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Cite this article: Shah U, Goel S (2014) Biomarker Driven Management of Metastatic Colorectal Cancer: How Far have we come? JSM Clin Oncol Res 2(5): 1038.

*Corresponding authorSanjay Goel, Department of Medical Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, 1695 Eastchester Road, Bronx NY 10461, USA, Tel: 7184058404; Fax: 7184058433; Email:

Submitted: 02 April 2014

Accepted: 30 April 2014

Published: 05 May 2014

Copyright© 2014 Goel et al.

OPEN ACCESS

Review Article

Biomarker Driven Management of Metastatic Colorectal Cancer: How Far have we come?Umang Shah1 and Sanjay Goel1,2*1Department of Oncology, Montefiore Medical Center, USA2Department of Medical Oncology, Albert Einstein College of Medicine, USA

BACKGROUNDIn the United States, colorectal cancer is the fourth most

common and the second leading cause of cancer mortality. In spite of current screening strategies 1 out of 5 patients still presents with metastatic disease. According to recent estimation provided by National Cancer Institute and National Center for health statistics, 71,830 men and 65,000 women will be diagnosed with colorectal cancer and 26,270 men and 24,040 women will die of the disease [1,2]. The management of patients with metastatic colorectal cancer (mCRC) has improved dramatically over the last 15 years. From a median overall survival (OS) of just 6 months with best supportive care (BSC), the best observed median OS has improved to around 30 months in select populations [3]. The current standard of care for mCRC commonly combines cytotoxic chemotherapy with biologic agents. At present, there are six different classes of drugs (three classes of cytotoxic agents, and three classes of biologic agents, namely anti EGFR, anti VEGF agents and multi-targeted tyrosine kinase inhibitor) available for the treatment of mCRC. Table 1 provides an overview of all agents that have been approved by the US Food and Drug Administration (FDA) for the treatment of mCRC, with their mechanism of action and side effect profile [2-6].

POTENTIAL PREDICTIVE BIOMARKERS FOR BIOLOGIC THERAPY

There are numerous review articles written on the management of mCRC and the reader is referred to these articles [2,6-9]. This article will mainly focus on the predictive and prognostic biomarkers and how these may be incorporated into routine clinical practice.

Predictive biomarkers

Cytotoxic agents : As far as the cytotoxic drugs are concerned, there has been little improvement in biomarker based therapy. Among all patients receiving 5-FU or the oral pro-drug capecitabine, about a third experiences dose limiting toxicity that can be severe to life-threatening. In 2007, Myriad genetics introduced Thera Guide 5-FUTM test that incorporates comprehensive analysis of DPYD (Dihydropyrimidine Dehydrogenase) and TYMS (Thymidylate Synthase) gene

mutations, which predicts risk of toxicity in patients receiving these drugs. The rationale behind this test is that the metabolism and clearance of 5-FU from body is carried out mainly by DPYD enzyme whose activity is altered by mutations in DPYD gene. After reaching the cellular interior, 5-FU binds to TYMS enzyme to inhibit DNA synthesis of tumor cells. The genetic mutation to TYMS gene could lead to under or overproduction of the enzyme which will either leave more unbound 5-FU or less availability of effective drug for a given dose respectively [10]. Though this test provides critical guidance to providers for a personalized chemotherapy, such tests are not routinely incorporated in clinical practice, and none of the guidelines or regulatory bodies recommends or mandate this test [4].

Similarly, for oxalilplatin, there have been a number of publications looking at the excision repair cross-complementation (ERCC) group 1, which is a key element in the nucleotide excision repair (NER) pathway, encoded by ERCC gene. Studies have included its polymorphism and gene expression analysis with prediction that ERCC1 has the potential to be used as a strong candidate biomarker, both predictive and prognostic, for colorectal cancer [11-17]. There are ongoing studies that select front line therapy with oxaliplatin or irinotecan based on ERCC expression by immunohistochemistry (IHC) staining, or gene expression of polymorphisms (NCT01703390, NCT01280643, NCT01071655, from clinicaltrials.gov). As of today, however, such pre testing is not part of regular clinical care. It is to be noted, that in lung cancer, where this gene was furthest along, there has been a setback since there have been problems identified with the IHC standardization [18].

Irinotecan remains the only cytotoxic agent that has incorporated a genetic test in its label. The enzyme UGT1A1 is responsible for the glucuronidation of bilirubin, and detoxification of SN-38, the active metabolite of irinotecan, by converting it to SN-38G (glucoronide). It is found deficient in its function by a single nucleotide polymorphism (SNP) in its promoter. The deficiency is most commonly associated with a homozygous 2 bp TA insertion in the TATA box promoter region of the UGT1A1

Keywords• Biomarker, Metastatic colorectal cancer• Predictive

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Drug (Class) Category Mechanism of action FDA indication (metastatic dz) Common side effect profile

5-FU/LV(Cytotoxic) Antimetabolite

(pyrimidine analog)

Non-competitive inhibition of

thymidylate synthase

1962: palliative treatment of colon cancer

1st, 2nd and Salvage therapy; use as a single agent and in

combination

Fatigue, stomatitis, nausea, diarrhea, myelosuppression,

hyperpigmentation, skin atrophy and hand-foot syndrome

Oxaliplatin(Cytotoxic)

Alkylating agent (platinum)

Inhibits DNA synthesis by forming inter and intra strand crosslinks with

DNA

2002: 2nd line with 5-FU, after irinotecan failure

2004: 1st line with 5-FU

Peripheral neuropathy (acute and chronic), nausea,

vomiting, diarrhea, fatigue and myelosuppression

Irinotecan(Cytotoxic) Camptothecin Inhibits topoisomerase I,

producing DNA breaks

1998: 2nd after failure of 5-FU based therapy 2000: 1st

line with 5-FU/LV

2 Dose limiting toxicities: diarrhea (all schedules) and myelosuppression (3- week

schedule), Other common side effects: nausea, vomiting, fatigue

Capecitabine(Cytotoxic)

Antimetabolite (pyrimidine analog) Prodrug of 5-FU

2001: 1st line when treatment with fluoropyrimidine

therapy alone is preferredHand foot syndrome, nausea,

diarrhea, stomatitis and fatigue.

Bevacizumab(Biologic)

Humanized monoclonal antibody

Binds to VEGF, inhibiting interaction between

VEGF and its receptor

2004: 1st line with 5-FU based therapy

2006: 2nd line with 5-FU based therapy

Asthenia, diarrhea,hypertension, headaches, stomatitis and leucopenia.

SeriousComplications: gastrointestinal

perforation, impairedwound healing, bleeding and

nephritic syndrome

Aflibercept(Biologic)

Recombinant fusion protein

Binds to VEGF-A, B and placental growth factor

(PGF)Inhibits VEGF

2012: In combination with FOLFIRI for patients progressed on oxaliplatin

based chemotherapy

Myelosuppression, hypertension, pain, diarrhea, fatigue, skin

hyperpigmentation, delayed wound healing

Cetuximab(Biologic)

Recombinant, chimeric, monoclonal antibody

Binds to EGFR, inhibiting binding of EGF

2004: single agent or with irinotecan, on irinotecan refractory or intolerant2009: amended only for

patients with KRAS lacking mutations in codon 12 and 13

1st, 2nd line and in salvage setting

acneiformrash, fatigue, dyspnea, diarrhea

and nausea.

Panitumumab(Biologic)

Recombinant, human, monoclonal antibody

Binds to EGFR, inhibiting binding of EGF

2006: single agent on chemorefractory (salvage

setting)2009: amended only for

patients with KRAS lacking mutations in codon 12 and 13

Skin rash, hypomagnesaemia, fatigue, nausea and diarrhea

Regorafenib(Biologic)

Small molecule multi-kinase inhibitor

Binds to theintracellular component of VEGFR-2 and -3, Ret,

Kit, platelet-derived growth factor

receptor (PDGFR), and Raf kinases

Inhibits VEGF

2012: As a single agent salvage therapy for patients

with good performance status progressed on other lines

Bleeding gums, cough, myelosuppression, rash,

palpitation

Table 1: Drug characteristics.

gene. Being a germ line SNP, it can be easily detected in peripheral blood. While the first genetic test to be approved in oncology, the practical implications are less clear, and this too has not found widespread acceptance [19-23].

Biologic agents

Vascular endothelial growth factor (VEGF/VEGFR) inhibitors: A lot of research has been conducted to identify

predictive biomarkers (eg. plasma angiogenic molecules (VEGF, PlGF), soluble VEGFR-2, basic fibroblast growth factor (bFGF), NRP-1, circulating plasma levels of small VEGF isoforms (121, 165) [24], and endothelial progenitor cells (EPCs) in response to anti-VEGF therapy in last few years. However, the results of the conducted studies were disappointing and there is no predictive biomarker available for this therapy. On a positive note though, researchers were able to conclude that the efficacy of bevcizumab

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Drugs Biomarker(Predictive) FDA approval Recommended

5-FluorouracilTheraGuide 5-FUTM No No

CapacitabineIrinotecan UGT1A1 Yes NoOxaliplatin ERCC No No

VEGF inhibitors VEGF SNP No No

EGFR inhibitors

KRAS-EXON 2 Yes YesKRAS-EXON 3,4 No No

NRAS-EXON 2,3,4 No NoBRAF No No

PIK3CA No NoPTEN No No

Ragorafenib -None N/A- N/A

Table 2: Biomarkers.

Line of Treatment Any RAS mutant (55-60%) Any RAS wild type (40-45%) BRAF mutant (5-9%)

1st LineFOLFOX/XELOX/

FOLFIRI+Bevacizumab

FOLFOX/XELOX/FOLFIRI

+Bevacizumab FOLFIRI+ EGFR inhibitor FOLFOXIRI+

Bevacizumab

2nd LineFOLFIRI/FOLFOX/

XELOX+ VEGFinhibitor

FOLFIRI/FOLFOX//XELOX+VEGF inhibitor

FOLFOX/XELOX+ Bevacizumab

EGFR inhibitor +- Chemotherapy

3rd Line Regorafenib EGFR inhibitor + Irinotecan Regorafenib Regorafenib

4th Line Best Supportive Care Regorafenib Best Supportive Care Best Supportive Care

Best Supportive Care

Table 3: Practical guidelines.

In any line of therapy, clinical trials are always recommended for consideration.

therapy is independent of the presence of KRAS and BRAF mutations. Similarly, there are no biomarkers available at present for small molecule oral multikinase inhibitor (regorafenib) [24-29].

Epidermal growth factor receptor (EGFR) inhibitors: The search for predictive biomarkers for EGFR-targeting agents are on surge with prime focus on downstream targets in EGFR signaling pathway such as KRAS, NRAS, BRAF and PIK3CA. Multiple studies and clinical trials have confirmed that the presence of KRAS mutation is associated with lack of effectiveness of EGFR-inhibitors (cetuximab and panitumumab), irrespective of their use as single agent or in combination with chemotherapy. Some studies have even shown that EGFR-inhibitors received by patients with a KRAS mutation are not only non-beneficial but also potentially harmful [29]. In accordance with FDA guidelines, a test for KRAS mutation status needs to be performed before the use of EGFR monoclonal antibodies, since cetuximab and panitumumab are only indicated for mCRC tumors that are KRAS wild-type. Though exon 2 (codons 12 and 13), with seven specific mutations, comprises more than 90% of all KRAS mutations, there are still subsets of KRAS and other NRAS or RAS family mutations to be considered. The findings of the PRIME study demonstrated that not only KRAS exon 2 mutations but the extended panel including KRAS exon 3 (codon 61) and exon 4 (codon 117 and 146) and NRAS mutations (including all the 3 codons, 4 exons as for KRAS) also predict a lack of response to EGFR inhibitors. It emphasized the requirement for more effective testing of mutations beyond KRAS codon 12/13 [30-32].

Other downstream effectors of EGFR: Mutations in protein encoded BRAF, are mutually exclusive to KRAS mutations and associated with a very poor prognosis even with standard combination therapy. Recent data suggested the use of FOLFOXIRI + bevacizumab as preferred option for this patient population [33,34]. Though there is uncertainty about this mutation’s validity as a negative predictive marker, it was suggested that EGFR-inhibitors (cetuximab and panitumumab) might have some activity. More research is needed with focus on treatment option with better survival outcomes [35].

Another effector PIK3CA, in its mutated form promotes cell growth and suppresses apoptosis in colorectal cancers and is regulated by the tumor suppressor PTEN (phosphatase and tensin homolog). Though PTEN is considered to be a predictive marker along with KRAS, there is a lot of inter-observer and antibody variability still prevails. In summary, multiple studies including from our group [36-40] and others have shown predictive value for this pathway, while multiple other studies have failed to do so [41,42].

Recent data suggested correlation between EGFR ligand expressions to EGFR antibodies. Patients with KRAS wild type who have higher proportions of ligands epiregulin and amphiregulin, found to have more sensitive to EGFR inhibitors compared to low ligand expression. The same is not applicable for patients with KRAS mutant tumors [43].

Table 2 summarizes all the predictive biomarkers and approval status from FDA [44-46].

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Prognostic biomarker

BRAF: The most frequent BRAF mutation observed is V600E, a missense mutation which leads to substitution of glutamic acid for valine [47]. The results of PETACC-3 trial, CRYSTAL trial, AGITG MAX trial and COIN trial have shown strong prognostic role of BRAF mutation in patients with metastatic colorectal carcinoma despite having uncertainty about its predictive value [4].

Practical Management Guidelines: We propose the following therapeutic approach based upon molecular testing incorporating the recommendations from NCCN as depicted in Table 3. It is highly recommended to always consider clinical trials at any time in the treatment course.

CONCLUSIONEven with different treatment options available, fluorouracil

(5-FU) still remains the most effective drug in our opinion. With better understanding of molecularly defined subgroups with different pathways of tumorigenesis of colorectal carcinoma, the unique tumor characteristics have been identified which further helps to guide the treatment alternatives. More clinical trials should focus on identifying potential biomarkers and target population that might have benefit from treatment which will help select the right treatment option and better predict the outcome.

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Cite this article

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