publication date: Jan. 19, 2018

Clinical Roundup

Blood test for eight cancer types provides framework for early detection

Johns Hopkins Kimmel Cancer Center researchers developed a single blood test that screens for eight common cancer types and helps identify the location of the cancer.

The test, called CancerSEEK, is a noninvasive, multianalyte test that simultaneously evaluates levels of eight cancer proteins and the presence of cancer gene mutations from circulating DNA in the blood.

The test is aimed at screening for eight common cancer types that account for more than 60 percent of cancer deaths in the U.S. Five of the cancers covered by the test currently have no screening test.

“The use of a combination of selected biomarkers for early detection has the potential to change the way we screen for cancer, and it is based on the same rationale for using combinations of drugs to treat cancers,” said Nickolas Papadopoulos, senior author and professor of oncology and pathology.

The findings were published online by Science on Jan. 18.

The investigators initially explored several hundred genes and 40 protein markers, whittling the number down to segments of 16 genes and eight proteins. They point out that this molecular test is solely aimed at cancer screening and, therefore, is different from other molecular tests, which rely on analyzing large numbers of cancer-driving genes to identify therapeutically actionable targets.

In the study, the test had greater than 99 percent specificity for cancer.

The test was evaluated on 1,005 patients with nonmetastatic, stages I to III cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung or breast. The median overall sensitivity, or the ability to find cancer, was 70 percent and ranged from a high of 98 percent for ovarian cancer to a low of 33 percent for breast cancer. For the five cancers that have no screening tests—ovarian, liver, stomach, pancreatic and esophageal cancers—sensitivity ranged from 69 percent to 98 percent.

“A novelty of our classification method is that it combines the probability of observing various DNA mutations together with the levels of several proteins in order to make the final call,” said Cristian Tomasetti, associate professor of oncology and biostatistics, who developed the algorithm. “Another new aspect of our approach is that it uses machine learning to enable the test to accurately determine the location of a tumor down to a small number of anatomic sites in 83 percent of patients.”

Although the current test does not pick up every cancer, it identifies many cancers that would likely otherwise go undetected.

“Many of the most promising cancer treatments we have today only benefit a small minority of cancer patients, and we consider them major breakthroughs. If we are going to make progress in early cancer detection, we have to begin looking at it in a more realistic way, recognizing that no test will detect all cancers,” says Bert Vogelstein, co-director of the Ludwig Center, Clayton Professor of Oncology and Howard Hughes Medical Institute investigator.

To zero in on the analytes for the CancerSEEK test, the research team pulled data from more than three decades of cancer genetics research generated at their Ludwig Center at Johns Hopkins, where the first genetic blueprints for cancer were created, as well as data from many other institutions.

The investigators said the CancerSEEK test will eventually cost less than $500. Additional testing is underway.

 

Study shows screening population for select genes is a cost-effective solution

A study published in the Journal of the National Cancer Institute indicates that screening the general population for mutations in specific genes is a more cost-effective way to detect people at risk and prevents more breast and ovarian cancers compared to only screening patients with a personal or family history of these diseases.

Current guidelines recommend that only those with a personal or family history that could indicate a greater risk of developing cancer be tested for gene mutations that can cause the disease. However, the successful use of testing for high-risk groups has led many to consider extending genetic testing for cancer to the whole population.

Recent technological advances in genomic medicine make large-scale genetic testing possible. The new study evaluated the cost effectiveness of screening the general population for ovarian and breast cancer genes, compared to only screening high-risk people. It found that population-based testing for mutations in specific genes in women over 30 years old was cost effective and prevented more cancers and deaths than only carrying out genetic testing in women whose personal or family history indicated a greater risk of developing cancer.

Mutations that cause cancer can occur in many people with no history to indicate a risk. These people are therefore not included in screening programs that target high-risk patients and the mutations remain undetected. The researchers of the new study estimate that implementing a program to test all women over the age of 30 could result in thousands fewer cases of ovarian and breast cancer in women in the US and UK.

The paper “Cost-effectiveness of population-based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women” is available at the Journal of the National Cancer Institute.

 

Polygenic hazard score predicts when men develop prostate cancer

An international team, led by researchers at the University of California San Diego School of Medicine, has developed a genetic tool for predicting age of onset of aggressive prostate cancer.

The tool, described in the Jan. 11 online issue of the BMJ (formerly the British Medical Journal), may potentially be used to help guide decisions about who to screen for prostate cancer and at what age.

Currently, detection of prostate cancer relies primarily upon the prostate-specific antigen screening blood test. But PSA testing is not good as a screening tool. While it reduces deaths from prostate cancer, indiscriminate PSA screening also produces false positive results and encourages over-detection of non-aggressive, slow-growing tumors.

Tyler Seibert, chief resident physician in the Department of Radiation Medicine and Applied Sciences at UC San Diego School of Medicine, senior author Anders Dale, professor and co-director of the Center for Translational Imaging and Precision Medicine at UC San Diego School of Medicine, and colleagues in Europe, Australia and the United States, used genome-wide association studies to determine whether a man’s genetic predisposition to developing prostate cancer could be used to predict his risk of developing the aggressive and lethal form of the disease.

GWAS search individual genomes for small variations, called single-nucleotide polymorphisms, that occur more frequently in people with a particular disease than in people without the disease. Hundreds or thousands of SNPs can be evaluated at the same time in large groups of people. In this case, researchers used data from over 200,000 SNPs from 31,747 men of European ancestry participating in the ongoing international PRACTICAL consortium project.

Using a method developed at UC San Diego, the researchers combined information from GWAS and epidemiological surveys to assess quantification for genetic risk at age of disease onset.

Genotype, prostate cancer status and age were analyzed to select SNPs associated with prostate cancer diagnosis. Then the data was incorporated into the polygenic hazard score, which involves survival analysis to estimate SNPs’ effects on age at diagnosis of aggressive prostate cancer.

The results led to a polygenic hazard score for prostate cancer that can estimate individual genetic risk. This score was then tested against an independent dataset, from the recent UK ProtecT trial, for validation.  

The study authors note that an individual’s genotype does not change with age, so the polygenic hazard score can be calculated at any time and used as a tool for men deciding whether and when to undergo screening for prostate cancer. This is especially critical for men at risk of developing prostate cancer at a very young age, before standard guidelines recommend consideration of screening.

 

Exelixis and Ipsen announce phase III trial results of Cabozantinib in advanced hepatocellular carcinoma

Exelixis Inc. and Ipsen announced detailed results of the pivotal phase III CELESTIAL trial in patients with previously treated advanced hepatocellular carcinoma, which will be presented in a late-breaking oral session at the 2018 ASCO-GI Symposium.

In CELESTIAL, cabozantinib provided a statistically significant and clinically meaningful improvement versus placebo in overall survival, the trial’s primary endpoint, at the planned second interim analysis (pre-specified critical p-value ≤ 0.021) for the population of second- and third-line patients enrolled in this study.

Median OS was 10.2 months with cabozantinib versus 8.0 months with placebo (HR 0.76, 95 percent CI 0.63-0.92; p=0.0049). Median progression-free survival was more than doubled, at 5.2 months with cabozantinib and 1.9 months with placebo (HR 0.44, 95 percent CI 0.36-0.52; p<0.0001).

Objective response rates per RECIST 1.1 were 4 percent with cabozantinib and 0.4 percent with placebo (p=0.0086). Disease control (partial response or stable disease) was achieved by 64 percent of the cabozantinib group compared with 33 percent of the placebo group.

In a subgroup analysis of patients whose only prior therapy for advanced HCC was sorafenib (70 percent of patients in the study), median OS was 11.3 months with cabozantinib versus 7.2 months with placebo (HR 0.70, 95 percent CI 0.55-0.88). Median PFS in the subgroup was 5.5 months with cabozantinib versus 1.9 months with placebo (HR 0.40, 95 percent CI 0.32-0.50). Adverse events were consistent with the known safety profile of cabozantinib.

The most common (≥10 percent) grade III or IV adverse events in the cabozantinib group compared to the placebo group were palmar-plantar erythrodysesthesia (17 percent vs. 0 percent), hypertension (16 percent vs. 2 percent), increased aspartate aminotransferase (12 percent vs. 7 percent), fatigue (10 percent vs. 4 percent), and diarrhea (10 percent vs. 2 percent).

Treatment-related grade V adverse events occurred in six patients in the cabozantinib group (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism and hepatorenal syndrome) and in one patient in the placebo group.

Sixteen percent of patients in the cabozantinib arm and three percent of patients in the placebo arm discontinued treatment due to treatment-related adverse events.

CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries.

The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017.

Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms during the blinded treatment phase of the trial.

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and PFS. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Based on available clinical trial data from various published trials conducted in the second-line setting of advanced HCC, the CELESTIAL trial design assumed a median OS of 8.2 months for the placebo arm.

A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in median OS (HR = 0.76) at the final analysis. Two interim analyses were planned and conducted at approximately 50 percent and 75 percent of the planned 621 events.

At the first interim analysis conducted by the independent data monitoring committee the observed hazard ratio was 0.71 and the p-value was 0.0041, which did not cross the stopping boundary for the first interim analysis (p ≤ 0.0037).

On Oct. 16, 2017, Exelixis announced that the independent data monitoring committee recommended that the trial be stopped for efficacy following review of the second planned interim analysis, as the trial had met its primary endpoint of OS (pre-specified critical p-value ≤ 0.021).

In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC.

Copyright (c) 2018 The Cancer Letter Inc.