By Colleen Austin, M.D. and Lynn Baxter, M.D.
From ATLANTA Medicine, 2012, Women’s Health, Vol. 83, No. 1
The diagnosis and management of breast cancer has evolved dramatically since the declaration of the War On Cancer 40 years ago and especially during the past decade. In addition to the developments in diagnosis and treatment, there has been a major paradigm shift in our understanding of the disease such that we increasingly focus on the intrinsic molecular subsets of breast cancer rather than viewing the disease as one entity.
There are over 200,000 cases of breast cancer per year in the United States with 40,000 deaths (1). After an increase in incidence during the 1990’s attributed to the increased use of screening, there has subsequently been a decrease. This has been attributed to the decline in use of hormone replacement therapy in part driven by the results of the Women’s Health Initiative (2). The decrease has largely been in estrogen receptor positive tumors with little decline in the incidence of ER negative malignancy.
During the past decade the mortality from breast cancer has also been declining. This decrease has been attributed to the benefits of screening and adjuvant therapy; thus far treatments for metastatic disease have had little impact on mortality. Unfortunately while having a lower incidence of breast cancer, African American women continue to experience higher mortality from the disease (3).
Risk factors for which adequate evidence exists include age, gender, race, family history, reproductive history, diet and lifestyle, alcohol use, smoking and exposure to radiation. A recent report from the Institute of Medicine extensively reviewed evidence for environmental factors contributing to breast cancer risk. Inadequate data exists for many suspected risks, and a focus on exposures in early prevention should include a healthy diet limiting fat and alcohol, avoiding weight gain especially after menopause, avoiding exposure to cigarette smoke and radiation, and limiting use of hormone therapy.
Germline mutations account for less than 10% of all breast cancer cases. In addition to BRCA 1 and 2 mutations, Li-Fraumeni, Cowden and Chek 2 mutations are important. All are autosomal dominant and include the risk of other malignancies as well. Obviously family history is an important consideration in determining the appropriateness of genetic testing. However referral for genetic testing should be considered in patients 45 or younger regardless of family history, in patients less that 50 with a limited family history and in patients less that 60 with triple negative breast tumors (5).
While there are many types of imaging used to evaluate for breast cancer, mammography is the gold standard. As Dr. Dan Kopans of Harvard likes to point out, it is the only test of any kind ever proven to reduce mortality from breast cancer.
Eight large, randomized controlled trials beginning in the 1960s showed a 20-30% decrease in mortality for women offered mammography (6) — and this was using technology from the 1960s and 70s! Digital mammography is rapidly becoming the new standard. It allows computer manipulation of the images and can reveal fine details not seen on film. Digital imaging has been demonstrated to be superior to film for cancer detection in women with dense breasts and women under age 50 (7). However, digital mammography still has some of the same limitations as film mammography. Things such as dense tissue and implants can obscure underlying cancers, and approximately 10% of patients having screening mammograms are recalled for additional imaging. Most of these patients do not have cancer, and the false positive recalls can be stressful. These limitations have led some people to advise against routine mammography, despite its proven benefits.
Fortunately, new technology is beginning to address these issues. The latest advance in mammographic imaging is digital breast tomosynthesis (also known as 3D mammography). In tomosynthesis, multiple images are obtained in an arc around the breast and then reconstructed in 1 mm slices. This allows radiologists to view the internal structures of the breast unobscured by overlapping tissue. In traditional 2-D mammography, tissue in one part of the breast can be superimposed on tissues from another to mask cancers or create the illusion of a mass. Tomosynthesis can overcome this problem, allowing us to detect more cancers and reduce recall rate. In fact, in studies that have been published so far, the recall rate has decreased by up to 40 % (8).
However, tomosynthesis still has limitations. It cannot find all cancers. For example, lobular cancers that do not create a mass or calcify will not stand out on tomosynthesis. Cancers that are equally dense with surrounding tissue can also be missed. Also, tomosynthesis will not eliminate all recalls. Patients with cancer will still need to be recalled and patients with real but benign lesions such as fibroadenomas will still need additional evaluation to exclude malignancy.
Like 2D mammography, tomosynthesis requires breast compression and radiation. In fact, the standard combination exam of 2D and 3D mammography delivers two to three times the radiation dose of a 2D mammogram. The radiation dose is still extremely low and well within FDA guidelines. The FDA also points out that the marked decrease in recalls for the extra views should offset the additional radiation from the initial exam. The combination exam has been shown to find the most cancers, and calcifications are still best evaluated with 2D digital mammography (9). Therefore, only the combination exam is approved by the FDA.
Another major advance in breast cancer imaging is the use of MRI. MRI has long been the gold standard for evaluating the integrity of silicone implants. It is now also increasingly being utilized to evaluate for breast cancer. MRI uses no compression or radiation, and it not only shows anatomy, but also uses intravenous contrast to evaluate physiologic changes in bloodflow patterns. Invasive cancers alter bloodflow patterns through angiogenesis and other mechanisms. MRI can identify these changes with great sensitivity. In fact, published studies show an almost 100% detection rate for invasive cancers (10). Unfortunately, MRI is not as sensitive for non-invasive cancers, since they do not reliably alter blood flow. In addition, benign lesions such as fibroadenomas, fibrocystic tissue, and papillomas can enhance with patterns that can mimic cancer. Bloodflow patterns can even change during different phases of the menstrual cycle. For these reasons, MRI cannot replace mammography, but is useful as a compliment in many situations.
MRI is now frequently used to evaluate patients with a new breast cancer diagnosis. It identifies additional unsuspected cancers in the ipsilateral breast in up to 1/3 of patients and finds unsuspected contralateral cancers in 4 to 6 percent of patients. It can find primary tumors in 90 percent to 100 percent of patients whose cancer is initially detected in an axillary lymph node (11). It is also useful for following patients on chemotherapy since its physiologic evaluation of blood flow can show a response earlier than anatomic studies such as mammography or ultrasound. In high risk screening patients, MRI finds unsuspected cancers in approximately 4 percent (12).
With all of the new tools available for breast imaging, what are the current recommendations for breast screening? The America Cancer Society recommends annual screening mammography for all women ages 40 and older. Annual MRI is recommended in addition to mammography for high- risk patients (those who are BRCA + or have a 20 percent greater lifetime risk of breast cancer). Screening for these high-risk patients should begin at age 30. Intermediate risk patients (15 to 20 pwecent lifetime risk) may wish to consider yearly MRI in addition to mammography. Research is ongoing in this population, which includes patients with a personal history of breast cancer. MRI screening is not recommended for average risk patients, since in a population with a low prevalence of cancer, the number of false positives would be unacceptably high.
Ultrasound screening is not generally recommended except for high-risk patients who cannot tolerate MRI (such as those with pacemakers). While ultrasound is quite useful as a diagnostic tool to evaluate a mass seen on mammography or palpated on clinical exam, it is hampered in the screening setting by issues of both sensitivity and specificity. While screening ultrasound can find some additional unsuspected cancers, it only finds 0.4% more than mammography (13), as opposed to 4 % more for MRI. Comparative studies have shown that ultrasound does not add any increased cancer detection to the combination of mammography and MRI. Moreover, ultrasound has a high rate of false positive recommendations for biopsy (14).
We’ve come a long way with breast imaging since those first mammography trials. Challenges still remain, and no current imaging test or combination of tests is perfect. However, with continued advances, we will hopefully be able to address current issues, decrease false positives, and find ways to identify more cancers at treatable stages. With improved tools for screening, earlier diagnosis is possible with opportunities to modify the extent of treatment. Breast conserving surgery is now the standard of care for patients with early malignancy. Acceptable margin width has declined, and neoadjuvant systemic therapy can often be used to reduce larger tumors making them amenable to breast conservation. Radiation therapy is a critical adjunct to breast conserving surgery, reducing recurrences by 25% (15).
Node sampling has also evolved in the direction of “less is more.” Sentinel node biopsy is now the standard of care, and two studies have demonstrated that complete axillary node dissection can be avoided when two or fewer nodes are involved in patients receiving subsequent radiation therapy (16, 17.)
The use of IMRT (Intensity Modulated Radiation Therapy) has improved the accuracy and uniform dosing of treatment. Although a five-week course of whole breast irradiation remains the standard, hypo fractionated regimens (Canadian Regimen) permit completion of treatment in half the time. Accelerated partial breast irradiation techniques (PBI) limit the treatment volume to the tumor bed and 1-2 cm surrounding margin. Treatment can be completed in five days. Although gaining in popularity, PBI is subject to continuing evaluation in clinical trials and its use is limited to patients over 45 years old with small node negative tumors (18).
Finally there are patients who may avoid radiation after breast conserving surgery: women over 70 with small ER positive tumors who are receiving adjuvant hormonal therapy (19). The use of radiation after breast conserving surgery for non-invasive tumors (DCIS) is also being reconsidered, and molecular profiling of the tumor may help predict which patients can avoid therapy (20). The evolving paradigm of the intrinsic tumor subtypes in breast cancer has had a major impact on the use of systemic treatment in this disease. Therapy is now individualized for hormone sensitive, HER 2 amplified, and “triple negative” tumors. The use of systemic treatment prior to surgery, so-called “neoadjuvant therapy” initially focused on patients with locally advanced disease. While no survival benefit has been associated with this approach, it is valuable in assessing response to systemic treatment and can be used to evaluate new therapies prior to large-scale trials.
Genomic studies of patient tumors have also helped individualize systemic therapy choices. Gene expression profiling provides a molecular signature of a patient’s cancer, which can be used to classify the risk for relapse and the benefit of a variety of treatment strategies. Many patients have avoided the toxicity of treatments, which would likely have contributed little to reducing their risk of recurrence.
Central to the paradigm shift in the management of breast cancer has been the elucidation of the molecular pathways critical for cell growth. Targeting these pathways has led to some of the most important advances in treatment (e.g. Traztuzumab for HER 2 overexpressing tumors). Among the large number of agents in the pipeline, many if not most will target critical steps in these pathways and hopefully will lead to significant progress including for those patients with metastatic disease.
With the rapid evolution in technology for diagnosis and treatment of breast cancer, it is likely that our approach to this disease will increasingly reflect the unique aspects of each tumor rather than a global approach to the disease. The results of many prior studies are likely compromised by our lack of understanding of this complexity. Fortunately in many instances tissue banking of tumor specimens from older studies has allowed the reevaluation of some of these issues, often with very different conclusions.
Perhaps the most gratifying aspect of the progress we have made in this disease is the increasing focus on“Survivorship.” Even patients with metastatic disease often live years, and programs directed at managing the aftermath of cancer treatments are receiving increased attention.
Lynn Baxter, M.D., is a board-certified radiologist who specializes exclusively in women’s imaging. She received her undergraduate degree from Duke University and her medical degree from the University of Pennsylvania. She completed her Radiology residency at Harvard’s Beth Israel Hospital and a Breast Imaging fellowship at Emory University. She is Director of Breast Imaging for Northside Radiology Associates and Chair of the Northside Hospital Breast Care Committee.
Colleen Austin, M.D., is a board-certified medical oncologist with a special interest in breast cancer. She received her undergraduate degree from Vassar College and her M.D. from State University of N.Y Upstate Medical School. She completed her residency in Internal Medicine and fellowship in Hematology and Oncology at Emory University School of Medicine. She currently chairs the Cancer Committee at Northside Hospital.
References
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4. Institute of Medicine: Breast Cancer and the Environment: A Life Course Approach. www.iom.edu/Reports/2011/Breast-Cancer-and-the -Environment-A-Life-Course Approach.aspx (Accessed on January 1, 2012.
5. National Comprehensive Cancer Network (NCCN) guidelines available online at www.nccn.org (Accessed on January 1,2012).
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11. Ibid.
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