Risk-based screening misses breast cancers in women in their forties

A study of breast cancers detected with screening mammography found that strong family history and dense breast tissue were commonly absent in women between the ages of 40 and 49 diagnosed with breast cancer. Results of the study were presented today at the annual meeting of the Radiological Society of North America (RSNA).

"Screening recommendations for this age group continue to be debated," said Bonnie N. Joe, M.D., Ph.D., associate professor in residence and chief of women's imaging at University of California, San Francisco (UCSF). "Recent publications have suggested risk-based screening based on family history and breast density. However, our study shows that this approach would miss a significant percentage of invasive cancers and could potentially be dangerous."

The retrospective study, conducted at UCSF, included 136 women between the ages of 40 and 49 with breast cancer identified by screening mammography between 1997 and 2012. Symptomatic patients undergoing diagnostic mammography and those with a personal history of breast cancer were excluded from the study. Patient family history, breast density, type of malignancy, lymph node status, and tumor receptor status were recorded.

"Notably, we found that almost 90 percent of the invasive cancers we would have missed using risk-based triage had positive receptor status, meaning they were very treatable and worth finding early," Dr. Joe said.

Of the 136 breast cancer cases identified, 50 percent were diagnosed as invasive, and 50 percent were diagnosed as ductal carcinoma in situ (DCIS), an early noninvasive form of breast cancer, although 88 percent of DCIS cases were intermediate or high grade.

A very strong family history was absent in 90 percent of patients, and extremely dense breast tissue was absent in 86 percent. Seventy-eight percent of patients had neither strong family history nor extremely dense breasts, including 79 percent of the cases of invasive disease.

"Our results show that by exclusively using a risk-based approach to screening mammography, we could potentially miss more than 75 percent of breast cancers in women in their 40s, thereby eliminating most of the survival benefit from screening mammography that has been previously shown in randomized controlled trials," Dr. Joe said.

Dr. Joe urges proponents of risk-based screening to continue research to find more effective means of risk-based triage.

"Neither family history nor breast density in combination or alone are sufficient risk factors to safely triage patients in risk-based screening," she explained.

Routine annual screening mammography has traditionally been recommended by organizations such as the American Cancer Society (ACS) and the American Medical Association (AMA) for all women beginning at age 40. In 2009, the United States Preventive Services Task Force (USPSTF) issued controversial new guidelines recommending screening with mammography every two years beginning at age 50.

"Based on our current knowledge and evidence shown in previous trials, it is still safest to get annual mammograms starting at age 40 in order to maximize the survival benefit of screening mammography," Dr. Joe said.

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3-D mammography improves cancer detection in dense breasts

A malignancy easily missed on 2-D mammography was clearly seen on 3-D mammography.

A major new study being presented at the annual meeting of the Radiological Society of North America (RSNA) has found that digital breast tomosynthesis, also known as 3-D mammography, has the potential to significantly increase the cancer detection rate in mammography screening of women with dense breasts.

Breasts are considered dense if they have a lot of fibrous or glandular tissue but not much fatty tissue. Research has shown that dense breasts are more likely to develop cancer, a problem compounded by the fact that cancer in dense breasts can be difficult to detect on mammograms.

Other imaging modalities like ultrasound and MRI are often used to help find cancers that can't be seen on mammograms, but both modalities have higher rates of false-positive findings, which are suspicious findings that turn out not to be cancer. This higher false-positive rate often results in more tests and unnecessary biopsies, making MRI and ultrasound expensive to implement in high-volume screening programs, according to study lead author Per Skaane, M.D., Ph.D., from the Department of Radiology at Oslo University Hospital in Oslo, Norway.

Dr. Skaane and colleagues have been studying tomosynthesis as a promising breast cancer screening option that addresses some of the limitations of mammography by providing 3-D views of the breast.

"Tomosynthesis could be regarded as an improvement of mammography and would be much easier than MRI or ultrasound to implement in organized screening programs," Dr. Skaane said. "So the intention of our study was to see if tomosynthesis really would significantly increase the cancer detection rate in a population-based mammography screening program."

The researchers compared cancer detection using full-field digital mammography (FFDM) versus FFDM plus digital breast tomosynthesis in 25,547 women between the ages of 50 and 69. Breast density was classified based on the American College of Radiology's Breast Imaging-Reporting and Data System (BI-RADS). The BI-RADS breast density scale runs from 1 to 4, with 1 being the least dense and 4 being the most dense.

There were 257 malignancies detected on FFDM and a combination of FFDM and tomosynthesis in the study group, including 105 in the density 2 group and 110 in density 3. Of the 257 cancers, 211, or 82 percent were detected with FFDM plus tomosynthesis, a significant improvement over the 163, or 63 percent, detected with FFDM alone.

FFDM plus tomosynthesis pinpointed 80 percent of the 132 cancer cases in women with dense breasts, compared to only 59 percent for FFDM alone.

"Our findings are extremely promising, showing an overall relative increase in the cancer detection rate of about 30 percent," Dr. Skaane said. "Stratifying the results on invasive cancers only, the relative increase in cancer detection was about 40 percent."

Tomosynthesis not only improved the cancer detection rate in women with dense breasts, it also helped increase detection for women in the "fatty breast" BI-RADS categories. The addition of tomosynthesis to FFDM improved the cancer detection rate from 68 percent to 84 percent in women with BI-RADS density 1 or 2 breasts.

"Our results show that implementation of tomosynthesis might indicate a new era in breast cancer screening," Dr. Skaane said.

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Triple-negative breast cancer patients should undergo genetic screening

Most patients with triple-negative breast cancer should undergo genetic testing for mutations in known breast cancer predisposition genes, including BRCA1 and BRCA2, a Mayo Clinic-led study has found. The findings come from the largest analysis to date of genetic mutations in this aggressive form of breast cancer. The results of the research appear in the Journal of Clinical Oncology.

"Clinicians need to think hard about screening all their triple-negative patients for mutations because there is a lot of value in learning that information, both in terms of the risk of recurrence to the individual and the risk to family members. In addition, there may be very specific therapeutic benefits of knowing if you have a mutation in a particular gene," says Fergus Couch, Ph.D., professor of laboratory medicine and pathology at Mayo Clinic and lead author of the study.

The study found that almost 15 percent of triple-negative breast cancer patients had deleterious (harmful) mutations in predisposition genes. The vast majority of these mutations appeared in genes involved in the repair of DNA damage, suggesting that the origins of triple-negative breast cancer may be different from other forms of the disease. The study also provides evidence in support of the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing of triple-negative breast cancer patients.

Triple-negative breast cancer is a specific subset of breast cancer that makes up about 12 to 15 percent of all cases. The disease is difficult to treat because the tumors are missing the estrogen, progesterone and HER-2 receptors that are the target of the most common and most effective forms of therapy. However, recent studies have suggested that triple-negative breast cancer patients might harbor genetic mutations that make them more likely to respond to alternative treatments like cisplatin, a chemotherapy agent, or PARP inhibitors, anti-cancer agents that inhibit the poly (ADP-ribose) polymerase (PARP) family of enzymes.

Dr. Couch and his colleagues decided to assess the frequency of mutations in predisposition genes in patients with triple-negative breast cancer to further delineate the role of genetic screening for individuals with the disease. The researchers sequenced DNA from 1,824 triple-negative breast cancer cases seen at 12 oncology clinics in the U.S. and Europe, as part of the Triple-Negative Breast Cancer Consortium.

They found deleterious mutations in almost 15 percent of triple-negative breast cancer patients. Of these, 11 percent had mutations in the BRCA1 and BRCA2 genes and the rest had mutations in 15 other predisposition genes, including the DNA repair genes PALB2, BARD1, and RAD51C. No mutations were found in predisposition genes involved in other processes like the cell cycle.

"Triple-negative breast cancers are different from all the other breast cancers," says Dr. Couch. "Other studies have suggested that this form of the disease might be associated with some defect in DNA repair, and our study verifies that. Our findings generate a whole new set of hypotheses about how triple-negative breast cancer might be arising, which could give us better ideas for prevention or new therapies for this disease."

The study also found that individuals with mutations in predisposition genes were diagnosed at an earlier age and had higher-grade tumors than those without mutations. The researchers used their dataset to assess whether the current screening guidelines would identify all the triple-negative individuals with mutations in the two most common predisposition genes, BRCA1 and BRCA2.

They found that the NCCN guidelines, which recommend screening when there is a family history of cancer or a diagnosis under age 60, missed only 1 percent of patients carrying mutations. In contrast, the UK's National Institute for Clinical Excellence (NICE) guidelines, which use the probability of actually finding a mutation to determine who should be tested, missed 24 percent of mutation carriers.

"Our results confirm that the NCCN guidelines are good, and provide evidence to support what they have recommended," says Dr. Couch. "But we think the NICE guidelines could be expanded to include more of the triple-negative breast cancer patients with mutations."

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Breast cancer vaccine shows promise in small clinical trial

A breast cancer vaccine developed at Washington University School of Medicine in St. Louis is safe in patients with metastatic breast cancer, results of an early clinical trial indicate. Preliminary evidence also suggests that the vaccine primed the patients' immune systems to attack tumor cells and helped slow the cancer's progression.

The study appears Dec. 1 in Clinical Cancer Research.

The new vaccine causes the body's immune system to home in on a protein called mammaglobin-A, found almost exclusively in breast tissue. The protein's role in healthy tissue is unclear, but breast tumors express it at abnormally high levels, past research has shown.

"Being able to target mammaglobin is exciting because it is expressed broadly in up to 80 percent of breast cancers, but not at meaningful levels in other tissues," said breast cancer surgeon and senior author William E. Gillanders, MD, professor of surgery. "In theory, this means we could treat a large number of breast cancer patients with potentially fewer side effects.

"It's also exciting to see this work progress from identifying the importance of mammaglobin-A, to designing a therapeutic agent, manufacturing it and giving it to patients, all by investigators at Washington University," he added.

The vaccine primes a type of white blood cell, part of the body's adaptive immune system, to seek out and destroy cells with the mammaglobin-A protein. In the smaller proportion of breast cancer patients whose tumors do not produce mammaglobin-A, this vaccine would not be effective.

In the new study, 14 patients with metastatic breast cancer that expressed mammaglobin-A were vaccinated. The Phase 1 trial was designed mainly to assess the vaccine's safety. According to the authors, patients experienced few side effects, reporting eight events classified as mild or moderate, including rash, tenderness at the vaccination site and mild flu-like symptoms. No severe or life-threatening side effects occurred.

Although the trial was designed to test vaccine safety, preliminary evidence indicated the vaccine slowed the cancer's progression, even in patients who tend to have less potent immune systems because of their advanced disease and exposure to chemotherapy.

"Despite the weakened immune systems in these patients, we did observe a biologic response to the vaccine while analyzing immune cells in their blood samples," said Gillanders, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. "That's very encouraging. We also saw preliminary evidence of improved outcome, with modestly longer progression-free survival."

Of the 14 patients who received the vaccine, about half showed no progression of their cancer one year after receiving the vaccine. In a similar control group of 12 patients who were not vaccinated, about one-fifth showed no cancer progression at the one-year follow-up. Despite the small sample size, this difference is statistically significant.

Based on results of this study, Gillanders and his colleagues are planning a larger clinical trial to test the vaccine in newly diagnosed breast cancer patients, who, in theory, should have more robust immune systems than patients who already have undergone extensive cancer therapy.

"If we give the vaccine to patients at the beginning of treatment, the immune systems should not be compromised like in patients with metastatic disease," Gillanders said. "We also will be able to do more informative immune monitoring than we did in this preliminary trial. Now that we have good evidence that the vaccine is safe, we think testing it in newly diagnosed patients will give us a better idea of the effectiveness of the therapy."

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