Technological advances signal shift toward individualized breast cancer screening

The debate about the value of mammography, long considered the gold standard for breast cancer detection, has raged for years.

The controversy intensified in 2014 in light of several new studies that offered conflicting conclusions about the benefits and risks of the screening method.

A study by Miller and colleagues — who analyzed 25-year follow-up data from a randomized screening trial conducted in Canada — showed women aged 40 to 59 years who underwent annual mammograms experienced similar breast cancer mortality as those who underwent physical examination or usual care (HR=0.99; 95% CI, 0.88-1.12). The results, published in February in BMJ, also revealed one of every five breast cancers detected during mammography was overdiagnosed, meaning they would not have caused symptoms or posed a threat during patients’ lifetimes.

Seven months later, a paper by Helvie and colleagues — who analyzed SEER data to assess changes in breast cancer diagnoses in the mammography era — revealed a 37% decrease in late-stage breast cancers from the late 1970s through 2009. The results, published in September in Cancer, also showed a reciprocal increase in early-stage breast cancers during that period.

These reports have added to the already-voluminous literature proponents and skeptics cite to tout mammography’s advantages and imperfections.

“Mammography is not a perfect screening tool and it does have limitations, particularly in women with dense breast tissue,” Sandhya Pruthi, MD, associate professor of medicine and past director of the Breast Diagnostic Clinic at Mayo Clinic in Rochester, Minn., told HemOnc Today. “This is where newer technologies come into play, as they are giving us a better ability to evaluate dense breast tissue.”

These technologies include tomosynthesis, multiparametric ¹⁸fluorodeoxyglucose PET MRI (¹⁸FDG PET-MRI) and multimodality imaging. All have demonstrated the ability to better distinguish malignant and benign breast tumors, study results show.

“With the newer 3-D technology, there are not only less patient callbacks and better detection of cancers, but also less anxiety for patents,” Pruthi said. “Consequently, this is a very exciting time.”

HemOnc Today spoke with several clinicians about these recent technological advances, the potential they have to improve the specificity and sensitivity of breast cancer screening, and the ways in which they could complement — or possibly replace — traditional mammography.

Tomosynthesis: ‘A useful adjunct’

One approach rapidly gaining acceptance is tomosynthesis.

During the tomosynthesis acquisition — which the FDA approved in 2011 for use in combination with digital mammography — an imaging machine takes multiple low-dose X-rays as it moves across the breast in an arc. A computer algorithm generates 1-mm-thick slices through the entire breast from the X-rays. The approach minimizes the influence of overlapping breast structures, making invasive cancers more conspicuous.

Single-institution studies suggest the addition of tomosynthesis to mammography can increase detection rates and reduce false-positives, leading some experts to suggest the technology eventually will replace the current standard of 2-D digital mammography.

“Traditional mammography is largely criticized for having false-positive results, which require patients to be called back for additional unnecessary imaging and biopsies, all of which causes anxiety and increases medical costs,” Sarah M. Friedewald, MD, section chief of breast imaging and co-medical director of Caldwell Breast Center at Advocate Lutheran General Hospital in Park Ridge, Ill., told HemOnc Today. “Also, it’s not a perfect test, as it does not identify all cancers.”

Friedewald and colleagues conducted a retrospective analysis of screening performance metrics from 13 breast centers in the United States to determine if the addition of tomosynthesis to traditional 2-D mammography improved performance of breast screening. The analysis included more 454,850 exams with either digital mammography plus tomosynthesis (n=173,663) or digital mammography alone (n=281,187).

The results, published in June in JAMA, showed the addition of tomosynthesis to digital mammography was associated with a lower rate of patient recalls and a higher cancer detection rate (see Table).

Researchers reported the same in situ cancer detection rate of 1.4 (95% CI, 1.2-1.6) per 1,000 screens in both groups. However, the addition of tomosynthesis to digital mammography was associated with a higher positive predictive value for recall (6.4% vs. 4.3%; difference, 2.1%; 95% CI, 1.7-2.5) and biopsy (29.2% vs. 24.2%; difference, 5%; 95% CI, 3-7).

“When we added 3-D mammography to standard digital 2-D mammography, we received more information. We found more invasive cancers while at the same time called fewer people back for unnecessary additional testing,” Friedewald said. “Our study looked at the patient population as a whole that was imaged with tomosynthesis. We didn’t evaluate individual characteristics of patients. Moving forward, we would like to look at patient age and breast density to determine if there are subpopulations that would benefit more with tomosynthesis, or if all groups benefit. This will help us guide screening.”

In a separate study, Julieanne S. Greenberg, MD, a radiologist with Washington Radiology Associates in Washington, D.C., and colleagues compared the clinical performance of 2-D digital mammography vs. that of combined 2-D and 3-D digital breast tomosynthesis. The analysis included more than 59,000 patients screened at a community-based radiology practice.

Results, published in June in the American Journal of Roentgenology, showed the addition of tomosynthesis to screening increased the overall cancer detection rate by 28.6% and increased detection of invasive cancers by 43.8%. The 3-D approach also reduced recall rates by 16.1%.

“Our results may be a bellwether for the impact of tomosynthesis on population-based breast cancer screening,” Greenberg said in a press release.

Although the number of centers that use tomosynthesis is on the rise, it is not reimbursed. It also is associated with greater radiation exposure than standard digital mammography, according to William J. Gradishar, MD, FACP, professor of medicine in the division of hematology and medical oncology at Northwestern University’s Feinberg School of Medicine.

“The problem with a lot of the imaging used right now is that some have more radiation risk, and other tests are showing more things when imaged,” said Gradishar, a HemOnc Today Editorial Board member. “The question then becomes whether you can distinguish from those things what is concerning and what is not. There is a typical sequence of events that occur when identifying something suspicious. There is a downstream effect.”

Tomosynthesis is a particularly good option for women with denser breasts, as well as those who have undergone breast surgery, according to Adam M. Brufsky, MD, PhD, FACP, professor of medicine, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh.

“The problem that some people have with tomosynthesis is the increased radiation exposure, but I personally do not think the extra radiation exposure is bad,” Brufsky, a HemOnc Today Editorial Board member, said in an interview. “[Tomosynthesis] is a useful adjunct to traditional digital mammography, and I think people should consider it very strongly.”

Combination imaging

Benign breast tumors detected with traditional screening methods often mimicked malignant tumors, so biopsies were necessary to make the final determination.

However, newer technologies are better able to characterize tumors detected during screening, so a substantial number of biopsies can be avoided, according to Katja Pinker-Domenig, MD, associate professor of radiology in the department of biomedical imaging and image-guided therapy at the Medical University of Vienna.

Pinker-Domenig and colleagues conducted a feasibility study to assess whether multiparametric ¹⁸FDG PET-MRI using dynamic contrast-enhanced MRI, diffusion-weighted imaging, 3-D proton MR spectroscopic imaging and ¹⁸FDG-PET improved differentiation of benign and malignant breast tumors.

The analysis included 76 women (mean age, 55.7 years) with imaging-detected abnormalities. Researchers determined 53 of the breast lesions were malignant and 23 were benign.

Results showed multiparametric ¹⁸FDG PET-MRI yielded a significantly higher area under the curve (AUC) than dynamic contrast-enhanced MRI (0.935 vs. 0.86; P=.044). Researchers also determined multiparametric ¹⁸FDG PET-MRI showed slight further improvement to multiparametric MRI with three parameters (AUC, 0.925; P=.317), and that use of multiparametric ¹⁸FDG PET-MRI would have reduced unnecessary breast biopsies recommended by multiparametric imaging with one or two parameters (P=.002 to .011).

“We are getting farther down the path of personalized medicine, where we have the ability to tailor therapy and diagnostics according to our patients’ needs,” Pinker-Domenig told HemOnc Today. “Not every cancer is the same. Breast cancer in one woman is not the same in another woman, and we can get a better understanding of this with these newer screening methods.”

Pinker-Domenig and colleagues acknowledged that performing a combined PET-MRI is less cost-effective than existing breast imaging methods. Yet, the potential of the combined method to significantly reduce unnecessary breast biopsies may improve cost-effectiveness, she said.

The capabilities of these new approaches also are likely to improve, she said.

“There is so much development going on in terms of software and hardware with imaging,” Pinker-Domenig said. “There are other parameters popping up that will make screening even more specific than it already is.”

‘Rapid’ MRI

Data have long supported the effectiveness of screening with annual MRI in select women.

A study published in July in Journal of Clinical Oncology suggested screening with annual MRI combined with mammography can be an important management option for women at high risk for breast cancer, such as those who harbor BRCA mutations.

Chiarelli and colleagues reviewed data on 2,207 women in the Ontario Breast Screening Program. The analysis included women with known mutations in BRCA or another gene associated with marked increased risk for breast cancer; untended first-degree relatives of gene mutation carriers; women whose family history was consistent with hereditary breast cancer syndrome or a ≥25% estimated lifetime breast cancer risk; and those who underwent radiation to the chest prior to age 30 years and at least 8 years prior to study enrollment.

Results showed recall rates of 4.7% (95% CI, 3.9-5.5) among women with abnormal mammogram and MRI; 6.4% (95% CI, 5.5-7.3) among women with abnormal mammography alone; and 15.1% (95% CI, 13.8-16.4) among women who had abnormal MRI alone.

Overall, screening detected 35 breast cancers (16.3 per 1,000; 95% CI, 11.2-22.2). Of these cancers, 23 (10.7 per 10,000; 95% CI, 6.7-15.8) were detected by MRI alone; 12 (5.8 per 1,000; 95% CI, 3-10) were detected by combined mammogram and MRI; and none were detected by mammogram alone.

Kuhl and colleagues conducted a prospective, observational study to evaluate the effectiveness of an abbreviated breast MRI screening protocol.

The cohort included 443 women at mild to moderate increased risk for breast cancer who underwent a combined 606 screening MRIs. All women had normal or benign digital mammograms, and the women with heterogeneously dense or extremely dense breasts (n=427) also had normal or benign ultrasounds.

The abbreviated protocol consisted of one pre- and one post-contrast acquisition and their derived images.

Study results showed MRI acquisition times were 17 minutes for the full diagnostic protocol vs. 3 minutes for the abbreviated protocol. Researchers also reported greater specificity (94.3% vs. 93.9%) and positive predictive value (24.4% vs. 23.4%) with the abbreviated protocol. The abbreviated protocol also resulted in an additional cancer yield of 18.2 per 1,000 screens.

“This is another interesting way to go with breast cancer screening — conduct a rapid MRI to look at dense breast tissue,” Pruthi said. “With this technique, the patient doesn’t have radiation exposure, as MRI uses magnetic energy, not X-ray.”

Mammography ‘still the standard’

In January 2013, the Swiss Medical Board — an independent entity created in Switzerland to improve health through research and training — was directed to conduct a review of mammography screening.

The panel — which consisted of a medical ethicist, clinical epidemiologist, clinical pharmacologist, oncologic surgeon, nurse scientist, lawyer and health economist — reviewed available data on mammography and recommended systematic screening programs be replaced with “systematic screening information” and that women be encouraged to make individual choices.

“It is easy to promote mammography screening if the majority of women believe that it prevents or reduces the risk of getting breast cancer and saves many lives through early detection of aggressive tumors. We would be in favor of mammography screening if these beliefs were valid. Unfortunately, they are not, and we believe that women need to be told so,” two panel members — Nikola Biller-Andorno, MD, PhD, of the Institute of Biomedical Ethics at the University of Zurich, and Peter Jüni, MD, of the Institute of Social and Preventive Medicine and Clinical Trials Unit Bern — wrote in an online essay published in April in The New England Journal of Medicine.

“From an ethical perspective, a public health program that does not clearly produce more benefits than harms is hard to justify,” Biller-Andorno and Jüni wrote. “Providing clear, unbiased information, promoting appropriate care, and preventing overdiagnosis and overtreatment would be a better choice.”

Despite the debate about mammography in the United States and the favorable outcomes shown with other modalities, the clinicians who spoke with HemOnc Today said they expect mammography will remain a key component of breast cancer screening for the foreseeable future.

“By catching the breast cancer early, we improve prognosis and women do better with their surgical options, as well,” Pruthi said.

Brufsky agreed.

“When used properly, mammograms do not do more harm than good,” Brufsky said. “It is like any other test that we have. The only real harm of a mammogram is the worry on the woman’s part about being diagnosed with a false-positive result, or about having an abnormality on a mammogram that requires them to undergo a biopsy. It is more psychological harm associated with the concerns about getting breast cancer.”

Many questions also remain unanswered about other screening approaches.

“There are all kinds of issues with respect to what the increased or decreased exposure to radiation is depending upon the technique used,” Gradishar said. “Also, are we finding more things than we really need to know about, and then subsequently pursuing them? Either way, mammography is still the standard, and it will be the standard to which other screening tests are compared.”

Although the science is not yet settled, each study offers new insights that provide the oncology community with greater understanding of the benefits and limitations of mammography, as well as the other screening approaches in development.

“We have to sit down with our patients and explain to them that there are limitations to each test and it’s not potentially for everyone,” Brufsky said. “The time it takes to sit the patient down and have a thorough discussion is the actual problem a lot of us have given our busy practices. I think this is the real issue with mammograms.”

Yet, those discussions — paired with a better understanding of the new methodologies under evaluation — could lead to more personalized screening approaches.

“MRIs, while a fabulous technology, are very expensive and create a lot of false-positives,” Brufsky said. “We may integrate MRI at some frequency, especially if it becomes cheaper. We may conduct tomosynthesis every year and then conduct an MRI every 5 years. We will never get to the point where we completely abandon screening with mammography, but I do think we will get to the point of individualizing screening much more based upon each woman’s risk and her desires.” – by Jennifer Southall

References:

Biller-Andorno N. N Engl J Med. 2014;370:1965-1967.

Chiarelli AM. J Clin Oncol. 2014;32:2224-2230.

Friedewald SM. JAMA. 2014;311:2499-2507.

Greenberg JS. AJR Am J Roentgenol. 2014;203:687-693.

Helvie MA. Cancer. 2014;120:2649-2656.

Kuhl CK. J Clin Oncol. 2014;32:2304-2310.

Miller AB. BMJ. 2014;348:g366.

Morris EA. J Clin Oncol. 2014;32:2281-2283.

Pinker K. Clin Cancer Res. 2014;20:3540-3549.

For more information:

Adam M. Brufsky, MD, PhD, FACP, can be reached at University of Pittsburgh, 300 Halket St., Suite 4628, Pittsburgh, PA 15213; email: brufskyam@upmc.edu.

Sarah M. Friedewald, MD, can be reached at Advocate Lutheran General Hospital, 1775 Dempster St., Park Ridge, IL 60068; email: sarah.friedewald@advocatehealth.com.

William J. Gradishar, MD, FACP, can be reached at Northwestern University Feinberg School of Medicine, NMH/Arkes Family Pavilion, 676 N. Saint Clair St., Suite 850, Chicago, IL 60611; email: w-gradishar@northwestern.edu.

Katja Pinker-Domenig, MD, can be reached at Medical University of Vienna, Spitalgasse 23, 1090 Wien, Austria; email: katja.pinker-domenig@meduniwien.ac.at.

Sandhya Pruthi, MD, can be reached at Mayo Clinic, 200 1st St. SW, c/o Gonda Building, Breast Diagnostic Clinic, Rochester, MN 55905; email: pruthi.sandhya@mayo.edu.

Disclosure: Brufsky, Friedewald, Gradishar, Pinker-Domenig and Pruthi report no relevant financial disclosures.

 

Should use of screening MRI be limited to women at high risk for breast cancer?

Yes. All women who are at high risk for developing breast cancer should receive breast MRI as an adjunct to yearly mammography.

Breast MRI has been found to be the most sensitive imaging modality for breast cancer detection, ranging between 90% and 98%. When combined with screening mammography, which is the only screening tool to show a mortality benefit, sensitivity is even greater.

High-risk patients have been defined by the American Cancer Society as individuals with a 20% to 25% or greater lifetime risk for breast cancer; those who have a BRCA1 or BRCA2 mutation; those who have not been tested but who have a first-degree relative with a mutation; women with one of three very specific syndromes; and women who underwent chest radiation treatment between the ages of 10 and 30 years.

Breast MRI is, however, associated with a higher false-positive rate. Therefore, prior to initiating a combined mammography/MRI screening program, the patient should be educated about the greater likelihood for callback and biopsy so she can determine whether this is acceptable for her.

The higher false-positive rate of breast MRI and the expense are the two primary reasons that the American Cancer Society, the Society of Breast Imaging and the American College of Radiology all recommend against screening MRI for women with a lifetime risk for breast cancer of less than 15%. There is ongoing research in the United States and Europe with the goal of offering a different kind of screening breast MRI that is less expensive and provides increased specificity, potentially more relevant as a screening tool for all.

 

Jessica Kuehn-Hajder, MD, is assistant professor of radiology in the division of breast imaging and the department of radiology at the University of Minnesota. She can be reached at Diagnostic Radiology, MMC 292, 420 Delaware St. SE, Minneapolis, MN 55455; email: jhajder@gmail.com. Disclosure: Kuehn-Hajder reports no relevant financial disclosures.

MRI using new fast protocols could be used for screening all women, regardless of risk.

In the current form of MRI screening — a 30-minute to 40-minute examination that costs thousands of dollars — MRI is not appropriate as a screening test for women at normal risk. There is a small risk associated with gadolinium, it is a very expensive test, and it is not available to everyone in more rural areas or in areas of lower socioeconomic status. Further, the data have not shown that those risks outweigh the benefits for normal-risk women. In addition, the false-positive rates are too high with this methodology.

Having said that, we know that MRI is the most sensitive test we have for identifying invasive breast cancer. If we could find a way to perform MRI at a lower cost and lower risk, do it in less time and reduce the harm, it really could be an alternative to mammography in women at normal or intermediate risk for breast cancer.

There is an excellent study from Germany that demonstrates that screening MRI in low- and intermediate-risk women identifies more than 18 cancers per 1,000 women. In that study, the cancers were primarily invasive cancers, nuclear grade 2 or 3, and were less than 1 cm in size. These likely are the cancers that we miss with screening mammography (Kuhl CK. J Clin Oncol. 2014;32:2304-2310).

We could consider offering it to women at intermediate risk to start. These women probably are underserved by mammography alone, especially if they have dense breasts. In order to detect those cancers that impact patient morbidity and mortality that mammography has traditionally missed, novel methods such as fast MRI are very important to consider as we move forward. Some progressive centers in the United States already are offering this examination.

Margarita L. Zuley, MD, is professor of radiology at the University of Pittsburgh and chief of breast imaging at Magee-Womens Hospital of UPMC. She can be reached at Magee-Womens Hospital of UPMC, 300 Halket St., Pittsburgh, PA 15213; email: zuleyml@upmc.edu. Disclosure: Zuley reports no relevant financial disclosures.