Cancers of the Colon and Rectum: Identical or Fraternal Twins?

Hong, Theodore S.; Clark, Jeffrey W.; Haigis, Kevin M.

doi:10.1158/2159-8290.cd-11-0315

Cited by 62 publications

(56 citation statements)

References 22 publications

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“…Supporting this concept, the frequency of pulmonary metastases was increased in patients of our cohort with rectal cancer. Here, tumors partly drain through the inferior rectal vein to the vena cava, potentially promoting hematogenous dissemination in the lungs [14].…”

Section: Discussionmentioning

confidence: 99%

Pattern and Dynamics of Distant Metastases in Metastatic Colorectal Cancer

et al. 2017

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Background: Few studies report the incidence of metastatic patterns in colorectal cancer. Furthermore, little is known about dynamic aspects of these metastases during the course of disease. Methods: This retrospective cohort study involved 385 patients who received anti-tumor treatment at our institution (Department of Medical Oncology, University Hospital Grosshadern, Ludwig-Maximilians-University Munich, Germany) for metastatic colorectal adenocarcinoma between 2007 and 2014. We reviewed all available imaging results of these patients to document the presence and detailed localization of metastases. Results: Most of the evaluated patients were initially diagnosed with metastases in the liver (70%), followed by the lungs (24%), distant lymph nodes (16%), and peritoneum (15%), besides rare anatomical sites (<5%). Colon and rectal cancer as well as synchronous and metachronous metastases differed with regard to the pattern of individual metastatic sites. The median time to first progressive disease (PD) with new metastases was 12.6 months. The time intervals between first and second as well as second and third PD with new metastases were comparable with 10.5 and 10.8 months, respectively. At initial diagnosis, the mean number of metastatic sites was 1.4 and increased to 2.6 at the third PD with new metastases. For patients with initially one metastatic site, the mean number increased to 2.2. Conclusion: The present analysis provides detailed information on the pattern and evolution of colorectal cancer metastases over time. Thus, it may establish the basis for prospective future research in this field.

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Section: Discussionmentioning

confidence: 99%

Pattern and Dynamics of Distant Metastases in Metastatic Colorectal Cancer

et al. 2017

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“…Interestingly, and consistently with the hypothesis of ADCC as an important mechanism of action of cetuximab against micrometastases, we found that carriers of 131R and/or 158F alleles had a significantly lower risk of distant failure than patients homozygous for 131H and/or 158V when cetuximab was added to the study sequential treatment. It is worth noting that additional signaling pathways beyond EGFR (i.e., IGF-1R pathway) which have been shown to cross-talk with EGFR downstream effectors and mediate the ADCC-independent therapeutic effects of cetuximab are more frequently activated and potentially more clinically relevant in rectal cancer than in colon cancer (36)(37)(38). Therefore, our findings could be potentially influenced by the specific location of the primary tumor and may not apply to a population of patients with colon cancer.…”

Section: Discussionmentioning

confidence: 99%

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

Sclafani

Castro

Cunningham

et al. 2014

Clinical Cancer Research

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Purpose: FcgR polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX AE cetuximab in high-risk, locally advanced rectal cancer.Experimental Design: FcgRIIa-H131R and FcgRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX ¼ 54, CAPOX-C ¼ 51). No deviation from the Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. FcgRIIa-131R (HR, 0.38; P ¼ 0.058) and FcgRIIIa-158F alleles (HR, 0.21; P ¼ 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P ¼ 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P ¼ 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P ¼ 0.017) and remained significant after adjusting for prognostic variables (P ¼ 0.003).Conclusion: This is the first study investigating FcgRIIa and FcgRIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

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“…Previous studies investigating this SNP were either restricted to patients with colon cancer or conducted in unselected CRC populations [7,[9][10][11][12][13][14][15][16]. However, differences exist between colon and rectal cancers with regards to tumour biology and treatment approach including frequency of microsatellite instability and BRAF mutation, prognostic relevance of KRAS mutation, miRNA expression profile and routine use of radiotherapy in LARC [21].…”

Section: Discussionmentioning

confidence: 99%

2188 Prognostic role of the LCS-6 KRAS variant in locally advanced rectal cancer: Results of the EXPERT-C trial

Sclafani¹,

Chau²,

Cunningham³

et al. 2015

European Journal of Cancer

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Background: Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. Patients and methods:We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.Results: A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). Conclusion:This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.

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Cancers of the Colon and Rectum: Identical or Fraternal Twins?

Cited by 62 publications

References 22 publications

Pattern and Dynamics of Distant Metastases in Metastatic Colorectal Cancer

Pattern and Dynamics of Distant Metastases in Metastatic Colorectal Cancer

FcγRIIaandFcγRIIIaPolymorphisms and Cetuximab Benefit in the Microscopic Disease

2188 Prognostic role of the LCS-6 KRAS variant in locally advanced rectal cancer: Results of the EXPERT-C trial

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