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Advances in Screening, Diagnosis, and Treatment of Breast Cancer
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Breast Cancer
Mayo Clin Proc, June 2004, Vol 79
Concise Review for Clinicians
Advances in Screening, Diagnosis, and Treatment of Breast Cancer BETTY A. MINCEY, MD, AND EDITH A. PEREZ, MD have been evolving. Advances in screening, diagnosis, and treatment of breast cancer continue to influence our approach to patients with this disease. Many improvements have been made as well in supportive care, including increased tolerability of therapy and notable amelioration of disease symptoms. Mayo Clin Proc. 2004;79:810-816
Breast cancer is the most common cancer in women in the United States; this year, approximately 215,900 new cases will be diagnosed. Mammography remains the cornerstone of screening, with technologies such as ultrasonography and magnetic resonance imaging having an increasingly defined role. Improved risk assessment and prevention strategies have been implemented, and current research in these areas includes better identification of patients at risk, the use of aromatase inhibitors and other agents to reduce risk, and the use of surrogate markers. Breast cancer staging has been optimized recently; also, local management of breast cancer, adjuvant systemic therapies, and treatment of patients with advanced disease
AI = aromatase inhibitor; CI = confidence interval; DCIS = ductal carcinoma in situ; ER = estrogen receptor; LCIS = lobular carcinoma in situ; NSABP = National Surgical Adjuvant Breast and Bowel Project; PR = progesterone receptor; STAR = Study of Tamoxifen and Raloxifene
B
reast cancer is the most common cancer in women in the United States, with incidence increasing about 0.5% per year. In the year 2004, an estimated 215,900 new cases of invasive breast cancer (stages I-IV) will be diagnosed, and about 40,100 women and 470 men will die of the disease.1 New strategies to decrease the risk of breast cancer are being studied and implemented. Although breast cancer is a leading cause of death in women (second only to lung cancer), mortality rates have declined recently. This reduction in mortality, despite the increase in incidence, is attributed to improvements in screening, diagnosis, and treatment.
The sensitivity of first mammography ranged from 71% to 96% in studies of a 1-year screening interval.2,3 The positive predictive value of abnormal mammographic results requiring biopsy ranged from 12% to 78% in these studies and increased with age.2,3 Young women at increased risk of breast cancer development should be advised to undergo mammography before age 40 years. Current guidelines suggest that women with BRCA1 or BRCA2 mutations should begin screening mammography at age 25 years or 10 years earlier than the youngest age at which breast cancer has been diagnosed in their family.4 Although it is intuitive to recommend this approach to women with a strong family history of breast cancer and unknown genetic makeup, data are not currently available to quantify benefit for this group. Unfortunately, mammography in these groups of young women has a sensitivity of only about 33% in most studies. Ultrasonography does not improve this sensitivity and is not recommended for screening; magnetic resonance imaging of the breast has a sensitivity of between 90% and 100% but is expensive and has not been endorsed for screening purposes.2,3 Ongoing trials are further exploring these technologies. The clinical breast examination is an important part of breast cancer screening and surveillance because up to 10% of breast cancers may be clinically evident while mammographically occult.2,3 The role of breast self-examination has not been well-defined.
SCREENING Despite controversy surrounding recent reports, mammography remains the cornerstone of breast cancer screening. Mammographic screening for early detection of breast cancer reduces mortality and is widely recommended as an integral part of annual preventive health care for all women beginning at age 50 years and continuing for as long as a woman’s life expectancy is at least 10 years. For women older than 40 years, most major health organizations recommend annual or semiannual screening mammography.2,3 From the Division of General Internal Medicine (B.A.M.), Multidisciplinary Breast Clinic (B.A.M., E.A.P.), and Division of Hematology and Oncology (E.A.P.), Mayo Clinic College of Medicine, Jacksonville, Fla. A question-and-answer section appears at the end of this article. Individual reprints of this article are not available. Address correspondence to Edith A. Perez, MD, Division of Hematology and Oncology, Mayo Clinic College of Medicine, 4500 San Pablo Rd, Jacksonville, FL 32224 (e-mail: [email protected]). Mayo Clin Proc. 2004;79:810-816
RISK ASSESSMENT For some women, the risk of developing breast cancer is high enough to warrant consideration of prevention strate810
© 2004 Mayo Foundation for Medical Education and Research
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Mayo Clin Proc, June 2004, Vol 79
gies in addition to screening and surveillance. Current methods for defining risk include use of the modified Gail model, use of the Claus model, and determination of BRCA mutation carrier status.4 The modified Gail model combines relative risks associated with age, race, age at menarche, number of previous breast biopsies, history of atypical ductal hyperplasia, and family history of breast cancer in first-degree relatives for estimation of 5-year and lifetime risks of breast cancer development in an individual woman. The online risk-assessment tool, located at www .breastcancerprevention.com, provides comprehensive information approved by the National Cancer Institute and includes a system of scoring an individual’s risk of developing breast cancer in the next 5 years and by age 80 years. A score of 1.66% or higher for the next 5 years indicates high risk. This model is reasonable for estimating risk in most women but may seriously underestimate risk in women with strong family histories of breast cancer. For such women, the Claus model, which considers only family history, can be used to estimate risk. In appropriate cases, genetic counseling and testing for mutations in BRCA1 or BRCA2 genes may be considered. None of the risk models consider a history of lobular carcinoma in situ (LCIS), which is primarily regarded as a risk factor rather than a precursor lesion and is associated with an annual risk of approximately 1% for breast cancer development in either breast. An additional risk factor is mammographic density. Breasts with larger amounts of connective and epithelial tissue appear denser than do breasts with more fat. Mammographically dense breast tissue is one of the strongest established risk factors for breast cancer, conferring a 4to 6-fold increased risk for women with the most dense breast tissue compared with those with the least dense.5 Mammographic density also decreases the sensitivity of mammography. The relative importance of mammographic density as a risk factor and the underlying mechanisms responsible for the increased risk in women with dense breast tissue are topics of ongoing research. PREVENTION Women with a substantially increased risk of breast cancer should be counseled regarding options for breast cancer prevention. Defining the level of risk that warrants intervention may be difficult and should be done on an individual basis, taking into account a woman’s age, comorbidities, and her own thoughts about her risk and how it affects her quality of life. Decisions regarding interventions such as chemoprevention or surgical prophylaxis must be highly individualized and will vary greatly among women with similar risk levels.
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Tamoxifen, a selective estrogen receptor (ER) modulator that has been used for years to treat breast cancer, is the only agent currently approved by the US Food and Drug Administration to decrease the risk of breast cancer. Its approval by this agency for prevention of breast cancer was based on the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study, in which a relative risk reduction of approximately 50% was observed for women with a 5-year risk of 1.66% or higher, as calculated by the modified Gail model (despite notable adverse effects among 13,388 women, including 3 women in the tamoxifen group who died of pulmonary emboli vs none in the placebo arm). A meta-analysis of 5 worldwide trials that evaluated tamoxifen vs placebo in women at increased risk of breast cancer revealed a 38% (95% confidence interval [CI], 28%-46%; P<.001) relative reduction in risk of breast cancer development at 5 years of follow-up.6 In terms of absolute numbers, patients in the placebo group had an approximate 13% risk of developing a ductal carcinoma in situ (DCIS) or invasive breast cancer during the study periods vs 7% of those in the tamoxifen arm. There was no effect on ER-negative breast cancer but a 48% relative decrease in ER-positive disease. However, the risk of endometrial cancer was increased (odds ratio, 2.4; 95% CI, 1.5-4.0), as was the risk of venous thromboembolism (odds ratio, 1.9; 95% CI, 1.4-2.7). Survival differences between tamoxifen and placebo have not been shown to date. Ongoing trials are evaluating other prevention strategies. The Study of Tamoxifen and Raloxifene (STAR), NSABP P-2 trial is comparing 5 years of tamoxifen use vs raloxifene use, another selective ER modulator, with eligibility determined as for the NSABP P-1 study by an estimated baseline risk of breast cancer higher than 1.66% at 5 years, based on the modified Gail model. The accrual goal for STAR is 19,000 women, which should be achieved this year. A large prevention study (MAP.3) about to begin at multiple medical centers in the United States and Canada will compare the effectiveness of the aromatase inhibitor (AI) exemestane, either alone or in combination with celecoxib, with placebo for reducing the risk of breast cancer in high-risk women. For women with a substantially elevated risk of breast cancer development, particularly those proved to carry mutations in BRCA1 or BRCA2, surgical options for prevention should be discussed.4 Available data regarding risk reduction with surgical prophylaxis indicate that bilateral mastectomy reduces the risk of breast cancer development by approximately 90% and that oophorectomy reduces the risk of breast cancer by approximately 50% if performed before menopause.4 These risk reductions are based on retrospective, observational studies and on more recent prospective observational studies of women at high risk.
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Three important areas of research in the prevention setting include better identification and definition of patients at increased risk of breast cancer development, the use of AIs, and the use of agents that may decrease the risk of hormone receptor–negative disease. Surrogate markers for breast cancer risk are being sought so that pilot trials of new agents can be completed with fewer participants in less time than is needed to show actual changes in cancer incidence. An example of a potential surrogate marker is mammographic density. Because it is not only measurable but also may be altered potentially by interventions such as selective ER modulators or AIs, mammographic density may prove to be a useful surrogate marker for both risk and risk reduction. A small, ongoing 1-year study (MAP.2) will determine the effectiveness of exemestane in reducing mammographic density. BREAST CANCER STAGING Most patients presenting with breast cancer have disease localized to the breast or to the breast and axillary lymph nodes; however, 40% to 50% eventually may develop metastatic disease. A new staging system became standard in 2003: the 6th American College of Physicians Staging,7 which assigns a stage from 0 to IV on the basis of the anatomical extent of the tumor, including invasiveness, size, and lymph node or distal involvement. Stage 0 (Tis) breast cancers are DCIS (or intraductal) carcinomas. Lobular carcinoma in situ increasingly is considered a risk factor for subsequent breast cancer, but it is still included as a malignancy in the most recent staging system and is classified as “Tis (LCIS).”7 Stages I through IV are invasive tumors, most commonly of the infiltrating ductal type. The histological subtype of breast cancer is not part of the staging system but is important for its potential influence on patient outcome. LOCAL MANAGEMENT OF PRIMARY BREAST CANCER The management of primary breast cancer, whether invasive or in situ, begins with local treatment. The only exclusion is LCIS, which is managed as a determinant of increased risk; in other words, management after a biopsy specimen shows LCIS does not require full excision, lumpectomy, or mastectomy. As a determinant of increased risk of subsequent breast cancer, LCIS is managed by observation (follow-up) and chemoprevention. Most women with newly diagnosed breast cancer have a choice between breast conservation therapy with lumpectomy and radiation or mastectomy. Although the chance of recurrence is higher with breast conservation therapy, the effect of both therapies on overall survival is the same. Women with large tumors or those with multifocal breast cancer often are not candidates for breast conservation.
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Sentinel lymph node evaluation has essentially become a standard of care as part of the staging of invasive breast cancer. Outside of clinical trials, if the sentinel lymph node is negative for tumor by hematoxylin and eosin pathological evaluation, then axillary node dissection is not performed. However, a full axillary node dissection is performed if the sentinel lymph node is positive for tumor. Ongoing clinical trials are evaluating the feasibility of obviating full dissection in patients whose sentinel lymph node is positive for malignancy. Routine evaluation of the sentinel lymph node in the setting of DCIS has not been established, although it is included sometimes in patients with multifocal or high-grade DCIS. External beam radiotherapy is a standard component of local treatment of patients with invasive breast cancer when breast conservation is undertaken.8 For women who have undergone mastectomy, this therapy is not routinely recommended unless the tumor is large (>5.0 cm), there is chest wall involvement, or more than 3 axillary lymph nodes are involved. The use of postmastectomy radiation therapy for patients with 1 to 3 lymph nodes positive for malignancy is controversial. Generally, radiation therapy after breast conserving surgery consists of whole breast external beam radiotherapy administered over 5 to 6 weeks, but new techniques are evaluating partial breast irradiation. Partial breast irradiation is administered generally to the portion of the breast that includes the tumor bed and an area of surrounding margin. One advantage of this technique is that it might allow the use of higher doses of radiation, shortening treatment duration from 5 to 6 weeks to only a few days.2,3 The necessity of radiation therapy is uncertain in women with small, low- to intermediate-grade DCIS undergoing lumpectomy of a tumor with negative margins. Several ongoing clinical trials are addressing this issue. For now, radiation therapy is a standard component of breast conservation in most women with DCIS. ADJUVANT SYSTEMIC THERAPY The goals of adjuvant systemic therapy include preventing the recurrence of primary breast cancer and decreasing the risk of death from the disease while ameliorating the risks of toxicity.9,10 Improvements in this area will depend on scientifically rigorous and well-designed clinical trials. Major areas of research include predictors of outcome and response using gene profiling, optimization of existing agents, and incorporation of biologically based treatments. Systemic therapy may consist of antiestrogen hormonal therapy, adjuvant chemotherapy, or both. Premenopausal or postmenopausal women with DCIS that expresses ER who are treated with lumpectomy with or without radiation have an approximate 50% relative benefit
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Mayo Clin Proc, June 2004, Vol 79
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Table 1. Aromatase Inhibitors (AIs) as Adjuvant Therapy for Postmenopausal Women With Hormonally Responsive Breast Cancer Prior adjuvant hormones
Randomization Duration of intervention
Median follow-up (mo)
Reduction in recurrence Relative†
Absolute‡
Relative reduction in contralateral breast cancer (%)
47
14%‡ (P=.03)
2.4% at 4 y
38
Placebo Letrozole
30
43% (P<.001)
6% at 4 y
46
Tamoxifen Exemestane
30.6
32% (P<.001)
4.7% at 3 y
56
Study*
No. of patients
ATAC12
9366
None
5y
Tamoxifen Anastrozole Tamoxifen + anastrozole†
MA.1713
5187
5 y of tamoxifen
5y
IES14
4742
2 or 3 y of tamoxifen
3 or 2 y§
Treatment
*ATAC = Arimidex, Tamoxifen Alone or in Combination; IES = International Exemestane Study; MA.17 = Letrozole vs Placebo After 5 Years of Tamoxifen. †In favor of AI. ‡Results of the combined arm similar to those of tamoxifen alone. §3 years after 2 years of tamoxifen, or 2 years after 3 years of tamoxifen.
in decreasing disease recurrence (but only a small absolute benefit, about 1%-2%) from the 5-year use of adjuvant tamoxifen; AIs currently are being evaluated in clinical trials for postmenopausal women. However, no evidence at this time suggests that these hormonal agents affect survival of patients with DCIS. Chemotherapy is not recommended as adjuvant therapy in the setting of DCIS. The selection of hormonal adjuvant therapy for women with invasive breast cancer depends on the menopausal status of the patient because the status determines the source of estrogen production (the ovaries in premenopausal women, peripheral tissues in postmenopausal women). Patients with resected invasive breast cancer whose tumors express ER and/or progesterone receptor (PR) typically receive 5 years of antiestrogen treatment in the form of tamoxifen; an even better approach appears to be the use of an AI (such as anastrozole) if the patient is postmenopausal.11,12 Clinical trials have shown that continuing to use tamoxifen after 5 years is not helpful (and may be detrimental in terms of increased tumor relapse). A recent study showed that the AI letrozole improves disease-free survival if used for 5 years in postmenopausal women who have completed 5 years of tamoxifen use and who are free of disease.13 Another recent study showed that for postmenopausal women with hormonally responsive tumors, it is better to switch to the AI exemestane after 2 to 3 years of tamoxifen use because exemestane significantly improves disease-free survival compared with 5 years of tamoxifen use.14 New clinical trials are comparing the efficacies of the following: 5 years of tamoxifen use followed by 5 years of AI use, 5 or even 10 years of AI use, or 2 to 3 years of tamoxifen use followed by AI use for the rest of the 5-year period of hormonal therapy. Three AIs are available for use in the United States: anastrozole, letrozole, and exemestane; only anastrozole has
been approved for the adjuvant setting, but approval of letrozole and perhaps exemestane for this indication is expected this year. Adjuvant AIs for postmenopausal women with hormonally responsive tumors are summarized in Table 1.12-14 For premenopausal women, one of the central issues related to hormonal therapy is the role of ovarian ablation as a substitute for, or in combination with, systemic chemotherapy. Several ongoing trials are addressing this issue, including the Suppression of Ovarian Function Trial (SOFT), IBCSG 24-02; the Tamoxifen and Exemestane Trial (TEXT), IBCSG 25-02; and the Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial, IBCSG 26-02; information is available at the Cancer Trials Support Unit (CTSU) Web site (www.ctsu.org). Combination chemotherapy is recommended for many premenopausal or postmenopausal women with invasive breast cancer who are eligible to receive adjuvant therapy. Adjuvant chemotherapy should be discussed with patients diagnosed as having invasive tumors larger than 1.0 cm.9,10 Many types of chemotherapy approaches are available, and recent data have provided a better understanding of optimal regimens. Anthracycline (doxorubicin or epirubicin)containing regimens are better than cyclophosphamide, methotrexate, 5-fluorouracil type of chemotherapy; thus, this latter regimen is used less frequently than it was 5 to 10 years ago. Taxanes (paclitaxel or docetaxel) improve disease-free and overall survival for patients with nodepositive breast cancer (data are pending regarding their therapeutic ratio in patients with node-negative breast cancer). Taxanes may be used either sequentially or concurrently with the anthracyclines, depending on the agent used. The typical duration of adjuvant systemic chemotherapy ranges from 2 to 6 months; the duration of older regimens was 6 months to 2 years. Variations in drug ad-
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ministration appear to alter the efficacy of chemotherapy, and newer trials are exploring this strategy. Treatment of patients with node-negative disease is evolving, and many ongoing trials are attempting to identify predictors of response and to select patients most likely to benefit from different therapies. In general, the same principles as those outlined for node-positive disease also apply to patients with node-negative breast cancer; however, although the relative improvements with chemotherapy are the same irrespective of whether the nodes are involved, the absolute improvements are expected to be lower for patients with node-negative disease because of their lower risk of breast cancer recurrence. If both chemotherapy and hormonal therapy are recommended, the chemotherapy is given first to minimize toxicity and improve efficacy. LONG-TERM FOLLOW-UP The role of routine diagnostic tests in patients who have undergone primary treatment of resected breast cancer has not been established. However, mammography performed every 6 months is generally recommended after lumpectomy and radiation until stabilization of the resection scar, and yearly thereafter. Yearly mammography is generally recommended for the contralateral breast because of the risk of new primary breast cancer in the other breast of approximately 0.5% per year. Blood tests (including so-called serum tumor markers, complete blood cell count, chemistry panel) and radiological studies (such as chest radiography, magnetic resonance imaging, computed tomography, bone scanning, or positron emission tomography) are not recommended routinely. History and physical examination by medical personnel is recommended about every 6 months for the first 5 years after diagnosis for most patients with resected invasive breast cancer, and specific diagnostic studies are guided by the clinical information elicited during those visits or if intervening problems are identified by the patient. In patients who will experience a recurrence of breast cancer, approximately 17% of recurrences will be diagnosed within 5 years of the initial diagnosis. Patients with breast cancer continue to be at risk for metastatic disease for 20 or more years after diagnosis; therefore, clinical vigilance and prompt diagnostic evaluation of suspicious symptoms and signs are recommended. The most common sites of metastatic disease are bone, liver, lungs, skin, and brain, but other sites such as the peritoneum and retina may be affected by breast cancer. MANAGEMENT OF LOCALLY ADVANCED/METASTATIC DISEASE As alluded to previously, about 40% to 50% of patients diagnosed as having stage I through III breast cancer may
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ultimately develop metastatic disease (although this number is expected to decrease with the institution of better adjuvant therapies). The goals of systemic chemotherapy in this setting are to ameliorate symptoms of breast cancer, optimize quality of life, delay disease progression, and prolong survival. The decision regarding therapy choice(s) for patients with metastatic breast cancer depends on several factors, including prior therapies that were administered in the adjuvant setting, biological characteristics of the tumor, sites of involvement, and the patient’s overall clinical condition (comorbid conditions, performance status). In general, hormonal approaches are considered appropriate for patients with hormonally responsive tumors (essentially defined as ER-positive and/or PR-positive) that involve bone or soft tissues or even asymptomatic visceral disease. Otherwise, chemotherapy is the first choice. Two critically important biological factors that must be remembered in making treatment decisions are ER and HER2 status, and all patients diagnosed as having metastatic breast cancer should have their tumor tested for both of these markers (preferably based on a new biopsy, but data from the original tumor are sometimes used) to determine whether the patient may benefit from targeted therapies against these proteins. Hormonal Therapy Although tamoxifen is recommended for premenopausal women with advanced disease, the luteinizing hormone–releasing hormone agonists offer another viable option. For postmenopausal women, the AIs have provided a therapeutic ratio superior to that of tamoxifen and have become the first agents of choice. Clinical trials are ongoing to determine whether there are meaningful differences in efficacy and tolerability among the 3 available AIs. An additional option for treating patients with hormonally responsive tumors is fulvestrant, a “pure” antiestrogen that appears to be slightly better or similar in efficacy to the AI anastrozole. Currently, use of fulvestrant is either as a substitute for AIs or, perhaps more commonly, after disease progression while the patient is taking antiaromatase agents. These hormonal agents may be used in sequence but not in combination. If tumors become refractory to hormonal therapy, if significant visceral disease is present, or if a tumor has no hormonal receptors, then chemotherapy is the treatment of choice. Treatment of Patients With HER2-Negative Disease The selection of systemic chemotherapy for patients with HER2-negative breast cancer continues to be a challenge because many options are available. Although the existing approaches do not lead to ultimate cure of the
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Mayo Clin Proc, June 2004, Vol 79
disease, management goals include amelioration of symptoms from the malignancy and improvements in the quality and duration of life. Some patients receive singleagent treatment, whereas others may benefit from combination therapies. In general, combination therapies lead to better response rates and time to progression, but not always to better survival, than do sequential single-agent approaches. No single chemotherapy regimen is best for all patients; however, many options are available because of clinical investigations that revealed the antitumor activity of anthracyclines (doxorubicin, epirubicin), antimetabolites (capecitabine, gemcitabine), and antitubulin agents such as the taxanes (paclitaxel, docetaxel) and vinorelbine. Overall, individualization of care is critically important. All patients with metastatic breast cancer should seek information regarding available clinical trials, which would be discussed in more detail by the medical oncologist. More than 50 new agents are being evaluated currently in clinical trials, especially agents targeting proteins and genes believed to be involved in the pathogenesis of breast cancer: antiangiogenesis agents (bevacizumab, SU-11248), antimetabolites (gemcitabine, pemetrexed), topoisomerase inhibitors (irinotecan), farnesyl transferase inhibitors (tipifarnib), epidermal growth factor receptor inhibitors (gefitinib, erlotinib, cetuximab, lapatinib), novel taxanes (ABI-007) and other tubulin-stabilizing agents (ixabepilone), raf-1 kinase inhibitors (BAY 43.9600), and others. Physicians and patients should seek available information from clinical trials to help improve the outcome of patients with advanced breast cancer. Treatment of Patients With HER2-Positive Disease Patients with HER2-positive disease (defined as either positive for HER2 gene amplification by fluorescence in situ hybridization or HER2 3+ positive protein overexpression by immunohistochemistry) are treated differently than are those with HER2-negative breast cancer, at least in terms of first-line chemotherapy for metastatic disease. If the tumor is ER-positive and/or PR-positive and HER2positive, hormonal therapy alone (without trastuzumab) may be appropriate if the patient has only soft tissue or bone disease and no evidence of rapidly progressive metastases. Patients with visceral disease or symptomatic progressive tumors that are no longer responding to hormones or are ER-negative and/or PR-negative should be treated with the anti-HER2 monoclonal antibody trastuzumab added to chemotherapy. This recommendation is based on the survival advantage of this approach compared with chemotherapy alone. It is recommended that trastuzumab not be
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used concurrently with anthracyclines because of an increased risk of cardiac toxicity. Trastuzumab therapy is associated with a small risk of congestive heart failure, which is managed with otherwise standard therapies for congestive heart failure (angiotensin-converting enzyme inhibitors, diuretics, β-blockers, digoxin). This cardiac toxicity appears to be different from that related to anthracyclines because it is not dose dependent, appears not to be associated with identifiable structural cardiac abnormalities, and tends to improve promptly with therapy in most patients.14 Ongoing clinical trials are evaluating the potential role of trastuzumab as part of adjuvant therapy for HER2-positive resected invasive breast cancer. SUPPORTIVE CARE ISSUES Many improvements have been made in supportive care, which translate into better tolerability of therapy and marked amelioration of disease symptoms. These advances include newer antiemetics, use of prophylactic growth factor support (to maintain neutrophils and hemoglobin), and bisphosphonates. The 2 bisphosphonates currently available, pamidronate and zoledronic acid (others are being investigated), are used in the setting of lytic bone metastases to ameliorate pain and decrease the risk of skeletalrelated events such as fractures. CONCLUSIONS Breast cancer management is a rapidly evolving field. New technologies are being incorporated to better understand the biology of this disease and to help identify the genes involved in prognosis and responsiveness to therapy. These findings, added to improved risk assessment and prevention strategies, as well as screening, diagnosis, treatment, and supportive care, hold great promise for the future. Education and translational clinical trials will be the key to success. REFERENCES 1. 2.
3.
4. 5.
Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29. Humphrey LL, Helfand M, Chan BKS, Woolf SH. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137(5, pt 1):347-360. Smith RA, Saslow D, Andrews Sawyer K, et al, High-Risk Work Group, Screening Older Women Work Group, Mammography Work Group, Physical Examination Work Group, New Technologies Work Group, Breast Cancer Advisory Group. American Cancer Society guidelines for breast cancer screening: update 2003. CA Cancer J Clin. 2003;53:141-169. Mincey BA. Genetics and the management of women at high risk for breast cancer. Oncologist. 2003;8:466-473. Boyd NF, Martin LJ, Stone J, Greenberg C, Minkin S, Yaffe MJ. Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention. Curr Oncol Rep. 2001;3:314321.
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Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet. 2003;361:296300. Green FL, Page DL, Fleming ID, et al, American Joint Committee on Cancer, eds. AJCC Cancer Staging Handbook: From the AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2002. Recht A. Integration of systemic therapy and radiation therapy for patients with early-stage breast cancer treated with conservative surgery. Clin Breast Cancer. 2003;4:104-113. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst. 2001;93:979-989. Mincey BA, Palmieri FM, Perez EA. Adjuvant therapy for breast cancer: recommendations for management based on consensus review and recent clinical trials. Oncologist. 2002;7:246-250. Pritchard KI. The best use of adjuvant endocrine treatments. Breast. 2003;12:497-508. ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer. 2003;98:1802-1810. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349:1793-1802. Coombes RC, Hall E, Gibson LJ, et al, Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350:1081-1092.
Questions About Breast Cancer 1. Which one of the following is not included in the Gail model for prediction of breast cancer risk? a. Presence of the BRCA1 gene mutation b. Family history of breast cancer in first-degree relatives c. History of atypical ductal hyperplasia d. Number of prior breast biopsies e. Age at menarche
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2. Which one of the following is the only agent currently approved by the US Food and Drug Administration to decrease the risk of primary breast cancer development? a. Raloxifene b. Tamoxifen c. Idoxifene d. Alendronate e. Risedronate 3. In which one of the following situations is external beam radiotherapy not routinely recommended? a. After lumpectomy for invasive breast cancer b. After mastectomy in patients with 1 to 3 involved axillary lymph nodes c. After mastectomy for patients with >3 involved axillary lymph nodes d. After mastectomy for a primary tumor >5 cm e. After lumpectomy for large DCIS (>2.5 cm) 4. Which one of the following is the current recommended duration of adjuvant tamoxifen treatment for patients with resected hormonally responsive breast cancer? a. 6 months b. 1 year c. 5 years d. 10 years e. For life 5. Which one of the following proteins is targeted by the monoclonal antibody trastuzumab? a. Raf-1 kinase b. HER1 c. HER2 d. HER3 e. HER4 Correct answers: 1. a, 2. b, 3. b, 4. c, 5. c
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Breast Cancer
Mayo Clin Proc, June 2004, Vol 79
Concise Review for Clinicians
Advances in Screening, Diagnosis, and Treatment of Breast Cancer BETTY A. MINCEY, MD, AND EDITH A. PEREZ, MD have been evolving. Advances in screening, diagnosis, and treatment of breast cancer continue to influence our approach to patients with this disease. Many improvements have been made as well in supportive care, including increased tolerability of therapy and notable amelioration of disease symptoms. Mayo Clin Proc. 2004;79:810-816
Breast cancer is the most common cancer in women in the United States; this year, approximately 215,900 new cases will be diagnosed. Mammography remains the cornerstone of screening, with technologies such as ultrasonography and magnetic resonance imaging having an increasingly defined role. Improved risk assessment and prevention strategies have been implemented, and current research in these areas includes better identification of patients at risk, the use of aromatase inhibitors and other agents to reduce risk, and the use of surrogate markers. Breast cancer staging has been optimized recently; also, local management of breast cancer, adjuvant systemic therapies, and treatment of patients with advanced disease
AI = aromatase inhibitor; CI = confidence interval; DCIS = ductal carcinoma in situ; ER = estrogen receptor; LCIS = lobular carcinoma in situ; NSABP = National Surgical Adjuvant Breast and Bowel Project; PR = progesterone receptor; STAR = Study of Tamoxifen and Raloxifene
B
reast cancer is the most common cancer in women in the United States, with incidence increasing about 0.5% per year. In the year 2004, an estimated 215,900 new cases of invasive breast cancer (stages I-IV) will be diagnosed, and about 40,100 women and 470 men will die of the disease.1 New strategies to decrease the risk of breast cancer are being studied and implemented. Although breast cancer is a leading cause of death in women (second only to lung cancer), mortality rates have declined recently. This reduction in mortality, despite the increase in incidence, is attributed to improvements in screening, diagnosis, and treatment.
The sensitivity of first mammography ranged from 71% to 96% in studies of a 1-year screening interval.2,3 The positive predictive value of abnormal mammographic results requiring biopsy ranged from 12% to 78% in these studies and increased with age.2,3 Young women at increased risk of breast cancer development should be advised to undergo mammography before age 40 years. Current guidelines suggest that women with BRCA1 or BRCA2 mutations should begin screening mammography at age 25 years or 10 years earlier than the youngest age at which breast cancer has been diagnosed in their family.4 Although it is intuitive to recommend this approach to women with a strong family history of breast cancer and unknown genetic makeup, data are not currently available to quantify benefit for this group. Unfortunately, mammography in these groups of young women has a sensitivity of only about 33% in most studies. Ultrasonography does not improve this sensitivity and is not recommended for screening; magnetic resonance imaging of the breast has a sensitivity of between 90% and 100% but is expensive and has not been endorsed for screening purposes.2,3 Ongoing trials are further exploring these technologies. The clinical breast examination is an important part of breast cancer screening and surveillance because up to 10% of breast cancers may be clinically evident while mammographically occult.2,3 The role of breast self-examination has not been well-defined.
SCREENING Despite controversy surrounding recent reports, mammography remains the cornerstone of breast cancer screening. Mammographic screening for early detection of breast cancer reduces mortality and is widely recommended as an integral part of annual preventive health care for all women beginning at age 50 years and continuing for as long as a woman’s life expectancy is at least 10 years. For women older than 40 years, most major health organizations recommend annual or semiannual screening mammography.2,3 From the Division of General Internal Medicine (B.A.M.), Multidisciplinary Breast Clinic (B.A.M., E.A.P.), and Division of Hematology and Oncology (E.A.P.), Mayo Clinic College of Medicine, Jacksonville, Fla. A question-and-answer section appears at the end of this article. Individual reprints of this article are not available. Address correspondence to Edith A. Perez, MD, Division of Hematology and Oncology, Mayo Clinic College of Medicine, 4500 San Pablo Rd, Jacksonville, FL 32224 (e-mail: [email protected]). Mayo Clin Proc. 2004;79:810-816
RISK ASSESSMENT For some women, the risk of developing breast cancer is high enough to warrant consideration of prevention strate810
© 2004 Mayo Foundation for Medical Education and Research
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gies in addition to screening and surveillance. Current methods for defining risk include use of the modified Gail model, use of the Claus model, and determination of BRCA mutation carrier status.4 The modified Gail model combines relative risks associated with age, race, age at menarche, number of previous breast biopsies, history of atypical ductal hyperplasia, and family history of breast cancer in first-degree relatives for estimation of 5-year and lifetime risks of breast cancer development in an individual woman. The online risk-assessment tool, located at www .breastcancerprevention.com, provides comprehensive information approved by the National Cancer Institute and includes a system of scoring an individual’s risk of developing breast cancer in the next 5 years and by age 80 years. A score of 1.66% or higher for the next 5 years indicates high risk. This model is reasonable for estimating risk in most women but may seriously underestimate risk in women with strong family histories of breast cancer. For such women, the Claus model, which considers only family history, can be used to estimate risk. In appropriate cases, genetic counseling and testing for mutations in BRCA1 or BRCA2 genes may be considered. None of the risk models consider a history of lobular carcinoma in situ (LCIS), which is primarily regarded as a risk factor rather than a precursor lesion and is associated with an annual risk of approximately 1% for breast cancer development in either breast. An additional risk factor is mammographic density. Breasts with larger amounts of connective and epithelial tissue appear denser than do breasts with more fat. Mammographically dense breast tissue is one of the strongest established risk factors for breast cancer, conferring a 4to 6-fold increased risk for women with the most dense breast tissue compared with those with the least dense.5 Mammographic density also decreases the sensitivity of mammography. The relative importance of mammographic density as a risk factor and the underlying mechanisms responsible for the increased risk in women with dense breast tissue are topics of ongoing research. PREVENTION Women with a substantially increased risk of breast cancer should be counseled regarding options for breast cancer prevention. Defining the level of risk that warrants intervention may be difficult and should be done on an individual basis, taking into account a woman’s age, comorbidities, and her own thoughts about her risk and how it affects her quality of life. Decisions regarding interventions such as chemoprevention or surgical prophylaxis must be highly individualized and will vary greatly among women with similar risk levels.
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Tamoxifen, a selective estrogen receptor (ER) modulator that has been used for years to treat breast cancer, is the only agent currently approved by the US Food and Drug Administration to decrease the risk of breast cancer. Its approval by this agency for prevention of breast cancer was based on the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 study, in which a relative risk reduction of approximately 50% was observed for women with a 5-year risk of 1.66% or higher, as calculated by the modified Gail model (despite notable adverse effects among 13,388 women, including 3 women in the tamoxifen group who died of pulmonary emboli vs none in the placebo arm). A meta-analysis of 5 worldwide trials that evaluated tamoxifen vs placebo in women at increased risk of breast cancer revealed a 38% (95% confidence interval [CI], 28%-46%; P<.001) relative reduction in risk of breast cancer development at 5 years of follow-up.6 In terms of absolute numbers, patients in the placebo group had an approximate 13% risk of developing a ductal carcinoma in situ (DCIS) or invasive breast cancer during the study periods vs 7% of those in the tamoxifen arm. There was no effect on ER-negative breast cancer but a 48% relative decrease in ER-positive disease. However, the risk of endometrial cancer was increased (odds ratio, 2.4; 95% CI, 1.5-4.0), as was the risk of venous thromboembolism (odds ratio, 1.9; 95% CI, 1.4-2.7). Survival differences between tamoxifen and placebo have not been shown to date. Ongoing trials are evaluating other prevention strategies. The Study of Tamoxifen and Raloxifene (STAR), NSABP P-2 trial is comparing 5 years of tamoxifen use vs raloxifene use, another selective ER modulator, with eligibility determined as for the NSABP P-1 study by an estimated baseline risk of breast cancer higher than 1.66% at 5 years, based on the modified Gail model. The accrual goal for STAR is 19,000 women, which should be achieved this year. A large prevention study (MAP.3) about to begin at multiple medical centers in the United States and Canada will compare the effectiveness of the aromatase inhibitor (AI) exemestane, either alone or in combination with celecoxib, with placebo for reducing the risk of breast cancer in high-risk women. For women with a substantially elevated risk of breast cancer development, particularly those proved to carry mutations in BRCA1 or BRCA2, surgical options for prevention should be discussed.4 Available data regarding risk reduction with surgical prophylaxis indicate that bilateral mastectomy reduces the risk of breast cancer development by approximately 90% and that oophorectomy reduces the risk of breast cancer by approximately 50% if performed before menopause.4 These risk reductions are based on retrospective, observational studies and on more recent prospective observational studies of women at high risk.
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Three important areas of research in the prevention setting include better identification and definition of patients at increased risk of breast cancer development, the use of AIs, and the use of agents that may decrease the risk of hormone receptor–negative disease. Surrogate markers for breast cancer risk are being sought so that pilot trials of new agents can be completed with fewer participants in less time than is needed to show actual changes in cancer incidence. An example of a potential surrogate marker is mammographic density. Because it is not only measurable but also may be altered potentially by interventions such as selective ER modulators or AIs, mammographic density may prove to be a useful surrogate marker for both risk and risk reduction. A small, ongoing 1-year study (MAP.2) will determine the effectiveness of exemestane in reducing mammographic density. BREAST CANCER STAGING Most patients presenting with breast cancer have disease localized to the breast or to the breast and axillary lymph nodes; however, 40% to 50% eventually may develop metastatic disease. A new staging system became standard in 2003: the 6th American College of Physicians Staging,7 which assigns a stage from 0 to IV on the basis of the anatomical extent of the tumor, including invasiveness, size, and lymph node or distal involvement. Stage 0 (Tis) breast cancers are DCIS (or intraductal) carcinomas. Lobular carcinoma in situ increasingly is considered a risk factor for subsequent breast cancer, but it is still included as a malignancy in the most recent staging system and is classified as “Tis (LCIS).”7 Stages I through IV are invasive tumors, most commonly of the infiltrating ductal type. The histological subtype of breast cancer is not part of the staging system but is important for its potential influence on patient outcome. LOCAL MANAGEMENT OF PRIMARY BREAST CANCER The management of primary breast cancer, whether invasive or in situ, begins with local treatment. The only exclusion is LCIS, which is managed as a determinant of increased risk; in other words, management after a biopsy specimen shows LCIS does not require full excision, lumpectomy, or mastectomy. As a determinant of increased risk of subsequent breast cancer, LCIS is managed by observation (follow-up) and chemoprevention. Most women with newly diagnosed breast cancer have a choice between breast conservation therapy with lumpectomy and radiation or mastectomy. Although the chance of recurrence is higher with breast conservation therapy, the effect of both therapies on overall survival is the same. Women with large tumors or those with multifocal breast cancer often are not candidates for breast conservation.
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Sentinel lymph node evaluation has essentially become a standard of care as part of the staging of invasive breast cancer. Outside of clinical trials, if the sentinel lymph node is negative for tumor by hematoxylin and eosin pathological evaluation, then axillary node dissection is not performed. However, a full axillary node dissection is performed if the sentinel lymph node is positive for tumor. Ongoing clinical trials are evaluating the feasibility of obviating full dissection in patients whose sentinel lymph node is positive for malignancy. Routine evaluation of the sentinel lymph node in the setting of DCIS has not been established, although it is included sometimes in patients with multifocal or high-grade DCIS. External beam radiotherapy is a standard component of local treatment of patients with invasive breast cancer when breast conservation is undertaken.8 For women who have undergone mastectomy, this therapy is not routinely recommended unless the tumor is large (>5.0 cm), there is chest wall involvement, or more than 3 axillary lymph nodes are involved. The use of postmastectomy radiation therapy for patients with 1 to 3 lymph nodes positive for malignancy is controversial. Generally, radiation therapy after breast conserving surgery consists of whole breast external beam radiotherapy administered over 5 to 6 weeks, but new techniques are evaluating partial breast irradiation. Partial breast irradiation is administered generally to the portion of the breast that includes the tumor bed and an area of surrounding margin. One advantage of this technique is that it might allow the use of higher doses of radiation, shortening treatment duration from 5 to 6 weeks to only a few days.2,3 The necessity of radiation therapy is uncertain in women with small, low- to intermediate-grade DCIS undergoing lumpectomy of a tumor with negative margins. Several ongoing clinical trials are addressing this issue. For now, radiation therapy is a standard component of breast conservation in most women with DCIS. ADJUVANT SYSTEMIC THERAPY The goals of adjuvant systemic therapy include preventing the recurrence of primary breast cancer and decreasing the risk of death from the disease while ameliorating the risks of toxicity.9,10 Improvements in this area will depend on scientifically rigorous and well-designed clinical trials. Major areas of research include predictors of outcome and response using gene profiling, optimization of existing agents, and incorporation of biologically based treatments. Systemic therapy may consist of antiestrogen hormonal therapy, adjuvant chemotherapy, or both. Premenopausal or postmenopausal women with DCIS that expresses ER who are treated with lumpectomy with or without radiation have an approximate 50% relative benefit
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Table 1. Aromatase Inhibitors (AIs) as Adjuvant Therapy for Postmenopausal Women With Hormonally Responsive Breast Cancer Prior adjuvant hormones
Randomization Duration of intervention
Median follow-up (mo)
Reduction in recurrence Relative†
Absolute‡
Relative reduction in contralateral breast cancer (%)
47
14%‡ (P=.03)
2.4% at 4 y
38
Placebo Letrozole
30
43% (P<.001)
6% at 4 y
46
Tamoxifen Exemestane
30.6
32% (P<.001)
4.7% at 3 y
56
Study*
No. of patients
ATAC12
9366
None
5y
Tamoxifen Anastrozole Tamoxifen + anastrozole†
MA.1713
5187
5 y of tamoxifen
5y
IES14
4742
2 or 3 y of tamoxifen
3 or 2 y§
Treatment
*ATAC = Arimidex, Tamoxifen Alone or in Combination; IES = International Exemestane Study; MA.17 = Letrozole vs Placebo After 5 Years of Tamoxifen. †In favor of AI. ‡Results of the combined arm similar to those of tamoxifen alone. §3 years after 2 years of tamoxifen, or 2 years after 3 years of tamoxifen.
in decreasing disease recurrence (but only a small absolute benefit, about 1%-2%) from the 5-year use of adjuvant tamoxifen; AIs currently are being evaluated in clinical trials for postmenopausal women. However, no evidence at this time suggests that these hormonal agents affect survival of patients with DCIS. Chemotherapy is not recommended as adjuvant therapy in the setting of DCIS. The selection of hormonal adjuvant therapy for women with invasive breast cancer depends on the menopausal status of the patient because the status determines the source of estrogen production (the ovaries in premenopausal women, peripheral tissues in postmenopausal women). Patients with resected invasive breast cancer whose tumors express ER and/or progesterone receptor (PR) typically receive 5 years of antiestrogen treatment in the form of tamoxifen; an even better approach appears to be the use of an AI (such as anastrozole) if the patient is postmenopausal.11,12 Clinical trials have shown that continuing to use tamoxifen after 5 years is not helpful (and may be detrimental in terms of increased tumor relapse). A recent study showed that the AI letrozole improves disease-free survival if used for 5 years in postmenopausal women who have completed 5 years of tamoxifen use and who are free of disease.13 Another recent study showed that for postmenopausal women with hormonally responsive tumors, it is better to switch to the AI exemestane after 2 to 3 years of tamoxifen use because exemestane significantly improves disease-free survival compared with 5 years of tamoxifen use.14 New clinical trials are comparing the efficacies of the following: 5 years of tamoxifen use followed by 5 years of AI use, 5 or even 10 years of AI use, or 2 to 3 years of tamoxifen use followed by AI use for the rest of the 5-year period of hormonal therapy. Three AIs are available for use in the United States: anastrozole, letrozole, and exemestane; only anastrozole has
been approved for the adjuvant setting, but approval of letrozole and perhaps exemestane for this indication is expected this year. Adjuvant AIs for postmenopausal women with hormonally responsive tumors are summarized in Table 1.12-14 For premenopausal women, one of the central issues related to hormonal therapy is the role of ovarian ablation as a substitute for, or in combination with, systemic chemotherapy. Several ongoing trials are addressing this issue, including the Suppression of Ovarian Function Trial (SOFT), IBCSG 24-02; the Tamoxifen and Exemestane Trial (TEXT), IBCSG 25-02; and the Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial, IBCSG 26-02; information is available at the Cancer Trials Support Unit (CTSU) Web site (www.ctsu.org). Combination chemotherapy is recommended for many premenopausal or postmenopausal women with invasive breast cancer who are eligible to receive adjuvant therapy. Adjuvant chemotherapy should be discussed with patients diagnosed as having invasive tumors larger than 1.0 cm.9,10 Many types of chemotherapy approaches are available, and recent data have provided a better understanding of optimal regimens. Anthracycline (doxorubicin or epirubicin)containing regimens are better than cyclophosphamide, methotrexate, 5-fluorouracil type of chemotherapy; thus, this latter regimen is used less frequently than it was 5 to 10 years ago. Taxanes (paclitaxel or docetaxel) improve disease-free and overall survival for patients with nodepositive breast cancer (data are pending regarding their therapeutic ratio in patients with node-negative breast cancer). Taxanes may be used either sequentially or concurrently with the anthracyclines, depending on the agent used. The typical duration of adjuvant systemic chemotherapy ranges from 2 to 6 months; the duration of older regimens was 6 months to 2 years. Variations in drug ad-
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ministration appear to alter the efficacy of chemotherapy, and newer trials are exploring this strategy. Treatment of patients with node-negative disease is evolving, and many ongoing trials are attempting to identify predictors of response and to select patients most likely to benefit from different therapies. In general, the same principles as those outlined for node-positive disease also apply to patients with node-negative breast cancer; however, although the relative improvements with chemotherapy are the same irrespective of whether the nodes are involved, the absolute improvements are expected to be lower for patients with node-negative disease because of their lower risk of breast cancer recurrence. If both chemotherapy and hormonal therapy are recommended, the chemotherapy is given first to minimize toxicity and improve efficacy. LONG-TERM FOLLOW-UP The role of routine diagnostic tests in patients who have undergone primary treatment of resected breast cancer has not been established. However, mammography performed every 6 months is generally recommended after lumpectomy and radiation until stabilization of the resection scar, and yearly thereafter. Yearly mammography is generally recommended for the contralateral breast because of the risk of new primary breast cancer in the other breast of approximately 0.5% per year. Blood tests (including so-called serum tumor markers, complete blood cell count, chemistry panel) and radiological studies (such as chest radiography, magnetic resonance imaging, computed tomography, bone scanning, or positron emission tomography) are not recommended routinely. History and physical examination by medical personnel is recommended about every 6 months for the first 5 years after diagnosis for most patients with resected invasive breast cancer, and specific diagnostic studies are guided by the clinical information elicited during those visits or if intervening problems are identified by the patient. In patients who will experience a recurrence of breast cancer, approximately 17% of recurrences will be diagnosed within 5 years of the initial diagnosis. Patients with breast cancer continue to be at risk for metastatic disease for 20 or more years after diagnosis; therefore, clinical vigilance and prompt diagnostic evaluation of suspicious symptoms and signs are recommended. The most common sites of metastatic disease are bone, liver, lungs, skin, and brain, but other sites such as the peritoneum and retina may be affected by breast cancer. MANAGEMENT OF LOCALLY ADVANCED/METASTATIC DISEASE As alluded to previously, about 40% to 50% of patients diagnosed as having stage I through III breast cancer may
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ultimately develop metastatic disease (although this number is expected to decrease with the institution of better adjuvant therapies). The goals of systemic chemotherapy in this setting are to ameliorate symptoms of breast cancer, optimize quality of life, delay disease progression, and prolong survival. The decision regarding therapy choice(s) for patients with metastatic breast cancer depends on several factors, including prior therapies that were administered in the adjuvant setting, biological characteristics of the tumor, sites of involvement, and the patient’s overall clinical condition (comorbid conditions, performance status). In general, hormonal approaches are considered appropriate for patients with hormonally responsive tumors (essentially defined as ER-positive and/or PR-positive) that involve bone or soft tissues or even asymptomatic visceral disease. Otherwise, chemotherapy is the first choice. Two critically important biological factors that must be remembered in making treatment decisions are ER and HER2 status, and all patients diagnosed as having metastatic breast cancer should have their tumor tested for both of these markers (preferably based on a new biopsy, but data from the original tumor are sometimes used) to determine whether the patient may benefit from targeted therapies against these proteins. Hormonal Therapy Although tamoxifen is recommended for premenopausal women with advanced disease, the luteinizing hormone–releasing hormone agonists offer another viable option. For postmenopausal women, the AIs have provided a therapeutic ratio superior to that of tamoxifen and have become the first agents of choice. Clinical trials are ongoing to determine whether there are meaningful differences in efficacy and tolerability among the 3 available AIs. An additional option for treating patients with hormonally responsive tumors is fulvestrant, a “pure” antiestrogen that appears to be slightly better or similar in efficacy to the AI anastrozole. Currently, use of fulvestrant is either as a substitute for AIs or, perhaps more commonly, after disease progression while the patient is taking antiaromatase agents. These hormonal agents may be used in sequence but not in combination. If tumors become refractory to hormonal therapy, if significant visceral disease is present, or if a tumor has no hormonal receptors, then chemotherapy is the treatment of choice. Treatment of Patients With HER2-Negative Disease The selection of systemic chemotherapy for patients with HER2-negative breast cancer continues to be a challenge because many options are available. Although the existing approaches do not lead to ultimate cure of the
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disease, management goals include amelioration of symptoms from the malignancy and improvements in the quality and duration of life. Some patients receive singleagent treatment, whereas others may benefit from combination therapies. In general, combination therapies lead to better response rates and time to progression, but not always to better survival, than do sequential single-agent approaches. No single chemotherapy regimen is best for all patients; however, many options are available because of clinical investigations that revealed the antitumor activity of anthracyclines (doxorubicin, epirubicin), antimetabolites (capecitabine, gemcitabine), and antitubulin agents such as the taxanes (paclitaxel, docetaxel) and vinorelbine. Overall, individualization of care is critically important. All patients with metastatic breast cancer should seek information regarding available clinical trials, which would be discussed in more detail by the medical oncologist. More than 50 new agents are being evaluated currently in clinical trials, especially agents targeting proteins and genes believed to be involved in the pathogenesis of breast cancer: antiangiogenesis agents (bevacizumab, SU-11248), antimetabolites (gemcitabine, pemetrexed), topoisomerase inhibitors (irinotecan), farnesyl transferase inhibitors (tipifarnib), epidermal growth factor receptor inhibitors (gefitinib, erlotinib, cetuximab, lapatinib), novel taxanes (ABI-007) and other tubulin-stabilizing agents (ixabepilone), raf-1 kinase inhibitors (BAY 43.9600), and others. Physicians and patients should seek available information from clinical trials to help improve the outcome of patients with advanced breast cancer. Treatment of Patients With HER2-Positive Disease Patients with HER2-positive disease (defined as either positive for HER2 gene amplification by fluorescence in situ hybridization or HER2 3+ positive protein overexpression by immunohistochemistry) are treated differently than are those with HER2-negative breast cancer, at least in terms of first-line chemotherapy for metastatic disease. If the tumor is ER-positive and/or PR-positive and HER2positive, hormonal therapy alone (without trastuzumab) may be appropriate if the patient has only soft tissue or bone disease and no evidence of rapidly progressive metastases. Patients with visceral disease or symptomatic progressive tumors that are no longer responding to hormones or are ER-negative and/or PR-negative should be treated with the anti-HER2 monoclonal antibody trastuzumab added to chemotherapy. This recommendation is based on the survival advantage of this approach compared with chemotherapy alone. It is recommended that trastuzumab not be
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used concurrently with anthracyclines because of an increased risk of cardiac toxicity. Trastuzumab therapy is associated with a small risk of congestive heart failure, which is managed with otherwise standard therapies for congestive heart failure (angiotensin-converting enzyme inhibitors, diuretics, β-blockers, digoxin). This cardiac toxicity appears to be different from that related to anthracyclines because it is not dose dependent, appears not to be associated with identifiable structural cardiac abnormalities, and tends to improve promptly with therapy in most patients.14 Ongoing clinical trials are evaluating the potential role of trastuzumab as part of adjuvant therapy for HER2-positive resected invasive breast cancer. SUPPORTIVE CARE ISSUES Many improvements have been made in supportive care, which translate into better tolerability of therapy and marked amelioration of disease symptoms. These advances include newer antiemetics, use of prophylactic growth factor support (to maintain neutrophils and hemoglobin), and bisphosphonates. The 2 bisphosphonates currently available, pamidronate and zoledronic acid (others are being investigated), are used in the setting of lytic bone metastases to ameliorate pain and decrease the risk of skeletalrelated events such as fractures. CONCLUSIONS Breast cancer management is a rapidly evolving field. New technologies are being incorporated to better understand the biology of this disease and to help identify the genes involved in prognosis and responsiveness to therapy. These findings, added to improved risk assessment and prevention strategies, as well as screening, diagnosis, treatment, and supportive care, hold great promise for the future. Education and translational clinical trials will be the key to success. REFERENCES 1. 2.
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Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29. Humphrey LL, Helfand M, Chan BKS, Woolf SH. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;137(5, pt 1):347-360. Smith RA, Saslow D, Andrews Sawyer K, et al, High-Risk Work Group, Screening Older Women Work Group, Mammography Work Group, Physical Examination Work Group, New Technologies Work Group, Breast Cancer Advisory Group. American Cancer Society guidelines for breast cancer screening: update 2003. CA Cancer J Clin. 2003;53:141-169. Mincey BA. Genetics and the management of women at high risk for breast cancer. Oncologist. 2003;8:466-473. Boyd NF, Martin LJ, Stone J, Greenberg C, Minkin S, Yaffe MJ. Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention. Curr Oncol Rep. 2001;3:314321.
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Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast-cancer prevention trials. Lancet. 2003;361:296300. Green FL, Page DL, Fleming ID, et al, American Joint Committee on Cancer, eds. AJCC Cancer Staging Handbook: From the AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2002. Recht A. Integration of systemic therapy and radiation therapy for patients with early-stage breast cancer treated with conservative surgery. Clin Breast Cancer. 2003;4:104-113. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst. 2001;93:979-989. Mincey BA, Palmieri FM, Perez EA. Adjuvant therapy for breast cancer: recommendations for management based on consensus review and recent clinical trials. Oncologist. 2002;7:246-250. Pritchard KI. The best use of adjuvant endocrine treatments. Breast. 2003;12:497-508. ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses. Cancer. 2003;98:1802-1810. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349:1793-1802. Coombes RC, Hall E, Gibson LJ, et al, Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350:1081-1092.
Questions About Breast Cancer 1. Which one of the following is not included in the Gail model for prediction of breast cancer risk? a. Presence of the BRCA1 gene mutation b. Family history of breast cancer in first-degree relatives c. History of atypical ductal hyperplasia d. Number of prior breast biopsies e. Age at menarche
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2. Which one of the following is the only agent currently approved by the US Food and Drug Administration to decrease the risk of primary breast cancer development? a. Raloxifene b. Tamoxifen c. Idoxifene d. Alendronate e. Risedronate 3. In which one of the following situations is external beam radiotherapy not routinely recommended? a. After lumpectomy for invasive breast cancer b. After mastectomy in patients with 1 to 3 involved axillary lymph nodes c. After mastectomy for patients with >3 involved axillary lymph nodes d. After mastectomy for a primary tumor >5 cm e. After lumpectomy for large DCIS (>2.5 cm) 4. Which one of the following is the current recommended duration of adjuvant tamoxifen treatment for patients with resected hormonally responsive breast cancer? a. 6 months b. 1 year c. 5 years d. 10 years e. For life 5. Which one of the following proteins is targeted by the monoclonal antibody trastuzumab? a. Raf-1 kinase b. HER1 c. HER2 d. HER3 e. HER4 Correct answers: 1. a, 2. b, 3. b, 4. c, 5. c
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