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Dr. Ruth Etzioni has received a seven-year Outstanding Investigator Award (OIA) from the National Cancer Institute so the Fred Hutchinson Cancer Center biostatistician and holder of the Rosalie and Harold Rea Brown Endowed Chair can pursue “Modeling and Analytics for Novel Cancer Diagnostics.”
The award, which comes with around $7.4 million in funding, will allow Etzioni and her team to build frameworks and tools to evaluate novel cancer diagnostics such as new nuclear imaging modalities and multi-cancer early detection tests, commonly referred to as liquid biopsies.
“The rapid pace at which new technologies are entering the marketplace makes rigorous evaluation via controlled studies infeasible for all but a few,” she said. “This means that while we typically have some data about diagnostic test performance, we frequently lack evidence regarding the outcomes that drive clinical and policy decisions.”
Etzioni plans to tackle this “data-evidence divide” by using modeling and analytics, tools she has honed over several decades investigating the benefits and harms of various types of cancer screening.
“Lab-developed tests can be marketed before they’re approved by the FDA [U.S. Food and Drug Administration],” she said. “There are some out there now and another dozen waiting in the wings. I’m hoping to help people understand whether these new tests are going to fulfill their promise.”
New tests still need the same old rigor
Etzioni said cancer diagnostics are in a revolutionary growth phase, with new technologies capable of detecting cancers from fragments of circulating DNA and stage disease through novel imaging agents and imaging tests that can detect whether a cancer has spread.
“The problem is, for many of these new technologies, we don’t know if they are making patients’ lives better,” she said. “They haven’t been evaluated with controlled studies to determine the true harms and benefits.”
Only last June, the NCI endorsed a $75 million, four-year pilot study to assess the efficacy of some of these new liquid biopsies. This will likely be followed with a much larger clinical trial to demonstrate that the tests actually save lives.
But that still leaves public health researchers like Etzioni, whose evaluations and insights are folded into national cancer screening guidelines, scrambling to catch up.
Numerous companies have created liquid biopsy tests including (but not limited to) Singlera Genomics, Guardant Health, Epic Sciences, Exact Sciences, Adela and Foundation Medicine. For around $950, consumers can buy a liquid biopsy test from GRAIL that claims to detect cancer signals from more than 50 cancers.
Other companies have created bespoke tests, such as Epic Sciences’ DefineMBC, designed to assess the relevant biology of metastatic breast cancer tumors from a single blood draw.
Blood tests for lung cancer, breast cancer, liver cancer and many others are available now or in the works and analysts predict the market will continue to grow at a “formidable rate.” According to a report by market research and consulting firm Vision Research Reports published in April, the market for liquid biopsies is expected to grow from less than $33.5 million in 2020 to around $7.96 billion by 2030. Analysts cite the country’s increasing cancer cases (blame the silver tsunami) and the public’s desire to avoid invasive biopsy procedures.
Etzioni is excited about the possibilities of liquid biopsies but worries the hype about the tests has already gotten ahead of the science.
“I’m hoping we can create a path forward using in-depth cancer modeling with real-world analytics to accelerate the evaluation of these novel cancer diagnostics,” she said. “Who wouldn’t want to get their cancer detected with just a drop of blood? But the history of cancer screening tells us that early detection is more complicated than we might think.”
You have cancer, but where?
The new grant will allow Etzioni to study many types of novel diagnostic tests used for a variety of cancers. But her application will focus on two types of new tests that are of great interest right now: liquid biopsies or multi-cancer early detection (MCED tests) and prostate-specific membrane antigen or PSMA-PET imaging for prostate cancer.
With regard to MCED tests, Etzioni said there are different types, with some that look for one or two specific cancers and others that test for more than 50 types of cancer.
“They’re picking up cell-free genetic material in the blood,” she said. “And some can pick up methylation signatures that are very tissue specific so you can tell what type of cancer it is. But it is a mix. Some tests are more accurate than others. Some give you choices of the first most likely cancer and the second most likely cancer.”
In addition to researching the accuracy of these tests, Etzioni will also consider what happens when someone receives a positive result. Should they get an actual tissue biopsy? A CT or PET scan? An ultrasound? Surgery?
Etzioni said a clinical pathway needs to be established to confirm the cancers detected via the new liquid biopsies.
“It’s really about making good decisions around these tests, both from the patient and the provider perspective,” she said. “We also need to know how these tests should be used alongside existing screening practices and what we can expect from these tests in terms of impact on cancer stage and mortality.”
And there are other questions that need to be sorted, such as which cancers should be included in these tests and how to help consumers know which test is right for them, especially with a potentially dizzying array of options.
“You can have sensitivity and specificity to detect cancer — but if it’s a very rare cancer, it’s not going to translate to a large number of lives saved,” she said. “And then there’s the big question of whether the insurance companies will pay for the test and subsequent imaging and treatment.”
TESTING THE TESTS
Fred Hutch’s Dr. Ruth Etzioni will use her Outstanding Investigator Award to look at new diagnostic technologies. She hopes to:
- Investigate risk prediction biomarkers (both pre- and post-diagnosis) in order to translate them into risk groups and treatment policies
- Explore at what point precision diagnostics can be most effective in terms of value, cost and benefit
- Study the patterns of new diagnostic technology dissemination and access by race/ethnicity, geography and insurance status
- Once the tests are adopted, link any changes in cancer incidence, stage and mortality in the NCI’s SEER cancer registry
Precision imaging for prostate cancer
Etzioni will also evaluate the benefits, harms and cost-effectiveness of another tool, a PSMA-PET scan that can now be used to discern the best treatment for prostate cancer patients.
PSMA-PET scans use an FDA-approved radioactive imaging agent such as 68Ga-PSMA-11 that binds to PSMA proteins, which are overexpressed in prostate cancer tumors. The PET scan picks up the concentrated PSMA tracer, pinpointing these tumors for more effective treatment.
Data from a previous study of this type of PET showed the new tracer capable of identifying metastatic prostate cancer lesions. In fact, many cancers were upstaged after its use, indicating a need for an escalation of treatment.
“Unfortunately, we don’t know yet whether these changes in therapy are extending survival or whether it’s overtreating these patients,” she said.
In collaboration with other investigators in the Prostate Cancer Research Program and the University of Washington’s Department of Nuclear Medicine, Etzioni plans to build a framework for supporting clinical decision-making around the use of PSMA-PET.
“We need to know how standard treatment approaches should be modified given the test results,” she said. “And we also need to know how to adapt our treatment pathways to properly integrate novel markers of risk.”
An outstanding investigator
Etzioni is a member of three national panels on prostate cancer early detection and serves on the American Cancer Society’s Screening Guideline Development Panel. She is also an American Statistical Association Fellow.
The Outstanding Investigator Award, according to the NCI, provides long-term support to accomplished investigators with outstanding records of cancer research productivity who propose to conduct exceptional research. The award is intended to give investigators the opportunity to take greater risks, be more adventurous in their lines of inquiry or take the time necessary to develop new techniques.
Etzioni hopes to use this award to expand her knowledge of cancer imaging and radiology, machine learning for image classification and liquid-biopsy-based prediction, and biomedical informatics so that “we can learn about how these tests are being used in real-world clinical settings.”
“I really want to educate the public about these tests and about what they need to know about new cancer tests in general,” she said. “The revolution in cancer diagnostics raises a host of new questions that we have never confronted before.”
Eventually, Etzioni wants to create a go-to resource in this space that researchers, patients, providers and the public can use to understand how to navigate their diagnostic test options, whether it’s deciding how to screen or biopsy or treat their cancer.
Also essential, making sure these emerging technologies are used equitably.
“Creating access to a large body of clinical data from which we can ascertain who is getting access to these technologies and their clinical outcomes will be a priority so that we can understand how they are impacting not only disease but also health costs and health disparities,” she said.
Etzioni said she’s also acutely aware of the connection between cancer diagnostics and precision oncology and hopes to bring Fred Hutch researchers working in diagnostic medicine across the center to develop fruitful collaborations that will support the institution’s precision oncology focus.
“If you want to have precision oncology, you’ve got to have diagnostics,” she said. “You need biomarkers and imaging to tell you who and how to treat and who and how to screen. We have outstanding investigators here working in radiology, nuclear medicine, liquid biopsy test development, pathology and data science. Together, we can move the field forward, not only by growing new technologies, but by learning how we use them optimally to improve cancer outcomes.”
