Making the Unknown Known

How genomic profiling is shedding light on a poorly understood type of cancer, Cancer of Unknown Primary

“We were in pure panic when 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.2 For more information on CUP

Dr Marlene Thomas, Head of Comprehensive Genomic Profiling Strategy, Roche, recognised through her work, just how difficult the CUP diagnosis was for patients:

Finding the genetic clues

The disease is also challenging for doctors, says Dr. Thomas. “For a physician, CUP means that your enemy is invisible to you,” she says. “It is really hard to see the patients suffer and pass away so soon after diagnosis, never knowing what that diagnosis really means to them and their families.”

At the same time that Dr. Thomas was experiencing the feeling of dealing with this enigmatic foe, Dr. Jeff Ross, Medical Director of Foundation Medicine Incorporated in Boston, was attempting to shed light on this devastating disease.

In 2010, Foundation Medicine, a cancer genomics start-up that Dr. Ross co-founded and is now owned by Roche, pioneered a highly advanced Next Generation Sequencing (NGS) method - comprehensive genomic profiling (CGP). CGP is a type of genomic testing that can be used in cancer to help find specific DNA changes, or determine the unique “fingerprint” or molecular makeup of a patient’s tumour to help discover what is making it grow and behave.3 Moreover, CGP has helped advance our understanding of the science behind the cancer, and ultimately match patients who possess specific alterations with targeted therapies.

In 2012, just as Foundation Medicine was beginning to generate a significant amount of genomic data on cancer patients, Dr. Ross realised 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 the primary site of origin of their cancer was, and no test had been performed that could prove the origin of the disease.” In essence, each of these patients was exactly like Sarah Knott.

In essence, Dr. Ross noticed specific genetic clues about the disease that suggested potential treatments—something that had evaded most oncologists confronting CUP.

“This is an area of total unmet medical need. 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 2018 when Foundation Medicine and Roche joined forces—building on the initial work of Jeff Ross and Prof. Alwin Krämer, an oncologist at the Heidelberg-based German Cancer Research Center.

Leveraging its legacy in oncology, experience in tackling complex diseases, and an extensive breadth of treatments, Roche developed a multi-site international study that would test the efficacy and safety of molecularly guided therapy for CUP patients.

They called the trial CUPISCO, which in Latin means “wish.

Making CUP personal

Tanya Knott, a 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, provides “the kind of patient-specific information that we never had, alleviating so much of the frustration we had to go through.” 

CUPISCO’s design of using CGP in combination with individual treatment decisions made by a molecular tumour board (comprising of pathologists, CUP specialists, genomicists, and the patient’s treating oncologist) represents significant innovation. Physicians are equipped with vital insights into what drives cancer growth – helping to improve understanding of CUP.

And because of the trial’s geographic scope, Dr. Ross says that targeted treatment will reach a broad range of patients.

CGP is increasingly being incorporated into clinical guidelines for CUP. For example, the National Comprehensive Cancer Network (NCCN) clinical guidelines for CUP now recommend CGP to identify actionable genomic alterations, and assessment of tumour mutational burden.2

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

“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. Thomas 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. Thomas says.


  1. Qaseem A, et al. Cancer of unknown primary: a review on clinical guidelines in the development and targeted management of patients with the unknown primary site. Cureus. 2019;2;11(9):e5552.

  2.  NCCN Clinical Practice Guidelines in Oncology: Occult Primary (Version 3.2023).

  3. Thomas DM, et al. Public Health Genomics. 2022; 25 (3-4): 70–79.

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