By Pierre Valette, Emmy and Peabody-Award winning journalist and TV producer

Photographer: Gabe Souza

“We were in pure panic that the oncologist did not know what it was,” says Tanya Knott, whose sister, Sarah, suffered from a rare condition called Cancer of Unknown Primary Origin or CUP for short.

“It was such a roller coaster ride going from one possible diagnosis to another—from uterine cancer, to lymphoma, to germ cell, then back to lymphoma,” Tanya explains. The fact is, none of Sarah’s oncologists ever knew with certainty what kind of cancer she had up until the day she passed away in 2015 at the age of 31.

CUP represents 3 to 5 percent of all cancer diagnoses.1 Its defining feature is, frustratingly, that there is no real defining feature: patients present with metastatic cancer, but the specific site of origin is unknown. And when physicians use the traditional approach to cancer—in which the disease and treatments are defined by the site of origin—they are often at a loss for a treatment plan. Indeed, the most common treatment for CUP, six rounds of platinum-based chemotherapy, is usually ineffective, resulting in a median overall survival rate of less than one year. For more information on CUP.

Dr. Andreas Beringer, International Medical Director of Personalised Healthcare at Roche, experienced firsthand as a neurosurgeon how difficult the CUP diagnosis was for patients. “It was really hard to see how they suffered, how they passed away so soon without realizing what this diagnosis means for them or their families,” he says.

The disease is also challenging for doctors, says Dr. Beringer. “For a physician, CUP means that your enemy is invisible to you,” he says. “It really negatively impacts your internal strength because you are completely blind. You don’t know whom to fight or how to fight.”

At the same time that Dr. Beringer was experiencing the “blindness” associated with CUP, Dr. Jeff Ross, Medical Director of Foundation Medicine Incorporated in Boston, was attempting to shed light on this frustratingly unknowable disease. He felt empowered to do so because of a unique approach to cancer diagnosis.

In 2010, Foundation Medicine, a cancer genomics start-up that Dr. Ross co-founded and is now owned by Roche, pioneered one of the most advanced Next Generation Sequencing (NGS) methods in the field. Foundation Medicine uses a combination of precise DNA sampling and sophisticated algorithms to provide a comprehensive genomic profile for each patient’s cancer. Using this genetic profile, Foundation Medicine’s clinical research team culls the world’s most up-to-date published cancer literature to match each patient’s genetic profile with the best-known treatment option or clinical trial. To date, Foundation Medicine has profiled more than 300,000 patients, and published over 400 papers based on its improved outcomes.

For more information about comprehensive genomic profiling and Foundation Medicine, please visit the Roche-Foundation Medicine.

In 2012, just as Foundation Medicine was beginning to generate a significant amount of genetic data on cancer patients, Dr. Ross realized how many of them were coming in with a CUP diagnosis. “Very quickly, I had assembled 200 CUP cases,” he says. “I made certain no one knew where their primary site was, and no test had been performed that could prove where their primary site was.” In essence, each of these patients was exactly like Sarah Knott.

“I was shocked, after we did our genetic analysis, to discover a treasure trove of possible target gene mutations against which an effective therapy existed,” Dr. Ross says. In essence, Dr. Ross noticed specific genetic clues about the disease that suggested potential treatments—something that had evaded most oncologists confronting CUP.

The implications for this discovery were profound. Dr. Ross recalls that when he submitted his findings to the Journal of the American Medical Association, the editors were so impressed that “they didn’t want to publish it in JAMA; they wanted to use it as the front page article of their new journal, JAMA Oncology.”

The article, Dr. Ross says, demonstrated that similar tests used on a CUP patient, could “find many different pathways for how to treat the patient that could end up with a far better outcome, and longer survival than the traditional chemotherapy approach.”

Soon after the publication, Foundation Medicine began to make treatment recommendations for CUP patients whose genetic tests revealed a pathway for which there was a known treatment. One of those patients was Heather, a 60-year-old woman from Maryland. In 2013, Heather’s doctors had discovered a malignant tumour in her brain that had been diagnosed as CUP.

“She probably would have died in less than a year with the standard chemotherapy treatment,” says Dr. Ross. But Foundation Medicine testing revealed a genetic alteration for which there was an effective therapy.

Receiving the Foundation Medicine report was a life-changing moment, Heather recalls: “After all the chemotherapy and still being sick, my doctors told me they found something that might help my case. And all of a sudden there was new hope.” Her doctors began the newly identified treatment immediately. Four years later, Heather recounts her experience: “the tumour shrunk, the side effects were negligible, I was enjoying life again and able to travel the world.”

Heather’s case and a dozen others, while only anecdotal, provided hope and motivation for Dr. Ross and his colleagues. “This is a total unmet medical need that we have. If we can take 20 to 30 percent of those patients for whom there’s a targeted therapy or immunotherapy and help extend their lives, then that’s a major breakthrough.”

The opportunity to make that ambition a reality came in 2015 when Foundation Medicine and Roche joined forces—building on the initial work of Jeff Ross and Dr. Alwin Krämer, an oncologist at the Heidelberg-based German Cancer Research Center.

Leveraging its global resources, experience in tackling complex diseases, and an extensive arsenal of effective treatments, Roche was able to help Foundation Medicine develop a multi-site international study that would test the efficacy and safety of molecularly guided therapy for CUP patients.

Over the past year, the research team completed its comprehensive genetic analysis of more than 4,500 patients, which identified nine of the most common genetic alterations for which a targeted and effective treatment already exists. These genomic alterations and related treatments define the trial’s nine treatment arms. To help determine the most appropriate treatment arm for each patient, the team created a CUP molecular tumour board—the first of its kind—comprised of pathologists, CUP specialists, and the patient’s treating oncologist.

They called the trial CUPISCO, which in Latin means “wish.” The trial’s first site launched in April 2018 and will ultimately enroll 790 patients across four continents before completing its final report in 2022. To succeed, it will need to show that, for a statistically significant number of patients, outcomes improve in each treatment arm.

Dr. Giulia Baciarello, an oncologist from Paris whose hospital is one of the trial sites, hopes the trial will lead physicians to approach CUP the way they do lung cancer: with many targeted treatments available for different genetic alterations, as opposed to a one-size-fits-all solution.

“This would allow us to provide each patient with a personalised treatment to improve overall survival,” Dr. Baciarello says, “and reduce the psychological trauma that patients and treating physicians experience.”

Although the CUPISCO trial will take more than four years to complete, it already holds significant promise for patients and oncologists alike.

Tanya Knott, the CUP patient advocate whose sister Sarah died from the disease in 2015, calls the CUPISCO trial “the most exciting development that’s happened for CUP patients.” The trial, she says, will provide “the kind of patient-specific information that we never had, alleviating so much of the frustration we had to go through.”

And because of the trial’s geographic scope, Dr. Ross says, that targeted treatment will reach a broad range of patients. “The partnership with Roche means that more patients in Europe, and even in smaller developing countries, may get access to cutting-edge drugs that, without this trial, they would have no access to,” he says.

Physicians will also benefit from the process, Dr. Baciarello says, pointing to the CUP molecular tumour board as an immediate, tangible benefit. “So few oncologists have any familiarity with CUP or how to treat it,” she says. “Instead of throwing up their hands, they’ll now have access to experts and precise molecular information that will help them manage the disease, and communicate clearly with patients.”

Indeed, Tanya Knott believes the tumour board will eliminate what she calls “multi-disciplinary team tennis:” the experience her sister had where “you’re going from one team, to the next, back to the next. You don’t belong anywhere. You’re kind of between slots. You’ve fallen in between the cracks.”

Dr. Ross shares this hope that the CUPISCO trial will be an important step to moving CUP out of the shadows.

“CUP patients are treated like a pariah,” says Dr. Ross. “It’s hard to have any public awareness, it’s hard to have support from societies, when people die so quickly,” he says. “If we’re able to make even small incremental changes, you’ll start to have support societies spearheaded by patients who live a little longer, and help provide support to newly diagnosed patients.”

Beyond the specifics of CUP, Dr. Ross and Dr. Beringer believe the study can serve as a model for a more personalised approach to the disease, in which specific treatments are identified—or discovered—based on the unique molecular make-up of each patient’s tumour.

“There is so much information in every tumour that holds the key to its cure that we might be missing. By its very nature, CUP demands that we integrate everything we know about the genetics of the patient’s cancer because it’s the only thing we have to go on. In this way, it’s the prototype for truly personalised medicine,” Dr. Beringer says.

Dr. Ross agrees: “The CUPISCO trial has the chance of being practice-changing.”


  1. Stella, G.M., et al. (2012) J Transl Med 10:12; 2. Urban, D. et al. (2013) Br J Cancer 109:1318-24

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