Role of Pharmacogenetics as Predictive Biomarkers of Response and/or Toxicity in the Treatment of Colorectal Cancer

Shriya Bhushan; Howard McLeod; Christine M. Walko

Clin Colorectal Cancer. 2009;8(1):15-21.

Irinotecan

Irinotecan exerts its chemotherapeutic effect by interaction with the enzyme topoisomerase I (topo I). Topoisomerase I plays a critical role in uncoiling DNA for replication and transcription by causing transient single-strand DNA breaks that are eventually repaired. Irinotecan stabilizes these breaks made by topo I, ultimately leading to DNA fragmentation and cell death.

Irinotecan is converted to the active metabolite, SN-38, which is then conjugated by UDP-glucuronosyl-transferase 1A1 (UGT1A1) to SN-38G and prepared for elimination.^[9,10] The UGT1A1*28 polymorphism is associated with reduced UGT1A1 expression and decreased glucuronidation of SN38. This results in increased toxicity because of increased blood levels of the active metabolite. The UGT1A1*28 polymorphism is characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter, ([TA]₇ TAA, instead of [TA]₆ TAA).^[11] Patients with the 7/7 genotype are at higher risk of developing irinotecan-associated neutropenia and diarrhea.

In July 2005, the Federal Drug Administration recommended an addition to the irinotecan package insert to include the UGT1A1*28 genotype as a risk factor for severe neutropenia. This decision was based upon the findings of 4 pharmacogenetic trials assessing the relationship between irinotecan toxicity and UGT1A1*28 genotype. A recent meta-analysis of 10 irinotecan pharmacogenetic studies enrolling a total of 825 patients assessed the correlation between irinotecan-induced hematologic toxicities in UGT1A1*28 patients, irinotecan dose, and overall toxicity.^[12] The results suggest the risk of experiencing irinotecan-induced hematologic toxicity for homozygous UGT1A1*28 patients is a function of the dose of irinotecan administered (Figure 3). The study supported the routine use of genotype when dosing irinotecan at high doses (> 200 mg/m²) but suggested that testing was of modest benefit at intermediate doses, such as the commonly used FOLFIRI (5-U/leucovorin [LV]/irinotecan) regimen that uses an irinotecan dose of 180 mg/m² every 14 days. UGT1A1*28 testing did not appear to have any utility at doses < 150 mg/m², unless the drug was administered concomitantly with a myelotoxin (eg, oxaliplatin).

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Irinotecan Metabolism and Mechanism of Action

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Relationships Between Irinotecan Dose and Incidence of Hematologic Toxicity in Patients with a UGT1A1*28/*28 Genotype (A) and in Those with a UGT1A1*1/*1 or UGT1A1*1/*28 Genotype (B)
Results from 10 samples (triangles in panel A and circles in panel B) were included in the analysis. Solid lines = predicted probabilities of experiencing hematologic toxicity under the generalized linear mixed model at any dose level in the original dose range. Dotted lines represent 95% confidence intervals.
Adapted from: Hoskins JM, et al. J Natl Cancer Inst 2007; 99:1290-5.

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Table 1. Clinical Biomarkers Used to Predict Response and/or Toxicity Associated With Chemotherapy for Colorectal Cancer
Drug	Biomarker	Role	Correlation with Outcomes
5-FU	TP	Converts 5-FU to FdUMP necessary for drug activity	Lower levels might lead to better response rates
	TS	Rate-limiting enzyme in the pyrimidine nucleotide synthesis, inhibition by 5-FU results in cytotoxicity	Lower levels might lead to better response rates
	DPD	Catalyzes the initial rate limiting step in the catabolism of 5-FU	Lower levels might lead to better response rates; however, deficiency can lead to fatal toxicities
Irinotecan	UGT1A1	Converts the active metabolite SN-38 to the inactive SN-38G	Homozygous UGT1A1*28 genotype is a risk factor for severe neutropenia at doses > 200 mg/m²
Oxaliplatin	ERCC1	Role in repair of DNA cross-links, including those induced by platinum agents	Defect in the repair system might be associated with increased sensitivity to the drug
Cetuximab Panitumumab	K-ras	Important component of EGFR downstream signaling pathways for cell proliferation	K-ras mutation is associated with lack of response and a shorter PFS and OS

Abbreviations: 5-FU = 5-fluorouracil; DPD = dihydropyrimidine dehydrogenase; EGFR = epidermal growth factor receptor; ERCC1 = excision repair cross-complementing; FdUMP = fluorodeoxyuridine monophosphate; OS = overall survival; PFS = progression-free survival; TP = thymidine phosphorylase; TS = thymidylate synthase; UGT1A1 = uridine diphosphate glucuronosyl transferase

Table 2. Predictive Biomarkers for Assessing Response and Toxicity Associated With 5-FU Administration
Study	Biomarker	Design	Sample Size	Conclusions
Metzger et al^[4]	TP	Measured TP levels in pretreatment biopsies in patients with CRC previously analyzed for TS expression levels and subsequently treated with 5-FU	38	Mean TP mRNA level in nonresponders was 2.6-fold higher than responders; the greatest increase in survival was seen for patients with both TS and TP below their respective nonresponse cutoff values (P = .0023) Low TS and TP expression levels in tumors predicted a response to 5-FU and better survival
Marsh et al^[28]	TS	Determined TSER genotype in patients with mCRC receiving bolus/infusion 5-FU using tumor samples	24	The homozygous TSER2 genotype was found in 22% of patients without response and 40% of responding patients; median survival was 16 months for TSER2 homozygous patients and 12 months for TSER3 homozygous patients Higher expression of TS (TSER3) is associatedwith lower response rates to 5-FU
Salonga et al^[29]	DPD	Measured DPD levels in pretreatment biopsies of patients with CRC who were subsequently treated with 5-FU	33	Tumors with lower DPD gene expressions had a response rate of 50%; DPD levels in tumor tissue are associated with tumor response to 5-FU

Abbreviations: 5-FU = 5-fluorouracil; CRC = colorectal cancer; DPD = dihydropyrimidine dehydrogenase; mCRC = metastatic colorectal cancer; TP = thymidine phosphorylase; TS = thymidylate synthase; TSER = thymidylate synthase enhancer region

Predictive Biomarkers for Assessing Response and Toxicity Associated With 5-FU Administration
Study	Biomarker	Design	Sample Size	Conclusions
Metzger et al^[4]	TP	Measured TP levels in pretreatment biopsies in patients with CRC previously analyzed for TS expression levels and subsequently treated with 5-FU	38	Mean TP mRNA level in nonresponders was 2.6-fold higher than responders; the greatest increase in survival was seen for patients with both TS and TP below their respective nonresponse cutoff values (P = .0023) Low TS and TP expression levels in tumors predicted a response to 5-FU and better survival
Marsh et al^[28]	TS	Determined TSER genotype in patients with mCRC receiving bolus/infusion 5-FU using tumor samples	24	The homozygous TSER2 genotype was found in 22% of patients without response and 40% of responding patients; median survival was 16 months for TSER2 homozygous patients and 12 months for TSER3 homozygous patients Higher expression of TS (TSER3) is associatedwith lower response rates to 5-FU
Salonga et al^[29]	DPD	Measured DPD levels in pretreatment biopsies of patients with CRC who were subsequently treated with 5-FU	33	Tumors with lower DPD gene expressions had a response rate of 50%; DPD levels in tumor tissue are associated with tumor response to 5-FU

Table 3. K- *ras* Mutation as a Predictive Biomarker for Assessing Response to EGFR-targeted Monoclonal Antibodies
Study	Design	Sample Size	Conclusions
Di Fiore et al^[20]	Retrospective K-ras mutation status was evaluated in tumor tissue samples from patients with CRC treated with cetuximab and either irinotecan or oxaliplatin after progressing on ≥ 1 previous regimen	59	K-ras mutation was detected in 27% of tumors. The RR was 0% for patients with K-ras mutation and 32% for patients with wild-type K-ras; K-ras mutation was associated with disease progression (P = .0005). mTTP was 3 months vs. 5.5 months for the patients with and without K-ras mutation, respectively (P = .015) Presence of K-ras mutations are highly predictive of cetuximab resistance in mCRC
Lievre et al^[19]	Retrospective K-ras mutation status was evaluated in primary or metastatic tumor tissue samples from patients with CRC treated with cetuximab and irinotecan after progressing on 1-4 previous regimens	89	K-ras mutation was detected in 27% of tumors. The RR was 0% for patients with K-ras mutation and 40% for patients with wild-type K-ras (P < .001); mPFS was 10.1 weeks vs. 31.4 weeks for the patients with and without K-ras mutation, respectively (P = .015); OS also favored patients with wild-type K-ras (10.1 months vs. 14.3 months; P = .026) Presence of K-ras mutations are highly predictive of cetuximab resistance in mCRC
De Roock et al^[21]	Retrospective K-ras mutation status was evaluated in tissue samples from patients with CRC treated with either cetuximab monotherapy or in combination with irinotecan after progressing on ≥ 1-5 previous regimens	113	K-ras mutation was detected in 40.7% of tumors. The RR was 0% for patients with K-ras mutation and 41% for patients with wild-type K-ras; mPFS was 12 weeks vs. 24 weeks for the patients with and without K-ras mutation, respectively (P = .074). OS also favored patients with wild-type K-ras (27.3 weeks vs. 43 months; P = .02) Presence of K-ras mutations are highly predictive of cetuximab resistance in mCRC
Amado et al^[30]	Prospective K-ras mutation status was evaluated in tumor samples from patients with CRC treated either with singleagent panitumumab and BSC or BSC alone, after progressing on ≥ 2 previous regimens	427	K-ras mutation was detected in 43% of tumors. In patients who received panitumumab, the RR was 0% for patients with K-ras mutation and 17% for patients with wild-type K-ras. mPFS was not affected by panitumumab in patients with K-ras mutations (7.4 weeks for panitumumab and BSC vs. 7.3 weeks for BSC). mPFS was improved in patients with wild-type K-ras who received panitumumab and BSC compared with BSC (12.3 weeks vs. 7.3 weeks; P < .0001) Presence of K-ras mutations are highly predictive of panitumumab resistance in mCRC

Abbreviations: BSC = best supportive care; mCRC = metastatic colorectal cancer; mPFS = median progression-free survival; mTTP = median time to progression; OS = overall survival; RR = response rate (complete response + partial response)

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