Predictive Biomarkers of Chemotherapy Efficacy in Colorectal Cancer: Results From the UK MRC FOCUS Trial

Braun, Michael; Richman, Susan D.; Quirke, Philip; Daly, Catherine; Adlard, Julian; Elliott, Faye; Barrett, Jennifer; Selby, Peter; Meade, Angela; Stephens, Richard; Parmar, Mahesh; Seymour, Michel

doi:10.1200/jco.2007.15.5580

Cited by 248 publications

(230 citation statements)

References 35 publications

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“…[4][5][6][7][8] These inconsistent results could partly be explained by the fact that immunohistochemistry (IHC) requires suitable and validated antibodies as well as standardized protocols, both of which have been difficult to obtain for Top1 and accordingly Top1 IHC has not yet reached the level for clinical implementation.…”

Section: Discussionmentioning

confidence: 99%

“…Recently a small study including 28 patients with mBC used a multi-omic molecular profile (MMP) including Topo1 to identify potential therapeutic targets and select individualized treatment. All patients were heavily pretreated with at least three prior treatment regimens (range [3][4][5][6][7][8][9][10][11][12]. Based on the MMP 14 patients were treated with irinotecan or irinotecan plus fluorouracil.…”

Section: Discussionmentioning

confidence: 99%

“…4,5 Also in the metastatic setting, high or moderate expression of Top1 protein correlated with improved survival benefit for patients receiving either irinotecan or oxaliplatin as first line treatment, compared with patients with low Top1 protein expression. 6 However, although using similar technologies, other studies have not found Top1 protein predictive of response in the metastatic setting. 7,8 Reduced levels of Top1 in BC cells have been associated to decreased sensitivity to camptothecin 9 and a single small (n 5 22) clinical study has reported increased levels of Top1 protein in primary tumors from patients with BC.…”

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confidence: 99%

“…6,12 Fluorescence in situ hybridization (FISH) is a validated clinical method to be used on FFPE tissue and it provides a direct measure of cancer cell gene aberrations on a cell to cell basis and may therefore provide more specific information than global genomics techniques. In order to facilitate future studies on the efficacy of irinotecan and other Top1 inhibitors in BC treatment we here report on TOP1 DNA aberrations as determined by TOP1 FISH in two independent cohorts (n 5 100 and n 5 205) from primary BC biopsies.…”

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confidence: 99%

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Topoisomerase‐1 gene copy aberrations are frequent in patients with breast cancer

Kümler

Balslev

Poulsen

et al. 2015

Intl Journal of Cancer

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Topoisomerase-1 (Top1) targeting drugs have shown promising efficacy in patients with metastatic breast cancer (BC). However, these drugs are rather toxic calling for development and validation of predictive biomarkers to increase the therapeutic index. As these drugs are targeting the Top1 protein and since no validated anti-Top1 antibodies for immunohistochemistry have been reported, we raised the hypothesis that TOP1 gene amplifications may serve as a proxy for the Top1 protein and thereby a biomarker of response to treatment with Top1 inhibitors in BC. The aim was to determine the prevalence of TOP1 gene copy gain in BC.The prevalence of TOP1 gene copy gain was investigated by fluorescence in situ hybridization with a TOP1/CEN-20 probemix in normal breast tissue (N 5 100) and in tissue from patients with metastatic BC in a discovery (N 5 100) and a validation cohort (N 5 205). As amplification of 20q including CEN-20 is common in BC a TOP1/CEN-2 probemix was applied to the validation cohort.More than 30% of the patients had gene copy numbers of 4 and ;20% of the patients had TOP1/CEN-20 ratios 1.5. The CEN-2 probe did not add any information.Gain of the TOP1 gene appears to be common in BC making the gene a potential biomarker for response to treatment with Top1 inhibitors. As 20q amplification is a common finding in BC and as no other suitable reference gene has yet been identified, TOP1 copy number may be a more valid method of detecting gain than using a gene/centromere ratio.Irinotecan is a semisynthetic derivative of the naturally occurring camptothecin. It is an inhibitor of the topoisomerase 1 (Top1) enzyme and for almost two decades, it has been a cornerstone in the treatment of colorectal cancer. 1 Irinotecan for the use in breast cancer (BC) has been investigated in several clinical trials. 2 Generally, studies have been small and non-randomized and response rates (RR) for irinotecan monotherapy have been in the range 5-23% whereas irinotecan combined with various chemotherapeutics have shown RR ranging from 14 to 64%. 2 Despite RR comparable to those seen for other second or third-line treatments in metastatic BC, irinotecan has not yet found a place in the treatment of BC. Recently, however, a randomized phase II study evaluated the long-acting Top1 inhibitor Etirinotecan in 70 taxane resistant patients with metastatic BC and found a RR of 29% when the drug was given as monotherapy as second or third-line treatment. This drug, which consists of irinotecan bound to a proprietary polyethylene glycol core, is currently evaluated in a randomized phase III study versus physicians choice of treatment. 3 As for most chemotherapeutics used today, no predictive biomarker exists for response to irinotecan. The predictive role of Top1 in patients with

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Topoisomerase‐1 gene copy aberrations are frequent in patients with breast cancer

Kümler

Balslev

Poulsen

et al. 2015

Intl Journal of Cancer

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“…Obwohl zahlreiche retrospektive Studien gezeigt haben, dass das Ansprechen der Chemotherapie mit einer ganzen Reihe von Biomarkern korreliert, ist die Zahl der prospektiven Studien mit einer klinisch brauchbaren Evidenz nur sehr gering [16]. So hat kürzlich erstmals die FOCUS-Studie im prospektiven Ansatz in der Palliativsituation belegen können, dass der immunhistologische Nachweis der Topoisomerase-1-Expression mit dem Therapieansprechen auf Irinotecan und Oxaliplatin korreliert [4]. Trotzdem erfolgt die Behandlung des kolorektalen Karzinoms für den überwiegenden Teil der Patienten noch nicht zielgerichtet mithilfe prädikti-ver Biomarker [16].…”

Section: Nicht Zielgerichtete Therapieunclassified

Molekulare Targets beim Kolonkarzinom

Röcken

2008

Pathologe

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The ZEB2‐dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer

et al. 2021

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Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)‐inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease‐free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2‐dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1‐overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2‐ERCC1 axis is a key determinant of chemoresistance in CRC.

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Predictive Biomarkers of Chemotherapy Efficacy in Colorectal Cancer: Results From the UK MRC FOCUS Trial

Abstract: Topo1 immunohistochemistry identified subpopulations that did or did not benefit from irinotecan, and possibly also from oxaliplatin. If verified independently, this information will contribute to the individualization of treatment for colorectal cancer.

Cited by 248 publications

References 35 publications

Topoisomerase‐1 gene copy aberrations are frequent in patients with breast cancer

Topoisomerase‐1 gene copy aberrations are frequent in patients with breast cancer

Molekulare Targets beim Kolonkarzinom

The ZEB2‐dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer

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