Hard Times for America's $100M Breast Cancer Screening Trial

Nick Mulcahy

February 13, 2020

Keren Sturtz, MD, is a believer in the largest-ever breast cancer screening trial, the Tomosynthesis Mammography Imaging Screening Trial (TMIST). The new trial is designed to learn whether tomosynthesis, also known as 3-D mammography, is better at finding ― and reducing the rate of ― potentially lethal cancers than older 2-D technology. The goal is to enroll 165,000 healthy women — at a pricetag of $100 million.

Sturtz, a practicing medical oncologist in Denver, Colorado, is used to getting fellow clinicians on board for research. As the physician head of a regional NCORP (National Community Oncology Research Project), she does the unsung work of enlisting community-based physicians into dozens of federally supported clinical trials.

Sturtz made a special effort for TMIST, which also aims to clarify which women benefit most from screening and at what time intervals. "I picked up the phone and cold-called radiologists at 26 hospitals…. It was a lot of work," she told Medscape Medical News. Every hospital said no.

Clinical trials often have struggles, especially with enrolling patients, and that's the case with TMIST. But the trial has another, more unusual obstacle: Doctors don't want to sign up, either. Sturtz is one of several physicians involved with the trial who told Medscape Medical News that TMIST is not easily garnering radiologists.

Sturtz says numerous hospitals declined to participate because their radiology departments had already swapped out 2-Ds for 3-Ds. "That's another way of saying they have already made up their minds [about which was the superior mammogram]," she said.

Peter Rubin, MD, a medical oncologist practicing in Portland, Maine, and physician head of an NCORP in that state, has met with enough resistance from radiologists about joining TMIST that he headed to Twitter in October to publicly solicit advice from peers about what to do. Even among those centers that currently use both 3-D and 2-D technology, he says in a Tweet, "radiologists don't feel there is equipoise ― ie 3-D has proven itself" to be superior to 2-D. And if that's the case, the study design is flawed, because a randomized trial cannot ethically assign patients to an inferior intervention.

TMIST is "huge waste of money," argued Daniel Kopans, MD, professor of radiology, Harvard University, Boston, Massachusetts, in an email to Medscape Medical News. "Radiologists who are experienced in using [3-D] for screening will not go back," Kopans said. "It would be malpractice since they know there are cancers that they will miss on [2-D] that they can find on tomosynthesis."

Kopans, who helped develop the first 3-D unit but no longer profits from its sales because his group's patent has expired, cites positive findings in tomosynthesis clinical trials. "Every study (hundreds of thousands of women) has shown that [3-D] detects more small (curable) invasive cancers than [2-D] while having the major advantage of reducing recalls from screening, which addresses a major concern for those who want to limit access to screening."

TMIST principal investigator Etta Pisano, MD, is unfazed. Some US radiologists believe 3-D is better, she concedes.

But better at what? asks Pisano, chief research officer, the American College of Radiology. She agrees that 3-D has been shown in trials to be more accurate in detecting breast cancers and at reducing undesirable callbacks. But she points out it has never been shown in the modern era of mammography that breast cancer screening reduces disease-related mortality.

"The question," Pisano said, "is not can we find more cancers, can we reduce call backs…. The question we are asking is, are we saving lives?"

The Rapid Rise of 3-D Mammogram

Planning for TMIST began in 2012, just 1 year after the US Food and Drug Administration (FDA) approved the first 3-D machine, according to a spokesperson for ECOG-ACRIN, the clinical trials group co-running the trial. At that point, tomosynthesis had just 3% of the mammography market, with fewer than 500 units in the United States, according to data from Hologic, one of four providers of 3-D units.

During a screening, most 3-D systems are used in conjunction with 2-D. First, two static images of the breast are taken (2-D), and then the unit moves in an arc, taking multiple images of the breast (3-D). Thus, 3-D is widely described as allowing clinicians to flip through the images like "pages in a book" and as offering a superior read of the breast.

TMIST study designers wanted to measure whether tomosynthesis saved lives, but using breast cancer death as the primary outcome would have necessitated a trial length of at least 20 years, Pisano observes. So TMIST used "advanced" cancers as a novel surrogate outcome. The plan is that over the course of 4.5 years, women will be screened annually to determine which imaging technology results in fewer advanced cancers, which include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease. These malignancies correlate with breast cancer mortality, Pisano explains.

TMIST was conceived before 3-D mammogram took off clinically. However, in the lag time between the initial trial design (2012) and study start date (2017), clinical practice in the United States and Canada shifted quickly. As of this November, 68% of all US mammography facilities had at least one 3-D unit. Currently, the technology accounts for 40% of the total number of accredited mammography units in the United States. And the 3-D market share has increased annually: 3D accounted for 24% of units in 2016, 30% in 2017, 35% in 2018, and 39% in 2019.

However, this accounting may understate the change that is occurring and may overrepresent 2-D units in use. That's because all 3-D units have a built-in 2-D function. The two components in a single machine are equally counted by the FDA ― even when 3-D is exclusively used, according to the American College of Radiology, which is now accrediting units on behalf of the FDA.

Given market trends, "3-D will probably be universally used" when TMIST is completed in 2030, predicts John Lewin, MD, radiologist, the Women's Imaging Center, Denver. His is the lone community practice enrolling patients in TMIST in Sturtz's clinical trials region, which includes Colorado, Washington, Utah, Alaska, and Montana.

Lewin, a former academic at the University of Colorado, supports the study but notes a drawback: that a surrogate endpoint for breast cancer mortality (ie, a reduction in advanced cancers) would still not yield level-I evidence of a mortality benefit. "This trial is not really going to show that 3-D saves lives," he observed, but it will provide a "deeper endpoint" than the number of cancers detected, as in, for example, the OSLO I and II trials.

So although TMIST may further show that the benefits of 3-D are valuable, Lewin says, he is doubtful that the landmark effort will have a landmark impact, because practice will already have largely changed by the study's end. "It's hard to do these trials. By the time you are done with them, technology has moved on and people have moved on," he said.

When told by Medscape Medical News about Lewin's comments, investigator Pisano said, "I don't have a crystal ball, so he may be right."

But she also doubts Lewin's vision.

Pisano highlights the fact that 9 years after the first approval, 3-D machines represent 40% of the market, citing the above-mentioned FDA data, "not 100%," she said. She also spotlights the cost of 3-D as an inhibitor of market change.

3-D costs about $50 more per screening than 2-D, which amounts to a lot of money across a large population that is screened annually, Pisano points out. Data from 2017 show that about 33 million screening mammographies are performed in the United States each. If physicians use 3-D screening exclusively, that's $1.65 billion in extra cost annually.

"This is an important study to figure out if our health system really does need to replace all breast imaging systems with tomosynthesis," she said.

It's also an important study for further establishing the safety of 3-D mammography, says Dawn Hershman, MD, director of breast oncology, Columbia University Medical Center, New York City.

"Sometimes we go down the wrong path because we think we know the answer to something but we don't," she told Medscape Medical News.

The practice of oncology has a history of employing new treatments and technologies before evidence of safety and efficacy are well established in clinical trials ― sometimes with tragic results, Hershman reminded. She cited recent data on poorer survival with minimally invasive surgery for cervical cancer.

Safety may be an issue with the 3-D mammogram, which uses x-ray, takes a few extra seconds than conventional 2-D, and thus is more toxic ― although not by much, observes Hershman, who is enrolled as a patient participant in the trial.The radiation is also within levels allowed by the FDA, say experts.

"Little Bit of a Hard Sell"

Originally, the trial planned on having 100 study sites in the United States and Canada. In a 2019 interview, Pisano suggested that the United States offered an abundant and sufficient pool of potential sites. "There are hundreds if not thousands of imaging sites nationwide, with state-of-the-art equipment and the infrastructure in place to take part," she said.

However, the study site number has since been increased to 150, because the trial has been slow to sign up women. TMIST organizers have been forced to look for participants beyond North America. Pisano says the study has now expanded to Asia and Europe and has one site in South America.

Currently, it has enrolled 22,838 women aged 45–74 years, after recruiting for more than 2½ years (since mid-2017), according to the National Cancer Institute.

Thus the trial must accrue another 142,161 women in the next 5½ years to meet its goal by the enrollment close date of 2025.

"They are having a hard time filling it," said Lewin. Still, his practice is providing a small, steady stream of enrollees – about 10 women a month.

They are having a hard time filling it. Dr John Lewin

Hershman offers TMIST to women who see her for breast cancer prevention. But she observes that the mushrooming availability of 3-D in the United States ― and related promotion from centers ― makes it increasingly difficult to find patients and radiologists who embrace the older 2-D technology. "It's a little bit of a hard sell," she admitted.

Both Hershman and Lewin wonder: what's the motivation for patients to join the study if a majority of mammography facilities already offer 3-D and a lot of insurance plans will pay for it? "That's a problem with the trial ― you can get 3-D off study, so there is no incentive to be on the study," said Lewin. He noted that unless their insurance covers it, women in the study have to pay for their mammogram.

Money is a barrier for hospitals and professionals, as well: While phoning potential study sites in the Western United States, Sturtz heard complaints about the study's low reimbursement rates. Some radiologists wanted to join the study, she says, but their hospital administrators nixed the idea for financial reasons.

Asked to address this issue, Pisano issued a statement: "The per-patient reimbursement may be lower than much smaller studies. However, the number of people to take part in TMIST dwarfs that of most treatment or industry-sponsored studies. Reimbursement volume, over time, can more than pay for the cost of taking part ― including a research assistant devoted to TMIST."

Pisano is confident the dual jobs of site accrual and patient enrollment will get done once enough hospitals and clinics get on board: "TMIST is the largest randomized breast cancer screening study ever conducted. Given the sheer size of the trial, the initial focus is to ensure that site accrual progresses first. Patient enrollment will follow. We...are confident that we will reach the 150 site mark by the end of 2020. We expect to reach the patient enrollment goal by 2025."

Currently, the trial has 105 sites.

The move to widen the trial's reach by moving overseas was surprising but was seen as good news to study observers. The TMIST study "will have a chance of succeeding if they are including sites from other countries that have less 3-D," said Hershman. She also heads up an NCORP in New York City, but she is not a TMIST investigator.

Hershman added that a patient's enrollment in any clinical trial is "highly related to the person who is recruiting them" and to that clinician's enthusiasm.

"This is a trial," she said, "that needs everyone's effort to meet its accrual goals."

TMIST has multiple objectives, points out Hershman. It is stratifying some women on the basis of risk (such as breast density and family history) for further screening assessment at 1- and 2-year intervals, with the goal of personalizing the intervention, she says.

The trial is also creating a repository of blood and oral swab specimens, which, along with participant genetic data, with the goal of, again, individualizing or optimizing screening strategies by tying molecular data to clinical outcomes in the trial.

"The great hope for this trial is that it will be able to answer a lot more than 3-D vs 2-D because it may help researchers develop models for who should be getting what and how often," noted Hershman.

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