By testing tumors, researchers hoped to identify women who could avoid chemotherapy without increasing their risk of a cancer recurrence. Voisin/Phanie/Science Sourcehide caption
A major study about the best way to treat early-stage breast cancer reveals that “precision medicine” doesn’t provide unambiguous answers about how to choose the best therapy.
“Precision doesn’t mean certainty,” says David Hunter, a professor of cancer prevention at Harvard’s T.H. Chan School of Public Health.
That point is illustrated in a large study published Wednesday in the New England Journal of Medicine, involving decisions about chemotherapy.
As is true for many cancers, breast cancer responds best to treatment when it is caught early, before it has spread throughout the body. Dr. Fatima Cardoso, the study’s lead author and a breast cancer specialist at the Champalimaud Clinical Center in Lisbon, Portugal, says that creates a conundrum for doctors and patients alike.
Because it’s the only opportunity to cure the cancer, “when in doubt we tend to treat” women with early-stage breast cancer, she told Shots. “So we know that we overtreat the patients with early breast cancer.”
That means that women could end up undergoing chemotherapy even if it wouldn’t really improve their survival odds.
Hoping to refine those treatment decisions, Cardoso helped organize a huge study throughout Europe to see whether a commercially available genetic test called MammaPrint could help reduce that overtreatment. More than 6,600 women participated at 112 institutions in nine nations.
Scientists identified women with breast cancer whose physical exams suggested they were at relatively high risk for having the cancer return eventually after surgery, but who seemed to be at low risk of recurrence based on the genetic test results.
They were invited to participate in the study, which would randomly assign them to have chemotherapy or not. “You know that chemotherapy is a treatment that scares people, so overall and for the majority of patients, it was not difficult to convince them,” Cardoso says.
The genomic test, which studies 70 distinct features of a tumor, did a pretty good job of predicting who was at low risk for recurrence of breast cancer and could therefore avoid the pain, discomfort and risks of chemotherapy. (The test, priced at $4,200, is covered by some insurance in the United States.)
The scientists found that 46 percent of women who were deemed to be at high risk of recurrence based on physical symptoms could actually skip chemotherapy with little consequence to their long-term survival.
But the test results weren’t always definitive. About 95 percent of women who skipped chemotherapy as a result of the genetic test results were free of metastasis five years later, but those who had the additional treatment did about 1.5 percentage points better, give or take.
“It’s possible that the benefit is zero, and it’s possible that’s 2 percent or maybe even a little more, you can’t be sure,” says Dr. Clifford Hudis, chief executive officer of the American Society of Clinical Oncology. He was not involved in the European study but co-wrote an editorial accompanying it. It would take another huge clinical trial to figure out whether chemotherapy does in fact add a small survival advantage.
But the study raises a bigger point here: The genomic test, as precise as it is, offers only probabilities, not absolute guidance. And that’s a lesson that applies to the whole new realm of precision medicine, which is billed as potentially transformative for medical care.
“The new tools will definitely be helpful, but they often will pose challenges about what the right decision is,” says Hunter, who wrote a perspective piece noting that people will need to develop a tolerance for uncertainty when using precision medicine tests.
Is it worth all the trouble of chemotherapy for women who are found to be at low risk for recurrence in this genomic test? That’s a tough call, because it requires grasping the rather abstract idea of improving survival odds by maybe just 1 percentage point.
“As humans, we’re notoriously poor at assessing risk and making those calculations,” Hunter says.
He says doctors and patients need better tools to understand and communicate the subtleties that are inherent in precision medicine.
Cardoso is already seeing this play out in her clinic. Women shown to be at low genetic risk on the MammaPrint test are usually opting not to have chemotherapy after their surgery. “But there always [are] some patients for whom 1 percent benefit is enough — and you need to respect the wishes of each individual patient.”
She says the women clearly benefit from the new information, even though it doesn’t provide an absolute answer.
An aggressive marketing campaign has made the EpiPen the go-to drug for treating anaphylaxis. Mark Zaleski/APhide caption
toggle captionMark Zaleski/AP
EpiPens are in your friend’s purse and your kid’s backpack. The school nurse has a few, as does Grandma.
The medicine inside — epinephrine — has been around forever, and the handy gadget that injects it into your leg is not particularly new either.
So members of Congress, responding to their angry constituents, want to know why the price of the EpiPen, which can reverse a life-threatening allergic reaction, has risen about fivefold in the past decade.
The wholesale price of a single pen was about $47 in 2007, and it rose to $284 this summer, according to Richard Evans, a health care analyst at SSR. But consumers can no longer buy a single pen, so the retail price to fill a prescription today at Walgreens is about $633, according to GoodRX.
It’s the latest in a string of controversies over rising drug prices that have caught the attention of lawmakers on Capitol Hill. At least three senators have called for investigations into the price of the EpiPen, and Sens. Charles Grassley, R-Iowa, and Richard Blumenthal, D-Conn., have sent letters to Mylan, the drug’s manufacturer, demanding an explanation for the increase.
Blumenthal went a step further. “I demand that Mylan take immediate action to lower the price of EpiPens for all Americans that rely on this product for their health and safety,” he wrote in a letter to the company.
Sen. Amy Klobuchar, D-Minn., has asked the Federal Trade Commission to investigate whether Mylan has violated antitrust laws in its marketing of the EpiPen.
And Hillary Clinton weighed in, calling the price increases “outrageous.”
“It’s wrong when drug companies put profits ahead of patients, raising prices without justifying the value behind them,” the Democratic presidential nominee said in a statement on her Facebook page.
Mylan spokeswoman Nina Devlin said in an email, “We have reached out to every member of Congress who has sent us a letter, and we look forward to meeting with them and responding to their questions as soon as possible.”
She did not immediately comment on Clinton’s statement.
The EpiPen is a long, plastic tube that automatically injects a dose of epinephrine — or adrenaline — into a person’s thigh to stop an allergic reaction. It’s easy to use and portable.
Mylan bought rights to the EpiPen in 2008 and launched an aggressive marketing and awareness campaign. That effort has made the so-called auto-injector a must-have for anyone with an allergy — perhaps to bee stings or tree nuts — that may trigger anaphylaxis, a life-threatening reaction in which the airwaves swell and close.
According to an account by Bloomberg Businessweek, the company considered selling off rights to the drug, which is an old product, but instead launched a campaign to boost sales. Revenue rose from $200 million to more than $1 billion a year.
The company itself touts its campaign “for increased anaphylaxis awareness” as what has helped drive prescriptions and sales of the device.
“Ensuring access to epinephrine — the only first-line treatment for anaphylaxis — is a core part of our mission,” Mylan said in a press release this week.
And certainly people with life-threatening allergies are better off with easy access to the drug.
But Mylan is better off too.
That’s because each EpiPen prescription creates a win-win sales cycle for Mylan.
An EpiPen prescription actually includes two injectors. The FDA in 2010 recommended that patients have access to two, in case the first doesn’t work, and Mylan complied by taking its single EpiPens off the market and offering them in two-packs.
But often one prescription is not enough. People want the pens at home, in their offices or schools, perhaps in the car. So they might buy three or more two-pen packs. Schools and businesses also often keep them on hand in case a student or customer has an unexpected reaction.
That’s how the drug has become a cash cow for Mylan, which last year moved its headquarters from the U.S. to the Netherlands.
But consumers are fed up. Almost 90,000 people signed a petition to Congress asking for an investigation. About 40,000 of those signatures came in on Wednesday.
Mylan says it is working to keep the medication cheap for consumers, by offering $100 coupons to offset high insurance copayments. In a statement released Monday, the company said about 80 percent of patients with insurance get the EpiPen free.
The statement didn’t mention the retail price or the price increases at all. Instead, the company focused on insurance policies with high deductibles that shift costs to patients.
“We encourage all patients and families to thoroughly review and understand their healthcare insurance coverage,” the statement said.
EpiPen’s name recognition means doctors who want to prescribe adrenaline to an allergy-prone patient usually just turn to it. There is no specific EpiPen generic, so pharmacists can’t substitute a cheaper alternative.
But that alternative does exist. Another auto-injector known as Adrenaclick is available in generic form at Wal-Mart for $141, according to GoodRX.
It’s unclear how far the threats of a congressional investigation into the EpiPen will go.
But the prospect does present one awkward situation. The CEO of Mylan, Heather Bresch, is the daughter of Sen. Joe Manchin, D-W.Va. In the time that the price of the EpiPen has been skyrocketing, so has Bresch’s compensation. Last year, she earned about $18.2 million, according to the New York Times. That’s up from about $2.5 million in 2007.
In earlier investigations into drug prices, the chiefs of many companies have been grilled and lectured harshly by lawmakers. It’s unclear whether the angry senators will be as inclined to be as aggressive with the daughter of one of their colleagues.
