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Use of molecular biomarkers to guide systemic therapy
Evidence review B1
NICE Guideline, No. 151
National Guideline Alliance (UK).
Molecular biomarkers to guide systemic therapy for colorectal cancer
This evidence review supports recommendation 1.4.1.
Review question
Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
Introduction
Systemic therapy for colorectal cancer includes a number of different chemotherapy drugs, including irinotecan, oxaliplatin and oral fluoropyrimidines as well as anti–EGFR targeted therapy with cetuximab and panitumumab. However, while some drugs offer benefits to certain patients, other patients may experience toxicity instead. Despite the range of options for systemic management, the effectiveness of specific treatments for individual patients has not been thoroughly assessed. Predictive biomarkers provide information about the effect of a therapeutic intervention on an outcome and therefore provide valuable insight to guide treatment decision making. Therefore, the aim of this review was to determine which predictive biomarkers should be used in the systemic management of colorectal cancer patients.
Summary of the protocol
Please see Table 1 for a summary of the population, prognostic/predictive factors, and outcomes (PFO) characteristics of this review.
Table 1
Summary of the PFO table.
For further details see the review protocol in appendix A.
Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual 2014. Methods specific to this review question are described in the review protocol in appendix A.
Declarations of interest were recorded according to NICE’s 2014 conflicts of interest policy until 31 March 2018. From 1 April 2018, declarations of interest were recorded according to NICE’s 2018 conflicts of interest policy. Those interests declared until April 2018 were reclassified according to NICE’s 2018 conflicts of interest policy (see Register of Interests).
Clinical evidence
Included studies
Twenty five studies were identified for this review, 9 systematic reviews (Dahabreh 2011, Des Guetz 2009, Huang 2014, Petrelli 2013, Shen 2019, Sorich 2015, Sun 2019, Yuan 2013, Zhu 2016) and 16 observational analyses of randomised controlled trials (RCTs) which were used to update the systematic reviews (Bertagnolli 2009, Gray 2011, Guren 2017, Hegeswich-Becker 2018, Hutchins 2011, Kennedy 2011, Modest 2016, Niedzwiecki 2016, Ogino 2009, Seligman 2016, Sinicrope 2011, Sinicrope 2015, Taib 2017, Vernook 2013, Yothers 2013, Zaanan 2018).
The included studies are summarised in Table 2.
Seven studies compared KRAS mutant versus wildtype (Dahabreh 2011, Hutchins 2011 Petrelli 2013, Modest 2016, Ogino 2009, Sinicrope 2011, Taib 2017).
Three studies compared RAS mutant versus wildtype (Guren 2017, Hegeswich-Becker 2018, Sorich 2015).
Eight studies compared BRAF mutant versus wildtype (Guren 2017, Hutchins 2011, Modest 2016, Sinicrope 2015, Seligman 2016, Taib 2017, Yuan 2013, Zhu 2016).
One study compared PIK3CA mutant versus wildtype (Huang 2014).
Five studies compared deficient versus proficient mismatch repair status (Bertagnolli 2009, Des Guetz 2009, Hutchins 2011, Sinicrope 2011, Zaanan 2018).
One study compared high versus low Immunoscore (Sun 2019).
Two studies compared high versus low ColDX risk (Kennedy 2011, Niedzwiecki 2016).
Three studies compared high versus low Oncotype-DX recurrence risk score (Gray 2011, Vernook 2013, Yothers 2013).
See the literature search strategy in appendix B and study selection flow chart in appendix C.
Excluded studies
Studies not included in this review with reasons for their exclusions are provided in appendix K.
Summary of clinical studies included in the evidence review
Summaries of the studies that were included in this review are presented in Table 2.
Table 2
Summary of included studies.
See the full evidence tables in appendix D and the forest plots in appendix E.
Quality assessment of clinical outcomes included in the evidence review
See the clinical evidence profiles in appendix F.
Economic evidence
Included studies
A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question.
Excluded studies
A global search of economic evidence was undertaken for all review questions in this guideline. See Supplement 2 for further information.
Economic model
No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.
Evidence statements
Clinical evidence statements
Comparison 1: KRAS mutant versus wildtype
Anti-EGFR targeted therapy
Critical outcomes
Response to systemic therapy
- High quality evidence from 22 observational studies (N=2242) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with KRAS mutations had poorer response to systemic therapy than patients with wildtype KRAS.
Progression-free survival with anti-EGFR targeted therapy
- High quality evidence from 16 observational studies (N=1945) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with KRAS mutations had poorer progression-free survival than patients with wildtype KRAS.
Disease-free survival with adjuvant anti-EGFR targeted therapy
- High quality evidence from 1 observational study (N=783) showed that in patients with stage II or III colorectal cancer treated with adjuvant chemotherapy ± anti-EGFR targeted therapy, those with KRAS mutations had poorer disease-free survival than patients with wildtype KRAS.
Important outcomes
Overall survival with anti-EGFR targeted therapy
- High quality evidence from 13 observational studies (N=1695) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with KRAS mutations had poorer overall survival than patients with wildtype KRAS.
- High quality evidence from 1 observational study (N=783) showed that in patients with stage II or III colorectal cancer treated with adjuvant chemotherapy ± anti-EGFR targeted therapy, those with KRAS mutations had poorer overall survival than patients with wildtype KRAS.
Bevacizumab
Critical outcomes
Response to systemic therapy
- High quality evidence from 12 observational studies (N=2266) showed that in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy, those with KRAS mutations had poorer response to systemic therapy than patients with wildtype KRAS.
Progression-free survival with bevacizumab
- High quality evidence from 17 observational studies (N=3095) showed that in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy, those with KRAS mutations had poorer progression-free survival than patients with wildtype KRAS.
Disease-free survival with bevacizumab
No evidence was identified to inform this outcome.
Important outcomes
Overall survival with bevacizumab
- High quality evidence from 17 observational studies (N=3095) showed that in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy, those with KRAS mutations had poorer overall survival than patients with wildtype KRAS.
Chemotherapy
Critical outcomes
Response to systemic therapy
No evidence was identified to inform this outcome.
Progression-free survival with chemotherapy
- High quality evidence from 5 observational studies (N=410) showed that in patients with metastatic colorectal cancer treated with chemotherapy, there was no important difference between the progression-free survival of those with KRAS mutations and those with wildtype KRAS.
Disease-free survival with chemotherapy
- High quality evidence from 1 observational study (N=784) showed that in patients with right sided stage II colorectal cancer treated with chemotherapy, those with KRAS mutations had poorer disease-free survival than patients with wildtype KRAS.
Important outcomes
Overall survival with chemotherapy
- High quality evidence from 5 observational studies (N=410) showed that in patients with metastatic colorectal cancer treated with chemotherapy, there was no important difference between the overall survival of those with KRAS mutations and those with wildtype KRAS.
- High quality evidence from 1 observational study (N=508) showed that in patients with stage II colorectal cancer treated with 5-FU based chemotherapy, there was no important difference between the overall survival of those with KRAS mutations and those with wildtype KRAS.
Comparison 2: RAS mutant versus wildtype
Anti-EGFR targeted therapy
Critical outcomes
Response to systemic therapy
- High quality evidence from 1 observational study (N=457) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with RAS mutations had poorer response to systemic therapy than patients with wildtype RAS.
Progression-free survival with anti-EGFR targeted therapy
- High quality evidence from 9 observational studies (N=5948) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with RAS mutations had poorer progression-free survival than patients with wildtype RAS.
Disease-free survival with adjuvant anti-EGFR targeted therapy
No evidence was identified to inform this outcome.
Important outcomes
Overall survival with anti-EGFR targeted therapy
- High quality evidence from 10 observational studies (N=6405) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with RAS mutations had poorer overall survival than patients with wildtype RAS.
Bevacizumab
Critical outcomes
Response to systemic therapy
No evidence was identified to inform this outcome.
Progression-free survival with bevacizumab
No evidence was identified to inform this outcome.
Disease-free survival with bevacizumab
No evidence was identified to inform this outcome.
Important outcomes
Overall survival with bevacizumab
- High quality evidence from 1 observational study (N=597) showed that in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy, those with RAS mutations had poorer overall survival than patients with wildtype RAS.
Comparison 3: BRAF mutant versus wildtype
Anti-EGFR targeted therapy
Critical outcomes
Response to systemic therapy
- High quality evidence from 22 observational studies (N=4660) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with BRAF mutations had poorer response to systemic therapy than patients with wildtype BRAF.
Progression-free survival with anti-EGFR targeted therapy
- High quality evidence from 21 observational studies (N=4203) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with BRAF mutations had poorer progression-free survival than patients with wildtype BRAF.
Disease-free survival with adjuvant anti-EGFR targeted therapy
- High quality evidence from 9 observational studies (N=3947) showed that in patients with stage II or III colorectal cancer treated with adjuvant chemotherapy ± anti-EGFR targeted therapy, those with BRAF mutations had poorer disease-free survival than patients with wildtype BRAF.
Important outcomes
Overall survival with anti-EGFR targeted therapy
- High quality evidence from 22 observational studies (N=4660) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with BRAF mutations had poorer overall survival than patients with wildtype BRAF.
- High quality evidence from 8 observational studies (N=1227) showed that in patients with stage II or III colorectal cancer treated with adjuvant chemotherapy ± anti-EGFR targeted therapy, those with BRAF mutations had poorer overall survival than patients with wildtype BRAF.
Bevacizumab
Critical outcomes
Response to systemic therapy
No evidence was identified to inform this outcome.
Progression-free survival with bevacizumab
- High quality evidence from 5 observational studies (N=829) showed that in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy, those with BRAF mutations had poorer progression-free survival than patients with wildtype BRAF, although there was uncertainty in the effect size.
Disease-free survival with bevacizumab
No evidence was identified to inform this outcome.
Important outcomes
Overall survival with bevacizumab
- High quality evidence from 5 observational studies (N=829) showed that in patients with metastatic colorectal cancer treated with bevacizumab ± chemotherapy, those with BRAF mutations had poorer overall survival than patients with wildtype BRAF.
Chemotherapy
Critical outcomes
Response to systemic therapy
- High quality evidence from 2 observational studies (N=1541) showed that in patients with metastatic colorectal cancer treated with chemotherapy, there was no clinically important difference between the response rates of those with BRAF mutations and those with wildtype BRAF.
Progression-free survival with chemotherapy
- High quality evidence from 7 observational studies (N=1693) showed that in patients with metastatic colorectal cancer treated with chemotherapy, there was no clinically important difference between the progression-free survival of those with BRAF mutations and those with wildtype BRAF.
Progression-free survival with chemotherapy
No evidence was identified to inform this outcome.
Important outcomes
Overall survival with chemotherapy
- High quality evidence from 7 observational studies (N=1951) showed that in patients with metastatic colorectal cancer treated with chemotherapy, those with BRAF mutations had poorer overall survival than patients with wildtype BRAF.
Comparison 4: PIK3CA mutant versus wildtype
Critical outcomes
Response to systemic therapy
- Moderate quality evidence from 9 observational studies (N=693) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with PIK3CA mutations had poorer response to systemic therapy than patients with wildtype PIK3CA.
Progression-free survival with anti-EGFR targeted therapy
- Moderate quality evidence from 4 observational studies (N=526) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with PIK3CA mutations had poorer progression-free survival than patients with wildtype PIK3CA.
Disease-free survival with anti-EGFR targeted therapy
No evidence was identified to inform this outcome.
Important outcomes
Overall survival with anti-EGFR targeted therapy
- Moderate quality evidence from 3 observational studies (N=508) showed that in patients with metastatic colorectal cancer treated with anti-EGFR targeted therapy ± chemotherapy, those with PIK3CA mutations had poorer overall survival than patients with wildtype PIK3CA.
Comparison 5: deficient versus proficient mismatch repair status (dMMR versus pMMR)
Critical outcomes
Response to systemic therapy
- High quality evidence from 5 observational studies (N=693) showed that in patients with metastatic colorectal cancer, there was no clinically important difference in response to chemotherapy between those with dMMR and those with pMMR.
Progression-free survival with chemotherapy
No evidence was identified to inform this outcome.
Disease-free survival with chemotherapy
- High quality evidence from 8 observational studies (N=5348) showed that in patients with metastatic colorectal cancer treated with chemotherapy, those with dMMR had better disease-free survival than patients with pMMR.
Important outcomes
Overall survival with chemotherapy
- High quality evidence from 5 observational studies (N=2141) showed that in patients with metastatic colorectal cancer treated with chemotherapy, those with dMMR had better overall survival than patients with pMMR.
Comparison 6: Immunoscore (high versus low)
Critical outcomes
Response to systemic therapy
No evidence was identified to inform this outcome.
Progression-free survival
No evidence was identified to inform this outcome.
Disease-free survival
- Low quality evidence from 5 observational studies (N=3992) showed that in patients with stage I to III colorectal cancer, those with high Immunoscore had poorer disease-free survival than patients with a low Immunoscore.
Important outcomes
Overall survival
- Low quality evidence from 5 observational studies (N=4188) showed that in patients with stage I to III colorectal cancer, those with high Immunoscore had poorer overall survival than patients with a low Immunoscore.
- Low quality evidence from 2 observational studies (N=612) showed that in patients with metastatic colorectal cancer, those with high Immunoscore had poorer overall survival than patients with a low Immunoscore.
Comparison 7: PD-L1 positive versus negative
Critical outcomes
Response to systemic therapy
No evidence was identified to inform this outcome.
Progression-free survival
No evidence was identified to inform this outcome.
Disease-free survival
No evidence was identified to inform this outcome.
Important outcomes
Overall survival with chemotherapy
- Moderate quality evidence from 10 observational studies (N=3481) showed that patients with PD-L1 positive colorectal cancer had poorer overall survival than patients with PD-L1 negative status.
Comparison 8: ColDX high risk versus low risk
Critical outcomes
Response to systemic therapy
No evidence was identified to inform this outcome.
Progression-free survival
No evidence was identified to inform this outcome.
Disease-free survival
- Low quality evidence from 2 observational studies (N=537) showed that in patients with stage II colon cancer, those with high ColDX risk score had poorer disease free survival than patients with a low risk score.
Important outcomes
Overall survival
- Low quality evidence from 2 observational studies (N=537) showed that in patients with stage II colon cancer, those with high ColDX risk score had poorer overall survival than patients with a low risk score.
Comparison 9: Oncotype-DX higher versus lower recurrence score
Critical outcomes
Response to systemic therapy
No evidence was identified to inform this outcome.
Progression-free survival
No evidence was identified to inform this outcome.
Disease-free survival
- Moderate quality evidence from 3 observational studies (N=3018) showed that in patients with stage II colon cancer, those with higher Oncotype-DX recurrence score risk score had poorer disease-free survival than patients with a lower recurrence risk score.
Important outcomes
Overall survival
- High quality evidence from 1 observational studies (N=892) showed that in patients with stage II colon cancer treated with adjuvant chemotherapy, those with higher Oncotype-DX recurrence score risk score had poorer overall survival than patients with a lower recurrence risk score.
Economic evidence statements
No economic evidence was identified which was applicable to this review question.
The committee’s discussion of the evidence
Interpreting the evidence
The outcomes that matter most
Response to systemic therapy was a critical outcome for this question because biomarkers could help identify patients most likely to benefit from systemic treatment. Similarly progression-free survival (for those with metastatic disease) and disease free survival (for those with non-metastatic disease) were critical because effective systemic treatment should influence these outcomes. Overall survival was an important outcome because the relationship between biomarkers, the choice of systemic therapy and overall survival is less clear. This is because biomarkers may be also prognostic factors which identify patients with poor outcomes regardless of which systemic therapy they receive.
The quality of the evidence
Evidence was available on all predictive biomarkers of interest. The quality of the evidence was assessed using modified GRADE and varied from low to high quality. Evidence was downgraded due to incomplete reporting of attrition rates and adjustment for confounders. In some evidence was downgraded because systemic therapy was not given or was not relevant to current practice. There was a potential selection bias in some studies due to the inclusion of only the subset of patients whose tumour tissue could be retrieved for biomarker tests.
Benefits and harms
The evidence showed that RAS and BRAF V600E mutations were predictive of response to anti-EGFR targeted therapy in people with metastatic colorectal cancer. In this group, people with RAS or BRAF V600E mutations also had poorer progression-free and overall survival than those without such mutations. By using biomarkers to identify patients unlikely to benefit from anti-EGFR targeted therapy, patients can be spared the side-effects associated with the treatment. Therefore, a recommendation was made to test all people with metastatic colorectal cancer suitable for systemic anti-cancer treatment for RAS (including both KRAS and NRAS) and BRAF V600E mutations.
In patients with KRAS wildtype metastatic disease the evidence indicated PIK3CA was a potential predictive biomarker of response to anti-EGFR targeted therapy but with a much smaller body of evidence than for RAS and BRAF the committee were not confident to make a recommendation for PIK3CA testing given it is not current practice.
The evidence showed that people with non-metastatic colorectal cancer with RAS or BRAF V600E mutations who were treated with anti-EGFR targeted therapy had poorer disease-free and overall survival than those without such mutations. The committee did not recommend RAS or BRAF testing in this group, however, because evidence does not support the use of adjuvant anti-EGFR targeted therapy in non-metastatic disease.
There was consistent evidence that disease-free and overall survival were better in those patients receiving chemotherapy with non-metastatic colorectal cancer and deficient mismatch repair (dMMR) when compared to those with proficient mismatch repair (pMMR). The committee considered that mismatch repair status could help guide treatment decisions, however NICE diagnostic guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer (DG27) already recommends testing for mismatch repair status in all people with colorectal cancer. For this reason the committee did not make a separate recommendation about mismatch repair testing but instead referred to the existing diagnostics guidance.
Evidence showed that Immunoscore and PD-L1 were associated with overall survival but given the lack of evidence about their association with response rate or progression-free survival the committee did not think there was strong enough evidence about its use to guide systemic treatment decisions and did not make a recommendation about it.
Evidence about CoIDX or Oncotype DX testing was limited to studies reporting overall and disease-free survival in stage II colon cancer. The committee considered that while these may be prognostic markers it was not appropriate to recommend their use for guiding systemic therapy choices.
Cost effectiveness and resource use
The committee considered the resource impact of their recommendations would be minimal as RAS testing is current practice and the additional BRAF V600E test can be done as part of the extended colorectal cancer molecular test panel.
References
Bertagnolli 2011
Bertagnolli M, Redston, M, Compton C., et al. (2011) Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer--a study of CALGB 9581 and 89803. Journal of Clinical Oncology 29(23): 3153–3162 [PMC free article: PMC3157981] [PubMed: 21747089]Dahabreh 2011
Dahabreh J, Terasawa T, Castaldi J et al. (2011) Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Annals of Internal Medicine, 154(1): 37–49 [PubMed: 21200037]Des Guetz 2009
Des Guetz G, Uzzan B, Nicolas P, et al. (2009) Microsatellite instability: A predictive marker in metastatic colorectal cancer? Targeted Oncology 4(1): 57–62 [PubMed: 19343302]Gray 2011
Gray R, Quirke P, Handley K, et al, (2011) Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer. Journal of Clinical Oncology 29(35): 4611–4619 [PubMed: 22067390]Guren 2017
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Modest, D, Ricard I, Heinemann V, et al. (2016) Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group. Annals of Oncology 27(9): 1746–1753 [PMC free article: PMC4999563] [PubMed: 27358379]Niedzwiecki 2016
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Appendices
Appendix A. Review protocol
Review protocol for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
Appendix B. Literature search strategies
Literature search strategies for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
Databases: Embase/Medline
Last searched on: 31/10/2018
| # | Search |
|---|---|
| 1 | exp colorectal neoplasms/ use ppez |
| 2 | (exp colorectal cancer/ or exp colon tumor/ or exp rectum tumor/) use emez |
| 3 | ((colorect* or colo rect* or colon or colonic or rectal or rectum) adj3 (adenocarcinoma* or cancer* or carcinoma* or malignan* or neoplas* or oncolog* or tumo?r*)).tw. |
| 4 | or/1–3 |
| 5 | exp *antineoplastic agent/ use emez or exp *antineoplastic agents/ use ppez |
| 6 | exp *Antineoplastic Protocols/ use ppez |
| 7 | exp *chemotherapy/ use emez |
| 8 | Cancer Vaccines/ use ppez |
| 9 | cancer vaccine/ use emez |
| 10 | cancer immunotherapy/ use emez |
| 11 | exp *antibodies, monoclonal/ use ppez |
| 12 | *monoclonal antibody/ use emez |
| 13 | ((anti canc* or anticanc* or anticarcinogen* or anti neoplas* or antineoplas* or cytotoxic*) adj2 (agent* or drug* or protocol* or regimen* or treatment* or therap*)).ti. |
| 14 | (SACT or chemotherap* or immunotherap* or biological agent* or biological therap*).ti. |
| 15 | systemic therap*.tw. |
| 16 | or/5–15 |
| 17 | exp *Ras proteins/ use ppez |
| 18 | (ras protein/ or k ras protein/ or oncogene n ras/) use emez |
| 19 | (((ras or kras or k ras or nras or n ras) adj2 (wildtype or wild type or wt or mutant or mutat* or protein or gene)) and (predict* or prognos*)).tw. |
| 20 | *Proto-oncogene proteins B-Raf/ use ppez |
| 21 | *B raf kinase/ use emez |
| 22 | ((Braf or b raf) adj3 v600e).tw. |
| 23 | exp *Phosphatidylinositol 3-Kinases/ use ppez |
| 24 | *phosphatidylinositol 3 kinase/ use emez |
| 25 | (PIK3CA and (predict* or prognos*)).tw. |
| 26 | DNA mismatch repair/ use ppez |
| 27 | *Mismatch repair/ use emez |
| 28 | ((mismatch or MMR) adj3 (deficien* or deficit* or proficien*)).tw. |
| 29 | ((Mismatch repair or MMR-d or MMR-p or dMMR or pMMR) and (predict* or prognos*)).tw. |
| 30 | *Microsatellite Instability/ use ppez or *microsatellite instability/ use emez |
| 31 | (microsatellite instability or microsatellite unstable or MSI-H).tw. |
| 32 | (MSI adj2 (cancer* or tumo?r* or test* or status)).tw. |
| 33 | exp *cd3 complex/ use ppez |
| 34 | *cD3 antigen/ use emez |
| 35 | *Cd8 antigens/ use ppez |
| 36 | *CD8 antigen/ use emez |
| 37 | (((cd3 or cd8) adj3 (antigen* or protein* or complex or immunoscore or immuno score)) and (predict* or prognos*)).tw. |
| 38 | Programmed Cell Death 1 Receptor/ use ppez |
| 39 | programmed death 1 receptor/ use emez |
| 40 | B7-H1 Antigen/ use ppez |
| 41 | programmed death 1 ligand 1/ use emez |
| 42 | ((PD1 or PD-1 or PDL-1 or PDL1 or PD-L1) and (predict* or prognos*)).tw. |
| 43 | (coldx or col dx or oncotype dx).tw. |
| 44 | or/17–43 |
| 45 | 4 and 16 and 44 |
| 46 | Letter/ use ppez |
| 47 | letter.pt. or letter/ use emez |
| 48 | note.pt. |
| 49 | editorial.pt. |
| 50 | Editorial/ use ppez |
| 51 | News/ use ppez |
| 52 | exp Historical Article/ use ppez |
| 53 | Anecdotes as Topic/ use ppez |
| 54 | Comment/ use ppez |
| 55 | Case Report/ use ppez |
| 56 | case report/ or case study/ use emez |
| 57 | (letter or comment*).ti. |
| 58 | or/46–57 |
| 59 | randomized controlled trial/ use ppez |
| 60 | randomized controlled trial/ use emez |
| 61 | random*.ti,ab. |
| 62 | or/59–61 |
| 63 | 58 not 62 |
| 64 | animals/ not humans/ use ppez |
| 65 | animal/ not human/ use emez |
| 66 | nonhuman/ use emez |
| 67 | exp Animals, Laboratory/ use ppez |
| 68 | exp Animal Experimentation/ use ppez |
| 69 | exp Animal Experiment/ use emez |
| 70 | exp Experimental Animal/ use emez |
| 71 | exp Models, Animal/ use ppez |
| 72 | animal model/ use emez |
| 73 | exp Rodentia/ use ppez |
| 74 | exp Rodent/ use emez |
| 75 | (rat or rats or mouse or mice).ti. |
| 76 | or/63–75 |
| 77 | 45 not 76 |
| 78 | limit 77 to (yr=“2000 - current” and english language) |
| 79 | remove duplicates from 78 |
Database: Cochrane Library
Last searched on: 31/10/2018
| # | Search |
|---|---|
| 1 | MeSH descriptor: [Colorectal Neoplasms] explode all trees |
| 2 | (((colorect* or colo rect* or colon or colonic or rectal or rectum) near/3 (adenocarcinoma* or cancer* or carcinoma* or malignan* or neoplas* or oncolog* or tumo?r*))):ti,ab,kw |
| 3 | #1 or #2 |
| 4 | MeSH descriptor: [Antineoplastic Agents] explode all trees |
| 5 | MeSH descriptor: [Antineoplastic Protocols] explode all trees |
| 6 | MeSH descriptor: [Cancer Vaccines] explode all trees |
| 7 | MeSH descriptor: [Antibodies, Monoclonal] explode all trees |
| 8 | ((anti canc* or anticanc* or anticarcinogen* or anti neoplas* or antineoplas* or cytotoxic*) near/2 (agent* or drug* or protocol* or regimen* or treatment* or therap*)):ti,ab,kw |
| 9 | ((chemotherap* or SACT or immunotherap* or biological agent* or biological therap*)):ti |
| 10 | (systemic therap*):kw,ab,ti |
| 11 | {or #4-#10} |
| 12 | MeSH descriptor: [ras Proteins] explode all trees |
| 13 | MeSH descriptor: [Genes, ras] this term only |
| 14 | ((((ras or kras or k ras or nras or n ras) near/2 (wildtype or wild type or wt or mutant or mutat* or protein or gene)) and (predict* or prognos*))):ti,ab,kw |
| 15 | MeSH descriptor: [Proto-Oncogene Proteins B-raf] this term only |
| 16 | (((Braf or b raf) near/3 v600e)):ti,ab,kw |
| 17 | MeSH descriptor: [Phosphatidylinositol 3-Kinases] explode all trees |
| 18 | ((PIK3CA and (predict* or prognos*))):ti,ab,kw |
| 19 | MeSH descriptor: [DNA Mismatch Repair] explode all trees |
| 20 | (((mismatch or MMR) near/3 (deficien* or deficit* or proficien*))):ti,ab,kw |
| 21 | (((Mismatch repair or MMR-d or MMR-p or dMMR or pMMR) and (predict* or prognos*))):ti,ab,kw |
| 22 | MeSH descriptor: [Microsatellite Instability] explode all trees |
| 23 | ((microsatellite instability or microsatellite unstable or MSI-H)):ti,ab,kw |
| 24 | ((MSI near/2 (cancer* or tumo?r* or test* or status))):ti,ab,kw |
| 25 | MeSH descriptor: [CD3 Complex] explode all trees |
| 26 | MeSH descriptor: [CD8 Antigens] explode all trees |
| 27 | ((((cd3 or cd8) near/3 (antigen* or protein* or complex or immunoscore or immuno score)) and (predict* or prognos*))):ti,ab,kw |
| 28 | MeSH descriptor: [Programmed Cell Death 1 Receptor] explode all trees |
| 29 | MeSH descriptor: [B7-H1 Antigen] this term only |
| 30 | (((PD1 or PD-1 or PDL-1 or PDL1 or PD-L1) and (predict* or prognos*))):ti,ab,kw |
| 31 | ((coldx or col dx or oncotype dx)):ti,ab,kw |
| 32 | {or #12-#31} |
| 33 | #3 and #11 and #32 with Cochrane Library publication date Between Jan 2000 and Dec 2018 |
Appendix C. Clinical evidence study selection
Clinical evidence study selection for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
Appendix D. Clinical evidence tables
Clinical evidence tables for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
Table 4. Clinical evidence tables (PDF, 682K)
Appendix E. Forest plots
Forest plots for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
Figure 2. Comparison 1: KRAS mutant versus KRAS wildtype – response to systemic therapy
Figure 4. Comparison 1: KRAS mutant versus KRAS wildtype – response to bevacizumab based therapy
Figure 6. Comparison 1: KRAS mutant versus KRAS wildtype – survival outcomes with chemotherapy
Figure 7. Comparison 2: RAS mutant versus RAS wildtype – response to anti-EGFR targeted therapy
Figure 9. Comparison 2: RAS mutant versus RAS wildtype – survival with bevacizumab based therapy
Figure 10. Comparison 3: BRAF mutant versus BRAF wildtype – response to anti-EGFR targeted therapy
Figure 13. Comparison 3: BRAF mutant versus BRAF wildtype – response to chemotherapy
Figure 14. Comparison 3: BRAF mutant versus BRAF wildtype – survival outcomes with chemotherapy
Figure 15. Comparison 4: PIK3CA mutant versus PIK3CA wildtype (in KRAS wildtype) – response rate
Figure 17. Comparison 4: PIK3CA mutant versus PIK3CA wildtype (in KRAS wildtype) : overall survival
Figure 18. Comparison 5: dMMR versus pMMR – response rate
Figure 19. Comparison 5: dMMR versus pMMR – disease-free survival
Figure 20. Comparison 5: dMMR versus pMMR – overall survival
Figure 21. Comparison 6: Immunoscore – disease free survival
Figure 22. Comparison 6: Immunoscore – overall survival
Figure 23. Comparison 7: PD-L1 positive versus PD-L1 negative – overall survival
Figure 24. Comparison 8: ColDX high versus low risk – disease-free survival
Figure 25. Comparison 8: ColDX high versus low risk – overall survival
Figure 26. Comparison 9: Oncotype DX – disease-free survival
Appendix F. GRADE profiles
GRADE profiles for the review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
Table 5. Clinical evidence profile for comparison 1: KRAS mutant versus wildtype
Table 6. Clinical evidence profile for comparison 2: RAS mutant versus wildtype
Table 7. Clinical evidence profile for comparison 3: BRAF mutant versus wildtype
Table 8. Clinical evidence profile for comparison 4: PIK3CA mutant versus wildtype
Table 10. Clinical evidence profile for comparison 6: Immunoscore high risk versus low risk
Table 11. Clinical evidence profile for comparison 7: PD-L1 positive versus negative
Table 12. Clinical evidence profile for comparison 8: ColDX high risk versus low risk
Appendix G. Economic evidence study selection
Economic evidence study selection for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
A global search of economic evidence was undertaken for all review questions in this guideline. See Supplement 2 for further information.
Appendix H. Economic evidence tables
Economic evidence tables for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
No economic evidence was identified which was applicable to this review question.
Appendix I. Economic evidence profiles
Economic evidence profiles for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
No economic evidence was identified which was applicable to this review question.
Appendix J. Economic analysis
Economic evidence for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
No economic analysis was conducted for this review question.
Appendix K. Excluded studies
Excluded clinical studies for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
Appendix L. Research recommendations
Research recommendations for review question: Which predictive biomarkers should be used in the systemic management of colorectal cancer patients?
No research recommendations were made for this review question.
Final
Evidence reviews
Developed by the National Guideline Alliance part of the Royal College of Obstetricians and Gynaecologists
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.
Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
- Review The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal No.150 and part review of technology appraisal No. 118): a systematic review and economic model.[Health Technol Assess. 2013]Review The clinical effectiveness and cost-effectiveness of cetuximab (mono- or combination chemotherapy), bevacizumab (combination with non-oxaliplatin chemotherapy) and panitumumab (monotherapy) for the treatment of metastatic colorectal cancer after first-line chemotherapy (review of technology appraisal No.150 and part review of technology appraisal No. 118): a systematic review and economic model.Hoyle M, Crathorne L, Peters J, Jones-Hughes T, Cooper C, Napier M, Tappenden P, Hyde C. Health Technol Assess. 2013 Apr; 17(14):1-237.
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- Review Improving disease control in advanced colorectal cancer: Panitumumab and cetuximab.[Crit Rev Oncol Hematol. 2010]Review Improving disease control in advanced colorectal cancer: Panitumumab and cetuximab.Rodríguez J, Viúdez A, Ponz-Sarvisé M, Gil-Aldea I, Chopitea A, García-Foncillas J, Gil-Bazo I. Crit Rev Oncol Hematol. 2010 Jun; 74(3):193-202. Epub 2009 Aug 22.
- Panitumumab monotherapy compared with cetuximab and irinotecan combination therapy in patients with previously treated KRAS wild-type metastatic colorectal cancer.[Curr Oncol. 2013]Panitumumab monotherapy compared with cetuximab and irinotecan combination therapy in patients with previously treated KRAS wild-type metastatic colorectal cancer.Kennecke H, Chen L, Blanke CD, Cheung WY, Schaff K, Speers C. Curr Oncol. 2013 Dec; 20(6):326-32.
- Review Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies.[Ann Med. 2006]Review Novel approaches to treatment of advanced colorectal cancer with anti-EGFR monoclonal antibodies.Zhang W, Gordon M, Lenz HJ. Ann Med. 2006; 38(8):545-51.
- Use of molecular biomarkers to guide systemic therapyUse of molecular biomarkers to guide systemic therapy
- Homo sapiens Rho GTPase activating protein 25 (ARHGAP25), transcript variant 5, ...Homo sapiens Rho GTPase activating protein 25 (ARHGAP25), transcript variant 5, mRNAgi|1423310397|ref|NM_001364819.1|Nucleotide
- Proteus anguinus mitochondrion, complete genomeProteus anguinus mitochondrion, complete genomegi|575669328|ref|NC_023342.1||gnl|N ENOMES|35428Nucleotide
- Wdr41 WD repeat domain 41 [Rattus norvegicus]Wdr41 WD repeat domain 41 [Rattus norvegicus]Gene ID:361879Gene
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