Multicohort Retrospective Validation of a Predictive Biomarker for Topoisomerase I Inhibitors.

PURPOSE: The camptothecin (CPT) analogs topotecan and irinotecan specifically target topoisomerase I (topoI) and are used to treat colorectal, gastric, and pancreatic cancer. Response rate for this class of drug varies from 10% to 30%, and there is no predictive biomarker for patient stratification by response. On the basis of our understanding of CPT drug resistance mechanisms, we developed an immunohistochemistry-based predictive test, P-topoI-Dx, to stratify the patient population into those who did and did not experience a response. PATIENTS AND METHODS: The retrospective validation studies included a training set (n = 79) and a validation cohort (n = 27) of gastric cancer (GC) patients, and 8 cohorts of colorectal cancer (CRC) patient tissue (n = 176). Progression-free survival for 6 months was considered a positive response to CPT-based therapy. Formalin-fixed, paraffin-embedded slides were immunohistochemically stained with anti-phospho-specific topoI-Serine10 (topoI-pS10), quantitated, and analyzed statistically. RESULTS: We determined a threshold of 35% positive staining to offer optimal test characteristics in GC. The GC (n = 79) training set demonstrated 76.6% (95% confidence interval, 64-86) sensitivity; 68.8% (41-88) specificity; positive predictive value (PPV) 92.5% (81-98); and negative predictive value (NPV) 42.3% (24-62). The GC validation set (n = 27) demonstrated 82.4% (56-95) sensitivity and 70.0% (35-92) specificity. Estimated PPV and NPV were 82.4% (56-95) and 70.0% (35-92) respectively. In the CRC validation set (n = 176), the 40% threshold demonstrated 87.5% (78-94) sensitivity; 70.0% (59-79) specificity; PPV 70.7% (61-79); and NPV 87.0 % (77-93). CONCLUSION: The analysis of retrospective data from patients (n = 282) provides clinical validity to our P-topoI-Dx immunohistochemical test to identify patients with disease that is most likely to respond to topoI inhibitors.

c-Cbl Expression Correlates with Human Colorectal Cancer Survival and Its Wnt/ß-Catenin Suppressor Function Is Regulated by Tyr371 Phosphorylation.

The proto-oncogene ß-catenin drives colorectal cancer (CRC) tumorigenesis. Casitas B-lineage lymphoma (c-Cbl) inhibits CRC tumor growth through targeting nuclear ß-catenin by a poorly understood mechanism. In addition, the role of c-Cbl in human CRC remains largely underexplored. Using a novel quantitative histopathologic technique, we demonstrate that patients with high c-Cbl-expressing tumors had significantly better median survival (3.7 years) compared with low c-Cbl-expressing tumors (1.8 years; P = 0.0026) and were more than twice as likely to be alive at 3 years compared with low c-Cbl tumors (P = 0.0171). Our data further demonstrate that c-Cbl regulation of nuclear ß-catenin requires phosphorylation of c-Cbl Tyr371 because its mutation compromises its ability to target ß-catenin. The tyrosine 371 (Y371H) mutant interacted with but failed to ubiquitinate nuclear ß-catenin. The nuclear localization of the c-Cbl-Y371H mutant contributed to its dominant negative effect on nuclear ß-catenin. The biological importance of c-Cbl-Y371H was demonstrated in various systems, including a transgenic Wnt-8 zebrafish model. c-Cbl-Y371H mutant showed augmented Wnt/ß-catenin signaling, increased Wnt target genes, angiogenesis, and CRC tumor growth. This study demonstrates a strong link between c-Cbl and overall survival of patients with CRC and provides new insights into a possible role of Tyr371 phosphorylation in Wnt/ß-catenin regulation, which has important implications in tumor growth and angiogenesis in CRC.

Racial differences in colorectal cancer survival at a safety net hospital.

BACKGROUND: While racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood. METHODS: We examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital's electronic medical record. Survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated. RESULTS: Black patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.70, CI 1.01-2.90, p=0.0467) for death. Though response to therapy emerged as a strong predictor of survival (HR=0.4, CI=0.2-0.7, p=0.0021), it was comparable between Blacks and Whites. CONCLUSIONS: Despite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce findings from previous studies showing lower colorectal cancer survival in Black patients, and also point to the importance of investigating other factors such as genetic and pathologic differences.

Arriving at the Right Diagnosis in an Era of Precision Medicine.

In the era of precision medicine and targeted therapy, diagnostic inaccuracy can have tremendous ramifications. We present the case of a 61-year-old man initially diagnosed with small cell lung cancer by pathology. Prior to initiating chemotherapy, multidisciplinary discussions led to an amendment of the diagnosis to medullary thyroid cancer.

c-Cbl mediates the degradation of tumorigenic nuclear ß-catenin contributing to the heterogeneity in Wnt activity in colorectal tumors.

Despite the loss of Adenomatous Polyposis Coli (APC) in a majority of colorectal cancers (CRC), not all CRCs bear hallmarks of Wnt activation, such as nuclear ß-catenin. This underscores the presence of other Wnt regulators that are important to define, given the pathogenic and prognostic roles of nuclear ß-catenin in human CRC. Herein, we investigated the effect of Casitas B-lineage lymphoma (c-Cbl) on nuclear ß-catenin, which is an oncoprotein upregulated in CRC due to loss-of-function APC or gain-of-function CTNNB1 mutations. Despite mechanistic rationale and recent discoveries of c-Cbl's mutations in solid tumors, little is known about its functional importance in CRC. Our study in a cohort of human CRC patients demonstrated an inverse correlation between nuclear ß-catenin and c-Cbl. Further investigation showed that the loss of c-Cbl activity significantly enhanced nuclear ß-catenin and CRC tumor growth in cell culture and a mouse xenograft model. c-Cbl interacted with and downregulated ß-catenin in a manner that was independent of CTNNB1 or APC mutation status. This study demonstrates a previously unrecognized function of c-Cbl as a negative regulator of CRC.

Update on the Management of Pancreatic Cancer in Older Adults.

Pancreatic cancer is more common in older adults, who are underrepresented in clinical trials and frequently under treated. Chronological age alone should not deter clinicians from offering treatment to geriatric patients, as they are a heterogeneous population. Geriatric assessment, frailty assessment tools, and toxicity risk scores help clinicians select appropriate patients for therapy. For resectable disease, surgery can be safe but should be done at a high-volume center. Adjuvant therapy is important; though there remains controversy on the role of radiation, chemotherapy is well studied and efficacious. In locally advanced unresectable disease, chemoradiation or chemotherapy alone is an option. Neoadjuvant therapy improves the chances of resectability in borderline resectable disease. Chemotherapy extends survival in metastatic disease, but treatment goals and risk-benefit ratios have to be clarified. Adequate symptom management and supportive care are important. There are now many new treatment strategies and novel therapies for this disease.

Impact of the 2008 U.S. Preventative Services Task Force recommendation on frequency of prostate-specific antigen screening in older men.

OBJECTIVES: To evaluate the effect of the 2008 U.S. Preventative Services Task Force recommendation against prostate-specific antigen (PSA) screening in men aged 75 and older on frequency of PSA screening in elderly men. DESIGN: Retrospective, cross-sectional analysis. SETTING: Fifteen community primary care practices in western Massachusetts. PARTICIPANTS: Men aged 65 and older with one or more annual physicals between January 1, 2006, and December 31, 2010. MEASUREMENTS: PSA testing was determined from the electronic health record. Mixed-effects logistic regression was used to model the rate of PSA testing over time for two age groups: 65 to 74, and 75 and older. RESULTS: Of the 7,833 men in this study, 60% were younger than 75. PSA screening rates were consistently lower in men aged 75 and older. Annual rates, adjusted for number of clinic visits, ranged from 12% to 28% in men aged 75 and older, and 37% to 49% in men aged 65 to 74. In the 2 years before the guideline was released, there was already a slow decline in screening rate in men aged 75 and older, whereas the screening rate in men aged 65 to 74 was rising. Compared to 2008, there was a 36% relative reduction in screening rate in 2009 and a 51% relative reduction in 2010 for men aged 75 and older, and a 12% relative reduction in screening rate in 2009 and a 24% relative reduction in 2010 for men aged 65 to 74. CONCLUSION: The 2008 recommendation appeared to reduce PSA screening rates in older men in 2009 and 2010; there was a substantial reduction in men aged 75 and older and a more modest reduction in men aged 65 to 74.