Faculty Opinions recommendation of Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer.

AbstractStudies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 “bulk” RNA-seq datasets (total n = 2269) and four single-cell RNA-seq datasets were included in this study. We constructed a “Signature associated with FOLFIRI resistant and Microenvironment” (SFM) that could discriminate both TME and drug sensitivity. Further, SFM subtypes were identified using K-means clustering and verified in three independent cohorts. Nearest template prediction algorithm was used to predict drug response. TME estimation was performed by CIBERSORT and microenvironment cell populations-counter (MCP-counter) methods. We identified six SFM subtypes based on SFM signature that discriminated both TME and drug sensitivity. The SFM subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics, specific enrichments of gene signatures, signaling pathways, prognosis, gut microbiome patterns, and tumor lymphocytes infiltration. Among them, SFM-C and -F were immune suppressive. SFM-F had higher stromal fraction with epithelial-to-mesenchymal transition phenotype, while SFM-C was characterized as microsatellite instability phenotype which was responsive to immunotherapy. SFM-D, -E, and -F were sensitive to FOLFIRI and FOLFOX, while SFM-A, -B, and -C were responsive to EGFR inhibitors. Finally, SFM subtypes had strong prognostic value in which SFM-E and -F had worse survival than other subtypes. SFM subtypes enable the stratification of CRC with potential chemotherapy response thereby providing more precise therapeutic options for these patients.

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1090 Plasma biomarkers for early prediction of chemotherapy response and toxicity in colorectal cancer

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(09)70383-0 ◽

2009 ◽

Vol 7 (2) ◽

pp. 112

Author(s):

W. Chua ◽

S. Randall ◽

M.J. McKay ◽

L. Horvath ◽

S.J. Clarke ◽

...

Keyword(s):

Colorectal Cancer ◽

Chemotherapy Response ◽

Early Prediction ◽

Plasma Biomarkers

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Methylated DNA markers for monitoring palliative chemotherapy response in advanced colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15511 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15511-e15511

Author(s):

Mojun Zhu ◽

Douglas W. Mahoney ◽

Kelli Burger ◽

Patrick H. Foote ◽

Karen A. Doering ◽

...

Keyword(s):

Colorectal Cancer ◽

Treatment Response ◽

Systemic Therapy ◽

Small Sample Size ◽

High Sensitivity ◽

Response Assessment ◽

Small Sample ◽

Chemotherapy Response ◽

Continuous Variables ◽

Methylated Dna

e15511 Background: Aberrantly methylated DNA marker (MDM) candidates are strongly associated with primary colorectal cancer (CRC) before treatment and detect CRC recurrence with high sensitivity when assayed from plasma. The relationship of these MDMs in association to chemotherapy treatment response is unknown. Methods: In a prospective cohort of patients receiving systemic therapy for advanced CRC, peripheral blood was collected serially during restaging visits. 15 patients were retrospectively identified to have partial response (PR), stable disease (SD) and progressive disease (PD) to treatment (n=5 for each group) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Using paired samples from each patient before and after response assessment, we analyzed 11 MDMs ( GRIN2D, ZNF671, ANKRD13B, QKI, VAV3, JAM3, SFMBT2, CHST2, ZNF568, FER1L4 and CNNM1) to assess correlation with treatment response. Cell-free DNA was extracted and bisulfite treated before MDMs were quantified by target enrichment long-probe quantitative-amplified signal assay and normalized to a methylated sequence of B3GALT6. Continuous variables are summarized as a median with corresponding interquartile ranges (IQR) and comparisons between subgroups were based on the Wilcox Rank Sums test. Results: The median interval between pre- and post-response assessment visits was 69 days (IQR: 63-83 days) and the level of tumor burden at pre-assessment was similar across all response types (Table 1). Patients with PD had higher levels of methylated GRIN2D, ZNF671 and ANKRD13B than those with PR or SD at baseline and may offer additional prognostic value over CEA which was similar in the PR and PD groups before treatment (Table 1). Elevation of pre-assessment MDMs preceded radiographic evidence of disease progression by 82 days (IQR 69-83 days). Conclusions: Three MDMs, GRIN2D, ZNF671 and ANKRD13B, were found to reflect treatment response (PD vs. PR + SD) as shown in the table. Although this pilot study was limited by a small sample size, it demonstrated the feasibility of using plasma-based MDMs in monitoring treatment response to systemic therapy for advanced CRC and should be compared to CEA in a larger study.[Table: see text]

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Does Nutritional Status Affect Treatment Tolarability, Response and Survival in Metastatic Colorectal Cancer Patients? Results of a Prospective Multicenter Study

10.21203/rs.2.22409/v1 ◽

2020 ◽

Author(s):

Karabulut Senem ◽

Dogan Izzet ◽

Cigdem Usul Afsar ◽

Karabulut Mehmet ◽

Sule Kahraman ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Nutritional Status ◽

Metastatic Colorectal Cancer ◽

Multicenter Study ◽

Cytotoxic Chemotherapy ◽

Response To Treatment ◽

Severe Malnutrition ◽

Chemotherapy Response ◽

Drug Induced

Abstract Background: The efficacy and tolerability of modern cytotoxic chemotherapy regimens used in malnourished metastatic colorectal cancer (mCRC) patients is uncertain. The aim of this study was to investigate the effect of malnutrition on efficacy and tolerability of cytotoxic chemotherapy and overall survival in mCRC patients.Methods: In this multicenter study, demographic, oncologic and nutritional data were collected prospectively from mCRC patients. Nutritional status of the patients were evaluated on the basis of NRI, BMI and WL before the first chemotherapy, after the first and second chemotherapy during 2 cycles of chemotherapy every 15 days. To determine the inter-treatment weight loss toxicity assessment was included to theese parameters after each chemotherapy. NRI calculation was performed as [1.51xserum albumin level (g/L)+41.7xcurrent weight/basic weight]. . NRIs were examined in 3 categories as ‘no malnutrition’ (NRI >97.5), ‘moderate malnutrition’ (97.5 ≥ NRI ≥83.5) or ‘severe malnutrition’ (NRI <83.5). Response to treatment and drug-induced toxicities were assessed based on Criteria in Solid Tumors (RECIST) 1.1 and National Cancer Institute CTCAE version 4.0 respectively.Results: One-hundred and thirty-seven mCRC patients were prospectively included. Median age was 48 (range 18-83). Primary location was colon in 66% of patients and 84% of their primary source was left colon. Malnutrition was detected in 39% of the cases. Response rate to treatment was twenty four percent. While there was no significant relationship between chemotherapy response and moderate/severe malnutrition (p=0.24), moderate/severe malnutrition was associated with multipl site of metastases, WHO PS of 1, over the median value of CEA/CA 19-9 levels (p=0.003, p=0.03, p<0.001, and p=0.02; respectively). Hypoalbuminemia and moderate/severe malnutrition were associated with all types of toxicity (p<0.001 and p<0.001). Moderate/severe malnutrition was associated with thrombocytopenia, and diarrhea following chemotherapy predominately, (p=0.02 and p=0.04; respectively). In moderate/severe malnutrition group median overall survival was prominently shorter than those with no malnutrition [6.6 moths (95%CI, 5.6-7.6) vs 11.9 moths (95% CI, 11.1-12.7) respectively, p<0.001].Conclusions: Our study showed that moderate/severe malnutrition in mCRC patients was associated with decreased overall survival and increased chemotherapy toxicity.

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KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Cells ◽

10.3390/cells9010219 ◽

2020 ◽

Vol 9 (1) ◽

pp. 219 ◽

Cited By ~ 3

Author(s):

Nuria Garcia-Carbonero ◽

Javier Martinez-Useros ◽

Weiyao Li ◽

Alberto Orta ◽

Nuria Perez ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Predictive Biomarkers ◽

Braf V600e ◽

Chemotherapy Response ◽

First Line ◽

Standard Chemotherapy ◽

Braf Mutations ◽

Kras Mutations ◽

Line Standard

KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

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Analysis of Mutational Spectra in Metastatic Colorectal Carcinoma: KRAS as an Indicator of Oxaliplatin-Based Chemotherapy

International Surgery ◽

10.9738/intsurg-d-17-00050.1 ◽

2019 ◽

Vol 103 (1-2) ◽

pp. 27-35 ◽

Cited By ~ 1

Author(s):

Chu-Cheng Chang ◽

Jen-Kou Lin ◽

Tzu-Chen Lin ◽

Wei-Shone Chen ◽

Jeng-Kai Jiang ◽

...

Keyword(s):

Colorectal Cancer ◽

Gene Mutations ◽

Cytotoxic Agents ◽

Chemotherapy Response ◽

Wild Type ◽

Primary Tumors ◽

Chemotherapeutic Regimen ◽

Mutational Spectra ◽

Response To Chemotherapy ◽

Mutation Spectra

Objective: Mutation spectra in colorectal cancer with metastasis and its response to chemotherapy. Summary of Background Data: No molecular markers are available for selecting the optimal chemotherapeutic regimen (irinotecan or oxaliplatin) for metastatic colorectal cancer (mCRC). Methods: We enrolled 161 mCRC patients who underwent surgery for their primary tumors at Taipei Veterans General Hospital from 2004 to 2010. The prevalence of gene mutations was measured and correlated with responses to different cytotoxic agents. Results: We detected 1,836 mutations in 12 genes. KRAS mutants affected 44.3% of the tumors. The rate of good response was insignificantly higher for patients with KRAS mutant tumors who received oxaliplatin-based chemotherapy compared with patients with KRAS wild-type tumors (65.6% versus 47.0%; P = 0.15). For patients who received irinotecan-based chemotherapy, the rate of good response was similar in patients with wild-type (55.0%; n = 11) and those with KRAS mutant tumors (54.5%; n = 12; P = 1). In patients with KRAS mutant tumors treated with an oxaliplatin-based regimen, the overall survival was 38.5 months (95% CI: 26.6–50.5 months), which was insignificantly better than that for patients treated with an irinotecan-based regimen (30.4 months; 95% CI: 15.8–45.1 months; P = 0.206). Conclusions: Our data could not come to the conclusion that patient with KRAS mutation mCRC may have better response with oxaliplatin-based first-line chemotherapy. Further study is needed to confirm the relationship between gene mutation and chemotherapy response.

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MiR-218 and miR-100 polymorphisms as markers of irinotecan-based chemotherapy response in metastatic colorectal cancer

International Journal of Colorectal Disease ◽

10.1007/s00384-019-03401-3 ◽

2019 ◽

Vol 34 (11) ◽

pp. 1871-1877 ◽

Cited By ~ 1

Author(s):

Dimitra-Ioanna Lampropoulou ◽

Gerasimos Aravantinos ◽

Konstantinos Laschos ◽

Theodosis Theodosopoulos ◽

Christos Papadimitriou ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Chemotherapy Response

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The Glasgow Microenvironment Score associates with prognosis and adjuvant chemotherapy response in colorectal cancer

British Journal of Cancer ◽

10.1038/s41416-020-01168-x ◽

2020 ◽

Author(s):

Peter G. Alexander ◽

Antonia K. Roseweir ◽

Kathryn A. F. Pennel ◽

Hester C. van Wyk ◽

Arfon G. M. T. Powell ◽

...

Keyword(s):

Colorectal Cancer ◽

Adjuvant Chemotherapy ◽

Chemotherapy Response

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Roles of Methylated DNA Biomarkers in Patients with Colorectal Cancer

Disease Markers ◽

10.1155/2019/2673543 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Zhiyao Ma ◽

Marissa Williams ◽

Yuen Yee Cheng ◽

Wai K. Leung

Keyword(s):

Colorectal Cancer ◽

Occult Blood ◽

Chemotherapy Response ◽

Methylated Dna ◽

Septin 9 ◽

Faecal Occult ◽

Related Transcription Factor ◽

Prediction Of Prognosis ◽

Low Sensitivity ◽

Serum Detection

Colorectal cancer (CRC) is a leading cancer globally; therefore, early diagnosis and surveillance of this cancer are of paramount importance. Current methods of CRC diagnosis rely heavily on endoscopy or radiological imaging. Noninvasive tests including serum detection of the carcinoembryonic antigen (CEA) and faecal occult blood testing (FOBT) are associated with low sensitivity and specificity, especially at early stages. DNA methylation biomarkers have recently been found to have higher accuracy in CRC detection and enhanced prediction of prognosis and chemotherapy response. The most widely studied biomarker in CRC is methylated septin 9 (SEPT9), which is the only FDA-approved methylation-based biomarker for CRC. Apart from SEPT9, other methylated biomarkers including tachykinin-1 (TAC1), somatostatin (SST), and runt-related transcription factor 3 (RUNX3) have been shown to effectively detect CRC in a multitude of sample types. This review will discuss the performances of various methylated biomarkers used for CRC diagnosis and monitoring, when used alone or in combination.

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Does panitumumab have a clinical benefit in cetuximab-refractory KRAS wild-type metastatic colorectal cancer?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.654 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 654-654

Author(s):

Toshiyasu Watanabe ◽

Eiji Shinozaki ◽

Sho Kijima ◽

Yoshihito Ohhara ◽

Yasutoshi Kuboki ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Tumor Marker ◽

Clinical Benefit ◽

Chemotherapy Response ◽

Chimeric Mouse ◽

Serum Tumor Marker ◽

Wild Type ◽

Tumor Marker Level ◽

Marker Level

654 Background: Panitumumab and cetuximab can be used in metastatic colorectal cancer (mCRC) and these drugs are IgG2 fully human and IgG1 chimeric (mouse/human) monoclonal antibody against the epidermal growth hactor receptor (EGFR) respectively. The efficacy of panitumumab as a salvage chemotherapy after cetuximab-based chemotherapy failure is not clarified. Methods: This study aimed to evaluate the panitumumab efficacy to KRAS wild-type mCRC patients who failed cetuximab-based chemotherapy. Response, progression-free survival (PFS) and serum tumor marker level (CEA and CA19-9), were assesed. We studied response by days from last cetuximab-based chemotherapy to panitumumab induction (C-P days). Results: 22 patients (11 men, 11 women, median age 54 years m4 0-78 n) were enrolled. All of thease patients were cetuximab-based chemotherapy refractory KRAS wild-type mCRC. After progression, they received panitumumab monotherapy (6 mg/kg every 2 weeks).The best response was SD 10/22 (45.5%), PD 11/22 (50%) and NE 1/22 (4.5%). Overall median PFS was 90 days (13 to 182). The patients C-P days less than 30 days were 15 patients(5:SD, 10:PD). The patients more than 79 days were 7 patient(5:SD, 1:PD, 1:NE). Serum tumor marker level was decreased more than 50% patients. Conclusions: This study suggested that it might be limited as possibility of clinical benefit with panitumumab administration after cetuximab failure.

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