Background & Aims-Biomarkers are needed to identify patients at risk of tumor progression following chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of therapy.

In this large cohort study, a pathCR is confirmed to be associated with better OS and RFS. The presence of a poorly differentiated tumor or SRCs reduces the likelihood of a pathCR. Future research should focus on molecular classifiers. Cancer 2017;123:4106-4113. © 2017 American Cancer Society.

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Purpose To validate pathologic markers of response to preoperative chemotherapy as predictors of disease-free survival (DFS) after resection of colorectal liver metastases (CLM). Patients and Methods One hundred seventy one patients who underwent resection of CLM after preoperative chemotherapy at 4 centers were studied. Pathologic response defined as proportion of tumor cells remaining (categorized complete (0%), major (<50%) or minor (≥50%)) and tumor thickness at tumor–normal liver interface (TNI) (categorized <0.5 mm, 0.5 mm-<5 mm and ≥5 mm)—were assessed by a central pathology reviewer and local pathologists. Results Pathologic response was complete in 8%, major in 49% and minor in 43%. Tumor thickness at the TNI was <0.5 mm in 21%, 0.5 mm-<5 mm in 56% and ≥5 mm in 23%.In multivariate analyses, using either pathologic response or tumor thickness at TNI, pathologic response (P=.002,.009), tumor thickness at TNI (P=0.015, <.001), duration of preoperative chemotherapy(P=.028,.043), number of CLM (P=.038,.037) and margin (P=.011,.016) were associated with DFS. In a multivariate analysis using both parameters, tumor thickness at TNI (P=.004,.015), duration of preoperative chemotherapy(P=.025), number of nodules(P=.027) and margin(P=.014) were associated with DFS. Tumor size by pathology examination was the predictor of pathologic response. Predictors of tumor thickness at the TNI were tumor size and chemotherapy regimen. There was near perfect agreement for pathologic response (κ=.82) and substantial agreement (κ=.76) for tumor thickness between central reviewer and local pathologists. Conclusion Pathologic response and tumor thickness at the TNI are valid predictors of DFS after preoperative chemotherapy and surgery for CLM.

Background: CDK9 inhibitors are antitumorigenic against solid tumors, including esophageal adenocarcinoma (EAC). However, efficacy of a CDK9 inhibitor combined with 5-fluorouracil (5-FU) and target proteins that are targeted by these agents in EAC are unknown. Methods: The anti-EAC efficacy of a new CDK9 inhibitor, BAY1143572, with and without 5-FU was assessed in vitro and in xenograft models in athymic nu/nu mice. Synergy between BAY1143572 and 5-FU in inhibiting cell proliferation was analyzed by calculating the combination index using CompuSyn software. Potential targets of BAY1143572 and 5-FU were identified by reverse-phase protein array. The effects of BAY1143572 and 5-FU on MCL-1 in vitro were analyzed by Western blotting, quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation assay. MCL-1 protein expression in tumors from patients with locoregional EAC treated with chemoradiation and surgery was assessed by immunohistochemistry. Results: BAY1143572 had dose-dependent antiproliferative and proapoptotic effects and demonstrated synergy with 5-FU against EAC in vitro. The median volumes of FLO-1 and ESO-26 xenografts treated with 5-FU plus BAY114352 were significantly smaller than those of xenografts treated with either agent alone ( p < 0.05). BAY1143572 downregulated MCL-1 by inhibiting HIF-1α binding to the MCL-1 promoter. 5-FU enhanced BAY1143572-induced MCL-1 downregulation and stable MCL-1 overexpression reduced the apoptosis induced by BAY1143572 and 5-FU in vitro. High patients’ tumor MCL-1 expression was correlated with shorter overall and recurrence-free survival. Conclusions: BAY1143572 and 5-FU have synergistic antitumorigenic effects against EAC. MCL-1 is a downstream target of CDK9 inhibitors and a predictor of response to neoadjuvant chemoradiation in EAC.