Data from A Cohort Study of Cyclin D1 Expression and Prognosis in 602 Colon Cancer Cases
Shuji OginoKatsuhiko NoshoNatsumi IraharaShoko KureKaori ShimaYoshifumi BabaSaori ToyodaLi ChenEdward L. GiovannucciJeffrey A. MeyerhardtCharles S. Fuchs
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<div>Abstract<p><b>Purpose:</b> Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1 can be blocked by CDK inhibitors, including p27 (<i>CDKN1B</i>) and p21 (<i>CDKN1A</i>, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1 hypomethylation].</p><p><b>Experimental Design:</b> Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1 overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer–specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1 methylation, CpG island methylator phenotype, MSI, BMI, <i>KRAS</i>, and <i>BRAF</i>.</p><p><b>Results:</b> Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (<i>P</i> = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; <i>P</i> = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% CI, 0.39-0.84; <i>P</i> = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% CI, 0.57-0.98; <i>P</i> = 0.036). Notably, the effect of cyclin D1 on survival might differ by MSI status (<i>P</i><sub>interaction</sub> = 0.008). Compared with tumors that were both cyclin D1–negative and MSI-low/microsatellite stable, the presence of either cyclin D1 or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65).</p><p><b>Conclusions:</b> Cyclin D1 overexpression is associated with longer survival in colon cancer.</p></div>Abstract: Metastatic colorectal cancer (CRC) is a topic of intense research. KRAS mutations have emerged as aggressive drivers of disease. Here we discuss the role of KRAS mutations in metastatic progression of CRC. We describe how KRAS has become a useful biomarker in metastatic CRC and examine where future trials may look to target KRAS mutant tumors for therapeutic benefit.
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Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10‐year periods from age 20 using recalled frequency and quantity of beverage‐specific consumption for 38,149 participants aged 40–69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose‐dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow‐up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04–1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer ( p homogeneity = 0.02). Alcohol intake was associated with increased risks of KRAS + (HR = 1.07, 95% CI: 1.00–1.15) and BRAF −/ KRAS − (HR = 1.05, 95% CI: 1.00–1.11) but not BRAF + tumors (HR = 0.89, 95% CI: 0.78–1.01; p homogeneity = 0.01). Alcohol intake is associated with an increased risk of KRAS + and BRAF −/ KRAS ‐ tumors originating via specific molecular pathways including the traditional adenoma‐carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma‐carcinoma pathway.
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Hematology
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Objective KRAS mutations in primary colorectal cancer(CRC)are predictive of nonresponse to anti-epidermal growth factor receptor(EGFR)antibodies in patients with metastatic colorectal cancer(mCRC).The aim of our study was to perform a systematic review to compare the mutational status of KRAS in primary CRC and metastases,and further to guide clinical practice.Methods Systematic computerized searches of the PubMed and Medline databases(up to May 30,2010)meeting specified search criteria were performed,followed by a further screening according to inclusive and exclusive criteria.Results A total of 553 matched primary CRC and non-lymph node metastases were available for the analysis of the KRAS status from 11 articles.There was no statically significant difference in mutation frequency of KRAS between primary CRC and metastases,[35.62% vs.37.25%,odds radio(OR)=0.93(95% CI 0.73-1.19),P=0.57].The discordant rate of KRAS mutations in primary and metastatic tumor was 7%(0~14%).Conclusions The systematic analysis showed a high concordance of the KRAS mutation status in primary CRC and corresponding metastases.Either the primary CRC or the metastases seem to be appropriate for the routine analysis of the KRAS status before anti-EGFR antibody therapy.Due to the high rates of heterogeneity,lymph node metastases are not suitable for diagnostic mutation analysis.
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KRAS mutation is present in 30%-50% of colorectal cancers and is associated with the inefficacy of anti-epidermal growth factor receptor therapy, while the impact of KRAS on survival is seldom discussed. The aim of this study was to elucidate the impact of KRAS status on the survival of patients with metastatic colorectal cancer.Two hundred and one patients with metastatic colorectal cancer were enrolled. Amplification and sequencing of the KRAS gene were performed, with the overall survival according to KRAS status analyzed.KRAS mutations were present in 72 (35.8%) of patients, including 55 (27.3%) codon 12 mutations and 17 (8.5%) codon 13 mutations. Lymphovascular invasion (hazard ratio 1.841, 95% confidence interval 1.043-3.247, p = 0.035) and KRAS mutation (hazard ratio 1.919, 95% confidence interval 1.104-3.333, p = 0.021) were independent prognostic factors for overall survival. The median overall survival for patients with KRAS mutation at codon 12 was 27.3 months, and was similar to those with KRAS mutation at codon 13 (20.4 months, p = 0.628).KRAS mutation is a poor prognostic factor in patients with metastatic colorectal cancer. In KRAS mutation metastatic colorectal cancer, mutation at codon 12 or at codon 13 had no relationship with prognosis.
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Objective To explore the efficacy and prognostic factors of cetuximab therapy for KRAS or all RAS wild-type(WT)metastatic colorectal cancer(mCRC).Methods We screened mCRC patients receiving at least two cycles of cetuximb and chemotherapy from those with KRAS WT(before November 2013)or all-RAS-WT(after November 2013)in the Department of Medical Oncology,Peking Union Medical College Hospital from November 2007 to December 2016. The relationship between the clinicopathological characteristics and the efficacy was retrospectively analyzed.Results A total of 60 patients were included. For the 34 patients receiving cetuximab as first-line treatment,the objective response rate(ORR)was 55.9%,and the progression-free survival and overall survival(OS)was 10 and 24 months,respectively. All-RAS-WT mCRC had significantly lower risk of progression than those with KRAS-only-WT(P=0.012),and left-sided colorectal cancer had higher ORR than right-sided colon cancer(62.1% vs. 0,P=0.033)during the first-line treatment. The median OS of the eight patients continuing cetuximab beyond first-line progression was 35.0(95%CI:23.6-46.4)months.Conclusions The efficacy of cetuximab for left-sided colorectal cancer was better than for right-sided colon cancer,and patients with all-RAS-WT have lower risk of progression than those with KRAS-only-WT. Patients benefiting from first-line cetuximab and continuing cetuximab beyond progression survive longer.
Progression-free survival
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Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor, has proven to be efficient in the treatment of metastatic colorectal cancer.We made a prospective study of the efficacy and toxicities of cetuximab-combination first-line (FOLFOX4) versus second/third-line (FOLFIRI) chemotherapy in 98 KRAS wildtype patients who had metastatic colorectal cancer.Wild-type KRAS had been identified by direct sequencing.Associations between clinical response/progression-free survival/overall survival/toxicities and cetuximab-combination chemotherapy timing were evaluated.The overall response rate was significantly higher for first-line treatment than for second/third-line treatment (relative risk = 1.707, 95% confidence interval = 1.121-2.598).Both progression-free survival and overall survival indicated significantly longer survival of first-line treatment than second/third-line treatment patients.This study is a validation of a molecular analysis of KRAS wild-type status for the prediction of response to cetuximab-combination chemotherapy for metastatic colorectal cancer patients; its predictive role was less prominent in the second/thirdline than in the first-line treatment patients.
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Abstract Although smoking is a major modifiable risk factor for many types of cancer, evidence for colorectal cancer is equivocal in Asian populations. Recent Western studies have proposed that the association between smoking and colorectal cancer is restricted to specific tumor molecular subtypes. However, no studies have evaluated the association according to tumor molecular subtypes in Asian populations. In a Japanese prospective population-based cohort study of 18 773 participants, we collected tumor tissues from incident colorectal cancer cases and evaluated KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B) mutation status using target sequencing. Multivariable-adjusted Cox proportional hazard model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of smoking with the risk of overall colorectal cancer and its subtypes defined by KRAS and BRAF mutation status. Among 339 cases, KRAS and BRAF mutations were identified in 164 (48.4%) and 16 (4.7%) cases, respectively. The multivariable-adjusted HR for ever smoking compared with never smoking was 1.24 [95% CI: 0.93–1.66], 1.75 [1.14–2.68], 0.87 [0.59–1.29], 1.24 [0.93–1.67] and 1.22 [0.38–3.93] for overall, KRAS wild-type, KRAS-mutated, BRAF wild-type and BRAF-mutated colorectal cancer, respectively. The statistically significant heterogeneity was indicated between KRAS mutation status (Pheterogeneity = 0.01) but not between BRAF mutation status. This study is the first to demonstrate that smokers have an approximately 2-fold higher risk of KRAS wild-type colorectal cancer than never smokers in an Asian population. Our findings support that smoking is a risk factor for colorectal cancer, especially for its subtype without KRAS mutations, in Asian populations.
Viral Oncogene
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Abstract Background: Overexpression of the EGFR is common in patients with a wide range of cancers and the EGFR is an important target for therapy with monoclonal antibodies (mAbs) based drugs. Of these, cetuximab and panitumumab have been approved for the treatment of patients with metastatic colorectal cancer (mCRC). However, therapeutic benefits are seen in a subset of such patients and the duration of response can also be short. Indeed, there is currently no reliable predictive biomarkers for the selection of patients who benefit from therapy with the anti-EGFR antibodies. While KRAS mutation is currently used as an important negative predictive biomarker for the response to therapy with anti-EGFR mAbs, not all patients with wild type KRAS gain benefit from therapy with anti-EGFR mAbs and objective responses have been reported in mCRC patients with KRAS mutations. Aim: The aim of this study was to investigate the predictive value of EGFR and its dimerization partner (i.e. all other members of the HER family) for the response to treatment with cetuximab in patients with wild-type KRAS status mCRC. Methods: Using immunohistochemistry (IHC) we investigated the co-expression and predictive value of all four members of the HER family, for the response to cetuximab in 144 mCRC patients and in 21 paired primary tumours and their metastatic sites. Results: Co-expression of all four members of the HER family were found in 10% of the cases examined. The expression of wtEGFR was an indicator of poorer overall survival and the membranous expression of HER2 and HER3 3+ intensity was associated with a shorter progression free survival (PFS). In contrast, the cytoplasmic expression of HER2 was associated with better PFS. In 48% and 71% of the cases examined, there were discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours, respectively. Conclusion: Our results implicate the importance of large prospective investigation of the expression level and predictive value of not only the therapeutic target (i.e. EGFR protein) but also its dimerization partners for the response to therapy with anti-EGFR mAbs and other forms of HER inhibitors in both the primary tumours and metastatic sites in colorectal cancer. Citation Format: Said A. Khelwatty, Soozana Puvanenthiran, Sharadah Essapen, Izhar Bagwan, Alan M. Seddon, Helmout Modjtahedi. Co-expression and predictive value of HER family members for the response to therapy with cetuximab in patients with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 350.
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