Predictive and Prognostic markers in the treatment of metastatic colorectal cancer (mCRC) – personalized medicine at work –

This article clarifies prognostic and predictive markers in the treatment of colorectal cancer. Multiple chemotherapeutic drugs are approved for metastatic colorectal cancer (mCRC), but available guidelines are often not helpful in directing drug selections. It would be desirable to define patient populations before chemotherapy by biomarkers that predict outcome and toxicities. RAS mutational evaluation remains the only established biomarker analysis in the treatment of mCRC. BRAF mutant tumors are associated with poor outcome. Chemotherapeutic combination therapies still remain the most active treatments in the armamentarium, and future trials should address the need to prospectively investigate and validate biomarkers.

5-FU remains the most used and most active drug in the treatment of mCRC. The antimetabolite 5-FU is a pyrimidine analogue that inhibits thymidylate synthase (TS) irreversibly. The successive lack of thymidine triphosphate inhibits DNA replication, resulting in cell death of rapid proliferative cells. With the exception of the monotherapeutic use of regorafenib and anti-EGFR antibodies cetuximab or panitumumab in further-line treatment, all regimens contain 5-FU or one of the orally available 5-FU prodrugs capecitabine, UFT (tegafur/uracil), or S1 (tegafur/gimeracil/oteracil). 5-FU is metabolized more than 80% in the liver by dihydropyrimidine dehydrogenase (DPD). TS and DPD have been extensively investigated in regard to their predictive value for 5-FU treatment.

A relative DPD deficiency with a higher possibility of grade 3/4 toxicity exists in 3% to 5% of patients, but a complete DPD deficiency causing serious adverse events is rare, with a frequency of 0.1%. Single-nucleotide polymorphisms (SNPs) within the DPD are responsible for the variability of DPD activity and 5-FU toxicity. Several studies demonstrated a correlation between DPD tumor expression and chemotherapeutic efficacy, and recently it has been shown that SNPs within the DPD may also predict outcome. However, as of now DPD is predictive for 5-FU toxicity rather than its efficacy.

TS is the primary target of 5-FU and has been extensively studied as a predictor for 5-FU efficacy. High intratumor TS expression was correlated with shorter OS in a large meta-analysis of 20 studies in both adjuvant and metastatic CRC. Cutoff differences and unresolved challenges to implement sound cross-center stable measurements of intratumor RNA expression levels make a clinical implementation difficult. SNPs to the TS gene are another approach to investigate TS as a predictive marker. SNPs are easy, inexpensive, and quick to access. Several SNPs in the TS gene have been described to be of potentially predictive value, but validation studies are lacking. To distinguish between the predictive and possible prognostic value of TS expression a control arm not containing 5-FU would be necessary, which is impossible to find in the treatment of mCRC.

No validated predictive marker for the use of 5-FU has been established as yet. DPD deficiency remains to be predictive for toxicity, although routine measurement of DPD is not current practice.

Oxaliplatin

Oxaliplatin forms inter-DNA and intra-DNA cross-links, which disrupt DNA replication and result in cell death. Oxaliplatin has essentially no single-agent activity in mCRC but is used in a variety of combinations with 5-FU (FUFOX, FOLFOX) or irinotecan (IrOx). DNA cross-links can be removed by the base excision repair system. One of the key components representing the rate-limiting process of the excision repair system is the excision repair cross-complementing group 1 (ERCC1) enzyme. The data on ERCC1 intratumor expression and efficacy in oxaliplatin-based chemotherapy is contradictory. In one first-line study low ERCC1 expression was associated with longer survival ; however, the CAIRO study investigating 506 primary tumor samples in patients treated with oxaliplatin in second and third line after CAPIRI or capecitabine first-line therapy was unable to confirm this observation, possibly because of changes in ERCC1 expression during first-line therapy. SNPs in ERCC1 have been tested for their predictive value but, again because of the lack of validation studies and controls, none has made it into clinical practice. The importance of intratumor ERCC1 levels for oxaliplatin efficacy and resistance is underlined by data showing that ERCC1 and DPD is upregulated in CRC samples after oxaliplatin-based first-line therapy for mCRC.

Recently the randomized phase II MAVERICC trial ( NCT01374425 ), prospectively testing ERCC1 expression as a biomarker for FOLFIRI or FOLFOX first-line treatment of mCRC, has completed recruitment. With a planned recruitment of 360 patients, this will be the first study prospectively stratifying for a biomarker in the treatment of mCRC.

Detoxification of oxaliplatin depends on glutathione S -transferase family members. SNPs have been shown to be of predictive value for oxaliplatin-dependent neurotoxicity and efficacy, but again validation studies are lacking so the value for clinical decision making is unclear.

Irinotecan

Irinotecan is hydrolyzed to SN38, which is a topoisomerase 1 (TOPO1) inhibitor. Inhibition of TOPO1 leads to inhibition of DNA replication and transcription by inducing single- and double-strand breaks and DNA fragmentation. SN38 is detoxified by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Genetic variants of UGT1A1 are associated with enzyme activity and irinotecan toxicity in regimens using higher doses of irinotecan. Irinotecan has shown single-agent activity after 5-FU failure, but is usually administered in combination with anti-EGFR therapy in further therapy lines or with 5-FU in first-line and second-line regimens. Defined by the mechanism of action and detoxification, biomarker development has been focused on TOPO1 and UGT1A1.

In UGT1A1, owing to the known toxicity issues, research on the predictive value has focused on SNPs. However, published results have been controversial, and it is hypothesized that an SNP signature might be predictive for irinotecan use.

The data on TOPO1 expression for prediction of irinotecan efficacy are controversial. The United Kingdom–based FOCUS trial tested 822 samples successfully for TOPO1 expression by immunohistochemistry. A high TOPO1 expression was associated with a significantly longer survival in both irinotecan-treated and oxaliplatin-treated patients, with a higher predictive value for irinotecan-treated patients. These data were confirmed in a smaller trial using fluorescence in situ hybridization, but the association with oxaliplatin use is not understood and a prospective trial is needed.

Aprataxin (APTX) is a gene involved in the repair of DNA strand breaks as caused by irinotecan. The immunohistochemical expression of APTX has suggested it to be of predictive value for irinotecan treatment in CRC, but no confirmation study has been conducted thus far ( Table 2 ).

Table 2

Overview of important predictive and prognostic factors in the treatment of metastatic colorectal cancer (mCRC)

Pathway	Marker	Value	Clinical Conclusion
EGFR	RAS mutation in KRAS and NRAS Exon 2 (codons 12, 13) Exon 3 (codons 59, 61) Exon 4 (codons 117, 146)	Negative predictive for the use of cetuximab and panitumumab	Established biomarker in the treatment of mCRC
EGFR	BRAF mutation	Negative prognostic value Possible negative predictive value for cetuximab and panitumumab	FOLFOXIRI may be discussed in a certain subpopulation
EGFR	PIK3CA mutation	Negative predictive value for the use of cetuximab and panitumumab is discussed but not validated	Not a validated biomarker, no clinical conclusion
EGFR	PTEN loss PTEN mutations	Negative predictive value has been discussed for both mutations and loss of expression	Not a validated biomarker, no clinical conclusion
EGFR	AREG EREG	Higher expression levels are associated with increased response to anti-EGFR therapy with cetuximab	Methodological problems in measuring expression levels and cutoff calculations are ongoing. Not to be used in clinical practice
VEGF	VEGF-A plasma levels	Higher VEGF-A plasma levels predict increase in bevacizumab efficacy	Methodological problems. Not to be used in clinical practice
VEGF	IL-8	Bevacizumab predictor as a VEGF-A independent proangiogenic factor	Methodological problems. Not to be used in clinical practice
VEGF	SNP	Predictive VEGF SNPs and VEGFR SNPs for bevacizumab.	Easy to measure but not validated. Not to be used in clinical practice
TS	TS expression	Predictive for 5-FU. Higher TS expression correlated significant in adjuvant and mCRC with shorter OS	Methodological problems. Not to be used in clinical practice. A 5-FU–free control arm is difficult to create
DPD	DPD deficiency	Complete deficiency is rare (0.1%) but even relative deficiency due to polymorphisms (3%–5%) are predictive for 5-FU toxicity	Screening is not recommended
BER	ERCC1 expression level	ERCC1 expression levels are predictive for oxaliplatin response in first-line treatment. Data on second and third-line treatment was inconclusive.	Results from a prospective randomized phase II trial are awaited. Not to be used in clinical practice as yet
GSTP1	SNP	SNPs have been predictive for oxaliplatin induced neurotoxicity	Easy to measure but not validated. Not to be used in clinical practice
TOPO1	TOPO1 expression	Higher TOPO1 expression has been associated with longer OS in irinotecan and oxaliplatin-treated patients	Methodological problems. Not to be used in clinical practice
UGT1A1	UGT1A1 SNPs	Genetic variations of UGT1A1 are predictive for irinotecan toxicity	Test is recommended in the USA. Regimen with lower irinotecan dosing do not have UGT1A1-related toxicity problems
Aprataxin	APTX expression	APTX is involved in repairing irinotecan-related DNA strand breaks	Not validated in a trial with a higher number of patients. Not to be used in clinical practice

Abbreviations: 5-FU, 5-fluorouracil; APTX, aprataxin; AREG, amphiregulin; DPD, dihydropyrimidine dehydrogenase; EGFR, epidermal growth factor receptor; EREG, epiregulin; FOLFOXIRI, leucovorin, 5-FU, oxaliplatin, irinotecan; IL-8, interleukin-8; OS, overall survival; PTEN, phosphatase and tensin homologue; SNP, single-nucleotide polymorphism; TPO1, topoisomerase 1; TS, thymidylate synthase; UGT1A1, uridine diphosphate glucuronosyltransferase 1A1; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Summary

Extended RAS analysis, including mutations of KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4, defines the subpopulation of patients that most likely benefit from anti-EGFR treatment. RAS currently remains the only established predictive biomarker in the treatment of mCRC. It only has negative predictive value, but should be assessed at first diagnosis of metastatic disease. BRAF mutations are the second biomarker that may be tested for. Patients with an excellent performance status and a BRAF mutant tumor can be considered for FOLFOXIRI therapy, as this has shown remarkable outcomes in a small phase II trial in patients bearing a BRAF mutant tumor. Several recent studies have suggested that gene-expression levels of EREG and AREG may be predictive biomarkers for EGFR inhibitors, although the validation and standardization of the technologies have limited the implementation of these biomarkers in the clinic. The mechanisms of action of anti-VEGF are too diversified, and no predictive factor has yet been identified or validated. New approaches looking for predictive proteins in the plasma are promising, helping to define the population that benefits from anti-VEGF treatment. New techniques such as NGS-based sequencing and whole-genome sequencing are becoming more widely used and affordable, and may help in the near future to detect novel biomarkers and guide treatment decisions. Although biomarker development during the past years has focused on targeted drugs, the most active substances in mCRC treatment remain cytotoxic chemotherapeutic drugs. To maximize the benefit/toxicity ratio, personalize treatment, and prolong OS, more efforts should be focused on biomarker development for 5-FU, oxaliplatin, and irinotecan.

Re-biopsies of tumor tissue and highly sensitive methods enabling clinicians to detect tumor changes during therapy in the blood will change concepts of treatment. The knowledge of resistance mechanisms and changes in tumor biology during therapy will help clinicians to make biologically rational decisions in the treatment sequence of mCRC.

The authors declare no conflict of interest.

Funding: Supported by the 5P30CA014089-27S1 grant, and the Daniel Butler Research Fund . S. Stintzing is supported by a postdoctoral fellowship from the German Cancer Aid (Mildred-Scheel Foundation , grant number 110422). S. Stremitzer is a recipient of an Erwin Schrödinger fellowship. A. Sebio is a recipient of a Rio Hortega Research Grant from the Insituto de Salud Carlos III ( CM11/00102 ).

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