Family members of patients with cancers of unknown primary (CUP) are at higher risk of developing CUP themselves, as well as cancers of the lung, pancreas, and colon and some cancers of the blood, according to a study in JAMA Oncology (doi:10.1001/jamaoncol.2015.4265).

Cancer usually develops in 1 location then spreads, but in 3% to 5% of cancer patients, the tissue where a cancer begins is unknown. In these patients, a cancer diagnosis is made because it metastasized to other sites. These cancers are called cancers of unknown primary (CUP), and prognosis for patients with CUP is very poor, with a median survival of 3 months.

Jewel Samadder, MD, lead researcher on the study, which was conducted at the University of Utah and Huntsman Cancer Institute (HCI) in Salt Lake City, was motivated to investigate CUP when a patient presented with abnormal fluid accumulation in the abdomen. After fluid removal, cancer cells were found but their primary source could not be determined, even after an extensive search involving imaging and endoscopy.

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The clinical team had very little information for the patient’s family about where the cancer started and whether they, as family members, were at increased risk, Samadder explained. Also distressing to patients with CUP and their family is the difficulty in determining treatment options the cancer would respond to best. This and the advanced nature of these cancers are likely responsible for patients’ poor outcomes.

To understand the familial risk associated with CUP and determine where these cancers may have originated, the researchers performed a retrospective study of patients with CUP diagnoses and their families between 1980 and 2010.

The researchers used the Utah Population Database (UPDB), a unique resource at HCI that links genealogy information of Utah families with demographic and medical information, including the Utah Cancer Registry.

They were able to identify 4160 patients with CUP diagnosed over a 30-year span, as well as which of these patients had family members who also had cancer diagnoses. These data were used to calculate the cancer risk by site for first-degree (parents, siblings, children), second-degree (uncles, aunts, grandparents, nephews, nieces), and first cousin relatives compared with randomly selected matched population controls who were cancer free.

Samadder explained that study results could have gone two ways. One is that relatives are not at increased risk for any one cancer, and cancer of unknown primary is some sort of bad luck event. His findings, however, did not show that result. What the researchers did find is that certain cancers pose increased risk for close, as well as distant, family members. In first-degree relatives, for example, increased risk was most important for lung, pancreatic, and colon cancers.

Among patients with CUP, first-degree relatives have a 35% increased risk of developing CUP, 37% increased risk for lung cancer, 28% increased risk for pancreatic cancer, and 20% increased risk for colorectal cancer, compared with relevant control populations.

Samadder said he can now give relatives of patients with CUP important information about their cancer risk. “This paper also suggests that these tissues, such as lung, pancreas, and colon, may be the primary sites for at least a portion of these cancers of unknown primary,” added Samadder.