Sci­en­tists study mir­a­cle pa­tients’ genes for wider can­cer ther­a­pies

The Washington Post Sunday - - FRONT PAGE - BY BRADY DEN­NIS

BOS­TON — Grace Silva and Karen Coak­ley are both 59, moth­ers living in the Bos­ton sub­urbs and pa­tients at Dana-Farber Can­cer In­sti­tute, where they have spent years wrestling with daunt­ing di­ag­noses.

While they have never met, the two women are con­nected in a way that goes be­yond their sim­i­lar sto­ries and their strug­gles with can­cer. They share an in­ti­mate and un­com­mon link, the sort of ge­netic bond pos­si­ble only in an age of pre­ci­sion medicine.

Silva is what re­searchers call an “ex­cep­tional re­spon­der,” the rare pa­tient who has a sur­pris­ing, dra­matic re­sponse to a drug. Coak­ley is the un­sus­pect­ing ben­e­fi­ciary of what sci­en­tists are now learn­ing from th­ese unique pa­tients.

In 2010, Silva was di­ag­nosed with anaplas­tic thy­roid can­cer, an ag­gres­sive and rapidly fa­tal

“What we’re try­ing to do with th­ese can­cers is find their Achilles’ heel.”

Bar­bara Con­ley, can­cer spe­cial­ist

dis­ease with no ef­fec­tive treat­ment. De­spite surgery, chemo­ther­apy and ra­di­a­tion, the can­cer spread to her lungs. As a last re­sort, she en­rolled in a small clin­i­cal trial the fol­low­ing year with other pa­tients with the same can­cer.

“It was a shot in the dark,” said Jochen Lorch, her on­col­o­gist.

Along with the other pa­tients, Silva got a drug called everolimus, ap­proved for ad­vanced kid­ney can­cer and some types of breast and pan­cre­atic can­cer. The other pa­tients died, but Silva’s tu­mors vir­tu­ally van­ished, to the as­ton­ish­ment of her doc­tors.

Such in­ex­pli­ca­ble re­ver­sals have al­ways ex­isted in medicine, but un­til re­cently, out­liers such as Silva re­mained lit­tle more than hope­ful anec­dotes.

That could be chang­ing. Silva’s story, and those of other ex­cep­tional re­spon­ders, have led to an in­trigu­ing set of ques­tions: Could re­searchers use tech­nolo­gies such as ge­netic se­quenc­ing to fig­ure out what made Silva’s tu­mor re­spond to treat­ment? Could they mine that data for clues that might help other pa­tients? Could they ul­ti­mately find a way to make the ex­cep­tional more rou­tine?

The quest to an­swer those ques­tions led them to Coak­ley, whose ovar­ian can­cer was pro­gress­ing de­spite years of treat­ments, and who found her­self won­der­ing whether she was out of op­tions and out of time.

Some­times an­swers emerge

In the past, a drug un­der devel­op­ment prob­a­bly would be writ­ten off as a fail­ure if, for ex­am­ple, 48 out of 50 pa­tients in a clin­i­cal trial ex­pe­ri­enced lit­tle or no ben­e­fit. But that left unan­swered why a hand­ful of pa­tients had “a Lazarus-like, un­be­liev­able re­sponse,” said Barry Tay­lor, a molec­u­lar on­col­o­gist at New York’s Me­mo­rial Sloan Ket­ter­ing Can­cer Cen­ter.

Maybe the drugs them­selves weren’t fail­ures, Tay­lor and other re­searchers thought. Maybe they were be­ing given to the wrong pa­tients. If they could fig­ure out which ge­netic wrin­kles caused a Grace Silva to re­spond so pro­foundly to a cer­tain drug, they might be able to find oth­ers — peo­ple whose tu­mors had the same mu­ta­tions — who would have the same ex­tra­or­di­nary re­ac­tion.

That would have been dif­fi­cult, if not im­pos­si­ble, just a few years ago, when it took weeks and cost mil­lions of dol­lars to decode an in­di­vid­ual’s DNA. To­day, far more pow­er­ful ge­netic se­quenc­ing costs less than $1,000 and can be done in hours.

Ma­jor can­cer hos­pi­tals such as Dana-Farber now rou­tinely se­quence the tu­mors of all pa­tients, al­low­ing re­searchers to cre­ate vast data­bases to study which gene mu­ta­tions drive cer­tain can­cers.

The Na­tional Can­cer In­sti­tute in the fall launched a na­tion­wide search for peo­ple with a va­ri­ety of can­cers who had unique re­sponses to treat­ments. It has al­ready iden­ti­fied scores and is hop­ing to iden­tify many more.

“What we’re try­ing to do with th­ese can­cers is find their Achilles’ heel and attack that,” said Bar­bara Con­ley, as­so­ciate direc­tor of NCI’s Can­cer Di­ag­no­sis Pro­gram.

The goal, she said, is to iden­tify ge­netic mark­ers that could lead to­ward bet­ter treat­ments for other pa­tients — in­volv­ing, per­haps, drugs that were aban­doned in early-phase tri­als be­cause they didn’t work for most par­tic­i­pants, or ap­proved med­i­ca­tions that might ben­e­fit more pa­tients than doc­tors re­al­ized.

Con­ley and oth­ers say the strat­egy, although promis­ing, is not fool­proof. While ev­er­im­prov­ing tech­nolo­gies al­low re­searchers to study can­cer tu­mors in un­prece­dented depth, some tu­mors con­tain many mu­ta­tions, and it can be hard to de­ter­mine which ones cause a cer­tain re­ac­tion to a drug.

But some­times, an­swers do emerge.

Cu­ri­ous about Silva’s re­mark­able re­sponse, in­ves­ti­ga­tors from Har­vard and the Mas­sachusetts In­sti­tute of Tech­nol­ogy an­a­lyzed sam­ples of her orig­i­nal tu­mor. They dis­cov­ered she had a mu­ta­tion in TSC2, one of two genes that reg­u­late a pro­tein path­way called mTOR, which her can­cer re­lied upon to grow. The drug she had re­acted to so strongly, everolimus, in­hibits mTOR, prob­a­bly ex­plain­ing why Silva had seen such an in­stant, lon­glast­ing ben­e­fit.

Even be­fore Silva, a pa­tient at Sloan Ket­ter­ing with ad­vanced blad­der can­cer had ex­pe­ri­enced a sim­i­lar re­ac­tion to the drug. That pa­tient’s blad­der can­cer had a ge­netic mu­ta­tion that was simi- lar to Silva’s thy­roid can­cer.

Nikhil Wa­gle, a med­i­cal on­col­o­gist at Dana-Farber, said that sug­gested to re­searchers that pa­tients whose can­cers have sim­i­lar mu­ta­tions “could be ex­tra­or­di­nary re­spon­ders, re­gard­less which kind of can­cer they might have. This re­ally spurred our in­ter­est.”

Doc­tors at the hos­pi­tal be­gan search­ing their data­base, try­ing to iden­tify other pa­tients with the same sort of ge­netic mu­ta­tion — re­gard­less of where their tu­mors were — for a small clin­i­cal trial of everolimus that would test their the­ory.

They soon turned up dozens of names.

Hope but still no cure

One of them was Karen Coak­ley, a soft-spo­ken woman who had spent much of the win­ter on a sofa in her home in Tewks­bury, north of Bos­ton. She didn’t know much about the ge­netic mu­ta­tions of her can­cer, but she did worry she wouldn’t see an­other win­ter.

“I have to be hon­est,” Coak­ley said while sit­ting in her yel­low sun­room on a re­cent morn­ing. “In Septem­ber, I didn’t think I would be here to­day.”

Di­ag­nosed in July 2008 with Stage 3 ovar­ian can­cer, Coak­ley had un­der­gone surgery and chemo­ther­apy, which sent her can­cer into re­mis­sion. But by 2011, it was back, and since then, she had cy­cled through a dizzy­ing se­ries of drugs. Most would work for a while, but the can­cer in­evitably would resur­face, and her doc­tor would move on to the next treat­ment on a list that was grow­ing shorter.

“It’s a roller coaster,” Coak­ley said.

In Septem­ber, she be­gan a leave of ab­sence from her job work­ing in ac­counts payable at a man­u­fac­tur­ing com­pany, un­sure she would ever re­turn. She watched the New Eng­land snow fall out­side her win­dow. She watched day­time TV and worked on puzzles but had en­ergy for lit­tle else.

In Fe­bru­ary, her on­col­o­gist at Dana-Farber told Coak­ley she was el­i­gi­ble for a new drug trial. Her tu­mor was very sim­i­lar to Silva’s, and doc­tors sus­pected Coak­ley might ben­e­fit from everolimus. “I think you need to do this,” the on­col­o­gist told Coak­ley.

Coak­ley be­gan tak­ing the drug in early March, swal­low­ing one pill at her kitchen ta­ble each morn­ing.

Af­ter the first month, a blood test showed a sharp drop in the lev­els of CA-125, a pro­tein pro­duced by ovar­ian can­cer cells. A month later, when her doc­tor called to say a scan showed her tu­mors were shrink­ing, she burst into tears in her drive­way.

Coak­ley re­turned to work at the end of March. She’s plan­ning a trip to New York soon to see a Broad­way show with one of her daugh­ters, and she and her hus­band are plan­ning to visit their other daugh­ter in Florida in the fall. They never used to look so far ahead on the cal­en­dar.

“It’s just al­lowed me more free­dom to do things,” Coak­ley said. “I don’t have this sen­tence hang­ing over my head.” Daniel, her hus­band of three decades who has been her chauf­feur, nurse and con­fi­dant through­out the seven-year or­deal, said the cou­ple feel “more com­fort­able now.”

Doc­tors are dis­cov­er­ing that even peo­ple whose can­cers have ge­netic mu­ta­tions they think might re­spond to a cer­tain drug of­ten do not, for rea­sons that re­main largely mys­ter­ies. And those who do re­spond of­ten don’t ben­e­fit in­def­i­nitely. Pre­ci­sion medicine, for all its prom­ise, is not a panacea.

Know­ing that, nei­ther Coak­ley nor her doc­tors use the word “cure.” None of them know how long everolimus will con­tinue to send her can­cer into retreat. Still, Coak­ley said, she is grate­ful for Silva and other ex­cep­tional re­spon­ders — none of whom she has met — as well as for the re­searchers smart enough to pin­point their key ge­netic similarities.

“I feel like I’ve got­ten a re­prieve,” she said. “I’ve got­ten my life back.”

‘God has a plan’

For all her good for­tune, Silva faces an un­cer­tain jour­ney.

Af­ter 18 months, the can­cer in her lungs be­came re­sis­tant to everolimus. Since 2013, Silva has tried sev­eral ther­a­pies aimed at head­ing off the spread of the dis­ease, with mixed re­sults.

Her most re­cent scans show that the can­cer in her lungs has grown, al­beit slowly. She is wait­ing to begin a new trial for a drug that tar­gets the same ge­netic mu­ta­tion in her can­cer but through a dif­fer­ent mech­a­nism. Her doc­tors hope the new treat­ment will spark a re­ac­tion sim­i­lar to the one she sur­prised them with years ago.

“Now, I’m ac­tu­ally ex­pect­ing a re­sponse,” said Lorch, her on­col­o­gist. “I’d be re­ally dis­ap­pointed if it didn’t work.”

Silva is aware of the on­go­ing trial at Dana-Farber and is glad that her ge­netic in­for­ma­tion and that of other ex­cep­tional re­spon­ders is be­gin­ning to ben­e­fit peo­ple like Coak­ley.

“I told my doc­tor . . . God has a plan here some­where; we just don’t un­der­stand it. This is hap­pen­ing for a rea­son, and maybe that rea­son is to help some­one else,” said Silva, who was born in Por­tu­gal but raised in Mas­sachusetts. “It’s giv­ing peo­ple hope.”

She’s also thank­ful for the time she might not have had, for the bless­ings each un­ex­pected year has brought. “I’m very grate­ful God gave me this time,” she said.

On a re­cent Wed­nes­day af­ter­noon, Silva was on the floor of her living room in Dart­mouth with the two grand­chil­dren she might never have met — Jae­lynn and Mad­dox — when her phone buzzed with a text.

“On my way to the hos­pi­tal, pretty sure I’m in la­bor,” read the mes­sage from her youngest daugh­ter. An­other grand­child was on the way, and once again, Silva would be there to meet him.

Later, as Silva loaded the chil­dren into her Honda CR-V for the six-mile ride to St. Joseph’s Hos­pi­tal, where her daugh­ter was un­der­go­ing a Cae­sarean sec­tion, an­other text ar­rived: “Healthy beau­ti­ful boy.” Soon came a pic­ture of the 7-pound 5-ounce new­born. “He’s got my nose,” Silva said, smil­ing.

In the hos­pi­tal’s ma­ter­nity word, Silva found her daugh­ter in a small re­cov­ery room, cradling her new­est grand­son, Con­ner, barely an hour old. She leaned over the bed, kissed them both and stroked the boy’s cheek.

“My good­ness,” she said. “Look at that face.”


Grace Silva, far left, who was di­ag­nosed in 2010 with an ag­gres­sive and rapidly fa­tal type of can­cer, leaves the house with grand­sonMad­dox San­tos and grand­daugh­ter Jae­lynn Martinez. Silva had a sur­pris­ing, dra­matic re­sponse to the can­cer drug everolimus. Sci­en­tists have mined her case for clues that might help other pa­tients, in­clud­ing Karen Coak­ley, near left, who was also pre­scribed everolimus be­cause her gene mu­ta­tions were sim­i­lar to Silva’s. Her tu­mors have shrunk, and she has re­turned to work.


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