Primary Tumor Location as Prognostic Factor in Metastatic CRC
Primary Tumor Location as Prognostic Factor in Metastatic CRC
Background We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC).
Methods We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided.
Results Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location.
Conclusions These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.
Tumors arising from the colorectal tract are a heterogeneous complex of diseases that result from the accumulation of distinctive genetic and epigenetic alterations. Despite increased understanding into the molecular pathways underlying colorectal cancer (CRC), relatively few biomarkers are prognostic for survival. Germline mutations in DNA mismatch repair genes, definitive of Lynch syndrome, in stage II/III disease and BRAF mutations in stage IV disease are notable exceptions.
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. In contrast, left-sided tumors are frequently infiltrating, constricting lesions, with a phenotype that involves chromosomal instability and aneuploidy. 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. 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.
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 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.
Abstract and Introduction
Abstract
Background We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC).
Methods We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided.
Results Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location.
Conclusions These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials.
Introduction
Tumors arising from the colorectal tract are a heterogeneous complex of diseases that result from the accumulation of distinctive genetic and epigenetic alterations. Despite increased understanding into the molecular pathways underlying colorectal cancer (CRC), relatively few biomarkers are prognostic for survival. Germline mutations in DNA mismatch repair genes, definitive of Lynch syndrome, in stage II/III disease and BRAF mutations in stage IV disease are notable exceptions.
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. In contrast, left-sided tumors are frequently infiltrating, constricting lesions, with a phenotype that involves chromosomal instability and aneuploidy. 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. 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.
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 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.
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