Phase II Trial of Target-guided Personalized Chemotherapy in First-line Metastatic Colorectal Cancer

Cubillo, Antonio; Rodríguez-Pascual, Jesús; López‐Ríos, Fernando; Plaza, Carlos; Ramírez, Elena; Álvarez, Rafael; Vicente, Emilio; Quijano, Yolanda; Hernando, O.; Rubio, Carmen; Perea, Sofía; Sánchez, Gema María Varo; Hidalgo, Manuel

doi:10.1097/coc.0000000000000045

Cited by 8 publications

(10 citation statements)

References 27 publications

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“…With so many potential targets for therapy, personalized treatments with existing drugs would be expected to show improved results. Early trials of personalized therapy based on mutation status of KRAS, BRAF, PI3KCA, and expression of Topo-I, ERCC1, TS, and TP did not show any improvement in PFS [Cubillo et al 2014]. However, some authors have proposed using KRAS, BRAF, PI3KCA, and PTEN mutation status as a signature to guide therapy [Bardelli and Siena, 2010;Sartore-Bianchi et al 2009].…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic resistance in colorectal cancer: a review

2015

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Colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. This is in spite of widespread, effective measures of preventive screening, and also major advances in treatment options. Despite advances in cytotoxic and targeted therapy, resistance to chemotherapy remains one of the greatest challenges in long-term management of incurable metastatic disease and eventually contributes to death as tumors accumulate means of evading treatment. We performed a comprehensive literature search on the data available through PubMed, Medline, Scopus, and the ASCO Annual Symposium abstracts through June 2015 for the purpose of this review. We discuss the current state of knowledge of clinically relevant mechanisms of resistance to cytotoxic and targeted therapies now in use for the treatment of CRC.

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Section: Discussionmentioning

confidence: 99%

Pharmacologic resistance in colorectal cancer: a review

2015

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“…In view of these results, more efforts are needed to validate them in prospective clinical trials. Two examples can be found in the works of Kim do and Cubillo (62,63); in the former, patients were randomized to receive either FOLFOX combination or a treatment according to genotypes for certain polymorphisms. In this group, FOLFOX was selected on the basis of XPD-751, GSTP-1-105, and XRCC1-399 genotypes.…”

Section: The Glutathione Systemmentioning

confidence: 99%

Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance

Martínez-Balibrea

Martínez-Cardús

Ginés

et al. 2015

Molecular Cancer Therapeutics

259

242

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Oxaliplatin was the first platinum drug with proven activity against colorectal tumors, becoming a standard in the management of this malignancy. It is also considered for the treatment of pancreatic and gastric cancers. However, a major reason for treatment failure still is the existence of tumor intrinsic or acquired resistance. Consequently, it is important to understand the molecular mechanisms underlying the appearance of this phenomenon to find ways of circumventing it and to improve and optimize treatments. This review will be focused on recent discoveries about oxaliplatin tumor-related resistance mechanisms, including alterations in transport, detoxification, DNA damage response and repair, cell death (apoptotic and nonapoptotic), and epigenetic mechanisms.

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“…Indeed, research on personalized treatment of mCRC patients beyond the confirmed negative predictive role of RAS mutations for anti-epidermal growth factor receptor (EGFR) antibodies is far from conclusive [10]. …”

Section: Introductionmentioning

confidence: 99%

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

et al. 2016

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Objective:Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. Methods: With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). Results: No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). Conclusion: Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens.

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Phase II Trial of Target-guided Personalized Chemotherapy in First-line Metastatic Colorectal Cancer

Abstract: Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.

Cited by 8 publications

References 27 publications

Pharmacologic resistance in colorectal cancer: a review

Pharmacologic resistance in colorectal cancer: a review

Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

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