Molecular Profiling and Companion Diagnostics: Where is Personalized Medicine in Cancer Heading?

Mukesh Verma

Disclosures

Personalized Medicine. 2014;11(8):761-771. 

In This Article

Selected Issues in Personalized Medicine

Heterogeneity

Intratumor heterogeneity is very common which can be interpreted due to different cellular morphology, gene expression, metabolism, motility and angiogenic, proliferative, immunogenic and metastatic potential. This heterogeneity arises due to selection forces in the cellular microenvironment. A large number of cell divisions present plenty of opportunities for the emergence of multiple mutants. The genetic heterogeneity translates into phenotypic heterogeneity. A systemic approach is needed to characterize the extent of clonal heterogeneity of different tumors and their subtypes.[73–77] It is however not known whether chemotherapy changes the tumor subtypes. Interaction among clones is a challenge to understand. Advances in our understanding of the genetic composition of cancer make these analyses feasible.

Resistance (Primary & Secondary)

Tumor resistance is the main cause of treatment failure in chemotherapy drugs. One of the potential reasons of resistance, whether primary or secondary, is the presence of small pumps (P-glycoproteins) on the surface of cancer cells. These cells actively move drugs from inside the cells to the outside. Tumors produce more amounts of P-glycoproteins to protect themselves from treatment drugs. Attempts are being made to target these glycoproteins. Sometime resistance arises due to gene amplification which overcomes the effect of drugs that reduce the expression of relication genes. Defective apoptosis is another cause of resistance. 'Secondary', 'delayed' or 'acquired' resistance is seen in patients who develop progression of cancer after an initial response of treatment.

Eradication

The best example in this category is the use of proton pump inhibitors in patients positive for Helicobacter pylori by keeping in consideration patient's polymorphism status in CYP2C19 and CYP3A4 and the type of antibiotic being used for the treatment. H. pylori is associated with gastric cancer. Triple therapy, with a combination of proton pump inhibitor (lansoparazole, rabeparazole or omiperazole) and two antibiotics (amoxicillin, chlarithromycin and metronidazole), is commonly used for H. pylori eradication. The pharmacokinetics and pharmacodynamics of pump inhibitors is altered depending on the polymorphism of CYP2C19 and CYP3A4, therefore, for each patient certain data are collected before deciding on the kind of treatment for curing the disease.

Lack of Drugs (FDA-approved, or Even Just Lack)

FDA regulated products account for about 20 cents of every dollar spent by American consumers each year. The number of drugs approved by the FDA used for treatment of cancer based on a person's genetic background is very low. However, the FDA has made it a priority to continue to evolve the FDA's regulatory processes in response to scientific developments that are critical for personalized therapeutics. The Genomics and Targeted Therapy Group in the Office of Clinical Pharmacology, Center for Drug Evaluation and Research is the group overseeing the approval of drugs with potential in personalized medicine. The main drugs approved by the FDA include vemurafenib/BRAFV600E (for metastatic or unresected melanoma), crizotinib (for NSCLC with abnormal ALK gene), dabrafenib and tramentinib (for unresected melanoma in patients with BRAFV600E and BRAFV600K mutation). The FDA is very strict about postmarketing surveillance of drugs used in personalized medicine and follow-up is conducted carefully.

Social/Ethical

Health networks (aggregation of individuals with its own leadership, goals and agenda) and an institution are powerful members of the healthcare ecosystem because of their potential influence in policy making, ethics, research and finance. Regarding ethical issues, although the Genetic Information Nondiscrimination Act passed in 2008, but many patients are concerned about potential genetic discrimination from mainly health insurance companies and sometimes employers. Complexity multiplies when the government requires testing and screening, and intervention. Another question is whether the public's health is actually improved by the knowledge gained from different sources. Whether people will actually use the test results to alter their behavior in ways that improve health is uncertain.

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