In most Western nations, the incidence and mortality rates for breast cancer rise dramatically with increasing age, and in the coming decades oncologists will be faced with managing an increasing number of older patients with breast cancer. Having the knowledge and tools to optimally treat this group will be essential. The challenge of caring for an older cancer patient is to provide treatment options that maximize long-term survival and account for life expectancy, comorbidities, and the effects of treatment on function. For example, a mild treatment-induced peripheral neuropathy can transform a functioning elder into one who is dependent on institutional care. Complicating matters, there is a paucity of data from randomized trials on the risks and benefits of our newer and increasingly effective treatments in older breast cancer patients. In this review we will discuss how to evaluate older breast cancer patients, including estimating survival, defining functional limitations, and providing guidelines for optimal adjuvant therapies.
We had a 78-year-old patient tell us recently, “I am too old to get breast cancer,” but sadly, she was wrong. A woman born today has an average life expectancy of 80 years. Less appreciated is that for women 70, 75, and 80 years of age, the average remaining life expectancy is 16, 12.5, and 10 years, respectively. Breast cancer in the US remains the most common cancer in women, with an incidence and mortality rate that rise dramatically with increasing age. Women below the age of 65 years have a breast cancer incidence of 82 per 100,000 women, while those 65 years and older have a rate that jumps to 404 per 100,000. Women 70 years of age and older comprise 30% to 40% of all breast cancer patients, and while the average age at diagnosis of breast cancer is now 61 years, the majority of deaths occur in women 65 years and older. Despite major advances in treatment, breast cancer remains only behind lung cancer as the leading cause of cancer death in women.
Advances in screening and adjuvant therapy have led to major reductions in breast cancer mortality rates, but these benefits have been less in older women. For example, data from National Vital Statistics Reports and the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute showed that the rate of breast cancer death in the general population relative to 1990 decreased 2.5% per year for patients aged 20 to 49 years, 2.1% annually for those aged 50 to 64 years, and 2% per year for those aged 65 to 74, but it decreased by only 1.1% per year for those 75 and older. In addition, death due to breast cancer in women newly diagnosed between 1980 and 1997 decreased by 3.6% per year in women less than 75 years old but only 1.3% per year in those 75 years and older (P < .01), with the absolute 10-year risk of breast cancer death decreasing 15.3% in women aged 50 to 64 years, but only 7.5% for those aged 75 and older.
Why are there disparate rates for older women? Some of this difference may be due to less use of screening mammography as women age, but the role of screening mammography in older women remains controversial, especially for those aged 75 and older. Probably the most important reason for this disparity in breast cancer–specific survival (which accounts for dying from other causes) is the less frequent use of potentially life-saving adjuvant therapies in these older patients, including post-operative radiation; endocrine therapy; chemotherapy; and, for patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) tumors, trastuzumab (Herceptin). Sometimes not offering state-of-the-art therapy to older patients represents “good clinical judgment,” but for many patients such “low-balling” of treatment is inappropriate and results in poorer survival. In this review, we discuss how to evaluate older patients, including assessment of functional status and estimating life expectancy, as well defining the role of post-operative radiation and systemic adjuvant therapy. (See the Table for a list of useful websites; excellent recent reviews of this topic are also available.[7,8])
Approach to the Older Patient
When discussing treatment options with older breast cancer patients, it is critical to determine whether breast cancer is the patient's major illness. Although the patient and family members will be concerned about the breast cancer, they may be less aware of the importance of other comorbidities and how they impact breast cancer management and life expectancy. For instance, many patients 70 years and older have substantial comorbidities that shorten life expectancy, such as hypertension, diabetes, and dementia. In one study of postmenopausal breast cancer patients, those 70 to 74 years of age had, on average, three comorbidities, and those 75 to 84 years old had four. This is important in that, among patients 70 years and older, about 85% of those with node-negative and 65% of those with node-positive breast cancer die of non–breast-cancer-related causes. Functional loss is also important and has a major impact on life expectancy. Identifying comorbid illness and functional loss and managing them appropriately are essential if one is to offer the most beneficial treatment options. For example, two 75-year-old women, patient A and patient B (see Figure 1), have various clinical and functional factors that must be considered before treatment options are presented. Although these patients are the same age, they are markedly different. In a model that uses these data to compute 5- and 9-year mortality, patient A and B have 5-year estimated mortality risks of 6% and 16%, and 9-year mortality risks of 15% and 75%, respectively(also see www.eprognosis.org).
The use of a comprehensive geriatric assessment (CGA) is the best way to estimate functionality in an older adult. The CGA is an interdisciplinary approach that evaluates key domains including physical function, psychosocial function and support, cognitive function, medication use (“polypharmacy”), and nutritional status. What is important for oncologists to know about CGA is that identifying problems can lead to interventions that can improve quality of life as well as survival. Realistically, it is not possible to refer all older patients for geriatric assessment—a 2- to 3-hour evaluation—nor are there enough geriatricians available to see the tsunami of older cancer patients in a timely manner. To circumvent this obstacle, new assessment tools have been developed that utilize a small amount of professional time for assessment of cognitive function, an “up and go test,” and assessment of performance status. Assessment of function includes evaluating the patient's ability to perform activities of daily living that are essential for patients to care for themselves at home (eg, bathing, dressing, toileting, walking), as well as instrumental activities of daily living that are essential for allowing independence in the community (eg, preparing meals, using the telephone, housework, taking medicines, managing finances), and documenting the number of falls within 6 months of cancer diagnosis. Depression, social support, and nutritional status are also self-evaluated using validated instruments. The abbreviated CGAs have been shown to be feasible in the cooperative group setting and should be performable in a busy office or clinic with only modest use of staff time. Patients identified as having major issues with physical or cognitive function, falls, depression, or psychosocial support can be referred to a geriatrician so that these issues can be addressed before treatment is selected. Another option is to use screening tools, such as the Vulnerable Elders Survey-13 (VES-13), to identify patients with functional impairment and poor self-reported health and then refer them for a more detailed geriatric assessment. Information obtained from the CGA will lead to a better plan of care that will shape the clinical decision for the patient and ultimately impact her quality of life. Often providers focus on the number of comorbidities, and less attention is focused on the type, severity, and duration of the comorbidity. When considering adjuvant therapy, patients with limited survival will almost never be candidates for chemotherapy.
Management of the Primary Lesion in Frail Patients or Those With Advanced Locoregional Disease
For patients with life expectancies of 5 years or more and resectable lesions, surgery remains the key to successful control of the primary tumor. A Cochrane analysis has shown that for older patients, primary endocrine therapy with tamoxifen was associated with survival outcomes similar to those of women treated with surgery, with or without endocrine therapy. However, the majority of women given tamoxifen alone had breast tumor progression by 5 years. Although aromatase inhibitors (AIs) might prove superior to tamoxifen in this setting, they are not likely to change these results greatly, and we recommend surgery for patients with life expectancies of more than 5 years. For older women with hormone receptor–positive (HR+) locally advanced breast cancer who are not candidates for tumor resection or who wish to increase their odds of breast preservation, neoadjuvant endocrine therapy can be of major benefit and makes many older patients candidates for breast-preserving surgery.
Adjuvant Radiation Therapy
There are randomized data on the use of tamoxifen (20 mg daily) with or without breast radiation (RT) for older women with early-stage breast cancer. One series enrolled 769 patients, (age ≥ 50 years) with pathologic T1 or T2 invasive cancers, negative margins, and pathologically negative axillary lymph nodes (except in patients 65 years and older who were eligible if pathologically or clinically node-negative). Whole-breast RT was given in a hypofractionated regimen of 40 Gy (16 fractions) followed by a boost of 12.5 Gy (5 fractions) to the lumpectomy site. The 5-year local relapse rate was 0.6% in the RT plus tamoxifen group and 7.7 % for those receiving tamoxifen alone (P < .05). This significant benefit for RT was noted in the more favorable T1 receptor–positive subgroup. There were no differences in distant relapse or overall survival, but such differences might not be expected in the relatively short follow-up of this favorable subgroup. A second randomized trial (Cancer and Leukemia Group B [CALGB] 9343) included 636 women 70 years and older with lumpectomy-treated T1, HR+, clinically or pathologically node-negative tumors. All patients received tamoxifen and were randomized to radiation or no radiation. After a median follow-up of 10.5 years, the incidence of locoregional recurrence was 2% in the tamoxifen and RT group compared with 9% in the tamoxifen-alone group. Breast cancer–specific survival was 98% for the tamoxifen-alone group and 96% for the tamoxifen/RT group, and while all-cause mortality was 43%, the vast majority of deaths were due to non–breast cancer causes.
The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis compared nearly 11,000 patients with early-stage breast cancer who received postoperative radiation or not in randomized clinical trials. The RT-treated group had an overall 16% absolute decrease (19% vs 35%) in the risk of breast cancer recurrence and a 4% absolute decrease (21% vs 25%) in the risk of dying from breast cancer—clearly showing that good local control correlates with improved survival. This analysis stratified women by age, and while the benefit was less in the older cohort (women 70 years and older), there was still an absolute overall reduction in the 10-year risk of a locoregional or distant recurrence of 8.9% (95% confidence interval [CI], 4.0–13.8). There were 1340 patients in the 70-and-older subset (see Table 3a in the web appendix of Ref. 22) and the benefits of radiation and tamoxifen in reducing locoregional and distant recurrence in these patients are presented in Figure 2A through 2C. Based on these absolute risk reductions, our recommendations for use of breast radiation are summarized in Figure 2D. Unlike the CALGB 9343 trial, which did not include information on grade, data from the EBCTCG suggests that patients with high-grade T1 tumors treated with adjuvant tamoxifen or an AI alone should be considered for adjuvant RT.
1. National Center for Health and Statistics. Tables on trends in health and aging; life expectancy. 2012. Available at: http://www.cdc.gov/nchs/fastats/lifexpec.Htm.
2. Altekruse SF, Kosary CL, Krapcho M, et al. SEER Cancer Statistics Review, 19752007. Bethesda, MD, National Cancer Institute, 2010.
3. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 2005;353:1784-92.
4. Smith BD, Jiang J, McLaughlin SS, et al. Improvement in breast cancer outcomes over time: are older women missing out? J Clin Oncol. 2011;
5. Nelson HD, Tyne K, Naik A, et al. Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151:727-37.
6. Hebert-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;22:3685-93.
7. Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol. 2012;13:e148-60.
8. Owusu C, Hurria A, Muss HB. Adjuvant therapy for older women with early-stage breast cancer: treatment selection in a complex population; ASCO Educational Book. Alexandria, Va: American Society of Clinical Oncology, 2012; pp 3-9.
9. 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;285:885-92.
10. Schairer C, Mink PJ, Carroll L, Devesa SS. Probabilities of death from breast cancer and other causes among female breast cancer patients. J Natl Cancer Inst. 2004;96:1311-21.
11. Yourman LC, Lee SJ, Schonberg MA, et al. Prognostic indices for older adults: a systematic review. JAMA. 2012;307:182-92.
12. Hurria A, Cirrincione CT, Muss HB, et al. Implementing a geriatric assessment in cooperative group clinical cancer trials: CALGB 360401. J Clin Oncol. 2011;29:1290-6.
13. Liu JJ, Extermann M. Comprehensive geriatric assessment and its clinical impact in oncology. Clin Geriatr Med. 2012;28:19.
14. Min LC, Elliott MN, Wenger NS, Saliba D. Higher vulnerable elders survey scores predict death and functional decline in vulnerable older people. J Am Geriatr Soc. 2006;54:507-11.
15. Extermann M. Measuring comorbidity in older cancer patients. Eur J Cancer. 2000;36:453-71.
16. Dittus K, Muss HB. Management of the frail elderly with breast cancer. Oncology (Williston Park). 2007;21:1727-34.
17. Hind D, Wyld L, Beverley CB, Reed MW. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev. 2006:CD004272.
18. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005; 23:5108-16.
19. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004;351:963-70.
20. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004;351:971-7.
21. Hughes KS, Schnaper LA, Cirrincione C, et al, and CALGB, ECOG, RTOG: lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer. J Clin Oncol. 2010;28(15s): abstr 507.
22. Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378:1707-16.
23. Blows FM, Driver KE, Schmidt MK, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;
24. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14:2738-46.
25. Chia S, Norris B, Speers C, et al. Human epidermal growth factor receptor 2 overexpression as a prognostic factor in a large tissue microarray series of node-negative breast cancers. J Clin Oncol. 2008;
26. 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;365:1687-717.
27. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal A breast cancer? J Clin Oncol. 2012;30:1260-3.
28. 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;28:1829-34.
29. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 2006;24:3726-34.
30. Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol. 2001;19:980-91.
31. Owusu C, Buist DS, Field TS, et al. Predictors of tamoxifen discontinuation among older women with estrogen receptor-positive breast cancer. J Clin Oncol. 2008;26:549-55.
32. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010;28:3784-96.
33. Muss HB, Busby-Whitehead J. Older women with breast cancer: slow progress, great opportunity, now is the time. J Clin Oncol. 2011;29:4608-10.
34. Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol. 2010;28:4120-8.
35. Miaskowski C, Shockney L, Chlebowski RT. Adherence to oral endocrine therapy for breast cancer: a nursing perspective. Clin J Oncol Nurs. 2008;12:213-21.
36. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet. 2012;379:432-44.
37. Jones S, Holmes FA, O'Shaughnessy J, et al.Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology research trial 9735. J Clin Oncol. 2009;
38. Freyer G, Campone M, Peron J, et al. Adjuvant docetaxel/cyclophosphamide in breast cancer patients over the age of 70: results of an observational study. Crit Rev Oncol Hematol. 2011;80:466-73.
39. Muss HB, Woolf S, Berry D, et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA. 2005;293:1073-81.
40. Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2009;360:2055-65.
41. Lyman GH. Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw. 2009;7:99-108.
42. Rajan S, Stearns S, Lyman G, Carpenter W. Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat. 2011;130:255-66.
43. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2012;30:1553-61.
44. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273-83.
45. Seymour MT, Thompson LC, Wasan HS, et al. Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRS FOCUS2): an open-label, randomised factorial trial. Lancet. 2011;377:1749-59.