Tu­mor gene test­ing urged to tell if drug tar­gets your can­cer

Kuwait Times - - HEALTH & SCIENCE -

Colon can­cer. Uter­ine can­cer. Pan­cre­atic can­cer. What­ever the tu­mor, the more gene mu­ta­tions lurk­ing in­side, the bet­ter chance your im­mune sys­tem has to fight back. That’s the premise be­hind the re­cent ap­proval of a land­mark drug, the first can­cer ther­apy ever cleared based on a tu­mor’s ge­net­ics in­stead of the body part it struck first. Now thou­sands of pa­tients with wors­en­ing can­cer de­spite stan­dard treat­ment can try this im­munother­apy - as long as ge­netic test­ing of the tu­mor shows they’re a can­di­date.

“It’s like hav­ing a lot­tery ticket,” said Johns Hop­kins on­col­o­gist Dr Dung Le, who helped prove the new use for the im­munother­apy Keytruda. “We’ve got to fig­ure out how to find these pa­tients, be­cause it’s such a great op­por­tu­nity for them.” To­day, doc­tors di­ag­nose tu­mors by where they orig­i­nate - breast can­cer in the breast, colon can­cer in the colon - and use ther­a­pies specif­i­cally tested for that or­gan. In con­trast, the Food and Drug Ad­min­is­tra­tion la­beled Keytruda the first “tis­sue-ag­nos­tic” treat­ment, for adults and chil­dren.

The rea­son: Seem­ingly un­re­lated can­cers oc­ca­sion­ally carry a com­mon ge­netic flaw called a mis­match re­pair de­fect. De­spite small stud­ies, FDA found the ev­i­dence con­vinc­ing that for a sub­set of pa­tients, that flaw can make solid tu­mors sus­cep­ti­ble to im­munother­apy doc­tors oth­er­wise wouldn’t have tried.

“We thought these would be the hard­est tu­mors to treat. But it’s like an Achilles heel,” said Hop­kins can­cer ge­neti­cist Bert Vo­gel­stein. And last month FDA Com­mis­sioner Scott Got­tlieb told a Se­nate sub­com­mit­tee his agency will sim­plify drug de­vel­op­ment for dis­eases that “all have a sim­i­lar ge­netic fin­ger­print even if they have a slightly dif­fer­ent clin­i­cal ex­pres­sion.” It’s too early to know if what’s be­ing dubbed pre- ci­sion im­munother­apy will have last­ing ben­e­fits, but here’s a look at the science.

Who’s a can­di­date?

Hop­kins es­ti­mates about 4 per­cent of can­cers are mis­match re­pair-de­fi­cient, po­ten­tially adding up to 60,000 pa­tients a year. Widely avail­able tests that cost $300 to $600 can tell who’s el­i­gi­ble. The FDA said the flaw is more com­mon in colon, en­dome­trial and gas­troin­testi­nal can­cers but oc­ca­sion­ally oc­curs in a list of oth­ers. “Say, ‘have I been tested for this?’” is Le’s ad­vice for pa­tients.

Mu­ta­tions and more mu­ta­tions

Most tu­mors bear 50 or so mu­ta­tions in var­i­ous genes, Vo­gel­stein said. Me­lanomas and lung can­cers, spurred by sun­light and to­bacco smoke, may have twice as many. But tu­mors with a mis­match re­pair de­fect can har­bor 1,500 mu­ta­tions.

Why? When DNA copies it­self, some­times the strands pair up wrong to leave a typo - a mis­match. Nor­mally the body spell checks and re­pairs those ty­pos. Without that proof­read­ing, mu­ta­tions build up, not nec­es­sar­ily the kind that trig­ger can­cer but by­standers in a grow­ing tu­mor.

The plot thick­ens

Your im­mune sys­tem could be a potent can­cer fighter ex­cept that too often, tu­mors shield them­selves. Merck’s Keytruda and other so-called check­point in­hibitors can block one of those shields, al­low­ing im­mune cells to rec­og­nize a tu­mor as a for­eign in­vader and at­tack. Un­til now, those im­munother­a­pies were ap­proved only for a few se­lect can­cers - Keytruda hit the mar­ket for melanoma in 2014 - and they work in­cred­i­bly well for some pa­tients but fail in many oth­ers. Learn­ing who’s a good can­di­date is crit­i­cal for drugs that can cost $150,000 a year and some­times cause se­ri­ous side ef­fects.

In 2012, Hop­kins doc­tors test­ing var­i­ous im­munother­a­pies found the ap­proach failed in all but one of 20 colon can­cer pa­tients. When per­plexed on­col­o­gists told Vo­gel­stein, “a light bulb went off.”

Sure enough, the one pa­tient who fared well had a mis­match re­pair de­fect and a “mind-bog­gling” num­ber of tu­mor mu­ta­tions. The more mu­ta­tions, the greater the chance that at least one pro­duces a for­eign-look­ing pro­tein that is a bea­con for im­mune cells, Vo­gel­stein ex­plained. It was time to see if other kinds of can­cer might re­spond, too.

What’s the data?

The strong­est study, pub­lished in the jour­nal Science, tested 86 such pa­tients with a dozen dif­fer­ent can­cers, in­clud­ing some who had en­tered hos­pice. Half had their tu­mors at least shrink sig­nif­i­cantly, and 18 saw their can­cer be­come un­de­tectable.

It’s not clear why the other half didn’t re­spond. Re­searchers found a hint, in three pa­tients, that new mu­ta­tions might form that could re­sist treat­ment. But after two years of Keytruda in­fu­sions, 11 of the “com­plete re­spon­ders” have stopped the drug and re­main can­cer-free for a me­dian of eight months and count­ing. Cather­ine “Katie” Rosen­baum, 67, is one of those successes. The re­tired teacher had her uterus re­moved when en­dome­trial can­cer first struck, but five years later tu­mors re­turned, scat­tered through her pelvis and colon. She tried treat­ment after treat­ment un­til in 2014, her doc­tor urged the Hop­kins study.

Rosen­baum took a train from Rich­mond, Vir­ginia, to Bal­ti­more for in­fu­sions ev­ery two weeks and then, after some fa­tigue and di­ar­rhea side ef­fects, once a month. Then the side ef­fects eased and her tu­mors started dis­ap­pear­ing.

A year into the study she was well enough to swim a mile for a Swim Across Amer­ica can­cer fundraiser. “Noth­ing else had worked, so I guess we could say it was a last hope,” said Rosen­baum, who now wants other pa­tients to know about the op­tion. — AP

RICH­MOND, Va: In this 2015 fam­ily photo, Cather­ine “Katie” Rosen­baum is seen at a can­cer fundraiser by Swim Across Amer­ica. — AP

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