The State of Personalized Medicine: The Role of Biomarkers

(Edi­tor’s Note: this is Part 1 of the new 3‑part series writ­ten by Dr. Evian Gor­don draw­ing from his par­tic­i­pa­tion at the Per­son­al­ized Med­i­cine World Con­gress on Jan­u­ary, 23, 2012 at Stan­ford University.)

On aver­age, the med­ica­tions pre­scribed for brain-relat­ed con­di­tions ben­e­fit approx­i­mate­ly 50% of patients. But which 50%?

Per­son­al­ized Med­i­cine seeks to move away from the cur­rent “1 size fits all, tri­al and error” approach that has been nec­es­sary because of a lack of evi­dence. Instead, it focus­es on match­ing the bio­log­i­cal char­ac­ter­is­tics of each per­son with the best med­ica­tion and dose for them. Tests that mea­sure these char­ac­ter­is­tics are called “bio­mark­ers”.

The bot­tom line of Per­son­al­ized Med­i­cine is to improve out­comes that mat­ter to both the doc­tor and the patient, and reduce the cur­rent costs. So far, the focus of Per­son­al­ized Med­i­cine has been in can­cer and some chron­ic med­ical con­di­tions. It is new to con­di­tions of brain health and to psychiatry.

Per­son­al­ized Med­i­cine is being dri­ven by the FDA (Fed­er­al Drug Admin­is­tra­tion in Wash­ing­ton) and is being adopt­ed to dif­fer­ent extents, by the stake­hold­er groups we will out­line in the third and final part of this series.

With the com­ple­tion of the Genome Project in 2003, expec­ta­tions were high that genet­ic vari­ants would help objec­tive­ly deter­mine diag­nos­tic cat­e­gories and pre­dict indi­vid­u­al­ized treat­ment response. But Genomics (“Pan-omics”) of the grow­ing num­ber of mol­e­c­u­lar mea­sures (Genes [DNA], Gene Expres­sion [RNA], Pro­teomics and Metabolomics) have to some extent “over­promised and under-deliv­ered”. This is espe­cial­ly true in Psy­chi­a­try where the con­di­tions we are tack­ling involve a com­plex com­bi­na­tion of genet­ics and gene-expe­ri­ence interactions.

But, oth­er med­ical con­di­tions are also com­plex, and involve gene-expe­ri­ence inter­ac­tions. Accord­ing to the Per­son­al­ized Med­i­cine Coali­tion (PMC) in Wash­ing­ton, there were 13 exam­ples of Per­son­al­ized Med­i­cine diag­nos­tic Bio­mark­ers and med­ica­tions in 2006 and 72 in 2011.

Spe­cif­ic out­comes in Can­cer are promis­ing for the devel­op­ment of Per­son­al­ized Med­i­cine in Psy­chi­a­try. Some exem­plar suc­cess­es are out­lined below.

Per­son­al­ized Med­i­cine Suc­cess­es in Medicine

Select­ed Exam­ples of Per­son­al­ized Med­i­cine Bio­mark­ers in Cancer:

• Her­ceptin ® (trastuzum­ab) treat­ment – is iden­ti­fied by the HER‑2/neu recep­tor – and is used in Breast can­cer: about 30% of can­cers have an over-expres­sion of HER‑2 pro­tein, which respond to Herceptin.
• Gleevec ® (Ima­tinib mesy­late) – is iden­ti­fied via BCR-ABL – and used to treat Chron­ic Myloid Leukemia: increas­es life expectan­cy from 5% — 95% at 5 years.
• Zelb­o­raf ®(Vemu­rafenib) – is iden­ti­fied by BRAFV600E – and used to treat Melanoma, where the late stage prog­no­sis is poor: 60% of patient have a defect in their DNA and the drug only ben­e­fits those with the V600E defect.
• Oth­er suc­cess­ful Per­son­al­ized Med­i­cine exam­ples of “Treat­ment – Bio­mark­er” com­bi­na­tions are in Colon Can­cer (Erbitux – EFGR), and Lung Can­cer (Xalko­ri – ALK).

There are also exam­ples of Bio­mark­ers that are not spe­cif­ic to 1 drug, but affect the metab­o­lism in the liv­er of many drugs, with effects on dosage. The best known exam­ple is the CYP 450 enzyme and its appli­ca­tion to Coumadin War­farin). PGx® Pre­dicts the CYP2C9 enzyme, which in car­dio­vas­cu­lar dis­ease pre­dicts the like­li­hood of adverse events with War­farin ther­a­py. The Amplichip® CYP2D6 is linked to approx­i­mate­ly 25% of all Psy­chi­atric drugs pre­scribed and can be used to avoid dose ‘tox­i­c­i­ty’ and pos­si­ble adverse events in indi­vid­u­als who are high metabolizers.

*Per­son­al­ized Med­i­cine Mol­e­c­u­lar Tests rec­om­mend­ed by the FDA are list­ed on the FDA’s web­site Here.

The Per­son­al­ized Med­i­cine Coali­tion (web­site here) pro­vides an excep­tion­al ongo­ing sum­ma­ry of new Bio­mark­ers in Per­son­al­ized Medicine.

The extent of the ben­e­fits of real world exam­ples of Per­son­al­ized Med­i­cine are grow­ing. I list three exam­ples below.

Dr Shankaran found that $604 mill could be saved per annum if Vectibix and Erbitux med­ica­tion for metasta­t­ic Col­orec­tal can­cer was restrict­ed to patients whose KRAS gene was not mutat­ed, since only they would be the patients like­ly to ben­e­fit (more here).

Dr Bark­er (for­mer Deputy Direc­tor of the Nation­al Can­cer Insti­tute) report­ed that can­cer fatal­i­ties have declined by 22% in men and 14% in women over the past 40 years, thanks in part to Per­son­al­ized Ther­a­pies such as Glee­vac and Tarceva.

A real world exam­ple of CYP is the pre­dic­tion that cor­rect per­son­al­ized dos­ing of War­farin could pre­vent 17,000 strokes in the U.S. and avoid 43,000 emer­gency room vis­its. The Mayo Clin­ic and Med­co test­ed this pre­dic­tion in 3,600 patients and found hos­pi­tal­iza­tions for heart rate patents were reduced by 30% (Epstein RS et al. J Amer­i­can Col­lege Car­di­ol­o­gy. 55:2804–12. 2010).

In con­trast to these suc­cess­es, most Per­son­al­ized Med­i­cine research in Psy­chi­a­try using mol­e­c­u­lar mea­sures alone have failed to repli­cate. Whilst dis­ap­point­ing, this is not sur­pris­ing, since 80% of human 25,000 genes have some effect on the brain.

To Be Continued…

New Series on Per­son­al­ized Med­i­cine and the Brain:

• Mon­day, Feb­ru­ary 13th: The State of Per­son­al­ized Med­i­cine (above)
• Mon­day, Feb­ru­ary 20th: Chal­lenges and Oppor­tu­ni­ties of Per­son­al­ized Med­i­cine in Psychiatry
• Mon­day, Feb­ru­ary 27th: Work­ing with Health Care Indus­try Stake­hold­ers Towards Brain-based Per­son­al­ized Medicine

– Dr Evian Gor­don is the Exec­u­tive Chair­man of the Brain Resource Com­pa­ny.  He ini­tial­ly drew upon  his sci­ence and med­ical back­ground to estab­lish the inter­dis­ci­pli­nary Brain Dynam­ics Cen­ter, in 1986.  Through the Brain Dynam­ics Cen­ter and its col­lab­o­ra­tive net­works, Dr Gor­don estab­lished an “inte­gra­tive neu­ro­science” approach, ground­ed in the use of stan­dard­ized meth­ods across mul­ti­ple types of data. Using this approach, Dr Gor­don found­ed the “Brain Resource Com­pa­ny”, that cre­at­ed the first inter­na­tion­al data­base on the human brain. The data­base is the asset which under­pins the devel­op­ment of new tools for brain health and its per­son­al­ized appli­ca­tion in the mar­ket, such as assess­ments of brain health, deci­sion sup­port sys­tems, and per­son­al­ized train­ing pro­grams. Brain Resource has also sup­port­ed the for­ma­tion of a non-prof­it 501c3 Foun­da­tion, called ‘BRAIN­net” (www.BRAINnet.net), through which sci­en­tists have access to many of these datasets for inde­pen­dent research.