Breast Cancer: Risk Assessment, Risk Reduction, and Advances in Diagnostic and Surgical Techniques

Return to Medscape coverage of: Oncology World Congress 2005

Breast Cancer: Risk Assessment, Risk Reduction, and Advances in Diagnostic and Surgical Techniques
DisclosuresAlbert B. Lowenfels, MD, FACS
With breast cancer now afflicting nearly 1 in 7 women in the United States, it was entirely appropriate for the first annual Oncology World Congress to dedicate a plenary session to discussing prevention and management of this common tumor. During the past 25 years, the mortality from breast cancer has fallen dramatically. In 1975, breast cancer mortality was 48.3/100,000, whereas by the year 2000, the estimated mortality rate had dropped to 38/100,000. But what is responsible for this gratifying change: More widespread use of screening, or more effective adjuvant therapy? One of the main points emphasized by several speakers was that both factors are important. Based on statistical models, roughly 46% of the reduction can be attributed to the effects of screening, with the residual decreases related to more effective adjuvant therapy.[1]
Preventing Breast Cancer in High-Risk Women
Victor G. Vogel, MD, MHS, Professor of Medicine and Epidemiology at the University of Pittsburgh, Pennsylvania, opened the discussion of breast cancer risk assessment and reduction by pointing out that invasive ductal breast cancer develops during several years, implying that to be effective, preventive measures must be instituted well before the onset of cancer. Many preventive agents, such as tamoxifen, act by blocking estrogen receptors, thereby interfering with the transcription process.
In 1998, Fisher and coworkers[2] reported the results of the large US tamoxifen breast cancer prevention trial, which demonstrated that therapy with tamoxifen caused a dramatic reduction in breast cancer incidence. Compared with placebo, tamoxifen use resulted in a 49% overall risk reduction, seen in all age groups and in all risk categories. The effect was particularly strong in women with atypical hyperplasia. Similar results were noted in 2 European trials reported during the same year.[3,4]
Despite its great promise, the use of this effective agent comes with significant drawbacks, mainly because it has potentially serious cardiovascular side effects. Dr. Vogel summarized the current strategies for patient selection as shown in the table.
Table 1. Indications and Potential Contraindications for Tamoxifen Usage
Positive Considerations
Possible Contraindications
History of lobular cancer in situ, lobular hyperplasia, or DCIS.
Prior stroke, TIA, DVT, pulmonary embolus
Premenopausal women with known BRCA1 or BRCA2 mutations
Cataracts (history or surgery)
Premenopausal women ≥ 35 years with 5-year probability of breast cancer ≥ 1.66% or postmenopausal women with 5-year risk for breast cancer ≥ 1.66% and favorable risk-benefit ratio*
Current hormone replacement therapy
*Risk as calculated from Gail model.[5]TIA = transient ischemic attack; DVT = deep vein thrombosis; DCIS = ductal carcinoma in situ
Patient-specific information about using the Gail model[5] for calculating a woman's risk for breast cancer can be obtained at: http://bcra.nci.nih.gov/brc/. This site provides a convenient way to calculate a woman's likelihood of developing breast cancer. For example, for a 55-year-old woman without ductal carcinoma in situ (DCIS), with a prior breast biopsy showing atypical hyperplasia, onset of menarche 12-13 years, first child born when patient was older than 30 years, and whose mother or sister had breast cancer, the risk for breast cancer would be 5.4%, compared with the population average of 1.5%.
Other preventive drug trials are currently under way. For example, the aim of the STAR trial (Study of Tamoxifen and Raloxifene) is to compare the effectiveness of tamoxifen and raloxifene in preventing breast cancer. Already, 19,000 women have joined the study with results expected to be reported in 2006.[6]
Role of Magnetic Resonance Imaging in Breast Cancer Screening
Despite the known effectiveness of mammography as a breast cancer screening tool, the effort to identify even better screening tools continues. How effective is magnetic resonance imaging (MRI) screening and when should it be used? Bruce L. Daniel, Associate Professor of Radiology, Stanford University, California, began his discussion by pointing out that mammography misses some tumors, and that cancers can develop between regular screening examinations. MRI has been available since 1986 and is performed after intravenous injection of a contrast agent, gadolinium, which enhances tumor visualization, perhaps because blood vessels in the tumor selectively pick up gadolinium.
A major advantage of MRI is that it detects small tumors without subjecting the patient to any radiation. But the technique is expensive ($1500-$3500) compared with $200-$300 for conventional mammography. Although, as yet no studies have reported that MRI breast screening results in improved survival, some have found that in high-risk women, MRI is more sensitive than mammography for discovery of small tumors.[7,8] Dr. Daniel concluded with these take-home points: (1) MRI screening is not recommended for the general population, but should be reserved for women at high risk for breast cancer; (2) women should be educated about the possibility of false-positive results; and (3) positive tumor results need to be confirmed with MRI-guided biopsy. These recommendations support those developed by a 2005 consensus conference on the use of MRI scans to detect breast cancer.[9]
Ductal Carcinoma in Situ: Who Should Receive Radiation and Hormonal Therapy?
Ductal carcinoma in situ (DCIS) afflicts an estimated 55,000 women in the United States each year, and questions about how to treat patients with this lesion continue to stir controversy among surgeons and oncologists. After adequate local tumor excision, do women with DCIS benefit from additional radiotherapy and tamoxifen? D. Lawrence Wickerham, MD, Associate Professor of Human Oncology, Drexel University School of Medicine, Pittsburgh campus, presented evidence favoring the use of radiotherapy and chemotherapy for patients diagnosed with DCIS. His recommendations are based on results of the US cooperative NSABP B-17 trial, which demonstrated that radiotherapy reduced the risk for recurrence by over 50%, and the NSABP B-24 trial, which found that adding tamoxifen resulted in an even greater benefit.[10]
Although he agrees that adjuvant therapy helps some patients with DCIS, Michael Lagios, MD, Clinical Associate Professor Pathology, Stanford University Medical Center, San Francisco, believes that for a subset of patients, radiotherapy therapy may be unnecessary. Omitting radiotherapy for this group would avoid the inconvenience of multiple trips to the hospital for radiotherapy for several weeks. This group includes women with small, less aggressive tumors with wide margins of excision. Selecting this subgroup of patients requires extremely meticulous examination of the resected specimen with many samples and the benefit of an experienced breast pathologist.
Participants in this session did not reach a firm agreement on the need for adjuvant therapy in every patient with DCIS. An analysis of the cost-effectiveness of radiation therapy following conservative surgery for DCIS estimated that radiotherapy adds roughly 0.09 extra years (about a month) of quality-adjusted life years (QALYs) at a cost of about $36,700 per QALY.[11] With respect to tamoxifen, 1 study from a large cancer center found that approximately one third of patients with DCIS eventually were offered and decided to accept tamoxifen therapy.[12]
Identification of Patients for Prophylactic Surgery
Is there a role for prophylactic breast removal in the small subset of women for whom the risk for breast cancer is very high? Benjamin O. Anderson, MD, Professor of Surgery, University of Washington, Seattle, presented information on the surgeon's role in identifying and treating these women. As did the other speakers, Dr. Anderson believes that the Gail model is the best available tool for risk estimation, allowing the oncologist and the surgeon to determine the likelihood that breast cancer will develop. For example, if the patient's family history is positive and if the patient has DCIS, then the risk for breast cancer is 11-fold higher than that of the general population. But the Gail model may underestimate the risk for cancer because it does not consider paternal family history, history of ovarian cancer in the family, or the age of onset of familial cancer.
We now know that BRCA1 and BRCA2 mutations greatly increase the lifetime risk for breast cancer, making patients who carry these genetic markers candidates for prophylactic ablative breast surgery. Testing should follow these steps: (1) obtain a complete family history to determine whether or not the patient belongs to a high-risk family; (2) test the affected person; and (3) if a known breast cancer gene is found, then consider testing other members of the family.
The main surgical option for high-risk patients is bilateral mastectomy. Because small amounts of residual breast tissue may be left attached to the chest wall, bilateral mastectomy reduces the risk for breast cancer by approximately 90%, rather than 100%.[13,14] Therefore, although this procedure greatly reduces the risk for eventually developing breast cancer, patients (and their physicians) must still be concerned about the small but real possibility of a breast cancer developing in residual breast tissue. Such prophylactic surgery does eliminate the need for screening mammography, however.
Other options are available for reducing the burden of breast cancer in high-risk women. Contralateral mastectomy is an option for women with unilateral breast cancer and a strong family history. Again, it does not completely eliminate the risk for contralateral breast cancer. Bilateral prophylactic oophorectomy reduces the risk for cancer in BRCA1 and BRCA2 carriers by roughly 50%; as an additional benefit, it eliminates the risk for ovarian cancer.[15]
Although prophylactic mastectomy is a disfiguring operation performed on an organ without known disease, for selected patients the procedure is beneficial. Reconstructive methods using muscle flaps, implants, or a combination of both methods are now available to improve the overall cosmetic result.
Summary
This plenary session focused on the dramatic improvements in the diagnosis, treatment, and prevention of breast cancer that have taken place during the past 25 years. Some of the key points covered include:
Mammographic screening and adjuvant therapy play roughly equal roles in reducing the overall burden of breast cancer;
Clinical trials demonstrate about a 50% reduction in breast cancer risk following the use of tamoxifen; however, the use of estrogen antagonists must be balanced against the added risk for cardiovascular disease, especially in obese, elderly patients;
Other drug trials using different, perhaps safer agents are under way with results anticipated during 2006;
The risk for recurrent cancer in women with DCIS can be reduced with adjuvant therapy, but controversy remains about whether all women need additional therapy, or whether there are women with favorable profiles for whom additional treatment may not be required;
Prophylactic surgery reduces the risk for breast cancer by about 90% and is an option for selected high-risk patients, ie, women with BRCA1 or BRCA2 mutations; and
Further advances in breast cancer prevention and therapy will depend on the continued recruitment of large numbers of patients for randomized clinical trials. Sales of the breast cancer research stamp (Figure) provide research funding for many breast cancer projects.
Figure. Through 2004, purchasing the 45-cent first-class breast cancer stamp has provided approximately $12.2 million for breast cancer research.
References
Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784-1792. Abstract
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388. Abstract
Veronesi U, Maisonneuve P, Costa A, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet. 1998;352:93-97. Abstract
Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet. 1998;352:98-101. Abstract
Costantino JP, Gail MH, Pee D, et al. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J Natl Cancer Inst. 1999;91:1541-1548. Abstract
Wickerham DL. Tamoxifen's impact as a preventive agent in clinical practice and an update on the STAR trial. Recent Results Cancer Res. 2003;163:87-95. Abstract
Kriege M, Brekelmans CT, Boetes C, et al; Magnetic Resonance Imaging Screening Study Group. Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351:427-437. Abstract
Leach MO, Boggis CR, Dixon AK, et al; MARIBS study group. Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet. 2005;365:1769-1778. Erratum in: Lancet. 2005;365:1848.
Silverstein MJ, Lagios MD, Recht A, et al. Image-detected breast cancer: state of the art diagnosis and treatment. J Am Coll Surg. 2005;201:586-597 Abstract
Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the national surgical adjuvant breast and bowel project experience. Semin Oncol. 2001;28:400-418. Abstract
Suh WW, Hillner BE, Pierce LJ, et al. Cost-effectiveness of radiation therapy following conservative surgery for ductal carcinoma in situ of the breast. Int J Radiat Oncol Biol Phys. 2005;61:1054-1061. Abstract
Yen TW, Hunt KK, Mirza NQ, et al. Physician recommendations regarding tamoxifen and patient utilization of tamoxifen after surgery for ductal carcinoma in situ. Cancer 2004;100:942-949.
Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340:77-84. Abstract
Meijers-Heijboer H, van Geel B, Van Putten WL, et al. Breast cancer after prophylactic bilateral mastectomy in women with BRCA1 or BRCA2 mutation. N Engl J Med. 2001;345:159-164. Abstract
Rebbeck TR, Levin AM, Eisen A, et al. Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst. 1999;91:1475-1479. Abstract
Copyright © 2006 Medscape.