The personal touch: genomics and the fight against cancer

“What you now see is that every can­cer is a rare can­cer.”

So says Emile Voest, pro­fes­sor of med­ical oncol­o­gy at the Nether­lands Can­cer Insti­tute, who was writ­ing in the jour­nal Nature. Voest was high­light­ing a rev­o­lu­tion­ary change in can­cer treat­ment over the past decade: the advance­ment of genomics.

Genomics is the study of how genes inter­act with one anoth­er and the envi­ron­ment. It has already had a mas­sive impact in oncol­o­gy. For exam­ple, Voest notes that 12 years ago, lung can­cer was clas­si­fied as either small cell or non-small cell. Today, it’s iden­ti­fied by near­ly 30 genom­ic muta­tions or changes. 

Iden­ti­fy­ing spe­cif­ic muta­tions in patients marks a rad­i­cal shift from one-size-fits-all treat­ment towards more per­son­alised ther­a­py. For exam­ple, it could pro­vide treat­ments for col­orec­tal can­cer with muta­tions in the so-called KRAS gene, which don’t respond to some stan­dard ther­a­pies. Like­wise, acute myeloid leukaemia car­ries muta­tions that make it resis­tant to drugs known as isoc­i­trate dehy­dro­ge­nase inhibitors; genomics could offer answers. 

A complex battle

Can­cer is far more com­plex than even the most vision­ary of sci­en­tists ever imag­ined.  

Twen­ty years ago, for exam­ple, researchers spec­u­lat­ed that germ cell tes­tic­u­lar can­cer might be attrib­ut­able to a sin­gle gene. How­ev­er, a team led by Pro­fes­sor Clare Turn­bull of the Insti­tute of Can­cer Research in Lon­don has found more than 40 genom­ic vari­ants asso­ci­at­ed with the dis­ease. 

Small won­der, then, that so many experts see such impor­tance in genomics. And there has been sig­nif­i­cant progress.  For exam­ple, Turn­bull was clin­i­cal lead on the 100,000 Genome Project, which sequenced 100,000 genomes from more than 80,000 NHS patients with can­cer or a rare dis­ease. This yield­ed poten­tial research leads in near­ly half the can­cer patients tak­ing part. 

To under­stand why all this is so remark­able, it’s impor­tant to under­stand the con­text. The ini­tial sequenc­ing of the full human genome took more than 10 years and cost in excess of £2 bil­lion. Using a blood sam­ple, an individual’s genome can now be sequenced in a day for less than £700.

Genom­ic med­i­cine is already sav­ing lives in a mul­ti­tude of ways. Take DYPD, a gene muta­tion car­ried by rough­ly 10% of the UK pop­u­la­tion that can make chemother­a­py harm­ful to the bone mar­row, poten­tial­ly killing the patient. Genomics advances mean doc­tors can now test patients for the muta­tion at a cost of £50 each, sav­ing lives and cut­ting costs for the NHS, notes Andrew Beg­gs, pro­fes­sor of can­cer genet­ics and surgery in the Insti­tute of Can­cer and Genomics Sci­ences at the Uni­ver­si­ty of Birm­ing­ham. 

Lack of awareness

How­ev­er, Beg­gs wor­ries about a lack of pub­lic and even pro­fes­sion­al aware­ness about the scope for can­cer pre­ven­tion. For exam­ple, Lynch syn­drome is a genet­ic con­di­tion that can increase the risk of bow­el can­cer by up to 80%. It also increas­es the risk of ovar­i­an, womb and oth­er can­cers. Beg­gs, who runs a Lynch syn­drome clin­ic, says it’s a rel­a­tive­ly com­mon con­di­tion, affect­ing about 1% of the UK pop­u­la­tion, but most are not aware of it.

One rea­son for this is cul­tur­al. Most peo­ple think of the NHS as an insti­tu­tion they turn to when they are feel­ing sick, but genom­ic med­i­cine points to a future when there will be an ever big­ger empha­sis on pre­ven­tive med­i­cine. Increas­ing­ly, fam­i­lies with a his­to­ry of genet­i­cal­ly linked can­cers will be asked to under­go test­ing and any nec­es­sary treat­ment to pre­vent the can­cers devel­op­ing at all. But Beg­gs says that some patients fear screen­ing because they do not want to face up to the idea that they could be at risk from a fatal dis­ease.

“Most peo­ple want to find out if they are at risk, but the peo­ple who don’t want to know tend to be in their late teens and ear­ly 20s. You can under­stand this. They are young and believe it will nev­er hap­pen to them. But some are scared,” he explains.

The answer, he says, lies in edu­ca­tion of both health­care pro­fes­sion­als and patients. GPs have a crit­i­cal role to play in iden­ti­fy­ing fam­i­lies at risk.

There are advan­tages to the NHS too. A sin­gle round of chemother­a­py in a pri­vate hos­pi­tal can cost up to £3,000, while can­cer drugs cost the NHS more than £2bn a year. While a sin­gle genom­ic treat­ment could cost up to £20,000, that’s cheap­er than “putting a patient through hos­pi­tal admis­sions with say five or six rounds of chemother­a­py that don’t work and that cause sig­nif­i­cant side effects”, Beg­gs notes. 

Statins, the wide­ly pre­scribed cho­les­terol-low­er­ing drugs, are anoth­er exam­ple of a cheap ther­a­py that has been found to have a ben­e­fi­cial effect in genom­ic treat­ment. Cost­ing as lit­tle as four pence per tablet, statins have been shown to reduce lev­els of P53, a tumour sup­pres­sor gene. P53  muta­tions can cause can­cer cells to grow and spread.

Statins are an exam­ple of repur­posed drugs – old med­i­cines used in new ways – that have long-estab­lished safe­ty records. They can avoid the need for expen­sive new med­i­cines. About 25,000 new sub­stances are test­ed for every mar­ket­ed med­i­cine that makes enough mon­ey to pay for its devel­op­ment. 

Genom­ic drug test­ing is also chang­ing clin­i­cal tri­al design. Tra­di­tion­al tri­als usu­al­ly com­pare one drug with anoth­er, with patients divid­ed into treat­ment groups. They remain on the tri­al from the start to the end – per­haps for sev­er­al years – irre­spec­tive of whether it is help­ing them. 

The ongo­ing Nation­al Lung Matrix Tri­al could change this. Through the tri­al – which is based on 11 treat­ment arms using dif­fer­ent drugs – Uni­ver­si­ty of Birm­ing­ham researchers match var­i­ous treat­ments to dif­fer­ent groups of lung can­cer patients accord­ing to genet­ic changes in their can­cers. If a par­tic­u­lar drug isn’t work­ing, that treat­ment arm is closed and a new one may be intro­duced. If a patient doesn’t respond to drug “A”, they can be switched to drug “B”. They may be in and out of the tri­al with­in two months. 

“In a tra­di­tion­al tri­al, patients receive broad spec­trum chemother­a­pies that don’t work half the time,” Beg­gs says. “Oncol­o­gy used to be like sharp-point­ed sticks and rocks. We now have more finesse and have moved to the med­ical equiv­a­lent of a scalpel.” 

Kinder treatment

Thir­teen region­al genom­ic cen­tres are now oper­at­ing in Eng­land. One of their goals is to iden­ti­fy the patients who may ben­e­fit most from from genom­ic test­ing. Anoth­er is to ensure more effec­tive use of med­i­cines, not just in can­cer, but in all health care. The NHS med­i­cines bill was about £17 bil­lion a year. How­ev­er, 50 per cent of med­i­cines are not tak­en as pre­scribed and one in 15 hos­pi­tal admis­sions occur because of adverse drug reac­tions accord­ing to a recent report in the Phar­ma­ceu­ti­cal Jour­nal. 

What is also dis­turb­ing is that the effec­tive­ness of drugs over­all ranges between 30 to 50 per cent. Advances in can­cer genomics is explain­ing why so much con­ven­tion­al chemother­a­py fails  – it does not tar­get the right muta­tions. Hope­ful­ly, genomics will also lead to kinder treat­ments. Severe side effects aris­ing from can­cer ther­a­py are all too com­mon. 

 There is, of course,  still a long way to go before the genom­ic rev­o­lu­tion meets its full poten­tial, but the suc­cess so far would have been unimag­in­able just a few years ago.