NCI May 'Kill' Major Mammography Trial, Says Advisor

Reevaluation Comes After Medscape Report

Nick Mulcahy

September 23, 2020

Earlier this month, an advisory board to the National Cancer Institute (NCI) overwhelmingly voted to form a working group to review the continued funding and running of its largest cancer screening trial. But the lone abstaining board member suggested that the reevaluation was a smoke screen for ending the $100 million Tomosynthesis Mammography Imaging Screening Trial (TMIST).

"We're going to have a working group to kill the trial," Peter Adamson, MD, of Sanofi, commented in an interpretation of the NCI's intent. The randomized trial, which began enrolling women in 2017, is comparing tomosynthesis, or 3-D mammography, with older, less expensive 2-D technology.

The NCI's move to reevaluate TMIST comes 6 months after Medscape Medical News reported that the projected 165,000-women study was lagging in enrollment of both patients and participating sites/physicians.

Enlisting sites is difficult, in part because radiologists ― informed by their experience and previous research results ― already believe that the 3-D technology is superior, commented two TMIST study investigators at that time.

Furthermore, experts who were quoted in the Medscape story said that radiology practice in the United States has substantially transitioned to 3-D and will continue to do so. This point was supported by a review of imaging market data.

At the September virtual meeting of the National Cancer Advisory Board, which was first reported by The Cancer Letter, Philip Castle, PhD, MPH, director of the NCI's Division of Cancer Prevention, said it was "time to reevaluate TMIST's feasibility and relevance."

There is also a need to "examine the utility of TMIST, given the unanticipated challenges due to the pandemic," he said, referring to low accrual of patients in 2020.

TMIST is "a huge budget item," and accrual has been a problem "for years ― essentially since the trial began," added Ned Sharpless, MD, director of the NCI.

Fourteen advisory board members voted in favor of creating the working group to review the trial. The lone abstention, as noted above, was from Adamson, who is global head of oncology development and pediatric innovation at Sanofi and is also professor emeritus, University of Pennsylvania, Philadelphia, Pennsylvania.

Adamson said that he was "not denying the impact" of COVID-19 but speculated that other clinical trials have had the same problem.

He also wondered whether COVID-19 was an "excuse" for bringing TMIST to a "public forum" and objected to the fact that TMIST investigators were not present and had not been invited to offer "an action plan" to remedy their trial's woes.

Castle explained that COVID-19 had reduced TMIST's monthly patient accrual by 50% from March to August compared with recent preceding months. The under-accrual "will likely result in delayed outcomes and escalating costs," Castle said.

However, TMIST was staggeringly behind in accrual even before COVID-19. The trial has averaged less than 1500 women a month over the past 2 years, yet it needed to average 5500 a month to meet accrual goals, Castle noted.

Further, Castle suggested that TMIST's contribution to mammography practice may be negligible, citing three factors: changes in the imaging market, earlier research results, and other ongoing major trials of 3-D mammography.

"[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," Castle said. Even with optimistic accrual projections, study completion and reporting would occur somewhere between 2029 and 2032 ― not in 2025, as originally planned, he added.

Currently, 68% of certified mammography facilities in the United States have one or more 3-D units, and 40% of all units are 3-D, he noted. (However, as previously reported, this latter statistic on total units is likely an undercount because all 3-D units have a built-in 2-D function, but the two components in a single machine are equally counted by the FDA ― even when 3-D is exclusively used.)

Castle also summarized earlier observational and randomized trial data on tomosynthesis mammography: "Evidence is already available suggesting that 3-D is no worse and probably better than 2-D."

Additionally, he reviewed three other European mammography trials involving 3-D technology (in the United Kingdom, Germany, and Norway) and said that they will contribute "additional informative data."

Notably, Adamson did not object to these critical points but said the "approach" taken by the NCI advisory board at this meeting was "incredibly disturbing."

NCI's Castle defended himself, saying "nowhere" in his presentation was there any mention that the trial would be "shut down."

NCI director Sharpless then interjected: "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," he added.

TMIST Investigators Respond

Medscape Medical News reached out to TMIST investigators for comment about the NCI's planned reevaluation ― and what it means.

Etta D. Pisano, MD, the study's principal investigator, accented the positive: "...we have heard nothing of suspending TMIST and are ready to work with NCI to reach TMIST endpoints more efficiently," she wrote in an email.

…we have heard nothing of suspending TMIST. Dr Etta Pisano

She also offered a positive spin on TMIST enrollment and trial site enlistment.

"Enrollment quadrupled and trial sites doubled in the 14 months prior to the COVID-19 pandemic. An unheard of 19% of the 30,000 women enrolled at 99 sites are African American," she observed.

The trial has "momentum," said Pisano, who is also chief research officer at the American College of Radiology.

NCI's Castle, however, noted that enrollment is far behind schedule; the 30,000 women who have been enrolled so far represent less than a quarter of the planned enrollment of 165,000 women, due by the end of 2020.

TMIST is designed to learn whether 3-D mammography is better at finding ― and reducing the rate of ― potentially lethal cancers than older 2-D technology.

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). This allows radiologists to flip through the images like pages in a book and is considered to offer a superior read of the breast.

TMIST uses "advanced" breast cancers as a novel surrogate outcome. The trial period is 4.5 years, during which women are screened annually to determine which imaging technology results in fewer advanced cancers. These include larger HER2-positive and triple-negative malignancies; those associated with positive nodes; and metastatic disease.

These malignancies correlate with breast cancer mortality, Pisano said.

"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," said Mitchell Schnall, MD, PhD, from the University of Pennsylvania. He is co-chair of the ECOG-ACRIN trial group, which is co-running TMIST.

"Look, we all know that 3-D 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 is worth it in terms of better outcomes for each person who has the experience," Schnall told Medscape Medical News.

"One size should not fit all in breast cancer screening, and the TMIST trial can show the way to a precision approach to screening," he said.

But, earlier this year, Daniel Kopans, MD, professor of radiology, Harvard University, Boston, Massachusetts, told Medscape Medical News that TMIST is "huge waste of money."

He believes that "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 [2-D] that they can find on tomosynthesis," said Kopans. He was involved in the development of the first 3-D unit but no longer profits from its sales because his group's patent has expired.

TMIST was conceived before 3-D mammogram took off clinically, which may explain the trial's enrollment and site participation woes. 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 to embrace the newer technology.

Nick Mulcahy is an award-winning senior journalist for Medscape. He previously freelanced for HealthDay and MedPageToday and had bylines in WashingtonPost.com, MSNBC, and Yahoo. Email: nmulcahy@medscape.net and on Twitter: @MulcahyNick.

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September 24, 2020 ― Editor's note: The headline of this story has been slightly changed for clarity. Also, an earlier version of this story misspelled Dr Philip Castle's name and mislisted his degrees.

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