Primary colorectal cancers and their subsequent hepatic metastases are genetically different: implications for selection of patients for targeted treatment.

PURPOSE: In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters. Here, we analyzed genetic differences between primary colorectal adenocarcinomas (CRC) and their respective hepatic metastasis. EXPERIMENTAL DESIGN: The primary CRC and the subsequent hepatic metastasis of 21 patients with CRC were analyzed using targeted deep-sequencing of DNA isolated from formalin-fixed, paraffin-embedded archived material. RESULTS: We have interrogated the genetic constitution of a designed "Cancer Mini-Genome" consisting of all exons of 1,264 genes associated with pathways relevant to cancer. In total, 6,696 known and 1,305 novel variations were identified in 1,174 and 667 genes, respectively, including 817 variants that potentially altered protein function. On average, 83 (SD = 69) potentially function-impairing variations were gained in the metastasis and 70 (SD = 48) variations were lost, showing that the primary tumor and hepatic metastasis are genetically significantly different. Besides novel and known variations in genes such as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, aberrations in the up/downstream genes of EGFR/PI3K/VEGF-pathways and other pathways (mTOR, TGFß, etc.) were also detected, potentially influencing therapeutic responsiveness. Chemotherapy between removal of the primary tumor and the metastasis (N = 11) did not further increase the amount of genetic variation. CONCLUSION: Our study indicates that the genetic characteristics of the hepatic metastases are different from those of the primary CRC tumor. As a consequence, the choice of treatment in studies investigating targeted therapies should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor.

Validation of serum amyloid α as an independent biomarker for progression-free and overall survival in metastatic renal cell cancer patients.

BACKGROUND: We recently identified apolipoprotein A2 (ApoA2) and serum amyloid α (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model. OBJECTIVE: Validate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs). DESIGN, SETTING, AND PARTICIPANTS: For training we used 114 interferon-treated mRCC patients (inclusion 2001-2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003-2009). MEASUREMENTS: Using Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect. RESULTS AND LIMITATIONS: Baseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA levels, patients were categorized in three risk groups, demonstrating accurate risk prognostication. SAA as a single biomarker showed equal prognostic accuracy when compared with the multifactorial MSKCC risk mode. Using receiver operating characteristic analysis, SAA levels >71 ng/ml were designated as the optimal cut-off value in the training cohort, which was confirmed for its significant sensitivity and specificity in the validation cohort. Applying SAA >71 ng/ml as an additional risk factor significantly improved the predictive accuracy of the MSKCC model in both independent cohorts. Changes in SAA levels after 6-8 wk of TKI treatment had no value in predicting treatment outcome. CONCLUSIONS: SAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management.