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Researchers Seek to Improve Early Cancer Detection With Gene-Based Tests

Nalley, Catlin

doi: 10.1097/01.COT.0000532459.17691.d1

The key to reducing cancer deaths is early detection. Researchers at the Johns Hopkins Kimmel Cancer Center in Baltimore are exploring how to use cancer gene discoveries to develop screening assays to improve survival rates among cancer patients.

A series of gene-based tests have the potential to improve the early detection of cancer for a number of patient populations, which in turn could lead to a decline in the rates of cancer mortality.

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Researchers developed CancerSEEK, a single test that screens for eight common cancer types that account for more than 60 percent of cancer deaths in the U.S. and helps identify the location of the cancer (Science 2018; doi:10.1126/science.aar3247). This noninvasive, multianalyte test “simultaneously evaluates levels of eight cancer proteins and the presence of cancer gene mutations from circulating DNA in the blood,” according to researchers.

Investigators evaluated the test on 1,005 patients with non-metastatic, stages I-III cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. They found that the median overall sensitivity was 70 percent and ranged from a high of 98 percent for ovarian cancer to a low of 33 percent for breast cancer. For ovarian, liver, stomach, pancreatic, and esophageal cancers—which have no screening tests—sensitivity ranged from 69-98 percent, researchers reported.

The study showed that the test had a specificity of greater than 99 percent. Among the 812 healthy controls, only seven false-positive results were produced.

“Very high specificity was essential because false-positive results can subject patients to unnecessary invasive follow-up tests and procedures to confirm the presence of cancer,” said Kenneth Kinzler, PhD, Professor of Oncology and Co-Director of the Ludwig Center, in a statement.

Additionally, study authors found that “CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83 percent of the patients.”

“This test represents the next step in changing the focus of cancer research from late-stage disease to early disease, which I believe will be critical to reducing cancer deaths in the long-term,” noted Bert Vogelstein, MD, Co-Director of the Ludwig Center, Clayton Professor of Oncology, and Howard Hughes Medical Institute investigator.

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Another recently developed detection tool, UroSEEK, utilizes urine samples to identify mutations in 11 genes or the presence of abnormal numbers of chromosomes that would signal the presence of DNA associated with bladder cancer or upper tract urothelial cancer (UTUC) (Elife 2018; doi:10.7554/eLife.32143).

“Bladder cancer is a huge health care issue because, while it might not be the most common cancer, it is certainly the most expensive,” George Netto, MD, a senior author on the UroSEEK paper, formerly at The Johns Hopkins University and currently Chair of Pathology at the University of Alabama-Birmingham, told Oncology Times. One of the reasons for this, he noted, is the lifelong journey of follow-up and surveillance required following diagnosis.

Given the lack of noninvasive approaches, researchers sought to develop a test for bladder and UTUC cancers that would detect disease sooner with a reduced financial burden. Netto and team studied 570 patients who were considered high-risk for bladder cancer. In this early detection cohort, investigators found that UroSEEK was 83 percent positive among patients who developed cancer. Sensitivity among patients who developed the disease increased to 95 percent when combined with cytology.

Additionally, UroSEEK, when utilized alongside cytology, detected mutations in 71 percent of patients (n=322) who had been treated for bladder cancer and were currently in the surveillance stage. Comparatively, recurrences were detected in only 25 percent of these patients when cytology was used alone.

Researchers also utilized UroSEEK on 56 patients with UTUC and found that 75 percent tested positive, including 79 percent of those with noninvasive tumors, Netto reported. Cytology alone detected UTUC in only 10 percent of these patients. The patients in this cohort were from Taiwan, an area where the incidence of UTUC is high due to environmental factors, including the medicinal use of herbs containing aristolochic acids. “This is truly an international study,” Netto said. “We wanted to make sure we were including different populations because we want to help not just people in the U.S., but beyond.”

Research to validate this test is ongoing and investigators plan to seek FDA approval. Given the added sensitivity of utilizing UroSEEK in combination with cytology, researchers believe this could improve the management of cancer patients and spare them from more invasive and expensive procedures such as cystoscopy.

“We do not want to replace cytology, which is the gold standard, but rather add UroSEEK to improve sensitivity,” Netto emphasized. “[UroSEEK] has the potential to make a huge difference in the management of the disease in both the early detection and surveillance settings.”

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Gynecologic cancers, specifically endometrial and ovarian, were the focus of another screening assay, which utilizes cervical fluid samples gathered during routine Pap tests.

“More than 86,000 U.S. cases of endometrial and ovarian cancer were diagnosed in 2017. Treatment often involves radical surgery and, in some cases, chemotherapy and radiation,” said Amanda Nickles Fader, MD, Director of the Johns Hopkins Kelly Gynecological Oncology Service, Department of Gynecology and Obstetrics, and a corresponding author on this study. “Approximately 25,000 women a year die of gynecological cancers.

“The problem is that, for these particular cancers, there is no approved screening test to detect disease at an earlier, more treatable or curable stage. Additionally, a good number of young women are diagnosed with these cancers and so, not only is survival an issue, but loss of fertility is also common,” she continued. “If we can detect cancer earlier using detection or screening tools, the potential to achieve more cures and also preserve fertility in young women could be realized.”

With PapSEEK, mutations in DNA that have been identified for specific cancers can be detected sooner. Researchers studied 1,958 samples from 1,658 women, including 658 endometrial or ovarian cancer patients and 1,002 healthy controls, Nickles Fader reported (Sci Transl Med 2018; doi:10.1126/scitranslmed.aap8793).

Utilizing the samples, the assay looked for mutations in 18 genes as well as aneuploidy, the presence of abnormal numbers of chromosomes in cells. Investigators collected Pap brush samples from 392 endometrial cancer patients and 245 ovarian cancer patients. “We found [PapSEEK] detected 81 percent of endometrial cancers and 33 percent of ovarian cancers,” Nickles Fader told Oncology Times.

Additionally, researchers obtained cervical fluid samples using a Tao brush, which extends further into the cervical canal and collects cells closer to the source of the potential cancer, Nickles Fader explained. “Detection increased to 93 percent in endometrial cancer patients and 45 percent in women with ovarian cancer,” she noted. There were no false-positive results.

Not satisfied with the detection rates among ovarian cancer patients, researchers hypothesized that “ovarian cancers that were inaccessible by Pap or Tao brush sampling due to anatomical or other factors might be detectable by the presence of circulating tumor DNA (ctDNA) in plasma.”

Utilizing assays for ctDNA in plasma along with PapSEEK on Pap brush samples increased the sensitivity of detecting ovarian cancer to 63 percent, according to Nickles Fader.

Current diagnostics do not always reliably distinguish between benign conditions and cancer, which can lead to unnecessary procedures or an inability to detect cancer. “Because of the high mortality associated with some gynecologic malignancies, cancer screening and detection are a huge priority,” Nickles Fader concluded. “The results demonstrate the overall potential of mutation-based diagnostics to detect these cancers, ideally at a stage when they are going to be more curable.”

Catlin Nalley is associate editor.

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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