A matter of technology, guidance and individualized risk

Mammography has long been the mainstay of breast cancer screening and has been credited with early detection of disease and decreased mortality.

However, mammography also has given rise to widespread debate, lack of consensus among professional medical societies and potential confusion for patients.

“The debate centers on several reports that have come out from different groups with varying recommendations,” Julie A. Margenthaler, MD, FACS, president-elect of the American Society of Breast Surgeons (ASBrS), professor of surgery in the section of endocrine and oncologic surgery at Washington University School of Medicine in St. Louis and surgeon at Siteman Cancer Center, said in an interview with HemOnc Today.

The longstanding debate again took off in 2016 when the U.S. Preventive Services Task Force reaffirmed their recommendation that women start annual mammography at age 50 years, whereas ASBrS guidelines recommend annual mammograms starting at age 40 years for average-risk women, Margenthaler said.

“What is really needed, though, is for all women to undergo a risk assessment, because there are many women who are at higher risk who need to have more tailored imaging programs,” she said.

Another area of uncertainty pertains to the value of digital breast tomosynthesis compared with 2D digital mammography in catching life-threatening cancers. Although the technology has increased cancer detection and recall rates, some studies suggest this hasn’t corresponded with an increase in detection of aggressive cancers, which may imply some cancers are being overdiagnosed.

HemOnc Today spoke with breast cancer experts about the differences among the breast cancer screening guidelines and the need for individualized recommendations, whether the introduction of digital mammography has contributed to overdiagnosis, the difference between 2D and 3D mammography, and how the COVID-19 pandemic may lead to early-stage cancers going undetected in the absence of screening.

Inconsistent recommendations

The biggest discrepancies among medical societies’ guidelines for mammography are related to age of initiation and frequency of screening.

American Cancer Society (ACS) guidelines stipulate that women aged 40 to 44 years should have the option to undergo annual mammography, but the guidance does not conclusively recommend yearly mammograms until age 45 years. After age 55 years, these guidelines state that a woman can switch to an every-other-year mammography schedule or continue annual screening.

In a joint recommendation, American College of Radiology (ACR) and Society for Breast Imaging (SBI) endorsed annual screenings beginning at age 40 years for women at average risk, specifying that women should undergo a risk assessment at age 30 years to determine whether earlier screening is needed. Women who have been diagnosed with breast cancer should be screened thereafter with MRI, the guidelines state.

The ACR/SBI guidelines also make special provisions for Black women, who are at higher risk for breast cancer mortality, triple-negative breast cancer, harboring BRCA mutations and having advanced disease at diagnosis. The guidelines recommend that all women, but especially those who are Black or of Ashkenazi Jewish descent, undergo a risk assessment by age 30 years to identify those at higher risk who can benefit from supplemental screening.

ASBrS recommends annual screening mammography beginning at age 40 years for all average-risk women after a formal risk assessment.

Although the USPSTF guidelines do not recommend screening mammography for women aged 40 to 49 years, they state that “the decision to start regular, biennial screening mammography before age 50 years should be an individual one and should take into account patient context, including the patient’s values regarding specific benefits and harms.”

According to Margenthaler, the USPSTF guidelines do not dispute the potential for early detection when mammography is initiated at a younger age.

“Even if you go back to the USPSTF report where they recommend starting mammography at age 50, it isn’t that they believed that women aged 40 to 50 years didn’t benefit from identification,” Margenthaler said. “They just didn’t feel it was a cost-effective strategy.”

Margenthaler maintained that by initiating mammograms at age 40 years, women have a better chance of being spared more intensive, costly treatments and retaining their ability to function at home and at work.

“This enables women in their 40s to save those really productive years, from the standpoint of motherhood and work,” Margenthaler said. “To me, that is something that is really neglected in that [USPSTF] report.”

According to results of a study conducted in the U.K., beginning annual breast cancer screening at age 40 or 41 years yielded a decrease in breast cancer mortality without adding significantly to overdiagnosis.

In that study, an update of the UK Age trial, researchers randomly assigned women aged 39 to 41 years to annual mammography (intervention arm, n = 53,883) or to standard of care, which was no screening until the National Health Service-recommended age of 50 years (control group n = 106,953; see article).

After 10 years of follow-up, Duffy and colleagues found a significant decrease in breast cancer mortality with earlier screening, with 83 deaths in the intervention arm vs. 219 in the control arm (RR = 0.75; 95% CI, 0.58-0.97).

However, this study is unlikely to resolve the debate over when to initiate breast cancer screening, Anthony B. Miller, MD, professor emeritus at Dalla Lana School of Public Health at University of Toronto, wrote in a related editorial.

“It could be argued that breast screening with mammography should not be initiated at any age, but rather women should be encouraged to practice breast awareness, with mammography used as a diagnostic test, while always remembering that in young women, mammography can be negative even in the presence of physically detectable breast cancer,” Miller wrote.

Each professional society’s guidelines can be linked to a quantifiable reduction in breast cancer mortality, according to Dana H. Smetherman, MD, MPH, MBA, FACR, chair of the ACR Commission on Breast Imaging.

She said when women follow the guidelines set forth by ACR/SBI and ASBrS, both of which advise initiating mammograms at age 40 years, there is an approximate 40% decrease in the risk for dying of breast cancer.

“Almost 12,000 women’s lives are saved per 100,000,” Smetherman told HemOnc Today. “If we follow a regimen where women have yearly mammograms from age 45 to 54 years and then every other year from 55 to 79 years, per ACS guidelines, the reduction of mortality risk drops to 31% and the number of women whose lives are saved per 100,000 drops to a little over 9,000.”

Using the USPSTF guidelines, the reduction in the risk for breast cancer death would drop to the low-20% range, Smetherman said.

“Then many fewer lives are saved per 100,000,” Smetherman told HemOnc Today. “You really do get a much bigger impact, both in the risk for dying of breast cancer and in the number of women whose lives are saved [with earlier screening].”

Impact on women

Beyond creating confusion for women, the differing screening guidelines also lead to various rates of false positives and unnecessary recalls.

Although ACS does not recommend mammography screening until age 45 years, women often prefer to begin annual mammography at around age 40 years, according to Robert Smith, PhD, senior vice president for cancer screening at ACS.

“We get the impression that most women favor annual screening, and they favor beginning screening right after the age of 40 [years],” he told HemOnc Today. “Regardless of how a doctor who refers women to mammography feels about the guidelines, they tend to be fairly responsive to what their patients want.”

Smith said although the USPSTF guidelines acknowledge that more lives are saved when women are screened beginning at age 40 years, the task force also argues that beginning screening at this age can lead to undue alarm for women.

“The USPSTF argues that, yes, you save more lives, but you don’t save that many more, and what you do is cause an awful lot of recall for additional imaging, which is stress-inducing,” he said. “Women might end up going to get a biopsy that turns out to be a false finding. There also will be overdiagnosis, which means women will be diagnosed with a cancer that is nonprogressive.”

Smith called this argument “speculative” and added that these guidelines are informed by the highest estimates of overdiagnosis.

“There’s a broad range of overdiagnosis estimates, and the [USPSTF guidelines] tend to embrace the higher rate,” he said. “The only way you can estimate overdiagnosis is by comparing a group that underwent screening over a long period of time and then was followed long-term with a group that did not undergo screening during that period. If there is excess breast cancer incidence at the end of that long period, that is basically an indicator that you wouldn’t have known about some of those cancers if you hadn’t undergone screening.”

Smith added that as stressful as they are, false positives or unnecessary recalls do not seem to dissuade women from having regular screenings. He emphasized that not all erroneous mammogram findings are the fault of the technology.

“We have a broad range of interpretive skills in this country. Mostly, radiologists reading mammograms are not specialists,” Smith said. “We could improve our recall rate to something close to the rate in Europe. You could argue that they recall too few women, but there is a point between their level and ours that is probably ideal.”

Given that each woman has a different risk for breast cancer, blanket guidelines may not be the ideal solution. Increasingly, emphasis has been placed on understanding a woman’s individual risk for breast cancer rather than relying on a “one-size-fits-all” age requirement.

To this end, the randomized WISDOM study is currently enrolling women aged 40 to 74 years in order to compare a risk-based, or personalized, screening approach with conventional annual breast cancer screening. The study seeks to enroll 100,000 women from across the country and has enrolled almost 30,000 women to date, according to the WISDOM website.

Participants in the study will be randomly assigned to undergo annual mammography or personalized screening based on factors such as family history, genetics, lifestyle and environment. If appropriate, they may be offered genetic counseling or testing.

Women will receive an initial risk assessment followed by annual assessments for 5 years thereafter.

Margenthaler said she is very much in favor of individualized risk assessment for all women aged 25 to 30 years.

“Breast surgeons are very much advocates for risk assessment,” she said. “You can individualize how women should be screened and whether they should have supplemental screening.”

That risk assessment needs to be reassessed on a regular basis, Smith added.

“The 25-year-old with no family history may have a mother diagnosed with breast cancer at age 46 the following year,” he said.

The digital difference

After receiving FDA approval in 2000, digital mammography held great promise as a means of decreasing unnecessary callbacks and reducing interval cancer diagnoses.

However, results of a study published in June showed the small increase in cancer detection provided by digital mammography did not equal a reduction in the rate of interval cancers.

“Interval cancers are representative of cancers that are fast-progressing and have become clinically detectable,” study author Rachel Farber, MPH, of the faculty of medicine and health in the School of Public Health at University of Sydney in Australia, said in an interview with HemOnc Today when the study was published. “If the increase in detection rate has increased the clinical utility of screening, then we would hope to see a subsequent decrease in the interval cancer rate. This would suggest that some of the additional screen-detected cancers were clinically important and otherwise would have rapidly progressed if left undetected.”

In the systematic review and meta-analysis, Farber and colleagues identified 24 studies with 16,583,743 screening examinations (film mammograms, n = 10,968,843; digital mammograms, n = 5,614,900), seven of which assessed interval cancer detection.

They found that the rate of cancer detection increased by 0.51 (95% CI, 0.19-0.83) per 1,000 screens and the recall rate increased by 6.95 (95% CI, 3.47-10.42) per 1,000 screens with digital vs. film mammography. A greater relative increase was seen in the detection rate for ductal carcinoma in situ (25.2%; 95% CI, 17.4-33.5) vs. invasive cancers (4%; 95% CI, 3-13).

Among the studies that reported interval cancers, researchers observed no change in the interval cancer rate per 1,000 screens following the switch to digital mammography (0.02; 95% CI, 0.06 to 0.03).

“The big issue is that we in America have tremendous difficulty with the concept that there is something that occurs in peoples’ breasts, prostates and lungs that, when biopsied, looks like cancer, but is not destined to grow, spread and kill,” Otis W. Brawley, MD, MACP, FASCO, FACE, Bloomberg Distinguished Professor of Oncology and Epidemiology at Johns Hopkins University and co-author of an editorial published alongside the Farber study, said in an interview with HemOnc Today at the time of the study’s publication. “That’s what we call overdiagnosis.”

Two types of digital mammography are in widespread use: conventional full-field digital mammography, which yields flat-plane, 2D breast images; and digital breast tomosynthesis, also known as 3D mammography. This newer type of mammography captures both 2D and 3D images of the breast.

“Digital 2D mammography storage is great; I can’t tell you how often we used to lose the film mammogram,” Brawley said. “Now, because it’s a file on someone’s hard drive or is saved to the cloud, we don’t lose it. It can be emailed for second opinions — that’s a great advantage.”

With 2D mammography, Smith said, compression of the breast can create overlapping tissue, which may appear as a mass.

“When you look at it through the 3D view, you have an opportunity to see that what you thought was a mass on the 2D view just isn’t there,” he said. “So that reduces the rate of recall.”

However, Brawley said the “new is better” mindset around digital mammography — specifically 3D mammography — not only may induce unnecessary panic but also can lead to unanticipated out-of-pocket expenses.

“There are women who go into mammography clinics and the person at the front desk offers them 3D mammography for $70 extra,” Brawley said. “If the patient doesn’t want to pay an out-of-pocket upcharge, the implication is that they don’t care about their health. This happens all the time. I keep hearing about women being shamed into paying for the 3D mammogram because [they’re told] it’s better.”

Brawley said he questions whether 3D mammography is better than 2D.

“In fact, it might yield results that aren’t useful to the patient in particular,” he said. “Medicine, like anything else, is a business and if I buy a new, great 3D mammography machine, I have to use it or defer the mortgage off of it.”

A study published in JAMA Network Open compared the screening capability of digital breast tomosynthesis vs. digital mammography in community practice based on patient age, screening round and breast density.

In the study, Lowry and colleagues assessed more than 1.5 million breast cancer screening examinations of women aged 40 to 79 years. They found that 3D mammography conferred the most benefit among women undergoing their initial screening mammogram. This demographic showed the greatest improvement in recall reduction (204 vs. 241 examinations per 1,000; RR = 0.84; 95% CI, 0.73-0.98) and cancer detection (8.8 vs. 5.9 per 1,000; RR = 1.5; 95% CI, 1.1-2.08) with digital breast tomosynthesis.

On later screenings, the differences varied by age and breast density subgroups. Recall rates appeared lower with 3D mammography for women with scattered fibroglandular density and heterogeneously dense breasts in all age groups, and cancer detection appeared consistently higher for women with heterogeneously dense breasts. However, women with extremely dense breasts did not show improvements with 3D mammography in the number of cancers detected or how many recalls occurred.

According to Smith, 2D and 3D mammography have value in detecting cancer in women with dense breasts.

“We know very clearly that it somewhat improves the detection rate in women with dense breasts,” he said. “It does not overcome extreme mammographic breast density, but from the beginning, we’ve seen an improvement.”

A large trial — Tomosynthesis Mammographic Imaging Screening Trial, or TMIST — seeks to compare 2D digital mammography with digital breast tomosynthesis. The study, which is supported by the NCI, aims to enroll 165,000 healthy women aged 45 to 74 years at 150 sites around world.

Smith, who is chair of the TMIST advisory committee, said the study should be revealing in terms of the overall diagnostic benefit of 3D mammography in detecting invasive cancers.

“People are excited about it,” he said. “The question we have to ask ourselves is, are we actually finding the same cancers with 3D as we’re finding with 2D, or is 3D picking up something that’s not so important to pick up and missing something that is important to pick up? That’s what this study is trying to observe, so we don’t just find ourselves enamored with the statistics.”

The impact of COVID-19

As it has been in all areas of medicine, the COVID-19 pandemic has been a disruptive force for mammography screening centers and patients.

Kevin S. Hughes, MD, FACS, breast surgeon and co-director of Avon Comprehensive Breast Evaluation Center at Massachusetts General Hospital, conducted a study on the impact of the pandemic on cancer screening and treatment.

He and colleagues evaluated data from a risk-assessment company gathered between Feb. 2 and April 11 from 55 breast imaging centers in 27 states. The use of risk assessment served as a proxy for the use of three breast cancer services: breast imaging, breast surgery and genetics consultation.

The results, published in Cancer, showed a steep decline in mammography, Hughes told HemOnc Today.

“We found that the number of mammograms done at these centers, which we estimated based on the number of risk assessments done at the centers, dropped about 95% in March of this year, pretty much at the same time the COVID problems began,” he said. “We would extrapolate that this is most likely a drop in screening mammography, that diagnostic mammography probably didn’t drop as much.”

Additionally, breast surgery decreased weekly by an average of 20.5%, according to the study. During the week of April 5, the use of genetics consultations dropped to 39.9% of the average weekly volumes prior to the pandemic.

“Genetic testing dropped because of the nonurgency of genetic testing or counseling, but these tests also can be done by phone and by mail,” Hughes said. “The genetic testing companies send a saliva kit to their home, and they send back a sample. So, the pick-up in telehealth probably softened the drop in genetic testing.”

Hughes said the decreases in breast cancer screening and treatment are creating delays in the detection of cancers. Additionally, patients with defined problems such as a lump or discharge may be afraid to come in for a consultation.

“I think we’re affecting the patients who have symptomatic cancers, as well,” he said.

The pandemic has created a backlog of patients who were not identified by screening, Hughes said, adding that as screening resumes, there will need to be adjustments to the way in which clinics handle their patient flow.

“There will probably be anywhere from 1 to 3 months’ worth of screening mammography that was not done,” he said. “That’s anywhere between 10% to 30% of the mammograms that should have been done each year. It’s not going to come back to normal immediately.”

According to Smith, centers also are not equipped to reopen in a way that stratifies patients by risk. He said facilities are not able to open to full volume, because they have had to ensure a more deliberate process of cleansing after each patient and maintaining distance.

“That’s something everybody is waking up to; we don’t have the systems in place that allow us to ensure the protection of higher-risk women over lower-risk women when we reopen,” he said. “There’s no doubt we’re going to see the effect of this. We just don’t know how serious that will turn out to be.” –

References:

American Cancer Society recommendations for the early detection of breast cancer. Available at: www.cancer.org/cancer/breast-cancer/screening-tests-and-early-detection/american-cancer-society-recommendations-for-the-early-detection-of-breast-cancer.html. Accessed Aug. 31, 2020.

The American Society of Breast Surgeons. Position statement on screening mammography. Available at: www.breastsurgeons.org/docs/statements/Position-Statement-on-Screening-Mammography.pdf. Accessed Aug. 31, 2020.

Duffy SW et al. Lancet Oncol.2020;doi:10.1016/S1470-2045(20)30398-3.

Farber R, et al. J Natl Cancer Inst. 2020;doi:10.1093/jnci/djaa080.

Lowry KP, et al. JAMA Netw Open. 2020;doi:10.1001/jamanetworkopen.2020.11792.

Miller AB. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30428-9.

Monticciolo DL, et al. J Am Coll Radiol. 2018;doi:10.1016/j.jacr.2017.11.034.

Siu AL, et al. Ann Intern Med. 2016;doi:10.7326/M15-2886.

WISDOM study. Available at: www.thewisdomstudy.org/. Accessed Aug. 31, 2020.

Yin K, et al. Cancer. 2020;doi:10.1002/cncr.33113.

For more information:

Otis W. Brawley, MD, MACP, FASCO, FACE, can be reached at 1550 Orleans St., Suite 1M16, Baltimore, MD 21287; email: [email protected].

Rachel Farber, MPH, can be reached at Camperdown NSW 2006, Australia; email: [email protected].

Kevin S. Hughes, MD, FACS, can be reached at 55 Fruit St., Boston, MA 02114; email: [email protected].

Julie A. Margenthaler, MD, FACS, can be reached at 4921 Parkview Place Floor 5, Suite: F, St. Louis, MO 63110; email: [email protected].

Dana H. Smetherman, MD, MPH, MBA, FACR, can be reached at 601 Jefferson Highway, Jefferson, LA 70121.

Robert Smith, PhD, can be reached at 250 Williams St. NW, Atlanta, GA 30303; email: [email protected].