Drug targets genetics of tumour
New treatment focuses on cancer’s genes rather than those of bodily part affected
Colon cancer, uterine cancer, pancreatic cancer — whatever the tumour, 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 to be cleared based on a tumour’s genetics instead of the bodily 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 tumour shows they’re a candidate.
“It’s like having a lottery ticket,” said Johns Hopkins oncologist Dr. Dung Le, who helped to 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.”
Doctors diagnose tumours by where they originate — breast cancer in the breast, colon cancer in the colon — and use therapies specifically tested for the organ. In contrast, the U.S. Food and Drug Administration labelled Keytruda the first “tissueagnostic” treatment, for adults and children.
The reason for this is that 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 tumours susceptible to immunotherapy doctors otherwise wouldn’t have tried.
“We thought these would be the hardest tumours to treat. But it’s like an Achilles heel,” Hopkins cancer geneticist Bert Vogelstein said.
Last month, FDA commissioner Scott Gottlieb told a U.S. 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 precision immunotherapy will have lasting benefits. Here’s a look at the science:
Who is a candidate?: Hopkins estimates about four per cent of cancers are mismatch repairdeficient, potentially adding up to 60,000 patients a year. Widely available tests that cost $300 to $600 US can tell who is eligible. The FDA said the flaw is more common in colon, endometrial and gastrointestinal cancers, but occasionally occurs in others.
“Say: ‘Have I been tested for this?’ ” is Le’s advice to patients.
Mutations and more mutations: Most tumours 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 tumours with a mismatch repair defect can harbour 1,500 mutations.
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 tumour.
The plot thickens: Your immune system could be a potent cancer fighter except that, too often, tumours shield themselves. Merck’s Keytruda and other socalled checkpoint inhibitors can block one of those shields, allowing immune cells to recognize a tumour 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 is 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 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 “mindboggling” number of tumour mutations. The more mutations, the greater the chance that at least one produces a foreignlooking protein that is a beacon for immune cells, Vogelstein said.
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 tumours 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 Rosenbaum, 67, of Richmond, Virginia, is one success. The retired teacher had her uterus removed after endometrial cancer struck. Five years later, tumours returned to her pelvis and colon. She tried several treatments until, in 2014, her doctor suggested joining the Hopkins study.
Her tumours started disappearing. A year into the study, she was well enough to swim a mile for a cancer fundraiser.