Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer

Tougeron, David; Lecomte, Thierry; Pagès, Jean‐Christophe; Villalva, Claire; Collin, Christine; Ferru, Aurélie; Jm, Tourani; Silvain, Christine; Levillain, P.; Karayan‐Tapon, Lucie

doi:10.1093/annonc/mds620

Cited by 96 publications

(62 citation statements)

References 42 publications

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“…16 A recent report has indeed suggested that the presence of low levels of KRAS mutant alleles are associated with a reduced response rate and progression-free survival in mCRC patients treated with EGFR-based therapies. 20 However, a major bias of this latter study is that patients that showed resistance to anti-EGFR agents were also in more advanced lines of therapy as compared with sensitive patients, and this unbalance might have clearly affected the results of this study. Actually, the presence of resistance mutations in a small fraction of tumor cells is unlikely to cause primary resistance, although it may lead to a reduced progression free survival as demonstrated for treatment with EGFR tyrosine kinase inhibitors and the T790M resistance mutations in non-small-cell lung carcinoma (NSCLC).…”

Section: Discussionmentioning

confidence: 90%

The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies

Esposito

Rachiglio

Porta

et al. 2013

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 90%

The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies

Esposito

Rachiglio

Porta

et al. 2013

Cancer Biology & Therapy

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“…Previous studies suggested that patients with mCRC tumors containing no more than 1%-2% of KRAS-mutated subclones may benefit from anti-EGFR therapies. 111,112 However, no cut-off level for KRASmutated ctDNA that predicts resistance to anti-EGFR therapies has yet been established, thus, it is not known, for example, whether detection of 1% of cfDNA harboring a RAS mutation in a clinically responding wild-type RAS tumor should prompt a change in treatment.…”

Section: Discussionmentioning

confidence: 99%

Future perspectives of circulating tumor DNA in colorectal cancer

et al. 2017

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Tumor biopsy is currently the gold standard for diagnosis and in determining cell signaling pathways involved in the development of treatment resistance. However, there are major challenges with this technique, including the need for serial sampling to monitor treatment resistance, which is invasive and also has the potential for selection bias due to intra-tumoral and inter-tumoral heterogeneity. These challenges highlight the need for more effective methods for obtaining Tumor samples. Liquid biopsy analyzes genetic material or tumor cells shed into the blood from the primary tumor and metastatic sites and consequently provides a comprehensive, real-time picture of the tumor burden in an individual patient. Indeed, liquid biopsy has the potential to revolutionize cancer management. Here, we review recent studies on the potential clinical applications of liquid biopsy using circulating tumor DNA in colorectal cancer, including screening, diagnosis, detection of minimal residual disease after surgery, detection of recurrence, prognosis, predicting treatment response, monitoring tumor burden or response during treatment, and tracking resistance. We also discuss recent data demonstrating the utility of detecting KRAS-mutated circulating tumor DNA, both at diagnosis to determine an appropriate treatment strategy and during anti-epidermal growth factor receptor therapy to predict treatment resistance. The future integration of liquid biopsy into clinical practice is discussed, together with alternative approaches and key questions that need to be answered in future clinical studies before this technology can be implemented and used routinely.

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“…There is no uniform standard for KRAS testing and the majority of commonly used, commercially available assays assess only point mutations at codons 12 and 13, and lack sufficient coverage to detect less frequent KRAS alterations, which have been shown to predict resistance to anti-EGFR therapy [57,58]. Molecular test results returned to treating physicians can be misleading because published validation for the majority of assays indicating performance limitations is not readily available.…”

Section: Discussionmentioning

confidence: 99%

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

Rankin¹,

Klempner

Erlich³

et al. 2016

The Oncologist

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Introduction. A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti‐epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed. Materials and Methods. We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid‐capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance. Results. We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non‐codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644 RAS/RAF wild‐type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti‐EGFR therapy in advanced CRC including mutations in PIK3CA, PTEN, EGFR, and ERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as microsatellite instability. Conclusion. Extended genomic profiling reliably detects alterations associated with lack of benefit to anti‐EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility. Implications for Practice: Comprehensive genomic profiling (CGP) detects diverse genomic alterations associated with lack of benefit to anti‐epidermal growth factor receptor therapy in advanced colorectal cancer (CRC), as well as targetable alterations in many other genes. This includes detection of a broad spectrum of activating KRAS alterations frequently missed by focused molecular hotspot testing, as well as other RAS/RAF pathway alterations, mutations shown to disrupt antibody binding, RTK activating point mutations, amplifications, and rearrangements, and activating alterations in downstream effectors including PI3K and MEK1. The use of CGP in clinical practice is critical to guide appropriate selection of targeted therapies for patients with advanced CRC.

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Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer

Cited by 96 publications

References 42 publications

The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies

The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies

Future perspectives of circulating tumor DNA in colorectal cancer

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

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