Implementing prognostic and predictive biomarkers in CRC clinical trials
TL;DR: Novel adaptive clinical trial designs that incorporate putative genomic prognostic/predictive markers in prospective randomized trials, will enable a clinical validation of these markers and may facilitate the implementation of these biomarkers into routine medical practice.
Abstract: Over the past two decades, several protein and genomic markers have refined the prognostic information of colorectal cancer (CRC) and helped to predict which patient group may benefit most from systemic treatment or targeted therapies. Of all these markers, KRAS represents the first biomarker integrated into clinical practice for CRC. Microarray-based gene-expression profiling has been used to identify prognostic signatures and to a lesser degree predictive signatures in CRC; however, common challenges with these types of studies are clinical study design, reproducibility, interpretation and reporting of the results. We focus on the clinical application of a range of published prognostic and predictive protein and genomic markers in CRC and discuss the different challenges associated with microarray-based gene-expression profiling. While none of these genomic signatures is currently in routine clinical use in CRC, novel adaptive clinical trial designs that incorporate putative genomic prognostic/predictive markers in prospective randomized trials, will enable a clinical validation of these markers and may facilitate the implementation of these biomarkers into routine medical practice.
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TL;DR: It is demonstrated that primary tumor location is an important prognostic factor in previously untreated mCRC and side of tumor origin should be considered for stratification in randomized trials.
Abstract: Tumors arising from the colorectal tract are a heterogeneous complex of diseases that result from the accumulation of distinctive genetic and epigenetic alterations (1,2). Despite increased understanding into the molecular pathways underlying colorectal cancer (CRC), relatively few biomarkers are prognostic for survival (1–3). Germline mutations in DNA mismatch repair genes, definitive of Lynch syndrome, in stage II/III disease and BRAF V600E mutations in stage IV disease are notable exceptions (4–6).
Biological and clinical evidence supports that proximal (right-sided) and distal (left-sided) CRCs follow different molecular pathways of carcinogenesis. Right-sided tumors are more likely to be diploid and to be characterized by mucinous histology, high microsatellite instability, CpG island methylation, and BRAF mutations (6–10). In contrast, left-sided tumors are frequently infiltrating, constricting lesions, with a phenotype that involves chromosomal instability and aneuploidy (7–9). Microarray studies of sporadic CRC biopsies demonstrate unique gene expression profiles for right- and left-sided cancers, potentially related to distinct embryonic origins and postnatal regulation (11,12). Extensive sequencing analyses described a characteristic branching pattern of cancer evolution supporting that tumor biology is characterized simultaneously by intratumor heterogeneity and the preservation of ancestral aberrations within the primary tumor and corresponding metastatic sites (13,14).
Previous attempts to evaluate the effect of primary tumor location on outcome in metastatic CRC (mCRC) have been complicated by sample size, a high degree of heterogeneity in received treatments, and limited information on molecular and pathologic features (15−17). The objectives of the present analysis were first to assess primarily the prognostic impact and secondly the predictive effect of primary tumor location for an antiangiogenic treatment by interrogating three large independent patient cohorts. Because of the prognostic significance of BRAF mutations and mucinous histology (5,6,18) and the association of these characteristics with right-sided mCRC, a multivariable model and a subgroup analysis in nonmucinous and BRAF wild-type cancers were used to separately assess outcomes in the PROVETTA study (chosen as an exploratory set based on availability of clinical and molecular features). The prognostic effect of primary tumor location was subsequently verified and validated using data from two large phase III trials.
374 citations
Cites background from "Implementing prognostic and predict..."
...a r t ic le Tumors arising from the colorectal tract are a heterogeneous complex of diseases that result from the accumulation of distinctive genetic and epigenetic alterations (1,2)....
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TL;DR: Using a novel NSCLC cohort together with a meta-analysis validation approach, a set of single genes with independent prognostic impact are identified and one of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.
Abstract: Purpose: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So fa ...
285 citations
Cites background from "Implementing prognostic and predict..."
...In breast and colorectal cancer, prognostic gene expression signatures have been validated in independent patient cohorts and are now tested in prospective randomized clinical trials [5-6]....
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TL;DR: The results suggest that CCAL is a crucial oncogenic regulator involved in CRC tumorigenesis and progression, and it is found that histone H3 methylation and deacetylases contributed to the upregulation of CCAL in CRC.
Abstract: Objective Long non-coding RNAs (lncRNAs) are emerging as key molecules in cancers, yet their potential molecular mechanisms are not well understood. The objective of this study is to examine the expression and functions of lncRNAs in the development of colorectal cancer (CRC). Methods LncRNA expression profiling of CRC, adenoma and normal colorectal tissues was performed to identify tumour-related lncRNAs involved in colorectal malignant transformation. Then, we used quantitative reverse transcription PCR assays to measure the tumour-related lncRNA and to assess its association with survival and response to adjuvant chemotherapy in 252 patients with CRC. The mechanisms of CCAL function and regulation in CRC were examined using molecular biological methods. Results We identified colorectal cancer-associated lncRNA (CCAL) as a key regulator of CRC progression. Patients whose tumours had high CCAL expression had a shorter overall survival and a worse response to adjuvant chemotherapy than patients whose tumours had low CCAL expression. CCAL promoted CRC progression by targeting activator protein 2α (AP-2α), which in turn activated Wnt/β-catenin pathway. CCAL induced multidrug resistance (MDR) through activating Wnt/β-catenin signalling by suppressing AP-2α and further upregulating MDR1/P-gp expression. In addition, we found that histone H3 methylation and deacetylases contributed to the upregulation of CCAL in CRC. Conclusions Our results suggest that CCAL is a crucial oncogenic regulator involved in CRC tumorigenesis and progression.
248 citations
TL;DR: This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing and recommends that microsatellite instability, a prognostic factor, be added to the abovementioned concomitant analysis.
Abstract: The KRAS oncogene is mutated in approximately 35%-45% of colorectal cancers, and KRAS mutational status testing has been highlighted in recent years. The most frequent mutations in this gene, point substitutions in codons 12 and 13, were validated as negative predictors of response to anti-epidermal growth factor receptor antibodies. Therefore, determining the KRAS mutational status of tumor samples has become an essential tool for managing patients with colorectal cancers. Currently, a variety of detection methods have been established to analyze the mutation status in the key regions of the KRAS gene; however, several challenges remain related to standardized and uniform testing, including the selection of tumor samples, tumor sample processing and optimal testing methods. Moreover, new testing strategies, in combination with the mutation analysis of BRAF, PIK3CA and loss of PTEN proposed by many researchers and pathologists, should be promoted. In addition, we recommend that microsatellite instability, a prognostic factor, be added to the abovementioned concomitant analysis. This review provides an overview of KRAS biology and the recent advances in KRAS mutation testing. This review also addresses other aspects of status testing for determining the appropriate treatment and offers insight into the potential drawbacks of mutational testing.
229 citations
TL;DR: The classifier was shown to be specific to stage II CRC and does not provide prognostic stratification of patients with stage III CRC and the robustness was shown across patient series, populations and different microarray versions.
Abstract: Background and aims Several clinical factors have an impact on prognosis in stage II colorectal cancer (CRC), but as yet they are inadequate for risk assessment. The present study aimed to develop a gene expression classifier for improved risk stratification of patients with stage II CRC. Methods 315 CRC samples were included in the study. Gene expression measurements from 207 CRC samples (stage I–IV) from two independent Norwegian clinical series were obtained using Affymetrix exon-level microarrays. Differentially expressed genes between stage I and stage IV samples from the test series were identified and used as input for L1 (lasso) penalised Cox proportional hazards analyses of patients with stage II CRC from the same series. A second validation was performed in 108 stage II CRC samples from other populations (USA and Australia). Results An optimal 13-gene expression classifier ( PIGR , CXCL13 , MMP3 , TUBA1B , SESN1 , AZGP1 , KLK6 , EPHA7 , SEMA3A , DSC3 , CXCL10 , ENPP3 , BNIP3 ) for prediction of relapse among patients with stage II CRC was developed using a consecutive Norwegian test series from patients treated according to current standard protocols (n=44, p Conclusion This study presents the development and validation of a 13-gene expression classifier, ColoGuideEx, for prognosis prediction specific to patients with stage II CRC. The robustness was shown across patient series, populations and different microarray versions.
176 citations
References
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TL;DR: The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression, a higher rate of objective response, a longer duration of response, and a lower rate of death at 1 year.
Abstract: Background The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. Methods We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide with (143 women) or without trastuzumab (138 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). Results The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 ...
10,532 citations
TL;DR: DNA microarray analysis on primary breast tumours of 117 young patients is used and supervised classification is applied to identify a gene expression signature strongly predictive of a short interval to distant metastases (‘poor prognosis’ signature) in patients without tumour cells in local lymph nodes at diagnosis, providing a strategy to select patients who would benefit from adjuvant therapy.
Abstract: Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.
9,664 citations
TL;DR: The gene-expression profile studied is a more powerful predictor of the outcome of disease in young patients with breast cancer than standard systems based on clinical and histologic criteria.
Abstract: Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...
5,902 citations
Journal Article•
TL;DR: The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms.
Abstract: In December 1997, the National Cancer Institute sponsored "The International Workshop on Microsatellite Instability and RER Phenotypes in Cancer Detection and Familial Predisposition," to review and unify the field. The following recommendations were endorsed at the workshop. (a) The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called microsatellite instability (MSI). (b) A panel of five microsatellites has been validated and is recommended as a reference panel for future research in the field. Tumors may be characterized on the basis of: high-frequency MSI (MSI-H), if two or more of the five markers show instability (i.e., have insertion/deletion mutations), and low-frequency MSI (MSI-L), if only one of the five markers shows instability. The distinction between microsatellite stable (MSS) and low frequency MSI (MSI-L) can only be accomplished if a greater number of markers is utilized. (c) A unique clinical and pathological phenotype is identified for the MSI-H tumors, which comprise approximately 15% of colorectal cancers, whereas MSI-L and MSS tumors appear to be phenotypically similar. MSI-H colorectal tumors are found predominantly in the proximal colon, have unique histopathological features, and are associated with a less aggressive clinical course than are stage-matched MSI-L or MSS tumors. Preclinical models suggest the possibility that these tumors may be resistant to the cytotoxicity induced by certain chemotherapeutic agents. The implications for MSI-L are not yet clear. (d) MSI can be measured in fresh or fixed tumor specimens equally well; microdissection of pathological specimens is recommended to enrich for neoplastic tissue; and normal tissue is required to document the presence of MSI. (e) The "Bethesda guidelines," which were developed in 1996 to assist in the selection of tumors for microsatellite analysis, are endorsed. (f) The spectrum of microsatellite alterations in noncolonic tumors was reviewed, and it was concluded that the above recommendations apply only to colorectal neoplasms. (g) A research agenda was recommended.
4,022 citations
TL;DR: In this paper, the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer was investigated.
Abstract: Background We investigated the efficacy of cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer and sought associations between the mutation status of the KRAS gene in tumors and clinical response to cetuximab. Methods We randomly assigned patients with epidermal growth factor receptor–positive colorectal cancer with unresectable metastases to receive FOLFIRI either alone or in combination with cetuximab. The primary end point was progression-free survival. Results A total of 599 patients received cetuximab plus FOLFIRI, and 599 received FOLFIRI alone. The hazard ratio for progression-free survival in the cetuximab–FOLFIRI group as compared with the FOLFIRI group was 0.85 (95% confidence interval [CI], 0.72 to 0.99; P=0.048). There was no significant difference in the overall survival between the two treatment groups (hazard ratio, 0.93; 95% CI, 0.81 to 1.07; P=0.31). There was a significant interaction between treatment group and KRAS ...
3,504 citations