NCI is reviewing whether it should continue with TMIST, its largest cancer screening trial

NCI questions continuation of $100 million 3D mammography trial

September 28, 2020
by John R. Fischer, Senior Reporter
The National Cancer Institute is reviewing whether it should continue with a $100 million 3D mammography trial that has been underway since 2017.

The agency’s National Cancer Advisory Board voted almost unanimously this month to form a working group to reevaluate whether it should keep funding and running its largest cancer screening study, the Tomosynthesis Mammography Imaging Screening Trial (TMIST). Dr. Peter Adamson, the lone board member who abstained, sees the reevaluation as a “smoke screen” for ending the trial, reported Medscape Medical News.

"We're going to have a working group to kill the trial," Adamson, global head of oncology development and pediatric innovation for pharmaceutical manufacturer Sanofi and professor emeritus at the University of Pennsylvania, told the publication.

Beginning in 2017, the purpose of TMIST is to investigate whether 3D mammography results in fewer advanced cancers than older, less expensive 2D technology. The trial, however, has come under criticism for its failure to enroll enough patients and participating sites and physicians. Initially projected to be a 165,000-woman study, the trial has accrued less than 1,500 women a month over the past two years, far below the average 5,500 it needed per month to meet its objective.

TMIST investigators in the past have said that recruiting patients and physicians is difficult due to radiologists already viewing 3D mammography as superior, based on their experience and prior research. Advisory board member Dr. Phillip Castle, MPH, director of the NCI's Division of Cancer Prevention, said that even with optimistic accrual projections, completing and reporting the study would need to be pushed back from its original planned date of 2025 to sometime between 2029 and 2032.

While he did not mention canceling the study during the virtual meeting, he asserted that changes in the imaging market, earlier research results and other ongoing major trials in 3D mammography might make TMIST’s contribution to mammography negligible, reported Medscape Medical News.

"[The] relevance of the [TMIST] data by the completion of the trial is uncertain because of 3-D market ... penetrance by the conclusion of the trial," he said, adding that monthly patient accrual for TMIST dropped by 50% from March to August due to the onset of COVID-19 and would “likely result in delayed outcomes and escalating costs.”

While Adamson does not deny the impact of COVID-19 on TMIST, he asserts that other clinical trials have encountered the same issue, and questions if the pandemic was used as an “excuse” for creating a public forum about TMIST. He also objected to TMIST investigators not being invited to present an “action plan” for increasing recruitment.

Dr. Etta D. Pisano, the principal investigator of the trial and chief research officer at the American College of Radiology, says she and her colleagues have heard nothing about ending TMIST. She says the primary goal of TMIST has often been "misportrayed" and is prepared to work with NCI to meet the objectives laid out for TMIST.

"It is not to determine whether digital breast tomosynthesis finds more cancers than standard 2-D digital mammography, but whether the newer technology may help reduce breast cancer deaths by finding more of the types of advanced cancers likely to kill women," she told HCB News, adding that there are several factors that set TMIST apart from earlier, technology-focused studies. "TMIST will develop the world's largest biorepository for women undergoing cancer screening and study the genetic basis of the development of breast cancer. Another important output of the trial may be more scientifically-based recommendations for personalized screening strategies, which is likely why the study has appealed to women who are not ideally served by current age-based screening strategies."

Enrollment for the trial quadrupled and sites where it was conducted doubled in the 14 months prior to the pandemic, according to Pisano. In addition, an unheard-of 19% of the 30,000 women enrolled at 99 sites were African-American, a population of people that carries higher risks of mortality when it comes to certain cancers.

One or more 3D mammography units are used by certified mammography facilities in the U.S., with 40% of all units being 3D. This is probably an understated figure, as all 3D units have a built-in 2D function. The FDA, however, equally counts both components in a single machine, even when 3D is used exclusively, according to Medscape Medical News.

The initial design of the trial was made in 2012, before 3D mammography rose in popularity, which may be a reason for its enrollment and site participation issues. The trial period for TMIST, which uses “advanced” breast cancers as novel surrogate outcomes, is 4.5 years. Women are screened annually to determine which imaging scanner results in fewer advanced cancers. They include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease, all of which correlate with breast cancer mortality, according to Pisano.

Mitchell Schnall, co-chair of the ECOG-ACRIN trial group, told HCB News that the trial is essential to improving the process of identifying high-risk patients and learning how to better utilize both technologies. “One size should not fit all in breast cancer screening, and the TMIST trial can show the way to a precision approach to screening. Look, we all know that 3D sees more lesions, but consequently, more women are having additional procedures, including biopsies and excisions. The question that TMIST asks is whether that huge expenditure of time, money, and psychological stress are worth it in terms of better outcomes for each person who has the experience. We need this trial to help us learn how to improve the process for identifying high-risk patients and how to utilize both of these technologies better."

Dr. Daniel Kpans, professor of radiology at Harvard University, who was involved with developing the first 3D unit, told Medscape Medical News earlier this year that TMIST was a “huge waste of money. Radiologists who are experienced in using [3-D] for screening will not go back. It would be malpractice since they know there are cancers that they will miss on 2D that they can find on tomosynthesis.”

NCI director Dr. Ned Sharpless also weighed in on the issues surrounding TMIST during the meeting. "There is no easy way to do this. TMIST is the most troubled of our trials [in prevention and screening] from an accrual point of view.”