ABSTRACT
PURPOSE: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. RESULTS: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. CONCLUSIONS: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biomarkers, Tumor/deficiency , Colorectal Neoplasms/pathology , Neoplasm Recurrence, Local/diagnosis , Smad4 Protein/deficiency , Adult , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/immunology , Chemotherapy, Adjuvant/methods , Colon/pathology , Colon/surgery , Colorectal Neoplasms/immunology , Colorectal Neoplasms/mortality , Colorectal Neoplasms/therapy , Disease-Free Survival , Drug Resistance, Neoplasm/immunology , Female , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Follow-Up Studies , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Male , Mice , Middle Aged , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/prevention & control , Prognosis , Prospective Studies , Rectum/pathology , Rectum/surgery , Smad4 Protein/immunology , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Positron emission tomography (PET) response criteria in solid tumors were recently proposed as a standardized method for the metabolic and quantitative assessment of response to chemotherapy. However, use of these criteria is limited in many institutions because of the need for exclusive software. This study was designed to clarify whether tumor to normal esophageal (T/N) ratio on (18)F-fluorodeoxyglucose PET/computed tomography could predict response to neoadjuvant chemotherapy and stratify prognosis in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Clinicopathological data were collected for 73 patients with ESCC who received neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil followed by curative resection. The right liver lobe and normal esophagus were utilized as reference tissues for diagnosing complete metabolic response (CMR). Statistical methods included Kaplan-Meier analysis and univariate and multivariate Cox proportional hazards regression analyses. RESULTS: CMR was achieved in 24 patients on the basis of maximum standardized uptake value (SUVmax) and in 11 on the basis of SUVmax evaluation with T/N ratio. Although prognosis was poorer in patients who achieved CMR than partial metabolic response based on SUVmax, the responses were significantly correlated with disease-free survival (DFS) based on SUVmax evaluation with T/N ratio (P = 0.0011). Receiver operating characteristic curve analysis showed that SUVmax evaluation with T/N ratio was the best predictor of pGrade 3. Multivariate analysis showed that SUVmax evaluation with T/N ratio was an independent predictor of DFS in patients with pGrade 1 pathologic response. CONCLUSIONS: SUVmax evaluation with T/N ratio is useful for evaluating the effects of neoadjuvant chemotherapy in patients with ESCC.