“Metastatic colorectal carcinoma (mCRC) treatment through K-ras testing may be feasible”


disease was achieved by 33% (27 out of 82 patients). Reported adverse effects included nausea, vomiting, and mild visual disturbances.


COLORECTAL CARCINOMA AND PERSONALISED CHEMO THERAPY Colorectal carcinoma, the third-most common cancer and third-leading cause of cancer death among American men and women, lends two examples of personalised chemotherapy. In the first example, K-ras, a human homolog of Kirsten rat sarcoma-2 virus oncogene, encodes for a small GTP binding protein that acts as a self-inactivating signal transducer in response to stimulation of a cell surface receptor, including the receptor EGFR. A K-ras mutation in codons 12 and 13 in exon 2 of the coding region yields a constitutively active protein. As K-ras is downstream of EGFR in the EGFR signal


Table 1 Oral targeted drug expenditures


Drug Dasatinib CML


Indication Cost/month ($) 8486


Erlotinib NSCLC 4903 Imatinib CML


8470


Lapatinib Breast Ca 4330 Sunitinib RCC


9533


Cost/month ($): average drug purchase price based on common dosing CML chronic myeloid leukemia NSCLC non-small cell lung carcinoma RCC renal cell carcinoma


14 www.lifesciencesmagazines.com


transduction pathway, such a mutation would, predictably, lead to impedance of anti-EGFR therapies such as cetuximab and panitumumab. Thus, differentiation of metastatic colorectal carcinoma (mCRC) treatment through K-ras testing may be feasible, and two groups have demonstrated that. Lievre and colleagues studied the usage of cetuximab, a recombinant human/ mouse chimeric monoclonal antibody that competitively inhibits normal ligand binding to the extracellular domain of EGFR, in mCRC. The presence of a K-ras mutation was associated with more disease resistance (p<0.001) and lower survival (p=0.00001) in patients with mCRC. Amado and colleagues conducted a similar trial using panitumumab, a recombinant human monoclonal antibody that competitively inhibits normal ligand binding to the extracellular domain of EGFR, in mCRC. Addition of panitumumab to best supportive care (BSC) in presence of a K-ras mutation was associated with lower response to and lower impact on progression-free survival (PFS) by panitumumab in patients with mCRC. Median PFS in patients without a K-ras mutation was 7.3 weeks (BSC) and 12.3 weeks (panitumumab + BSC). In patients with a K-ras mutation, median PFS was 7.3 weeks (BSC) and 7.4 weeks (panitumumab + BSC).


A second example of personalised chemotherapy in colorectal carcinoma is


provided by UGT1A1*28 polymorphism and does not involve targeted drugs. The UGT1A1, or uridine diphosphate glucuronosyltransferase 1 family polypeptide A1, gene encodes for a major enzyme involved in bilirubin and irinotecan glucuronidation (hence, inactivation). More specifically, the homozygous mutant of UGT1A1*28 has been associated with decreased enzymatic activity and glucuronidation (inactivation) of SN-38, an active metabolite of irinotecan, which may account for increased irinotecan- associated hematologic toxicity. The prevalence of this homozygous mutant appears to differ between ethnic groups. Non-specific dose reductions are recommended for patients “known to be homozygous for the UGT1A1*28 allele.”


CONCLUSION In closing, personalised chemotherapy is still in its infancy with small target populations and rare complete responses. Molecular features of oncologic diseases are, however, now rising above clinical features in terms of standing. Coupled with that is the increased availability of reliable, predictive, and timely biomarker tests which will assist in clarifying a particular chemotherapy regimen for a given patient. ■


ML


 REFERENCES References available on request (magazine@informa.com)


LEARNMORE


The Molecular Diagnosis track at the Medlab Congress is taking place on January 25th


. The Medlab Congress, part of


the Arab Health Exhibition & Conference, will be held at the Dubai Trade Centre from 23-26th of January 2012. To register your place as a delegate, and find out more information about all the Medlab conference streams, visit the website www.arabhealthonline.com and click on the Medlab tab.


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