Coming of Age: Breast Cancer in Seniors HYMAN B. MUSS

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1 The Oncologist Understanding and Treating Triple-Negative Breast Cancer Across the Age Spectrum Coming of Age: Breast Cancer in Seniors HYMAN B. MUSS The University of North Carolina Lineberger Cancer Center, Chapel Hill, North Carolina, USA Key Words. Breast cancer Geriatric assessment Adjuvant chemotherapy Triple-negative breast cancer Estrogen receptor Progesterone receptor HER-2 receptor Disclosures: Hyman B. Muss: Consultant/advisory role: Wyeth, Pfizer, Amgen, Roche, Bristol-Myers Squibb, Boehringer- Ingelheim, Sandoz, Abraxis; Research funding/contracted research: Numerous trials at The University of North Carolina (UNC); author is not principal investigator on any project; all support is to UNC and author has no signatory authority over any UNC account. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. ABSTRACT In the U.S., cancer is a disease of aging. The average 65- year-old patient has an anticipated life expectancy of 20 years, and clinicians should take this into account when making breast cancer management decisions. However, older breast cancer patients can present with wide variations in health status, and treatment in older patients should therefore include a careful evaluation of comorbidities, physical function, polypharmacy, and other issues that could potentially impact a patient s ability to undergo chemotherapy without excessive risk. Evaluation tools are under development, including potential molecular markers, to identify which older patients are the best candidates for chemotherapy, as well as those more susceptible to actually developing cancer. Standard chemotherapy regimens are just as effective in older patients as they are in the younger population, and can substantially prolong life expectancy when used in the right patients. This article discusses breast cancer in seniors, including the epidemiology of breast cancer in these patients, the potential impact of comorbidities, and effective adjuvant therapy in selected older patients. The Oncologist 2010;15(suppl 5):57 65 INTRODUCTION Cancer is a disease associated with aging in the U.S. population, and breast cancer is no exception. However, effective treatment of older breast cancer patients can be complicated by multiple comorbidities and the potential toxicity of proposed therapies. Meanwhile, many women remain active and healthy with advancing years and would benefit from effective treatment. This article discusses breast cancer management issues in seniors, specifically cancer and aging, the epidemiology of breast cancer in seniors, the impact of comorbidities on life expectancy and treatment decisions, and the role of adjuvant chemotherapy and hormonal therapies in older breast cancer patients. Data from the National Cancer Institute s Surveillance Epidemiology and End Results (SEER) program show that more than half of all cancers occur in patients aged 65 years. This includes about 25% aged years, one quarter aged years, and almost 10% aged 85 years [1]. The average 65-year-old patient has an anticipated life expectancy of 20 years, and clinicians should take this into account when making breast cancer management decisions. Even a patient at the age of 75 should expect another 12 Correspondence: Hyman B. Muss, M.D., University of North Carolina Lineberger Cancer Center, Campus Box 7305, 170 Manning Drive, Chapel Hill, North Carolina 27599, USA. Telephone: ; Fax: ; muss@med.unc.edu Alpha- Med Press /2010/$30.00/0 doi: /theoncologist.2010-S5-57 The Oncologist 2010;15(suppl 5):

2 58 Breast Cancer in Seniors years of life, on average, which is rather substantial. Meanwhile, many cancers, such as triple-negative breast cancers, frequently relapse early. Thus, a 75-year-old woman with a high risk for breast cancer recurrence, and with an average life expectancy of 12 years, should be considered for the best of treatments. Another SEER registry analysis confirmed that the average age of a breast cancer patient is about 63 years, and the incidence increases dramatically with age. In terms of mortality rates, most women who die as a result of breast cancer in the U.S. are now aged 65 years (Fig. 1) [2]. Patients are often shocked to learn that cancer is a disease of older people. The average age of cancer patients is now approximately 67 years in the U.S., but the public still associates cancer with younger people. GERIATRIC ASSESSMENT:A MULTIDISCIPLINARY APPROACH In evaluating older patients with breast cancer, a key issue is whether the cancer is the patient s major illness. For instance, patients frequently present with ductal cancer in situ at the age of 75, but they also have hypertension, mild dementia, and other problems. Although the patient and family are understandably worried about the breast cancer, the real issue is the patient s other illnesses. Therefore, in older patients, it is critical to identify the most important medical problem. For example, two 80-year-old women could present very differently. On the one hand, a woman could remain active and working late in life, and on the other hand, a woman could be in a nursing home with mild dementia and poor physical function. Although they both might present with the same breast cancer stage and similar breast cancer characteristics, the management issues in these two patients are dramatically different. One strategy to assess geriatric patients is to define their physical function and estimated survival. This includes determining the functional status of the patient in their ability to perform daily tasks such as dressing themselves, walking, and cooking meals, for example. The issue of comorbidity is also important. Clinicians should carefully evaluate comorbid illnesses in the patient, in addition to their cancer. Nutrition is another important issue. Whereas weight loss is desired in many younger patient populations, in older people weight loss can lead to loss of muscle mass and shorter survival with poor function. Cognition should also be considered in older patients, because they might have a poor understanding of proposed treatment. In addition, cancer treatments can affect mental status. Likewise, psychosocial support and the potential for Figure 1. Surveillance, Epidemiology and End Results : Breast cancer incidence and mortality rates. From National Cancer Institute. Surveillance Epidemiology and End Results (SEER). Available at gov/csr/1975_2007/index.html, accessed September 21, substantial polypharmacy issues play important roles in therapeutic decisions. As expected, comorbidity or coexisting illnesses increase dramatically with age. For instance, a 70-year-old patient has an average of two or three comorbid illnesses. This is important because common comorbid illnesses such as chronic obstructive pulmonary disease (COPD), diabetes, and high blood pressure all independently shorten life expectancy. The addition of breast cancer further interferes and competes with these other diseases for survival impact. Patients in their 80s have an average of five other significant illnesses affecting survival. This is in comparison with younger people in their 50s, who frequently have only one or two other serious illnesses (Fig. 2) [3]. Physical function is an important factor that impacts survival. One analysis of 4,516 patients aged 70 years evaluated the functional morbidity index, based on selfreported scoring of their physical function. Scoring was based on the ability to bathe, shop, walk several blocks, or push or pull an object. In those reporting a high degree of functional loss, approximately one third did not survive 2 years, whereas people with excellent function had a low mortality risk. Therefore, in addition to comorbid illnesses, clinicians need to know the functional status of geriatric patients (Fig. 3) [4]. GERIATRIC ASSESSMENT TOOLS FROM THE CANCER AND LEUKEMIA GROUP B A national, coordinated effort is currently under way through the Cancer and Leukemia Group B (CALGB) cooperative group to develop brief geriatric assessment instruments for use in the clinic. Arti Hurria, M.D., at the City of Hope cancer center developed one mostly self-administered instrument that takes about 30 minutes. This tool is important because it can identify those patients who are

3 Muss 59 Figure 2. Total number of comorbidities by age. Adapted from Yancik R, Wesley MN, Ries LA et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001;285: , with permission. Copyright 2001 American Medical Association. All rights reserved. Figure 3. Function and survival: age 70. most vulnerable to treatment and in whom comorbidity and functional loss are key. Geriatricians are in short supply, and clinicians responsible for breast cancer management need an effective, easy-to-administer tool to assess and optimize care of these older patients. Another analysis of SEER data evaluated the cause of death in women with breast cancer aged 70 years across the spectrum of breast cancer, from in situ cancer, to patients with localized node-negative disease, to patients who had positive nodes, to those with metastatic cancer. Besides women with metastatic breast cancer, women with other stages of the disease, including those with node-positive cancer, were more likely to die from a comorbid illness, such as COPD, diabetes, stroke, or heart disease (Fig. 4) [5]. It is therefore important to assess physical function as well as coexisting illnesses in older breast cancer patients. One current research effort is evaluating molecular markers of aging, so that patients could potentially undergo simple blood tests to predict the likelihood of encountering myelosuppression or other problems. For instance, one exciting new marker, expression of p16, a weak tumor suppressor gene, has been found to increase 10-fold between the ages of 20 and 80 years and is associated with cellular senescence in almost all organ systems (Fig. 5) [6]. This marker therefore has the potential to help evaluate patients with cancer. Patients with low p16 expression may have not aged as quickly and may have a good degree of reserve, either in white cells, immune cells, or liver or kidney cells. These patients might do well with treatment. Patients with high p16 expression are more likely to have white cells that do not proliferate as well, that is, are the most senescent, and thus greater myelosuppression. Researchers have been measuring p16 RNA levels in the T cells of peripheral blood samples as a marker of aging. This method, in addition to standard geriatric assessment and comorbid illness evaluation, may provide clinicians with a molecular tool for estimating survival as well as treatment toxicity. ADJUVANT THERAPY IN OLDER PATIENTS In the adjuvant treatment of breast cancer in both older and younger patients, the goal is to improve the curability of the patient. Clinicians need to realize that, in older patients, the recurrence risk is similar to that of younger patients when adjusting for stage, and that life expectancy is the key to decision making. Life expectancy is based on comorbidity and physical function, and healthy elders should therefore be considered for the same treatments as younger patients. Undertreatment has been linked to poor outcomes, regardless of patient age. One analysis focused on distant disease-free survival in patients treated according to the 1992 St. Gallen treatment guidelines, such as receiving postop-

4 60 Breast Cancer in Seniors Figure 4. Cause of death after approximately 28 years of follow-up: white women aged 70 years with breast cancer (395,000 patients ). From Schairer C, Mink PJ, Carroll L et al. Probabilities of death from breast cancer and other causes among female breast cancer patients. J Natl Cancer Inst 2004;96: , by permission of Oxford University Press. Figure 5. p16 RNA expression: A marker of cell senescence that exponentially increases with age. From Liu Y, Sanoff HK, Cho H et al. Expression of p16 INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell 2009;8: , with permission. erative breast radiation or taking tamoxifen, versus patients whose treatment did not conform to these simple guidelines. The researchers reported an approximately 20% improvement in distant disease-free survival in patients treated according to the guidelines. Clinicians should therefore be careful not to undertreat older patients based on age alone (Fig. 6) [7]. BREAST CANCER SUBTYPES IN OLDER PATIENTS In breast cancer management, it is helpful to think of three distinct subtypes of breast cancer. This includes the largest group of older patients, the 60% 80% who are estrogen receptor (ER)-positive and human epidermal growth factor receptor (HER)-2-negative. This is also the most common presentation in older breast cancer patients. These patients are a very heterogeneous group and are divided into luminal A patients, who have high ER expression and do well with endocrine therapy, and luminal B patients, who realize more benefit with chemotherapy and less benefit from endocrine therapy. Other subtypes include the HER-2-negative ER-negative progesterone receptor negative, or triple-negative, population. These patients comprise about 15% of the general breast cancer population as well as the population of older patients, so triple-negative disease is a major issue. THERAPEUTIC OPTIONS IN OLDER PATIENTS The major question in many older patients concerns the added value of chemotherapy in the large population of ERpositive HER-2-negative patients. Tamoxifen, in particular, has been demonstrated to have value in older patients. In one 15-year analysis of tamoxifen given for 5 years, tamoxifen demonstrated a dramatic benefit in older women, with a 50% lower annual odds for recurrence and a 40%

5 Muss 61 Figure 7. Tamoxifen for 5 years: Decreasing annual odds for recurrence or death (15-year follow-up). From Early Breast Cancer Trialists Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;365: , with permission. Figure 6. Undertreatment and guidelines: Distant diseasefree survival. From Hébert-Croteau N, Brisson J, Latreille J et al. Compliance with consensus recommendations for systemic therapy is associated with improved survival of women with node-negative breast cancer. J Clin Oncol 2004;22: Reprinted with permission American Society of Clinical Oncology. All rights reserved. lower annual odds of dying as a result of breast cancer (Fig. 7) [8]. Aromatase inhibitors are now available, and their role is being better defined as trials mature. Regardless of trial design, aromatase inhibitors tend to result in lower recurrence rates than seen with tamoxifen, by about 3% 5%. Meanwhile, these agents so far have only demonstrated a small nonsignificant effect of about 1% on survival, and cost has been an important barrier to therapy. However, it is important to consider these agents in the elderly, if possible, because of their low toxicity profiles. Unlike tamoxifen, there are no greater risks for vascular events, endometrial cancer, or other toxicities associated with aromatase inhibitors. Reflective of the American Society of Clinical Oncology guidelines, aromatase inhibitors should be considered for all postmenopausal women at some time in their course of treatment, and perhaps as an initial treatment for many older patients [9]. One large international cooperative group study conducted by the National Cancer Institute of Canada compared letrozole with placebo in women who had received 5 years of tamoxifen as adjuvant therapy. An analysis of the subset of patients aged 70 years focused on some of the toxicities that are of concern in older patients, and found that toxicity profiles were the same between letrozole and placebo in these older patients. Toxicities studied included fatigue, nausea, depression, arthralgia/myalgia, vaginal Figure 8. Letrozole versus placebo after 5 years of tamoxifen in patients aged 70 years with early stage-breast cancer. Letrozole, n 681; placebo, n 642. From Muss HB, Tu D, Ingle JN et al. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol 2008;26: Reprinted with permission American Society of Clinical Oncology. All rights reserved. dryness, and increases in cholesterol levels. These findings were somewhat reassuring about the toxicity profile of letrozole and its use in older patients (Fig. 8) [10]. Adjuvant! Online is another helpful tool for evaluating therapeutic effect in older patients. This program is unique because it takes into account U.S. census data on age; when a patient s age is entered, the program adjusts for the average life expectancy for patients this age in the U.S. population. In addition, users can input an estimate of comorbidity or coexisting illness [11]. To demonstrate the utility of Adjuvant! Online, a case was plotted of a patient 71 years of age, presenting with a 2-cm, grade 2, node-positive, hormone receptor positive breast cancer. The program estimates 10-year survival data and illustrates the relative value of chemotherapy (Fig. 9). Entering data into Adjuvant! Online based on patients in perfect health, even with no adjuvant therapy but just surgery alone,

6 62 Breast Cancer in Seniors Figure 9. Ten-year survival: value of chemotherapy. Patient aged 71 years with 2.0-cm tumor, grade 2, one to three positive lymph nodes, estrogen receptor positive. Abbreviations: Adj Rx, adjuvant treatment; AI, aromatase inhibitor; CMF, cyclophosphamide, methotrexate, and fluorouracil; Gen, generation; T, tamoxifen; Tam, tamoxifen. Based on information from Adjuvant! Online. Available at accessed April 26, Figure 10. Cancer and Leukemia Group B trial design. Abbreviations: AC, doxorubicin and cyclophosphamide; CMF, cyclophosphamide, methotrexate, and fluorouracil. Reprinted from Early Breast Cancer Trialists Collaborative Group (EBCTCG). Adjuvant chemotherapy in oestrogenreceptor-poor breast cancer: patient-level meta-analysis of randomised trials. Lancet 2008;371:29 40, with permission from Elsevier. Table 1. Trial summary Standard therapy Capecitabine p-value n of patients (%) 326 (100) 307 (100) Relapse-free 89% 80%.001 a survival Overall survival 93% 88% 0.02 a Maximum grade 60%, AC 34% 3 5 toxicity 70%, CMF Completed all courses 92%, AC 62%, CMF 80% a Multivariate analysis. Abbreviations: AC, doxorubicin and cyclophosphamide; CMF, cyclophosphamide, methotrexate, and fluorouracil. From Muss HB, Berry DA, Cirrincione CT et al.; CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2010;360: , with permission. 71% of those patients will survive 10 years. With the addition of tamoxifen or an aromatase inhibitor, the likelihood of 10- year survival increases to approximately 75%. There is a modest improvement with chemotherapy regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF) or doxorubicin and cyclophosphamide (AC) for four cycles, and perhaps even more improvement when using more aggressive chemotherapy in this group. Meanwhile, the same analysis in patients with poor health suggests that only one third survive at 10 years because of their comorbid illnesses. In addition, the benefits of all therapies are diminished. In this way, Adjuvant! Online can help clinicians use comorbidity, in addition to age, to make treatment decisions [11]. Another recent analysis from the Arimidex, Tamoxifen, Alone or in Combination trial used the Oncotype DX genome assay in patients who had received tamoxifen or an aromatase inhibitor and had not received chemotherapy [12]. In that analysis, even patients with one to three positive nodes who had very low recurrence scores tended to do well with endocrine therapy alone and had very low probabilities of distant metastasis at 10 years. In patients with four or more nodes, there was a higher risk for recurrence, even with low recurrence scores. Oncotype DX, which as a genetic tool is more accurate in factoring in the degree of ER expression and tumor grade, has the potential to be a valuable tool in clinical decision making for older patients [12]. THERAPEUTIC FINDINGS IN OLDER TRIPLE-NEGATIVE PATIENTS Another meta-analysis from the Early Breast Cancer Trials Collaborative Group looked at relapse-free and overall survival in a very large group of patients, the majority (70% 80%) of whom were likely triple negative. Focusing on patients aged years, about 60% of whom were node positive, there was a 6% absolute lower risk for dying as a result of breast cancer with the use of older chemotherapy regimens alone, including CMF or AC (Fig. 10) [13]. With the addition of taxanes and other more aggressive therapies, including new treatments, these results will continue to improve. These findings confirm that older, healthy patients with triple-negative breast cancer should be considered for treatment with state-of-the-art chemotherapy. The CALGB cooperative group looked specifically at women aged 65 years with early-stage breast cancer, randomizing patients to six cycles of either CMF or AC chemotherapy, which is considered standard therapy, or the oral fluorouracil prodrug capecitabine. Researchers were hoping that capecitabine would be noninferior in older patients, providing clinicians with an adjuvant approach to older patients

7 Muss 63 Figure 11. Relapse-free and overall survival by treatment regimen and hormone receptor status. The Kaplan Meier plot of this unplanned analysis for both relapse-free and overall survival is shown above. The dashed lines indicate patients treated with CMF or AC, and the solid lines indicate patients treated with capecitabine. The panels on the left show relapse-free survival. For patients with hormone receptor positive tumors in the upper left panel, there is little difference in relapse-free survival by treatment. For receptor-negative tumors in the lower left panel, there is a substantial benefit for standard therapy over capecitabine. Similar differences are seen for overall survival in the panels on the right. Abbreviations: AC, doxorubicin and cyclophosphamide; CMF, cyclophosphamide, methotrexate, and fluorouracil. From Muss HB, Berry DA, Cirrincione CT et al.; CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2010;360: , with permission. with breast cancer who faced issues related to more aggressive i.v. chemotherapy. They found that standard therapy was better than capecitabine, with marked, highly significant longer relapse-free and overall survival times favoring standard chemotherapy with CMF or AC. Toxicity was less likely with capecitabine than with standard therapy, but there were no deaths from standard therapy in this entire randomized trial of 600 patients, but two deaths in the capecitabine group. Moreover, 92% of older patients tolerated four cycles of standard AC chemotherapy very well and received all doses, which was not true with CMF or capecitabine (Table 1) [14]. In an unplanned subset analysis, the researchers confirmed that the greatest therapeutic benefit in these older patients was in those with triple-negative breast cancer. Overall, there was a marked improvement in patients with triple-negative breast cancer that favored standard chemotherapy, which underscores the value of chemotherapy in older patients with the triple-negative phenotype. There were no differences in outcome among the regimens for patients with hormone receptor positive tumors (Fig. 11) [14]. HER-2-POSITIVE BREAST CANCER IN OLDER PATIENTS A summary of adjuvant trials with trastuzumab demonstrated the substantial value of trastuzumab added to chemotherapy in almost all studies that compared chemotherapy and trastuzumab with chemotherapy alone (Fig. 12). For instance, the Breast Cancer International Research Group (BCIRG) 006 study compared AC chemotherapy plus docetaxel and trastuzumab with chemo-

8 64 Breast Cancer in Seniors Figure 12. Current Breast Cancer International Research Group trial 660: disease-free survival third planned analysis. Abbreviations: AC-T, doxorubicin and cyclophosphamide followed by docetaxel; AC-TH, doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab; CI, confidence interval; HR, hazard ratio; TCH, docetaxel, carboplatin, and trastuzumab. From Slamon D, Eiermann W, Robert N et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC3T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC3 TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients: BCIRG 006 study [abstract 62]. Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 9 13, therapy that omitted anthracyclines, a nonanthracycline regimen of docetaxel, carboplatin, and trastuzumab. In Figure 12, which illustrates disease-free survival, the two trastuzumab-containing chemotherapy regimens show similar benefits. There were no significant differences between these treatments, suggesting that older patients can do well with nonanthracycline chemotherapy that includes trastuzumab (Fig. 12) [14]. This could be an important therapeutic option in older patients, because trastuzumab-related cardiotoxicity is age related, and older people as a group are more likely to have trastuzumab-related toxicity. Another CALGB analysis explored the roles of more intensive versus less intensive chemotherapy in 6,600 node-positive patients in randomized trials of different chemotherapy regimens, including 600 patients aged 65 years. In all these trials, the more intensive chemotherapy was superior to the less intensive therapy. This was an important analysis of the role of therapy in older patients, because there were overall differences among treatment regimens. Researchers observed a 5% 10% greater overall survival rate favoring the more aggressive modern chemotherapy regimens for all age groups (Fig. 13) [16]. However, older patients had poorer overall survival because of death from other causes after 20 years of follow-up. They also had greater serious and life-threatening toxicity. These data indicate that older patients receiving state-of-the-art chemotherapy derive benefits similar to those of younger patients. Figure 13. Overall survival versus chemotherapy regimen and age group. The figure compares overall survival by chemotherapy intensity for two age groups, those aged 50 years (A), and those aged 65 years (B). For both groups, patients receiving more chemotherapy (solid line) had a significantly higher overall survival rate. Similar findings were found in the 51-to-64-year-old age group. From Muss HB, Woolf S, Berry D et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 2005;293:

9 Muss 65 CONCLUSIONS Older patients with breast cancer who are healthy should first be considered for clinical trials. Data from these patients are needed for better clinical decision making. For those not eligible or unwilling to participate in trials, standard treatments should be considered. Meanwhile, in vulnerable patients who have undergone a geriatric assessment, clinicians need to think carefully about the side effects of therapy, especially chemotherapy. For example, grade 1 or 2 neuropathy, which could be adequately tolerated in a younger patient, could mean a fall and an end to independent living in an older patient. With these considerations in mind, clinicians can present adequate treatment options that maximize outcomes in older patients with breast cancer. REFERENCES 1 National Cancer Institute. Surveillance Epidemiology and End Results (SEER). Available at accessed April 26, National Cancer Institute. Surveillance Epidemiology and End Results (SEER). Available at accessed September 21, Yancik R, Wesley MN, Ries LA et al. Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 2001; 285: Walter LC, Brand RJ, Counsell SR et al. Development and validation of a prognostic index for 1-year mortality in older adults after hospitalization. JAMA 2001;285: Schairer C, Mink PJ, Carroll L et al. Probabilities of death from breast cancer and other causes among female breast cancer patients. J Natl Cancer Inst 2004;96: Liu Y, Sanoff HK, Cho H et al. Expression of p16 INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell 2009;8: Hébert-Croteau N, Brisson J, Latreille J et al. Compliance with consensus recommendations for systemic therapy is associated with improved survival of women with node-negative breast cancer. J Clin Oncol 2004;22: Early Breast Cancer Trialists Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005; 365: Visvanathan K, Chlebowski RT, Hurley P et al. American Society of Clinical Oncology clinical practice guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol 2009;27: Muss HB, Tu D, Ingle JN et al. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol 2008;26: Adjuvant! Online. Available at accessed April 26, Dowsett M, Cuzick J, Wale C et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: A TransATAC study. J Clin Oncol 2010;28: Early Breast Cancer Trialists Collaborative Group (EBCTCG). Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials. Lancet 2008;371: Muss HB, Berry DA, Cirrincione CT et al.; CALGB Investigators. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2010;360: Slamon D, Eiermann W, Robert N et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC3T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC3TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients: BCIRG 006 study [abstract 62]. Presented at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 9 13, Muss HB, Woolf S, Berry D et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 2005;293: