PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

Hypoxia is a hallmark of solid tumors that drives malignant progression by altering epigenetic controls. In breast tumors, aberrant DNA methylation is a prevalent epigenetic feature associated with increased risk of metastasis and poor prognosis. However, the mechanism by which hypoxia alters DNA methylation or other epigenetic controls that promote breast malignancy remains poorly understood. We discovered that hypoxia deregulates TET1 and TET3, the enzymes that catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby leading to breast tumor-initiating cell (BTIC) properties. TET1/3 and 5hmC levels were closely associated with tumor hypoxia, tumor malignancy, and poor prognosis in breast cancer patients. Mechanistic investigations showed that hypoxia leads to genome-wide changes in DNA hydroxymethylation associated with upregulation of TNFa expression and activation of its downstream p38-MAPK effector pathway. Coordinate functions of TET1 and TET3 were also required to activate TNFa-p38-MAPK signaling as a response to hypoxia. Our results reveal how signal transduction through the TET-TNFa-p38-MAPK signaling axis is required for the acquisition of BTIC characteristics and tumorigenicity in vitro and in vivo, with potential implications for how to eradicate BTIC as a therapeutic strategy. Cancer Res; 75(18); 3912-24. Ó2015 AACR.

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Background The incidence rate of newly developed gallstone disease after gastrectomy for gastric cancer is thought to be higher than that in the general population. However, the presentation and management of these gallstones remain under debate, and the role of prophylactic cholecystectomy remains questionable. Methods Data on adult patients who were diagnosed with gastric cancer and received gastrectomy between 2000 and 2011 were extracted from the Taiwan National Health Insurance Research Database. A patient was excluded if he or she had gallstone disease or received cholecystectomy before the index date. The incidence of newly developed gallstone disease and its subsequent management were recorded. Data were analyzed to evaluate the factors associated with gallstone development and treatment options. Results A total of 17,325 gastric cancer patients who underwent gastrectomy were eligible for analysis. During the follow-up period (mean 4.1 years; median, 2.9 years), 1280 (7.4%) patients developed gallstone disease and 560 (3.2%) patients subsequently underwent cholecystectomy. The in-hospital mortality for cholecystectomy was 1.8% (10/560). Development of gallstone disease was associated with older age, total gastrectomy, duodenal exclusion, diabetes, cirrhosis, and more comorbidities. Factors associated with the use of cholecystectomy to treat gallstone disease included younger age, fewer comorbidities, medical center admission, and presentation as cholecystitis. Conclusions Although few patients required further gallbladder removal after gastrectomy for gastric malignancy, the increased mortality rate for subsequent cholecystectomy was worth noting. The decision to undergo prophylactic cholecystectomy might be individualized based upon patient characteristics and the surgeon's discretion.

These findings suggest that HMMR and SDC1 involved in the ECM-receptor interaction signaling pathway could act as effective independent prognostic biomarkers for breast ductal carcinoma.