Comparison of microsatellite instability and chromosomal instability in predicting survival of patients with T3N0 colorectal cancer.

BACKGROUND: At least 2 apparently independent mechanisms, microsatellite instability (MSI) and chromosomal instability, are implicated in colorectal tumorigenesis. Their respective roles in predicting clinical outcomes of patients with T3N0 colorectal cancer remain unknown. METHODS: Eighty-eight patients with a sporadic T3N0 colon or rectal adenocarcinoma were followed up for a median of 67 months. For chromosomal instability analysis, Ki-ras mutations were determined by single-strand polymerase chain reaction, and p53 protein staining was studied by immunohistochemistry. For MSI analysis, DNA was amplified by polymerase chain reaction at 7 microsatellite targets (BAT25, BAT26, D17S250, D2S123, D5S346, transforming growth factor receptor II, and BAX). RESULTS: Overall 5-year survival rate was 72%. p53 protein nuclear staining was detected in 39 patients (44%), and MSI was detected in 21 patients (24%). MSI correlated with proximal location (P <.001) and mucinous content (P <.001). In a multivariate analysis, p53 protein expression carried a significant risk of death (relative risk = 4.0, 95% CI = 1.6 to 10.1, P =.004). By comparison, MSI was not a statistically significant prognostic factor for survival in this group (relative risk = 2.2, 95% CI = 0.6 to 7.3, P =.21). CONCLUSIONS: p53 protein overexpression provides better prognostic discrimination than MSI in predicting survival of patients with T3N0 colorectal cancer. Although MSI is associated with specific clinicopathologic parameters, it did not predict overall survival in this group. Assessment of p53 protein expression by immunocytochemistry provides a simple means to identify a subset of T3N0 patients with a 4-times increased risk for death.

Appropriateness of colonoscopy in Europe (EPAGE II). Screening for colorectal cancer.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for screening for colorectal cancer (CRC) in asymptomatic individuals without personal history of CRC or polyps, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews, and primary studies regarding colonoscopy for screening for colorectal cancer was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy in these circumstances. RESULTS: Available evidence for CRC screening comes from small case-controlled studies, with heterogeneous results, and from indirect evidence from randomized controlled trials (RCTs) on fecal occult blood test (FOBT) screening and studies on flexible sigmoidoscopy screening. Most guidelines recommend screening colonoscopy every 10 years starting at age 50 in average-risk individuals. In individuals with a higher risk of CRC due to family history, there is a consensus that it is appropriate to offer screening colonoscopy at < 50 years. EPAGE II considered screening colonoscopy appropriate above 50 years in average-risk individuals. Panelists deemed screening colonoscopy appropriate for younger patients, with shorter surveillance intervals, where family or personal risk of colorectal cancer is higher. A positive FOBT or the discovery of adenomas at sigmoidoscopy are considered appropriate indications. CONCLUSIONS: Despite the lack of evidence based on randomized controlled trials (RCTs), colonoscopy is recommended by most published guidelines and EPAGE II criteria available online (http://www.epage.ch), as a screening option for CRC in individuals at average risk of CRC, and undisputedly as the main screening tool for CRC in individuals at moderate and high risk of CRC.

Can resistance to trastuzumab be reversed by endocrine therapy? Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with ER-positive, HER-2 positive, advanced breast cancer: a proof-of-concept trial (SAKK 23/03)

Introduction: Trastuzumab (T) is a cornerstone in the treatment of patients with HER2-overexpressing advanced breast cancer and development of resistance to T is a major therapeutic problem. HER-2 is part of a highly interactive signaling network that may impair efficacy of endocrine therapy. A sequential treatment design was chosen in this trial to ensure complete resistance to single agent therapy before receiving both a non-steroidal aromatase inhibitor (AI) and T. Any kind of clinical activity with combined treatment of AI and T after progression of single agent treatments could indicate restoration of sensitivity as a consequence of cross-talking and networking between both pathways. Methods: Key eligibility criteria included postmenopausal patients (pts.) with advanced, measurable, HER-2 positive (assessed by FISH, ratio (≥2)), HR positive disease and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in an adjuvant or advanced setting. Pts. received standard dose T monotherapy either weekly or three-weekly in step 1 and upon disease progression, continued T in combination with letrozole in step 2. The primary endpoint was clinical benefit response (CBR: CR, PR or SD for at least 24 weeks (+/- 1 week) according to RECIST) in step 2. Results: Thirteen pts. were enrolled in five centers in Switzerland. In step 1, six pts. (46%) achieved CBR. Median time to progression (TTP) was 161 days (Range: 50 - 627). Based on data collected until the end of May 2010, CBR was observed in seven out of the eleven evaluable pts. (64%) in step 2, including one pt. with partial response. Four of the seven pts. within step 2 that achieved CBR also had CBR in step 1. Seven out of eleven pts. have documented tumor progression during step 2 treatment. Median TTP for all eleven pts. was 184 days (range 61 - 471). Mean time on study treatment (TTP in step 1 plus TTP in step 2) for pts. reaching step 2 was 380 days (range 174 - 864). Adverse events were generally mild. Conclusion: Results of this proof-of-principle trial suggest that complete resistance to both AI and T can be overcome in a proportion of pts. by combined treatment of AI and T, as all pts. served as their own control. Our results appear promising for a new treatment strategy which offers a chemotherapy-free and well-tolerated option for at least a subset of the pts. with HR positive, HER-2 positive breast cancer. Further trials will need to corroborate this finding.

Discovery of a 29-gene panel in peripheral blood mononuclear cells for the detection of colorectal cancer and adenomas using high throughput real-time PCR.

Colorectal cancer (CRC) is the second leading cause of cancer-related death in developed countries. Early detection of CRC leads to decreased CRC mortality. A blood-based CRC screening test is highly desirable due to limited invasiveness and high acceptance rate among patients compared to currently used fecal occult blood testing and colonoscopy. Here we describe the discovery and validation of a 29-gene panel in peripheral blood mononuclear cells (PBMC) for the detection of CRC and adenomatous polyps (AP). Blood samples were prospectively collected from a multicenter, case-control clinical study. First, we profiled 93 samples with 667 candidate and 3 reference genes by high throughput real-time PCR (OpenArray system). After analysis, 160 genes were retained and tested again on 51 additional samples. Low expressed and unstable genes were discarded resulting in a final dataset of 144 samples profiled with 140 genes. To define which genes, alone or in combinations had the highest potential to discriminate AP and/or CRC from controls, data were analyzed by a combination of univariate and multivariate methods. A list of 29 potentially discriminant genes was compiled and evaluated for its predictive accuracy by penalized logistic regression and bootstrap. This method discriminated AP >1cm and CRC from controls with a sensitivity of 59% and 75%, respectively, with 91% specificity. The behavior of the 29-gene panel was validated with a LightCycler 480 real-time PCR platform, commonly adopted by clinical laboratories. In this work we identified a 29-gene panel expressed in PBMC that can be used for developing a novel minimally-invasive test for accurate detection of AP and CRC using a standard real-time PCR platform.

Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance.

Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models.

Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis.

BACKGROUND: Data addressing the outcomes and patterns of recurrence after pulmonary metastasectomy (PM) in patients with colorectal cancer (CRC) and previously resected liver metastasis are limited. METHODS: We searched the PubMed database for studies assessing PM in CRC and gathered individual data for patients who had PM and a previous curative liver resection. The influence of potential factors on overall survival (OS) was analyzed through univariate and multivariate analysis. RESULTS: Between 1983 and 2009, 146 patients from five studies underwent PM and had previous liver resection. The median interval from resection of liver metastasis until detection of lung metastasis and the median follow-up from PM were 23 and 48 months, respectively. Five-year OS and recurrence-free survival rates calculated from the date of PM were 54.4 and 29.3 %, respectively. Factors predicting inferior OS in univariate analysis included thoracic lymph node (LN) involvement and size of largest lung nodule ≥2 cm. Adjuvant chemotherapy and whether lung metastasis was detected synchronous or metachronous to liver metastasis had no influence on survival. In multivariate analysis, thoracic LN involvement emerged as the only independent factor (hazard ratio 4.86, 95 % confidence interval 1.56-15.14, p = 0.006). CONCLUSIONS: PM offers a chance for long-term survival in selected patients with CRC and previously resected liver metastasis. Thoracic LN involvement predicted poor prognosis; therefore, significant efforts should be undertaken for adequate staging of the mediastinum before PM. In addition, adequate intraoperative LN sampling allows proper prognostic stratification and enrollment in novel adjuvant therapy trials.

Training primary care physicians in shared decision making for colorectal cancer screening : Insights from the first statewide colorectal cancer screening program in Switzerland

Background: The State of Vaud has launched the first population-based, organized, colorectal cancer screening program in Switzerland for the population aged 50 to 69. Each primary care physician (PCP) has been invited to participate in an interactive session preparing them to enroll patients in the screening program. We aimed at testing the impact of an interactive seminar for PCPs on their intention to discuss the options of no screening, screening with the fecal-immunological test (FIT) and colonoscopy. We measured attitude, intentions and knowledge through questionnaires filled by PCPs before and after a 2.5 hour-long interactive seminar. The main outcome was the proportion of physicians foreseeing to offer coloscopy vs FIT on an equal basis. Physicians estimated the proportion of their patients prescribed a fecal occult blood test (FOBT) vs coloscopy over the months before the seminar and after the interactive seminar. We used a clinical vignette to test for knowledge about screening indications. The interactive seminar included powerpoint presentations with quizzes and clickers, an 8-minute video presenting a shared decision making (SDM) consultation around CRC screening and distribution of educational materials such as a SDM decision aid and background epidemiological information.

Colorectal Cancer Screening in Switzerland: Cross-Sectional Trends (2007-2012) in Socioeconomic Disparities.

BACKGROUND: Despite universal health care coverage, disparities in colorectal cancer (CRC) screening by income in Switzerland have been reported. However, it is not known if these disparities have changed over time. This study examines the association between socioeconomic position and CRC screening in Switzerland between 2007 and 2012. METHODS: Data from the 2007 (n = 5,946) and 2012 (n = 7,224) population-based Swiss Health Interview Survey data (SHIS) were used to evaluate the association between monthly household income, education, and employment with CRC screening, defined as endoscopy in the past 10 years or fecal occult blood test (FOBT) in the past 2 years. Multivariable Poisson regression was used to estimate prevalence ratios (PR) and 95% Confidence Intervals (CI) adjusting for demographics, health status, and health utilization. RESULTS: CRC screening increased from 18.9% in 2007 to 22.2% in 2012 (padjusted: = 0.036). During the corresponding time period, endoscopy increased (8.2% vs. 15.0%, padjusted:<0.001) and FOBT decreased (13.0% vs. 9.8%, padjusted:0.002). CRC screening prevalence was greater in the highest income (>$6,000) vs. lowest income (≤$2,000) group in 2007 (24.5% vs. 10.5%, PR:1.37, 95%CI: 0.96-1.96) and in 2012 (28.6% vs. 16.0%, PR:1.45, 95%CI: 1.09-1.92); this disparity did not significantly change over time. CONCLUSIONS: While CRC screening prevalence in Switzerland increased from 2007 to 2012, CRC screening coverage remains low and disparities in CRC screening by income persisted over time. These findings highlight the need for increased access to CRC screening as well as enhanced awareness of the benefits of CRC screening in the Swiss population, particularly among low-income residents.

Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion.

Carcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. To address this question we characterized the interaction between fibroblasts and SW620 and HT29 colorectal cancer cells in 2D and 3D co-culture models in vitro. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin αvβ5. Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-αvβ5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion.

Participation rates for organized colorectal cancer screening programmes: an international comparison.

OBJECTIVE: Participation, an indicator of screening programme acceptance and effectiveness, varies widely in clinical trials and population-based colorectal cancer (CRC) screening programmes. We aimed to assess whether CRC screening participation rates can be compared across organized guaiac fecal occult blood test (G-FOBT)/fecal immunochemical test (FIT)-based programmes, and what factors influence these rates. METHODS: Programme representatives from countries participating in the International Cancer Screening Network were surveyed to describe their G-FOBT/FIT-based CRC screening programmes, how screening participation is defined and measured, and to provide participation data for their most recent completed screening round. RESULTS: Information was obtained from 15 programmes in 12 countries. Programmes varied in size, reach, maturity, target age groups, exclusions, type of test kit, method of providing test kits and use, and frequency of reminders. Coverage by invitation ranged from 30-100%, coverage by the screening programme from 7-67.7%, overall uptake/participation rate from 7-67.7%, and first invitation participation from 7-64.3%. Participation rates generally increased with age and were higher among women than men and for subsequent compared with first invitation participation. CONCLUSION: Comparisons among CRC screening programmes should be made cautiously, given differences in organization, target populations, and interpretation of indicators. More meaningful comparisons are possible if rates are calculated across a uniform age range, by gender, and separately for people invited for the first time vs. previously.

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.

The consensus molecular subtypes of colorectal cancer.

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.