Cristobal T. Sanhueza

Whole Blood mRNA Expression-Based Prognosis of Metastatic Renal Cell Carcinoma

The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters. We analyzed whole blood mRNA expression in metastatic clear cell renal cell carcinoma (mCCRCC) patients and compared it to the MSKCC score for predicting overall survival. In a discovery set of 19 patients with mRCC, we performed whole transcriptome RNA sequencing and selected eighteen candidate genes for further evaluation based on associations with overall survival and statistical significance. In an independent validation of set of 47 patients with mCCRCC, transcript expression of the 18 candidate genes were quantified using a customized NanoString probeset. Cox regression multivariate analysis confirmed that two of the candidate genes were significantly associated with overall survival. Higher expression of BAG1 [hazard ratio (HR) of 0.14, p < 0.0001, 95% confidence interval (CI) 0.04–0.36] and NOP56 (HR 0.13, p < 0.0001, 95% CI 0.05–0.34) were associated with better prognosis. A prognostic model incorporating expression of BAG1 and NOP56 into the MSKCC score improved prognostication significantly over a model using the MSKCC prognostic score only (p < 0.0001). Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.

Serum chromogranin-A-based prognosis in metastatic castration-resistant prostate cancer

Objective:To determine the prognostic value of serum chromogranin-A (CGA) in a two-cohort study of men with metastatic castrate resistant prostate cancer (mCRPC) and to compare with circulating tumor cells (CTCs)-based prognosis.Patients and methods:A two-cohort-based evaluation for serum CGA for prognostication in CRPC stage was performed using a screening cohort of 256 men with mCRPC and an independent validation cohort of 92 men with mCRPC. In both cohorts, men receiving proton pump inhibitors and those with non-castrate levels of testosterone (>50u2009ng/dl) were excluded. Serum CGA was measured in a homogeneous automated immunofluorescent assay using time-resolved amplified cryptate emission. In the validation cohort, CTC enumeration was also performed using the FDA-cleared CELLSEARCH® CTC test. Cox proportional hazard regression models were used for prognostic association of serum CGA and CTC counts with overall survival.Results:In the screening cohort, 200 men were eligible for analysis. The median serum CGA was 100.3u2009ng/mL (interquartile range: 67–161.3) and 34/200 were above the reference range. In the subset of men with Gleason scoresu2009≥u20098, elevated CGA was associated with shorter overall survival [hazard ratio (HR) 2.19, pu2009=u20090.017]. In the validation cohort for 71 men eligible for analysis, the median serum CGA was 90u2009ng/mL (interquartile range: 55–156) and 31/71 patients had an elevated CGA. 51% of patients had a Gleason scoreu2009≥u20098 and 66/71 patients had CTCs enumerated with 26/66 with a CTC countu2009≥u20095 per 7.5u2009ml blood sample (unfavorable). Both elevated serum CGA (HR: 1.91, pu2009=u20090.043) and unfavorable CTC counts (HR: 2.97, pu2009=u20090.0012) were adversely associated with overall survival and patients withu2009≥u20095 CTCs and elevated serum CGA had the shortest overall survival (HR: 3.76, pu2009=u20090.008).Conclusion:Elevated serum CGA was negatively associated with OS in men with mCRPC. Serum CGA represents a prognostic biomarker that may complement CTC enumeration.

Outcome of Mismatch Repair‐Deficient Metastatic Colorectal Cancer: The Mayo Clinic Experience

BACKGROUNDnDeficiencies in the DNA mismatch repair system cause errors during DNA replication, which in turn give rise to microsatellite instability (MSI). The impact of MSI on survival in metastatic colorectal cancer (mCRC) is unclear. This cohort study aims to investigate the prognostic and predictive value of MSI in mCRC prior to the immune therapy era.nnnMATERIALS AND METHODSnA total of 75 MSI-high (MSI-H) mCRC patients (pts) and 75 matched (age, gender, disease sidedness, metachronous/synchronous) microsatellite-stable (MSS) mCRC pts were identified from 1,268 mCRC pts who had MSI/mismatch repair test results at Mayo Clinic Rochester between January 1992 and July 2016. A retrospective review was conducted by using data from electronic medical records. Statistical analyses utilized the Kaplan-Meier method, log-rank test, and Cox proportional hazards models.nnnRESULTSnThe MSS group was well matched to the MSI-H group based on age, gender, location, and chronicity of metastatic disease. MSI-H mCRC pts had earlier disease recurrence (median time from initial diagnosis to metastatic disease diagnosis, MSI-H group 12.9 vs. MSS group 20.9 months, pu2009=u2009.034). Median overall survival (OS) was 28.1 and 37.4 months for MSI-H and MSS pts, respectively (pu2009=u2009.99). In total, 94.7% of MSI-H pts and 98.7% of MSS pts had fluoropyrimidine-based chemotherapy for metastatic disease, and there was no difference in OS between these two groups (32.3 vs. 37.4 months, pu2009=u2009.91). Forty-three MSI-H and thirty-nine MSS pts had metastasectomy and/or ablation of metastases (pu2009=u2009.51) with longer median OS compared with pts without metastasectomy (MSI-H: 82.0 vs. 13.9, p < .001; MSS: 69.9 vs. 19.7, pu2009<u2009.001). Age <65 years, BRAF wild type, and metastasectomy were associated with better OS in univariate analysis. Only metastasectomy remained statistically significant in multivariate analysis (pu2009<u2009.001).nnnCONCLUSIONnIn mCRC, patients with MSI-H tumors have similar, but numerically shorter, median overall survival compared with those with MSS tumors. In both groups, metastasectomy and ablation of metastatic disease should be considered to optimize OS.nnnIMPLICATIONS FOR PRACTICEnThis study clearly demonstrated the survival benefits that aggressive metastasectomy provides in selected microsatellite instability-high metastatic colorectal cancer patients. This could be meaningful practice-changing information that has been long awaited.

Prognostic factors and benefits of adjuvant therapy after pancreatoduodenectomy for ampullary adenocarcinoma: Mayo Clinic experience

INTRODUCTIONnAmpullary adenocarcinoma is a rare entity with limited data on prognostic factors. The aim of this study is to identify prognostic factors and assess the benefit of adjuvant therapy in patients with ampullary adenocarcinoma who underwent pancreatoduodenectomy.nnnMETHODSnA cohort of 121 consecutive patients underwent pancreatoduodenectomy for ampullary adenocarcinoma from 2006 to 2016xa0at Mayo Clinic in Rochester, MN. All patients were confirmed by independent pathologic review to have ampullary carcinoma. Patient survival and its correlation with patient and tumor variables were evaluated by univariate and multivariate analysis.nnnRESULTSnFifty three patients (45%) received adjuvant therapy (34 patients had chemotherapy alone, while 19 patients received both chemotherapy and radiation therapy). Fifty seven percent of the patients were diagnosed with advanced stage disease (Stage IIB or higher). Nearly all patients (98.3%) had negative surgical margins. Median overall survival (OS) was 91.8 months (95% CI:52.6 months-not reached). In multivariate analysis, excellent performance status (ECOG: 0), adjuvant therapy, and advanced stage remained statistically significant. Adjuvant therapy was independently associated with improved disease free survival (Hazard ratio [HR]:0.52, Pxa0=xa00.04) and overall survival (HR:0.45, Pxa0=xa00.03) in patients with advanced disease.nnnCONCLUSIONSnAdjuvant therapy was associated with improved survival in patients with resected ampullary cancer, especially with advanced stage disease. A multi-institutional randomized trial is needed to further assess the role of adjuvant therapy in ampullary adenocarcinoma.

Clinical and Novel Biomarkers in the Management of Prostate Cancer

Opinion statementClinical outcomes in prostate cancer after initial screening and treatment for organ-confined disease and in advanced stage after drug intervention can be heterogeneous. Serum prostate-specific antigen which has a modest value as a screening biomarker while widely used in practice in all subsequent stages has limitations for prognostication or prediction of drug efficacy. Recent advances in genomic sciences and the identification of the mutational landscape of organ-confined and advanced-stage disease have contributed to the development of molecular biomarker profiling in addition to serum prostate-specific antigen. Genomic biomarkers are in development for application to screening for lethal disease subtypes, monitoring of disease recurrence after initial treatments, prognostication, as well as for prediction of drug efficacy. The application of translational molecular profiling in prostate cancer has the potential to enhance clinical management and outcomes in the future. Molecular biomarkers in development in organ-confined disease include both DNA- and RNA-based candidate and pathway-based biomarkers. In advanced-stage disease, molecular biomarker profiling has emerged for identifying therapeutic targets, prediction of drug efficacy, and for prognostication of survival that includes germline single nucleotide profiling and somatic aberrations including copy number variation and mutations and RNA-based profiling. This review summarizes the current state of clinical biomarkers used in practice, their limitations, and novel molecular biomarkers being developed for several clinical endpoints in early- and late-stage cancer.