherapy combined with PTR had a significantly higher 1-year survival rate (60.7%) and 2-year survival rate (32.7%) compared to those who only received chemotherapy (43.8% and 18.4%, respectively; p < 0.0001). Independent prognostic factors identified by Cox proportional analysis were age, location of the primary tumor, type of tumor, M stage, metastasectomy and PTR. Patients who received chemotherapy combined with PTR had a significantly improved prognosis (HR 0.586, 95% CI 0.497–0.691, p < 0.0001). All subgroups demonstrated a survival advantage for patients who received chemotherapy in combination with PTR. Conclusions: Our findings suggest that patients with BM from CRC may benefit from chemotherapy combined with PTR. Our analysis also identified age, location of the primary tumor, type of tumor, M stage, metastasectomy, and PTR as independent prognostic risk factors for CRC patients with synchronous BM.