What role do biomarkers serve in Cancer research and treatment?

 

-By Dr. Akash G Prabhune

 

 

Bio-markers are defined by National cancer institute USA “as a biologic specimen that may be a marker of exposure to a substance, its metabolism, or an integration of exposure and metabolism”.(“Biomarkers,” 2017). In simple words, a biomarker could be a blood-based test, gene sequence or mutation,mRNA, expression profile or tissue proteinthat could be used to differentiate an affected patient from a person without the disease.(“Cancer biomarkers – ScienceDirect,” 2017). Biomarkers have recently gained popularity with recent surge in pharmacogenomic data which lead to identification of variety of potential biomarkers which would facilitate early detection and diagnosis of variety of cancers.(Kumar et al., 2006). The drug industry also found utilities of biomarkers for enhancing the dose selection, safety, effectiveness of a drug during clinical trials. Table 1. Presents the list of potential uses of biomarkers in oncology.

Table 1. Potential uses for cancer biomarkers.
Use Example Reference
Estimate risk of developing cancer BRCA1 germline mutation (breast and ovarian cancer) (D.F. Easton, D. Ford, D.T. Bishop, 1995; Levy-Lahad and Friedman, 2007)
Screening Prostate specific antigen (prostate cancer) (K. Lin, R. Lipsitz, T. Miller, S. Janakiraman, 2008)
Differential diagnosis Immunohistochemistry to determine tissue of origin (Kulkarni et al., 2012)
Determine prognosis of disease 21 gene recurrence score (breast cancer) (Berry, 2008)
Predict response to therapy KRAS mutation and anti-EGFR antibody (colorectal cancer) (C.J. Allegra et al., 2009)
HER2 expression and anti-Her2 therapy (breast and gastric cancer) (Bang et al., 2010)
Estrogen receptor expression (breast cancer) (Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), 2011)
Monitor for disease recurrence AFP, LDH, βHCG (germ cell tumor) (Gilligan et al., 2010)
Monitor for response or progression in metastatic disease CA15-3 and CEA (breast cancer) (Harris et al., 2007)

From the above table, we can get the idea on extensive applications of biomarkers in oncology research from early screening till therapeutic phases of cancer.

BRCA1 and BRCA2 are the earliest known biomarkers, a paper published in 1995 demonstrated that the women with mutation on BRCA1 gene were estimated to have cumulative risk for breast cancerrises to 54% by age 60 years (95% CI 27%-71%). The corresponding estimated cumulative risk of ovarian cancer was 30% (95% CI 8%-47%). A second study conducted in 2007 on BRC2 estimated that BRCA2 carriers had a breast cancer risk of 84% (95% CI 43%–95%), and an ovarian cancer risk of 27% (95% CI, 0–47%)(Levy-Lahad and Friedman, 2007). This lead to establishment of BRCA1 and BARCA2 as the genetic biomarkers for breast and ovarian cancer screening. Further studies on animal models demonstrated that inhibition of BRCA1 and BRCA2 gene expression might prevent the progression of breast cancer also decrease the risk of lymphomas and leukaemia’s in certain cases.(Friedenson, 2007)

It is crucial for diagnosis of cancer to determine the tissue of origin, immunochemistry is the method which uses immune-stains as a biomarker to detect the tissue of origin in metastasis cases with an accuracy of 64% (95% CI 50% – 80%). The newer approach of gene expression profiling which uses gene expression as a biomarker is gaining popularity with diagnostic accuracy of 90% (95% CI 75%-92%). (Kulkarni et al., 2012) A prognostic biomarker is the one which informs about the likely outcome of cancer (e.g. disease progression, disease recurrence, complete cure, death) independent of the treatment effect. PIK3CA is a prognostic biomarker for metastatic breast cancer which showed in a trial conducted; that women with tumours having a PIK3CA mutation had worse progression-free survival compared with women with PIK3CA wild-type tumours regardless of treatment they received, with a hazard ratio (HR) of 0.64 (95% CI, 0.43 to 0.93) compared with 0.67 (95% CI, 0.50 to 0.89) respectively.(Ballman, 2015a) A predictive biomarker is the one which shows the treatment effect (experimental compared with control) is different for biomarker-positive patients compared with biomarker-negative patients. In case of non-small cell lung cancer treatment with erlotinib the patients with tumourshaving EGFR mutation had HR of 0.10 (95% CI, 0.04 to 0.25; P < .001) compared erlotinib with placebo, whereas the EGFR wild-type group had an HR of 0.78 (95% CI, 0.63 to 0.93; P = 0.019).Here a EGFR gene mutation played a role of predictive biomarker. (Ballman, 2015b)

The biomarker with therapeutic importance are the ones which alter the drug metabolism in the body. CYP2D6 is a biomarker which is an isoenzyme that metabolizes 25-30% of all clinically used medications, including dextromethorphan, beta blockers, antiarrhythmics, anti-depressants, antipsychotics, morphine derivatives, and many other drugs. Variability in the interindividual responses to these agents is often caused by genetic polymorphisms in CYP2D6 leads to either a reduction or complete loss of activity of the drug to rapid metabolism or the medication is excreted un-metabolized from the body.(“Genetic Basis of Drug Metabolism,”2017) Biomarkers do play crucial role in drug discovery and FDA and many other regulatory agencies use biomarkers as adjuvant in establishing the safety and efficacy of drug. FDA recommends voluntary submission of data on biomarkers but biomarkers are not used in making regulatory judgments pertaining to the safety or effectiveness of a drug. (Vogel et al., 2010)

To conclude biomarkers, play vital role in every stage of cancer management and many of the known valid biomarkers are used to define the treatment plan in various cancer treatments. The pharmacogenomic data on biomarkers might help to step closer to realize the dream of personalized medicine, their needs to be agreed standards upon for what determines the validity of a biomarker as there is high number of variation observed in general population. As there is no central agency to regulate and validate the specified use of biomarkers the question remains who will validate the biomarkers, and when? Once these questions are answered biomarkers can open the new frontiers in cancer research and treatment.

References

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