HHS Public Access Author manuscript Author Manuscript
Clin Cancer Res. Author manuscript; available in PMC 2016 August 15. Published in final edited form as: Clin Cancer Res. 2015 August 15; 21(16): 3578–3580. doi:10.1158/1078-0432.CCR-14-2900.
CCR 20th Anniversary Commentary: RAS as a Biomarker for EGFR-Targeted Therapy for Colorectal Cancer—From Concept to Practice E. Ramsay Camp1,2,3 and Lee M. Ellis4,5 1Department
Author Manuscript
2Hollings 3Ralph
of Surgery, Medical University of South Carolina, Charleston, South Carolina
Cancer Center, Medical University of South Carolina, Charleston, South Carolina
H. Johnson VA Medical Center, Charleston, South Carolina
4Department
of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston,
Texas 5Department
of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
Summary
Author Manuscript
Clinical data support the use of EGFR mAbs in patients with metastatic colorectal cancer (mCRC) with wild-typeRAS status. This notion, hypothesized in the review article by Camp, Ellis, and colleagues in the January 1, 2005, issue of Clinical Cancer Research, serves as an example of the successful application of basic science principles to clinical practice. The exclusion of patients with mCRC with Ras mutated tumors from therapy with EGFR mAbs has led to improved outcomes while sparing patients unnecessary and potentially harmful therapy.
Introduction
Author Manuscript
The therapeutic potential of mAbs targeting the EGFR was established by promising preclinical studies and subsequent early phase clinical trials in patients with metastatic colorectal cancer (mCRC) (1). Ultimately, in 2004, the FDA approved the human-mouse chimeric EGFR mAb, cetuximab, for use in chemotherapy-refractory patients with mCRC. Similarly, panitumumab, a fully human EGFR mAb, was FDA approved for similar indications in 2006, and ultimately both drugs were subsequently approved in the first line setting in combination with chemotherapy. However, the earliest clinical trials investigating
Corresponding Author: Lee M. Ellis, Department of Surgical Oncology, Unit 1484, PO Box 301402, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77230. Phone: 713-792-6926; Fax: 713-792-4689; [email protected]. Disclosure of Potential Conflicts of Interest L.M. Ellis is a consultant/advisory board member for Celgene, Eli Lilly, and Genentech/Roche. No potential conflicts of interest were disclosed by the other author. Authors’ Contributions Conception and design: E.R. Camp, L.M. Ellis Writing, review, and/or revision of the manuscript: E.R. Camp, L.M. Ellis
Camp and Ellis
Page 2
Author Manuscript
EGFR mAbs in mCRC, demonstrated that these agents only provided modest benefit when used in combination with chemotherapy. Around this time, a concerted effort to identify predictive markers for EGFR targeted therapies was undertaken simultaneous to advances in genomic sequencing.
Author Manuscript
As principal investigator (PI) of a laboratory, the senior author of this manuscript (L.M.E.) learned early on in his career that the best way to educate a trainee on a topic was to have them write a review article. This strategy exposes trainees to the entire field of the topic of interest, requiring a critical evaluation of the literature, and identifying knowledge gaps. In 2004, the first author of this manuscript (E.R.C.) entered the laboratory and was tasked with writing a review on resistance to EGFR targeted therapies. At this time, EGFR mutations in lung cancer were being identified as markers of sensitivity to EGFR tyrosine kinase receptor inhibitors (2). Our laboratory had been interested in growth factor receptors and downstream intracellular signaling, with a focus on Src in collaboration with G. Gallick at MDACC. In reviewing the literature and applying our own knowledge of cell signaling, the general topics of this review inClinical Cancer Research (CCR) focused on the following as resistance factors to EGFR targeted therapies: 1) the presence of redundant tyrosine kinase receptors,2) increased angiogenic signaling,3) existence of specific EGFR mutations, and 4) constitutive activation of downstream mediators (3). This last proposed mechanism of resistance was not based on actual data, but a simple hypothesis: if an important intracellular pathway is constitutively activated by a mutation, then blocking signaling at the cell surface would be ineffective.
Author Manuscript Author Manuscript
In our original schematic drawing describing this hypothesis, we listed several activated downstream intermediates as potential resistance pathways. One, in particular, has demonstrated clinical utility in selecting patients with mCRC for EGFR mAb therapy. The therapeutic relevance of downstreamRAS mutations on EGFR mAb efficacy in patients with mCRC highlights the importance of understanding the molecular basis of malignant disease in order to improve personalized medicine. We recognize that this concept is the basis of many preclinical and clinical studies: but at the time of writing this review, there were no publications that had discussed or hypothesized that mutatedRAS or other constitutively activated signaling intermediates could serve as markers of resistance (or even detriment) in patients with mCRC. However, at that time there were several studies examining the role of mutatedRAS as a resistance marker for EGFR tyrosine kinase inhibitors in lung cancer (4,5); other investigators had hypothesized thatRAS could be a resistance marker for EGFR targeted therapies, and this occurred simultaneous to, or shortly after, our publication. Soon after the publication of our review in January 2005, there were several studies examining the role ofKRAS in EGFR mAb resistance, suggesting that others had this idea and had already begun studies. However, we have not identified any publication prior to ours in CCR addressing this topic. Of course, since then we have learned that additionalRAS mutations may render patients resistant to EGFR mAb therapy (6).
ConstitutiveRAS Pathway Activation Impact on EGFR mAb Therapy In 2006, a retrospective study of 30 patients with mCRC treated with cetuximab (mostly combined with chemotherapy) was the first clinical study to correlate KRAS mutational
Clin Cancer Res. Author manuscript; available in PMC 2016 August 15.
Camp and Ellis
Page 3
Author Manuscript
status with resistance to EGFR mAb therapy (7). In this small study, patients with tumors harboring aKRAS mutation demonstrated a 0% response rate. Overall survival (OS) in cetuximab treated patients was significantly shorter in those patients withKRAS mutations when compared with patients with wild-type (WT)KRAS (6.9 versus 16.3 months, p=0.016). A subsequent investigation confirmed the clinical significance ofKRAS mutations as predictive markers for cetuximab or panitumumab therapy for patients with mCRC (8). Furthermore, this study was the first to demonstrate a causal relationship between activatingKRAS mutation (Gly12Val) and decreasedin vitro response to cetuximab therapy in human colon cancer cell lines.
Author Manuscript Author Manuscript
A landmark retrospective analysis of a prospective randomized trial in 392 chemotherapy refractory patients with mCRC comparing cetuximab treatment with best supportive care (BSC) solidified the significance ofKRAS mutational status in clinical practice (9). OS in patients with WTKRAS tumors was significantly longer in patients treated with cetuximab compared to patients who received BSC (9.5 versus 4.8 months, p
Clin Cancer Res. Author manuscript; available in PMC 2016 August 15. Published in final edited form as: Clin Cancer Res. 2015 August 15; 21(16): 3578–3580. doi:10.1158/1078-0432.CCR-14-2900.
CCR 20th Anniversary Commentary: RAS as a Biomarker for EGFR-Targeted Therapy for Colorectal Cancer—From Concept to Practice E. Ramsay Camp1,2,3 and Lee M. Ellis4,5 1Department
Author Manuscript
2Hollings 3Ralph
of Surgery, Medical University of South Carolina, Charleston, South Carolina
Cancer Center, Medical University of South Carolina, Charleston, South Carolina
H. Johnson VA Medical Center, Charleston, South Carolina
4Department
of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston,
Texas 5Department
of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
Summary
Author Manuscript
Clinical data support the use of EGFR mAbs in patients with metastatic colorectal cancer (mCRC) with wild-typeRAS status. This notion, hypothesized in the review article by Camp, Ellis, and colleagues in the January 1, 2005, issue of Clinical Cancer Research, serves as an example of the successful application of basic science principles to clinical practice. The exclusion of patients with mCRC with Ras mutated tumors from therapy with EGFR mAbs has led to improved outcomes while sparing patients unnecessary and potentially harmful therapy.
Introduction
Author Manuscript
The therapeutic potential of mAbs targeting the EGFR was established by promising preclinical studies and subsequent early phase clinical trials in patients with metastatic colorectal cancer (mCRC) (1). Ultimately, in 2004, the FDA approved the human-mouse chimeric EGFR mAb, cetuximab, for use in chemotherapy-refractory patients with mCRC. Similarly, panitumumab, a fully human EGFR mAb, was FDA approved for similar indications in 2006, and ultimately both drugs were subsequently approved in the first line setting in combination with chemotherapy. However, the earliest clinical trials investigating
Corresponding Author: Lee M. Ellis, Department of Surgical Oncology, Unit 1484, PO Box 301402, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77230. Phone: 713-792-6926; Fax: 713-792-4689; [email protected]. Disclosure of Potential Conflicts of Interest L.M. Ellis is a consultant/advisory board member for Celgene, Eli Lilly, and Genentech/Roche. No potential conflicts of interest were disclosed by the other author. Authors’ Contributions Conception and design: E.R. Camp, L.M. Ellis Writing, review, and/or revision of the manuscript: E.R. Camp, L.M. Ellis
Camp and Ellis
Page 2
Author Manuscript
EGFR mAbs in mCRC, demonstrated that these agents only provided modest benefit when used in combination with chemotherapy. Around this time, a concerted effort to identify predictive markers for EGFR targeted therapies was undertaken simultaneous to advances in genomic sequencing.
Author Manuscript
As principal investigator (PI) of a laboratory, the senior author of this manuscript (L.M.E.) learned early on in his career that the best way to educate a trainee on a topic was to have them write a review article. This strategy exposes trainees to the entire field of the topic of interest, requiring a critical evaluation of the literature, and identifying knowledge gaps. In 2004, the first author of this manuscript (E.R.C.) entered the laboratory and was tasked with writing a review on resistance to EGFR targeted therapies. At this time, EGFR mutations in lung cancer were being identified as markers of sensitivity to EGFR tyrosine kinase receptor inhibitors (2). Our laboratory had been interested in growth factor receptors and downstream intracellular signaling, with a focus on Src in collaboration with G. Gallick at MDACC. In reviewing the literature and applying our own knowledge of cell signaling, the general topics of this review inClinical Cancer Research (CCR) focused on the following as resistance factors to EGFR targeted therapies: 1) the presence of redundant tyrosine kinase receptors,2) increased angiogenic signaling,3) existence of specific EGFR mutations, and 4) constitutive activation of downstream mediators (3). This last proposed mechanism of resistance was not based on actual data, but a simple hypothesis: if an important intracellular pathway is constitutively activated by a mutation, then blocking signaling at the cell surface would be ineffective.
Author Manuscript Author Manuscript
In our original schematic drawing describing this hypothesis, we listed several activated downstream intermediates as potential resistance pathways. One, in particular, has demonstrated clinical utility in selecting patients with mCRC for EGFR mAb therapy. The therapeutic relevance of downstreamRAS mutations on EGFR mAb efficacy in patients with mCRC highlights the importance of understanding the molecular basis of malignant disease in order to improve personalized medicine. We recognize that this concept is the basis of many preclinical and clinical studies: but at the time of writing this review, there were no publications that had discussed or hypothesized that mutatedRAS or other constitutively activated signaling intermediates could serve as markers of resistance (or even detriment) in patients with mCRC. However, at that time there were several studies examining the role of mutatedRAS as a resistance marker for EGFR tyrosine kinase inhibitors in lung cancer (4,5); other investigators had hypothesized thatRAS could be a resistance marker for EGFR targeted therapies, and this occurred simultaneous to, or shortly after, our publication. Soon after the publication of our review in January 2005, there were several studies examining the role ofKRAS in EGFR mAb resistance, suggesting that others had this idea and had already begun studies. However, we have not identified any publication prior to ours in CCR addressing this topic. Of course, since then we have learned that additionalRAS mutations may render patients resistant to EGFR mAb therapy (6).
ConstitutiveRAS Pathway Activation Impact on EGFR mAb Therapy In 2006, a retrospective study of 30 patients with mCRC treated with cetuximab (mostly combined with chemotherapy) was the first clinical study to correlate KRAS mutational
Clin Cancer Res. Author manuscript; available in PMC 2016 August 15.
Camp and Ellis
Page 3
Author Manuscript
status with resistance to EGFR mAb therapy (7). In this small study, patients with tumors harboring aKRAS mutation demonstrated a 0% response rate. Overall survival (OS) in cetuximab treated patients was significantly shorter in those patients withKRAS mutations when compared with patients with wild-type (WT)KRAS (6.9 versus 16.3 months, p=0.016). A subsequent investigation confirmed the clinical significance ofKRAS mutations as predictive markers for cetuximab or panitumumab therapy for patients with mCRC (8). Furthermore, this study was the first to demonstrate a causal relationship between activatingKRAS mutation (Gly12Val) and decreasedin vitro response to cetuximab therapy in human colon cancer cell lines.
Author Manuscript Author Manuscript
A landmark retrospective analysis of a prospective randomized trial in 392 chemotherapy refractory patients with mCRC comparing cetuximab treatment with best supportive care (BSC) solidified the significance ofKRAS mutational status in clinical practice (9). OS in patients with WTKRAS tumors was significantly longer in patients treated with cetuximab compared to patients who received BSC (9.5 versus 4.8 months, p
