Background

Despite numerous discoveries regarding the molecular genesis and progression of primary cancers, the biology of metastasis remains poorly understood. Compared to very large numbers of circulating tumor cells that are now known to accompany nearly all cancers, a relatively limited number of lesions actually develop in most patients with metastases. We hypothesized that phenotypic changes driven by differential gene expression in a finite subpopulation of tumor cells render those cells capable of metastasis and sought to identify key pathways through analysis of gene expression in primary and metastatic lesions from the same patients.

Methods

We compared whole-genome expression in 4 matched samples of primary and metastatic sarcoma, then evaluated candidate genes with differential expression via quantitative PCR in 30 additional matched sets, tumor tissue immunostaining, siRNA loss-of-function in a sarcoma cell migration assay, and clinical correlation with overall and disease-free survival after metastasectomy.

Results

Comparison of microarray signals identified differential expression of cell adhesion genes, including upregulation of KRT7 and MUC1 in metastases; KRT7 and MUC1 upregulation was confirmed in 22 (73%) and 20 (67%) matched sets of metastatic/primary tumors, respectively. Silencing of KRT7 and MUC1 via targeted siRNAs suppressed sarcoma cell migration in vitro, and a significant correlation (two-sided) was observed between both KRT7 and MUC1 expression in metastases and overall patient survival.

Conclusion

KRT7 and MUC1 may play a significant role in enabling sarcoma metastasis, and they may therefore be important prognostic biomarkers as well as potential targets for therapeutic prevention of metastasis.

Background

To evaluate the safety and tolerability of docetaxel/carboplatin regimen in the post-operative setting of patients with non-small cell lung cancer (NSCLC).

Methods

Enrolment of 133 patients with stage Ib - IIIa NSCLC was undertaken in an open-label, single arm study to assess the safety and tolerability of docetaxel (75 mg/kg) and carboplatin (AUC 5.5) administered for 3 cycles after resection for curative intent. The primary endpoint of the study was safety, as reflected by a febrile neutropenia rate of <10%. Other endpoints assessed protocol compliance and the impact of minimally invasive surgical technique.

Results

Patient accrual was completed at 1 center in the US and 10 centers in China in <6 months. Febrile neutropenia complicated treatment in 12 patients (9.0%), below the predetermined safety threshold of 14 patients. Four VATS and 8 open thoracotomy patients experienced febrile neutropenia (P=0.26). Completion of the three-cycle adjuvant regimen was achieved in 86% (95% CI, 77-95%) of patients. Sixty-two of 66 VATS patients compared to 53 of 67 open thoracotomy patients received all three doses according to protocol (P<0.01). Thirteen serious adverse events (9.8%) and no deaths were attributed to the study regimen.

Conclusions

In this rapidly accrued study, docetaxel and carboplatin were well-tolerated in the adjuvant treatment of NSCLC. Adjuvant treatment compliance was higher among patients undergoing a minimally invasive surgical approach. (ClinicalTrials.gov number NCT00883675).