While vacationing at her son’s Florida home in February 2014, Vita O’Kane found it impossible to enjoy her midwinter getaway because of her nonstop cough. For the New Jersey retiree and her husband, Tom, the visit was meant as an escape after a string of daunting health crises. In 2012, she underwent grueling chemotherapy, surgery, and radiation treatments for stage 2 breast cancer. A year later, she endured 32 rounds of radiation to tackle basal cell skin cancer on the tip of her nose. And even before her pair of cancer diagnoses, O’Kane had confronted an ovarian cancer scare.
As unflinching as O’Kane had become, though, she never imagined the diagnosis that lay ahead. It also never occurred to her that her doctors could be wrong.
O’Kane had X-rays at a Fort Lauderdale hospital. They showed a large mass in her right lung; days later oncologists in Philadelphia agreed that O’Kane, a nonsmoker, now faced lung cancer that had spread to her brain — a diagnosis with a dismal prognosis.
“Every time I went over one hurdle, there was another one waiting,” says O’Kane, now 75. “I just got so used to it that nothing fazed me anymore. But I assumed the doctors were correct.”
Just as she began lung cancer chemotherapy, one of her doctors decided to go beyond standard diagnostic pathology tests. A 50-gene sequencing profile of O’Kane’s lung tumor revealed its DNA to be an exact match of a sample taken from her breast two years earlier. It also shared HER2-positive status — a characteristic fueling cancer cells’ growth and division that can be effectively controlled with targeted drugs.
The upshot? O’Kane didn’t have lung cancer; she had breast cancer — again. Her breast cancer had recurred and had progressed to stage 4. She had lost three weeks undergoing treatment for a type of cancer she didn’t have. The good news was that the new, correct diagnosis meant less chemotherapy overall and fewer side effects.
“I don’t think I’d be here if my treatment hadn’t changed,” says O’Kane, whose disease is stable and who harbors no hard feelings about her misdiagnosis. “I think the care I’ve been getting is far better than what I would have gotten 10 years ago. I can’t say enough good things about the gene sequencing or the education the doctors have. I’ve been through hell for the past five years, but I’m still very optimistic.”
Cancer misdiagnoses like O’Kane’s are particularly unsettling; the scary fact is that most people will experience at least one diagnostic error in their lifetime, according to the Institute of Medicine. But precision medicine in cancer — which can classify tumors according to their molecular features and genetic mutations rather than their tissue of origin — is increasingly bridging the gap to resolve cancer misdiagnosis. It can influence treatments and potentially improve outcomes.
Abevy of research supports the idea that diagnostic mistakes are not rare. A 2015 committee report by the National Academies of Sciences, Engineering, and Medicine sheds fresh light on diagnostic errors, which are estimated to affect one in 20 American adults seeking outpatient care each year. Among hospitalized patients, an estimated 40,000 to 80,000 die needlessly each year in the U.S. due to misdiagnoses.
And a 2016 Johns Hopkins study suggests that medical errors, which include misdiagnoses, should rank as the third leading cause of death in the U.S. — just behind heart disease and cancer.
But prior to the 2015 report from the National Academies, “diagnostic errors had been largely ignored and people didn’t perceive them as a problem,” says Mark L. Graber, who helped spearhead the effort as founder and president of the Society to Improve Misdiagnosis in Medicine. “Diagnostic errors are happening everywhere diagnoses are being made.”
Because cancer misdiagnoses may allow a potentially life-threatening disease to advance or become untreatable, they top the list of reasons for medical malpractice lawsuits, Graber says. And it’s not just cancer. Misdiagnoses occur across a wide swath of diseases and conditions, from infections and cardiovascular ailments to diabetes, asthma, and anemia. Graber says that although most diagnostic errors occur in common conditions, anyone who happens to be an outlier — that is, a person who either has a rare disease or who has a common disease presenting with vague symptoms or in an unusual way — is at an increased risk.
He says there are many reasons for misdiagnoses, some of which are obvious. “Not having enough time during the patient visit is a big problem, and lots of doctors would say it’s the biggest one,” Graber explains.
Part of the problem also lies with doctors’ inclination to look for the most logical, common cause of symptoms underlying a wide range of possible ailments. Jocelyn Chapman, an assistant professor of gynecologic oncology at the University of California, San Francisco (UCSF), says the inability to recognize outliers is a problem that can be traced to medical education. In medical school, she explains, new physicians are taught, “When you hear hoofbeats, think horses, not zebras.
“That’s the way diagnostic medicine has worked since the dawn of it,” she adds. “When a patient has chest pain, doctors first evaluate for a heart attack — not aortic dissection, which is incredibly rare. When you have a jaundiced woman with a mass in her pancreas, the most likely cancer is pancreatic cancer, not metastatic lung or ovarian cancer.”
Fueled by decades of research and ever-improving gene sequencing technology, scientists can now tease apart the genetic changes that cause many cancers to grow and spread, as well as determine that some of the same mutations can be found in different types of cancer. But deciding when the expensive technology, which can cost $5,000 per case, is warranted is a critical first step, experts say.
Chapman’s jaundice example stems from her firsthand involvement in the 2014 case of a 54-year-old woman who arrived at a California hospital with jaundice and extreme weight loss. A CT scan showed a large mass at the head of her pancreas, and a biopsy indicated stage 4 pancreatic cancer that had spread throughout her abdomen, including to an ovary. Pancreatic cancer is a highly aggressive malignancy that quickly kills most of its victims.
Once at UCSF Medical Center, the patient rapidly deteriorated, and Chapman was surprised when a colleague decided to order a 236-gene analysis of her tumor cells. But Chapman was even more astonished when the results uncovered a complex combination of genomic alterations — including BRCA and TP53 mutations — observed much more commonly in high-grade ovarian cancer.
“To me it was one of those aha moments, when I realized the power of molecular sequencing,” recalls Chapman, who was still in fellowship training at the time. The discovery prompted doctors to administer platinum-based chemotherapy — not usually given for pancreatic cancer — that produced a “life-changing” response, reversing the woman’s organ failure and stabilizing her disease.
While Chapman admits the patient’s ovarian cancer prognosis is still not good, “she didn’t die that week, which was the expected outcome,” Chapman says. “In her case, she ended up getting surgery and a period of time in complete remission.” More than two years later, the woman is still alive.
An Educated Guess
How many of the 1.6 million people diagnosed with cancer in the U.S. every year are actually misdiagnosed? And how many cancer cases get missed?
“There’s absolutely no way to know how many of these cases go unrecognized,” Chapman acknowledges. “I think it happens across cancer, and it’s most impactful in advanced cancers. It’s an undefined problem, but we probably see the tip of the iceberg here at a university in terms of what kind of misdiagnosis is going on.”
But while conventional laboratory techniques to diagnose cancers are widely considered accurate, they’re also somewhat subjective and require an educated guess by highly trained pathologists, says Jennifer Shih Winn, O’Kane’s doctor and a medical oncologist at Fox Chase Cancer Center in Philadelphia.
“Depending on how these tiny cancer cells look under a microscope, we can tell what kind of cancer it is or might be,” Winn explains. Known as immunohistochemistry, the time-honored technique analyzes both the type and behavior of biopsied cells by adding various colored stains to them that are chosen at a pathologist’s discretion depending upon his or her suspicions.
“Sometimes they add a second or third color to combine all the info they have to make the most likely guess,” she adds, estimating this diagnostic technique is “probably 98 percent accurate” for all cancers.
On the other hand, DNA tumor profiling techniques rely less on human interpretation and more on automated technology to reveal tumors’ molecular characteristics. Increasingly, oncologists are using sequencing in an attempt to tease out the extent to which genomic signatures are shared across tissues, which can not only help doctors accurately diagnose cancers, but identify the most appropriate treatment.
For example, research published in the journal Cell in 2014 on more than 3,500 specimens from 12 types of cancer revealed that several malignancies could be grouped into common subtypes, notably squamous cell lung cancer, head and neck cancer, and bladder cancer typified by TP53 gene mutations. This information, “while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes,” according to the paper.
Newer clinical research, known as basket trials, lumps together patients whose different tumor types — such as breast, ovarian, or colorectal — feature similar patterns of genetic mutations. All patients in a basket trial are treated with the same drug or drug combination. But scientists can also flip those findings to expand their knowledge of tumor characteristics, thereby enhancing future diagnostic accuracy, experts say.
“Once you’ve identified treatment that is curative for someone with a combination of gene mutations, the next step is to do sequencing for everyone who comes in who has cancer. And if they have that combination, that’s the drug they get,” Chapman says. “That’s how you turn it around to impact care going forward.”
A More Refined Diagnosis
Despite its increasing usefulness, tumor sequencing is not yet standard for all cancer patients upon diagnosis. But specific types of malignancies — such as breast, ovarian, colorectal, and lung cancers, as well as melanoma and certain leukemias — are more likely to receive this extra scrutiny, because they exhibit established genetic mutations that would signal the use of an approved targeted therapy, according to the National Cancer Institute.
“Refining melanoma diagnoses by BRAF mutations or, for breast cancers, HER2 or BRCA mutations — those are the refinements of diagnosis that change what treatments make sense to offer patients, and those are the ones for which genetic sequencing is being used routinely,” Chapman says. “I think it’s a matter of time before most cancer types have at least some molecular refinement that helps triage either treatments or diagnoses.”
Steadily dropping costs for tumor sequencing will undoubtedly push that agenda forward — within reason, Winn and Chapman agree.
“It’s hard to put a number on it, but there’s a hefty percentage of cancers that are very straightforward and easy to diagnose. So I don’t think pathologists are going to be going away — it’s not a matter of computers and robots automating diagnosis,” Chapman notes. “I do think, though, that tumor sequencing will grow cheap enough, especially for solid tumors, to become pretty standard to do initially.”
In cancer caught late and diagnosed when already metastatic, between 10 percent and 20 percent of tumors are unclassifiable, even for expert pathologists, Chapman says. Tumor sequencing carries the potential to make the largest difference in those cases. “There will be more and more scenarios in which sequencing will be done because it’s cheap,” she says.
Winn adds: “Right now we’re walking the line of using some traditional techniques and incorporating them with what’s new, but we’re trying to pick and choose more and more genes to be tested. At some point, the balance will be toward more gene testing.”
Misdiagnosis not only can kill you, it can waste your time, harm your psyche, and empty your bank account.
“It can change your whole life if you’re given a diagnosis you don’t have and you’re psychologically consumed by that,” Graber says “[It can] produce tremendous anger and disappointment about being diagnosed too late.”
While Vita O’Kane’s quickly corrected diagnosis prevented lasting harm, Winn believes her patient’s faulty lung cancer verdict could have had deep financial repercussions. The two HER2 targeted treatments O’Kane is receiving — including Herceptin (trastuzumab) and Perjeta (pertuzumab) — aren’t FDA-approved for lung cancer patients, Winn says.
“All those fancy treatments that would have been used off-label often bring a huge financial burden to the family,” Winn says. “Insurance could easily deny them, but in breast cancer, all of those treatments are standard and would be covered.”
And clearly, it’s not just patients who are touched by diagnostic errors — or corrections. Chapman noticed that when her patient with ovarian cancer received an accurate diagnosis, the woman’s family benefited as well.
“This woman has three sisters and two daughters, most of whom have been tested for BRCA mutations. Some are making decisions about surgery for breast and ovarian cancer prevention,” Chapman says.
“This is another thing that struck us in this particular case. We’re not just talking about a patient. We’re also talking about a network of family members whose futures were impacted by the genetic underpinnings of the patient’s diagnosis,” she adds. “This has huge impact on their futures — [their finances], their well-being, their contribution to society.”