A 38-year-old woman underwent initial screening mammography that revealed bilateral dense breast tissue. According to an evaluation by the radiologist, the evaluation was considered incomplete and additional imaging is recommended (BI-RADS 0). The patient’s past medical history is unremarkable. She has never had any previous breast mass or undergone mammography in the past. Her family history is significant in that her mother died of breast cancer at 45 years of age. On examination, extensive fibrocystic changes are found to be present in both breasts, and no dominant mass is identified. The examination results for both axillary areas are unremarkable.
What is the most likely diagnosis?
What complications are associated with these changes?
ANSWERS TO CASE 11: Breast Cancer Risk and Surveillance
Summary: The patient is a 38-year-old woman with a high-risk profile for breast cancer based on the maternal premenopausal breast cancer history, an unreliable breast examination because of dense fibrocystic changes, and a mammogram that is somewhat difficult to interpret due to increased density.
• Most likely diagnosis: Dense breast tissue in a patient with high-risk family profile.
• Complications: These changes can lead to difficulty in detecting breast carcinoma by physical examination and mammography.
1. Learn the relationship between benign breast changes and borderline malignant changes in breast cancer development (Table 11–1).
Table 11–1 • BENIGN BREAST LESIONS AND RELATIVE RISK OF BREAST CANCER
2. Understand the management principles for patients at risk for breast cancer development.
3. Learn the management options for patients with benign breast lesions, borderline malignancies, and high-risk profiles.
For this patient, whose mother developed premenopausal breast cancer and who has clinically benign, dense fibrocystic changes in both breasts and a screening mammogram that was difficult to interpret, there is no uniform approach to treatment. The ultimate decision regarding therapy or surveillance is based on patient risk factors, her concerns about the threat of breast cancer, the effectiveness of surveillance, and the anticipated cosmetic resultsof a biopsy and/or treatment. These factors must be explored with the patient during the initial consultation. In this case, breast ultrasonography would provide additional information and should be done to establish a baseline evaluation. For an intermediate- to high-risk patient, it may be worthwhile to consider chemoprevention strategies ranging from dietary supplements to the administration of antiestrogens. Additional consideration for this patient with a family history of premenopausal breast cancer is the possibility of BRCA mutations; therefore, additional queries regarding family history of breast and/or ovarian cancers should be made. If the history is suspicious, genetic counseling and testing should be considered. Breast MRI may or may not be beneficial depending on the patient’s final assessment of breast cancer risk.
APPROACH TO: Surveillance and Management of High-Risk Patients
BREAST IMAGING REPORTING AND DATA SYSTEM (BI-RADS): This is a quality assurance guide designed and published by the American College of Radiology to standardize breast imaging reporting and facilitate outcome monitoring. The fifth edition of the BI-RADS atlas will be published during 2012. This classification system is applied for all reports on mammography, breast ultrasound, and breast MRI. Images are categorized from 0 to 6, with specific recommendations attached to each of the categories.
Category 0: Assessment is incomplete; additional imaging evaluation is needed.
Category 1: Negative. Recommend routine annual screening mammography for women older than 40 years.
Category 2: Benign findings. Recommend routine annual screening mammography for women older than 40 years.
Category 3: Probable benign finding. Recommend initial short-term imaging follow-up (usually 6-month). (Malignancy rate <2%.)
Category 4: Suspicious abnormality. Biopsy should be considered. Category 4 can be also subdivided into 4A, 4B, and 4C. (Malignancy rates of 3%-94% dependent on the subcategories.)
4A: Findings need intervention with a low suspicion for malignancy
4B: Findings with intermediate suspicion for malignancy
4C: Findings of moderate concerns but not classic for malignancy
Category 5: Highly suggestive of malignancy and requires biopsy or surgical excision. (>95% malignancy.)
Category 6: Known biopsy-proven malignancy.
INVASIVE LOBULAR CARCINOMA: Make up only 10% to 15% of all breast cancers. These frequently do not appear as dominant breast masses but instead as focal thickening (resembling fibrocystic changes). Mammography of these lesions has a tendency to be negative. Detection is by physical examination, magnetic resonance imaging (MRI), and ultrasonography.
ATYPICAL DUCTAL HYPERPLASIA: When this condition is diagnosed during core-needle biopsy, 25% to 40% of patients have ductal carcinoma in situ diagnosed on excisional biopsy.
SCREENING MAMMOGRAPHY: Radiologic procedure for the examination of breast tissue with approximately 10% to 15% false-negative and 10% false-positive rates. The false-negative rate in younger patients (40-49 years) is higher and may approach 25%; consequently, the cost-benefit of screening mammography for 40- to 49-year-old women has been hotly debated. Roughly 20% of patients undergoing biopsies for mammographic abnormalities are found to have carcinoma.
ULTRASONOGRAPHY: Imaging using sound waves that can visualize small solid and cystic lesions (2-5 mm). It may be useful for the evaluation of cystic lesions and evaluating a low-risk patient with a palpable abnormality and a negative mammogram. When identified by ultrasound, a benign-appearing cyst characterized by the absence of septation and a solid component has a 99.5% negative predictive value for cancer; additional application of breast ultrasound is to differentiate benign and malignant characteristics of solid breast masses.
CHEMOPREVENTION: Tamoxifen (20 mg/d for 5 years) has been approved for chemoprevention in high-risk patients and has been reported to reduce the occurrence of subsequent cancer among high-risk patients. Chemoprevention must be weighed against the risks of thromboembolic complications, endometrial cancer, and the side effects of tamoxifen.
STAR (STUDY OF TAMOXIFEN AND RALOXIFENE) TRIAL: This randomized controlled trial enrolled over 19,000 high-risk patients to chemoprevention using tamoxifen or raloxifene. The patients were selected based on GAIL scores. This study found that women in the two arms of the study experienced similar rates of subsequent cancer development. However, women who received raloxifene had 29% fewer venous thromboembolic complications in comparison to those who received tamoxifen.
BREAST MRI: A useful technique for defining the local extent of breast cancers. It is sensitive in identifying small cancers in the breasts but lacks specificity in that lesions identified as abnormal may not be cancerous (sensitivity, 90%-95%; the specificity varies depending on the study population with increasing specificity in higher-risk groups). Since 2007, the American Cancer Society has recommended breast MRI screening as an adjunct to mammography in patients with BRCA mutations and untested first-degree relatives with BRCA mutations, patients with lifetime cancer risk of greater than 20% to 25%, patients with prior chest wall radiation, and patients and first-degree relative with Li-Fraumeni syndrome (p53 mutations).
Familial Risk Factors
The risk of developing breast cancer increases 1.8-fold in a woman whose mother or sister has had breast cancer diagnosed. This risk is further increased if the disease was diagnosed in the first-degree relative at a premenopausal age (3.0-fold risk) or if it was bilateral breast cancer (4.0- to 5.4-fold if postmenopausal and 9.0-fold if premenopausal). In addition, some families carry a genetic predisposition for breast cancer in the BRCA1or BRCA2 gene. Whereas only 5% to 10% of cancers are attributed to mutations of the BRCA genes, the diagnosis of a BRCA1 or BRCA2 gene carrier significantly increases the lifetime risk of developing breast cancer by 3- to 17-fold.
Approach to Patient Treatment
Treatment options for benign breast lesions vary from patient to patient depending on each patient’s risk factors, personal concerns regarding cancer risk versus breast cosmesis, and the ability to continue close breast surveillance. Low-risk benign lesions can be observed or excised based on the patient’s clinical presentation and/or preference. A high-risk lesion or a patient with a high-risk history may opt for excision with observation and/or chemoprevention with antiestrogen therapy and close observation. Selective patients with a strong family history or known BRCA mutation may be treated with prophylactic mastectomy and/or bilateral oophorectomy. Regardless of the treatment selected, all high-risk patients should be followed with annual mammography and a physical examination and instructed on performing monthly breast self-examination (Table 11–2).
Table 11–2 • NATIONAL COMPREHENSIVE CANCER NETWORK HIGH-RISK SCREENING ALGORITHM (>25 y of age)
Screening ductal lavage: A technique sometimes applied in the surveillance of patients with high-risk lesions or high-risk profiles. It involves aspiration of the areola to induce nipple discharge. The effluent produced is analyzed by cytology. Screening duct lavage may identify patients with early lesions who should be screened with more aggressive techniques, including ductography, ductoscopy, or MRI. The application of ductal lavage remains quite limited at this time.
11.1 A 44-year-old woman underwent a stereotactic core biopsy of a suspicious mammographic lesion in the left breast. The biopsy revealed lobular carcinoma in situ (LCIS). Which of the following is the most appropriate management recommendation for this patient?
A. Left mastectomy
B. Left partial mastectomy and radiation therapy
C. Tamoxifen, clinical examination, and mammography every 2 years
D. Raloxifene, clinical examination, and mammography every 6 months
E. Tamoxifen, clinical examination, and mammography every 6 months
11.2 Which of the following factors is associated with the highest risk of developing breast cancer?
A. Less than 25 years of age
B. First-degree relative with breast cancer
C. Previous breast biopsy
D. Mutation of the BRCA1 gene
11.3 A 37-year-old woman, who has multiple family members with breast cancer, is noted to have a BRCA1 mutation. She is counseled about her 50% to 70% lifetime risk of breast cancer. She asks whether mastectomy would be advisable. Which of the following states regarding prophylactic mastectomy is most accurate?
A. Prophylactic mastectomy is an acceptable treatment option.
B. Prophylactic mastectomy is rare if ever indicated.
C. Unilateral prophylactic mastectomy is the preferred method.
D. Prophylactic mastectomy is an acceptable treatment option only when the patient agrees to undergo immediate breast reconstruction.
E. Prophylactic mastectomy should only be considered after the failure of chemoprevention
11.4 Which of the following statements is most accurate regarding mammography?
A. The radiation has led to pulmonary malignancies.
B. Its primary role is to determine a malignant versus a benign condition of masses found on physical examination.
C. Its main role is to detect nonpalpable breast masses.
D. It is more accurate in younger patients.
E. Annual mammography is effective in identifying 99% of all breast cancers at their early “preclinical” stages.
11.5 A 41-year-old woman with a significant family history of breast cancer, including her mother who developed breast cancer at the age 62, underwent a stereo-tactic core biopsy of a suspicious left breast mammographic abnormality. The biopsy revealed the presence of atypical ductal hyperplasia (ADH). Which of the following is the most appropriate treatment option?
A. Tamoxifen chemoprevention
B. Raloxifene chemoprevention
C. Left breast biopsy with needle localization
D. Left modified radical mastectomy
E. Tamoxifen chemoprevention and surveillance mammography every 6 months
11.6 A 33-year-old woman has a strong family history of breast cancer, including breast cancer occurrence in her mother at age 44 and history of breast cancer in a sister at age 40. She is concerned about her risk of cancer development but does not wish to have prophylactic mastectomies performed. Which of the following management options is considered most acceptable?
A. Prophylactic breast radiation and raloxifene.
B. Begin annual screening mammography and clinical breast examinations.
C. Recommend counseling and genetic testing, initiate annual mammography, breast MRIs, clinical breast examinations, and raloxifene therapy.
D. Recommend mammography, breast MRIs, and clinical follow-up every 3 to 6 months.
E. Recommend counseling and genetic testing; if no abnormalities identified, begin surveillance mammography and clinical breast examinations at age 40.
11.1 D. The findings of LCIS carry a 10-fold increased risk of subsequent breast cancer, and this increased risk is bilateral. LCIS is considered a marker for subsequent breast cancer and not an early stage of existing breast cancer. The subsequent breast cancer development can be in the form of invasive ductal cancer or invasive lobular cancer. Left mastectomy and left partial mastectomy are not acceptable options given the nature of LCIS and the distribution of potential future breast cancers in this patient. Surgical excision may be beneficial when the patient’s biopsy shows LCIS with atypia. Based on the increased risk of future breast cancers, intensified surveillance and chemoprevention are justifiable. The STAR trial was a randomized trial that compared tamoxifen to raloxifene for chemoprevention, and this trial observed fewer venous thromboembolic complications and side effects among patients treated with raloxifene, thus suggesting that raloxifene may be better for chemoprevention in the high-risk patients. Long-term surveillance is necessary for all patients with LCIS because the average time to subsequent cancer development is 10 to 15 years.
11.2 D. BRCA1 gene carriers have a 3- to 17-fold increased risk for breast cancer development. Female carriers of the BRCA1 gene have a 56% to 85% lifetime risk of developing breast cancer and a 15% to 45% risk of developing ovarian cancer. Breast cancer history in a female first-degree relative is associated with 1.8-fold increase in cancer risk. SEER (Surveillance Epidemiology and End Results) database showed that the risk of invasive breast cancer is 7.1% among women with LCIS followed for a period of 10 years.
11.3 A. Prophylactic mastectomy is an acceptable management option for some patients with high-risk profile, who have received sufficient counseling regarding risks and benefits of all options. When performed, prophylactic mastectomy is often bilateral and reconstruction following prophylactic mastectomy is individualized based on patient’s desires. A patient with a BRCA1 mutation has a very high lifetime risk for breast cancer and ovarian cancer, and risk-reducing therapies such as prophylactic mastectomy and prophylactic oophorectomy are reasonable options for some patients after appropriate counseling.
11.4 C. The main purpose of mammography is to detect nonpalpable breast cancers. Surveillance mammograms have not been shown to increase the risk of other malignancies. Patients should be informed that mammography is less effective in identifying invasive lobular carcinoma, which makes up approximately 15% of all breast cancers; therefore, mammography alone would not be effective for the early identification of breast cancers.
11.5 C. The diagnosis of ADH by core-needle biopsy has been demonstrated to be associated with the findings of invasive or in situ ductal carcinoma during subsequent excisional biopsies. ADH is believed to represent a carcinogenic progression of the ductal epithelial cells. Even if the subsequent excisional biopsy demonstrates no evidence of cancer, the patient should be advised of her increased cancer risk and the need for clinical follow-up and surveillance mammography. Chemoprevention could be considered appropriate only after the subsequent excisional biopsy demonstrates no evidence of malignancy.
11.6 C. This patient’s family history of premenopausal breast cancers is quite suspicious for familial breast cancer syndromes produced by BRCA mutations. Genetic testing is a reasonable recommendation after appropriate counseling regarding the implications, consequences, and management option for individuals and family members with BRCA mutations. For the very high-risk patients such as this, annual surveillance mammography, breast MRI, and clinical breast examinations should begin at age 25 or 5 to 10 years prior to the earliest familial case. Chemoprevention with raloxifene or tamoxifen has been demonstrated to reduce the risk of subsequent breast cancer in high-risk patients; however, its application may be associated with side effects and complications. Complications and side effects are less common with raloxifene. Mammograms performed every 3 to 6 months on a routine basis may be associated with increased risk of radiation-exposure–related injuries and is not recommended. Prophylactic breast radiation has not been shown to reduce subsequent breast cancer risks and is not an option.
The primary role of mammography is the detection of nonpalpable breast masses.
Having a first-degree relative with breast cancer, especially if this individual is premenopausal and the disease is bilateral, represents a risk factor for developing mammary cancer.
Mammography in younger women under 30 years tends to be less sensitive because of the possibility of dense fibrocystic changes.
Raloxifene is just as effective as tamoxifen in chemoprevention for high-risk patients, and it is associated with fewer complications and side effects.
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Saslow D, Boetes C, Burke W, et al. American Cancer Society Guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57:75-89.
Smith RA, Cokkinides V, Brooks D, Saslow D, Brawley OW. Cancer screening in the United States, 2010. A review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin. 2010;60:99-119.
Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006;295:2727-2741.