As the aging population in the United States continues to grow, the incidence of diseases of the elderly, such as breast cancer, are increasing. Many more elderly women are expected to be diagnosed with new breast cancers, most of them in an early stage. Appropriate treatment of these women is important, as they have poorer outcomes when undertreated. In this review, we will discuss the biology and treatment of early breast cancer in elderly women. We will focus on the role of comorbidity and its effect on life expectancy, treatment decisions, current recommendations for primary treatment with surgery, radiation and neoadjuvant strategies, and adjuvant treatment including local radiation therapy and systemic treatment with endocrine therapy, chemotherapy, and newer agents. Finally we will discuss the importance of clinical trials in the elderly.
Mortality from breast cancer is decreasing, yet breast cancer incidence is rising in the United States and, as the population grows and ages, so does the absolute number of new breast cancers diagnosed. The increase in new breast cancers will be particularly dramatic in the elderly, as increasing age remains the greatest risk factor for developing the disease. Breast cancer is the most common cancer diagnosis in US women, with a current median age of 61 years old at diagnosis. Moreover, most women who die of breast cancer are over the age of 65 (Figure 1). It is estimated that by 2030, 20% of Americans will be 65 years and older. If cancer incidence rates continue to rise, it is estimated that absolute numbers of new breast cancer cases will double by 2050, the majority being in older women. It is therefore becoming increasingly important to understand how to treat elderly women with early breast cancer.
Stage at Presentation and Tumor Biology
The biologic characteristics of breast cancer in older women are different from those in younger women, but whether these differences result in tumors with a more indolent prognosis is controversial. Older women are more likely to express estrogen (ER) and progesterone receptors (PR), which improves their prognosis by making them candidates for adjuvant endocrine therapy (Figure 2). As women age, their breast cancers are associated with a decreased expression of markers of tumor growth and aggressiveness, including lower tumor grade, a lower S-phase fraction, more frequent diploidy, normal p53 levels, lack of HER2 (cerbB2) and epidermal growth factor receptor expression, and a lower probability of being node-positive. Regardless of age, infiltrating ductal carcinoma is the most common pathologic subtype.
Diab and colleagues reviewed tumor biology and outcomes from the Surveillance, Epidemiology and End Results (SEER) database in women over 65 years old and found that despite markedly decreased rates of surgery, radiotherapy (RT), and chemotherapy, older women with breast cancer had a good prognosis. Women over the age of 70 with node-negative tumors had an 8-year overall survival equivalent to that of the non-breast cancer age-matched population; women with lymph node-positive tumors had only a modest decrease in overall survival. The authors suggest that older women have more indolent disease and require less screening and treatment, but these conclusions are controversial.[6,7]
Singh et al reviewed outcomes of women with early breast cancer treated with mastectomy alone from 1927 to 1987 at a single institution and found that breast cancer was not more indolent in the 251 women who were over 70 years old. Compared to younger women, the older women were less likely to have lymph node-positive tumors. However, when stage was accounted for, mortality rates were similar across age groups. Women over 70 with node-negative disease had lower distant disease-free survival than patients from 40 to 70 years old (65% vs 81% at 10 years, P = .018). Patients with node-positive disease, however, did not have a significantly different overall survival at 10 years (33% vs 38%).
In treating older women with breast cancer, it is important to account for the increased effect that comorbidity, limitations in functional status, and decreased life expectancy have in balancing the risks and benefits of both primary and adjuvant treatment.
Comorbidity and Mortality
The presence of other, coexisting medical conditions can affect a woman's ability to tolerate specific treatments and decreases the non-breast cancer survival rate, regardless of age. As age increases, the risk of death from causes other than breast cancer increases (Figure 3). Satariano and Ragland noted a significant decrease in 3-year overall survival and an increase in non-breast cancer mortality in women with multiple comorbid conditions. Yancik et al found that six comorbidities—diabetes, renal failure, stroke, prior malignancy, liver disease, and smoking—predicted increased mortality in postmenopausal women with breast cancer.
Carey et al have created a useful prognostic index for 2-year mortality in community dwelling elders over 70 years old. Using a point scale of six items, age, gender, self-report of one activity of daily living, one instrumental activity of daily living, and two measures of physical functioning patients could reliably be divided into low-, intermediate-, and high-risk groups with a 3%-5%, 11%-12%, and 34%-36% 2-year mortality, respectively.
Functional status impacts survival independently of age and comorbidity, and poor performance status (as measured by tools such as the Karnofsky and Eastern Cooperative Oncology Group [ECOG] performance scales) correlates with worse outcomes in cancer patients.
Comprehensive Geriatric Assessment
The National Comprehensive Cancer Network and the International Society of Geriatric Oncology (SIOG) recommend the use of a comprehensive geriatric assessment (CGA) when planning treatment in the elderly. The CGA is a structured evaluation of multiple domains, including physical and functional status (activities of daily living, instrumental activities of daily living, and performance status), comorbidity, socioeconomic issues, polypharmacy, nutritional status, and geriatric syndromes (delirium, dementia, depression, incontinence, falls, spontaneous bone fractures, failure to thrive, neglect, and abuse).
The CGA has been tested in oncologic practice and has been found to detect problems that directly affect cancer treatment. The primary barrier to the routine use of CGA in oncology practice is time, but a short CGA, tailored for use in the outpatient oncology setting, is being tested.[12,15] Regardless of whether a formal CGA is used, when evaluating the elderly patient particular attention should be paid to cognition (memory and orientation), comorbidity (psychiatric, neuropsychiatric, and medical), polypharmacy, social issues (living conditions, caregivers, and transportation), dependence in activities of daily living, and the presence of geriatric syndromes.
Dr. Muss is a consultant for a Pfizer DSMB, Ortho Biotech, Genentech, and Amgen; has ownership interest in Amgen; has received research grants from AstraZeneca, Aventis, Bristol-Myers Squibb, Merck, GlaxoSmithKline, Ortho Biotech/Tibotech, Aureon, Celgene, Coley, Genentech, Genetics Institute, ImClone, Ligand, Lilly, Novartis, Pfizer, Sandoz, and Schering; fellowship support from Ortho, Amgen, Sanofi-Aventis, and MGI; honoraria from Network Oncology Communication, Neil Love Communications, American Pharmaceutical, and Meditech Ltd; and is on the board of directors and advisory committees of the American Society of Clinical Oncology; and has given expert testimony for RMF/Harvard Medical. Dr. Witherby is a stockholder/has a financial relationship with Johnson & Johnson and Amgen.
1. Jemal A, Murray T, Ward E, et al: Cancer statistics. CA Cancer J Clin 55:10-30, 2005.
2. US Cancer Statistics Working Group. United States Cancer Statistics: 1998-2002, Incidence and Mortality, Web-Based Report Version. Atlanta; Department of Health and Human Services, Centers for Disease Control Prevention, and National Cancer Institute; 2005. Available at www.cdc.gov/cancer/npcr/uscs. Accessed July 11, 2006.
3. Public Health and Aging: United States and worldwide. JAMA 289:1371-1373, 2003.
4. Eppenberger-Castori S, Moore DH Jr, Thor AD, et al: Age-associated biomarker profiles of human breast cancer. Int J Biochem Cell Biol 34:1318-1330, 2002.
5. Diab SG, Elledge RM, Clark GM: Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 92:550-556, 2000.
6. Basche M, Byers T: Re: Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 93:64-65, 2001.
7. Weiss NS: Re: Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 93:65-66, 2001.
8. Singh R, Hellman S, Heimann R: The natural history of breast carcinoma in the elderly: Implications for screening and treatment. Cancer 100:1807-1813, 2004.
9. Satariano WA, Ragland DR: The effect of comorbidity on 3-year survival of women with primary breast cancer. Ann Intern Med 120:104-110. 1994.
10. Yancik R, Wesley MN, Ries LA, et al: Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285:885-892, 2001.
11. Carey EC, Walter LC, Lindquist K, et al: Development and validation of a functional morbidity index to predict mortality in community-dwelling elders. J Gen Intern Med 19:1027-1033, 2004.
12. Extermann M, Overcash J, Lyman GH, et al: Comorbidity and functional status are independent in older cancer patients. J Clin Oncol 16:1582-1587, 1998.
13. Extermann M, Aapro M, Bernabei R, et al: Use of comprehensive geriatric assessment in older cancer patients: Recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG). Crit Rev Oncol Hematol 55:241-252, 2005.
14. Extermann M, Meyer J, McGinnis M, et al: A comprehensive geriatric intervention detects multiple problems in older breast cancer patients. Crit Rev Oncol Hematol 49:69-75, 2004.
15. Extermann M: Measurement and impact of comorbidity in older cancer patients. Hem Onc Clin North Am 35:181-200, 2000.
16. Wanebo HJ, Cole B, Chung M, et al: Is surgical management compromised in elderly patients with breast cancer? Ann Surg 225:579-586, 1997.
17. Singletary SE, Shallenberger R, Guinee VF: Breast cancer in the elderly. Ann Surg 218:667-671, 1993.
18. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 349:546-553, 2003.
19. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002.
20. Cutuli B, Aristei C, Martin C, et al: Breast conserving therapy for stage I-II breast cancer in elderly women. Int J Radiat Oncol Biol Phys 60:71-76, 2004.
21. Grube BJ, Hansen NM, Wei Y, et al: Surgical management of breast cancer in the elderly patients. Am J Surg 182:359-364, 2001.
22. de Haes JCJM, Curran D, Aaronson NK, et al: Quality of life in breast cancer patients aged over 70 years, participating in the EORTC 10850 randomised clinical trial. Eur J Cancer 39:945-951, 2003.
23. O'Connell JB, Maggard MA, Ko CY: Cancer-directed surgery for localized disease: decreased use in the elderly. Ann Surg Oncol 11:962-969, 2004.
24. Morrow W, White J, Moughan J, et al: Factors predicting the use of breast conserving therapy in stage I and II breast carcinoma. J Clin Oncol 19:2254-2264, 2001.
25. Audisio RA, Bozzetti F, Gennari R, et al: The surgical management of elderly cancer patients: Recommendations of the SIOG task force. Eur J Cancer 40:926-938, 2004.
26. Mandelblatt JS, Kerner JF, Hadley J, et al: Variations in breast carcinoma treatment in older medicare beneficiaries: Is it black or white? Cancer 95:1401-1414, 2002.
27. Martelli G, Miceli R, De Palo G, et al: Is axillary lymph node dissection necessary in elderly patients with breast carcinoma who have a clinically uninvolved axailla. Cancer 97:1156-1163, 2003.
28. Gennari R, Rotmensz N, Perego E, et al: Sentinel node biopsy in elderly breast cancer patients. Surg Oncol 13:193-196, 2004.
29. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165-4174, 2003.
30. Eiermann W, Paepke S, Appfelstaedt J, et al: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12:1527-1532, 2001.
31. Deutsch M: Radiotherapy after lumpectomy in very old women. Am J Clin Oncol 25:48, 2002.
32. Vinh-Hung V, Verschaegen C: Breast-conserving surgery with or without radiotherapy: Pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality. J Natl Cancer Inst 96:115-121, 2004.
33. 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 351:963-970, 2004.
34. 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 351:971-977, 2004.
35. Truong PT, Lee J, Kader HA, et al: Locoregional recurrence risks in elderly breast cancer patients treated with mastectomy without adjuvant radiation therapy. Eur J Cancer 41:1267-1277, 2005.
36. Akhtar SS, Allan SG, Rodger A: A 10-year experience of tamoxifen as primary treatment of breast cancer in 100 elderly and frail patients. Eur J Surg Oncol 17:30-35, 1991.
37. Fentiman IS, Christiaens MR, Paridaens R, et al: Treatment of operable breast cancer in the elderly: A randomised clinical trial EORTC 10851 comparing tamoxifen alone with modified radical mastectomy. Eur J Cancer 39:309-316, 2003.
38. Robertson JF, Ellis IO, Elston CW, et al: Mastectomy or tamoxifen as initial therapy for operable breast cancer in elderly patients: 5-year follow-up. Eur J Cancer 28A:908-910, 1992.
39. Gazet JC, Ford HT, Coombes RC, et al: Prospective randomized trial of tamoxifen vs surgery in elderly patients with breast cancer. Eur J Surg Oncol 20:207-214, 1994.
40. Mustacchi G, Ceccherini R, Milani S, et al: Tamoxifen alone versus adjuvant tamoxifen for operable breast cancer of the elderly: Long-term results of the phase III randomized controlled multicenter GRETA trial. Ann Oncol 14:414-420, 2003.
41. Fennessy M, Bates T, MacRae K, et al: Late follow-up of a randomized trial of surgery plus tamoxifen versus tamoxifen alone in women aged over 70 years with operable breast cancer. Br J Surg 91:699-704, 2004.
42. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19:3808-3816, 2001.
43. 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 19:980-991, 2001.
44. Extermann M, Balducci L, Lyman GH, et al: What threshold for adjuvant chemotherapy in older breast cancer patients? J Clin Oncol 18:1709-1717, 2000.
45. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005.
46. Polychemotherapy for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet 352:930-942, 1998.
47. Goss PE, Ingle JN, Martino S, et al: Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262-1271, 2005.
48. Baum M, Buzdar AU, Cuzick J, et al, for the ATAC Trialists Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002.
49. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005.
50. Coombes RC, Hall E, Gibson LJ, et al: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081-1092, 2004.
51. Jakesz R, Jonat W, Ganat M, et al: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: Combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455-462, 2005.
52. Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003.
53. Desch CE, Hillner BE, Smith TJ, et al: Should the elderly receive chemotherapy for node-negative breast cancer? A cost-effectiveness analysis examining total and active life-expectancy outcomes. J Clin Oncol 11:777-782, 1993.
54. Crivellari D, Bonetti M, Castiglione-Gertsch M, et al: Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: The International Breast Cancer Study Group Trial VII. J Clin Oncol 18:1412-1422, 2000.
55. Fisher B, Jeong JH, Anderson S, et al: Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: Updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst 96:1823-1831, 2004.
56. Fisher B, Jeong JH, Bryant J, et al: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: Long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364:858-868, 2004.
57. Fargeot P, Bonneterre J, Roche H, et al: Disease-free survival advantage of weekly epirubicin plus tamoxifen versus tamoxifen alone as adjuvant treatment of operable, node-positive, elderly breast cancer patients: 6-year follow-up results of the French adjuvant study group 08 trial. J Clin Oncol 22:4622-4630, 2004.
58. Muss HB, Woolf S, Berry D, et al: Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 293:1073-1081, 2005.
59. Lichtman SM, Skirvin JA: Pharmacology of antineoplastic agents in older cancer patients. Oncology (Williston Park) 14:1743-1755, 2000.
60. Shapiro CL, Recht A: Drug therapy: Side effects of adjuvant treatment of breast cancer. N Engl J Med 344:1997-2008, 2001.
61. Dees EC, O'Reilly S, Goodman SN, et al: A prospective, pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest 18:521-529, 2000.
62. Gelman RS, Taylor SG: Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: The elimination of age trends with doses based on creatinine clearance. J Clin Oncol 2:1406-1414, 1984.
63. Balducci L, Lyman GH, Ozer W: Patients aged > or = 70 are at high risk for neutropenic infection and should receive hematopoietic growth factors when treated with moderately toxic chemotherapy. J Clin Oncol 19:1583-1585, 2001.
64. National Comprehensive Cancer Network: Guidelines for supportive care: Myeloid growth factors, version 1.2006. Available at www.nccn.org. Accessed July 12, 2006.
65. Lyman GH, Kuderer N, Agboola O, et al: Evidence-based use of colony-stimulating factors in elderly cancer patients. Cancer Control 10:487-499, 2003.
66. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979.
67. Kimmick GG, Shelton BJ, Case LD, et al: Long-term follow up of a phase II trial studying a weekly doxorubicin-based multiple drug adjuvant therapy for stage II node-positive carcinoma of the breast. Breast Cancer Res Treat 72:233-243 2002.
68. Doyle JJ, Neugut AI, Jacobson JJ, et al: Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study (abstract 6085). Breast Cancer Res Treat 94(suppl 1):S278, 2005.
69. Hurria A, Rosen C, Zuckerman E, et al: Effect of adjuvant chemotherapy (CRx) on the cognitive function of older patients (pts) with breast cancer (BC): Results from a prospective study (abstract 8204). Proc Am Soc Clin Oncol 23(16S):779s, 2005.
70. Du XL, Osborne C, Goodwin JS: Population-based assessment of hospitalizations for toxicity from chemotherapy in older women with breast cancer. J Clin Oncol 20:4636-4642, 2002.
71. Hurria A, Brogan K, Panageas KS, et al: Pattern of toxicity in older patients with breast cancer receiving adjuvant chemotherapy. Breast Cancer Res Treat 92:151-156, 2005.
72. De Maio E, Gravina A, Pacilio C, et al: Compliance and toxicity of adjuvant CMF in elderly breast cancer patients: A single center experience. BMC Cancer 5:30, 2005.
73. Crivellari D, Bonetti M, Castiglione-Gertsch M, et al: Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluoruracil and tamoxifen for elderly patients with breast cancer: The International Breast Cancer Study Group Trial VII. J Clin Oncol 18:1412-1422, 2000.
74. Colleoni M, Price KN, Castiglione-Gertsch M, et al: Mortality during adjuvant treatment of early breast cancer with cyclophosphamide, methotrexate, and fluorouracil. International Breast Cancer Study Group. Lancet 354:130-131, 1999.
75. Yardley DA, Loesch DM, Greco FA, et al: Preliminary toxicity results from a phase III multi-centered trial comparing weekly docetaxel to CMF as adjuvant treatment for high risk breast cancer patients who are not candidates for anthracyclines. (abstract 1061). Breast Cancer Res Treat 88(suppl 1):S62, 2004.
76. Piccart-Gebhart MJ, Proctor M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005.
77. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005.
78. The HERA study team. Trastuzumab (H: Herceptin) following adjuvant chemotherapy (CT) significantly improves disease-free survival (DFS) in early breast cancer with HER2 overexpression: The HERA trial (abstract 11). Breast Cancer Res Treat 94(suppl 1):S9, 2005.
79. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999.
80. Kemeny MM, Peterson BL, Kornblith AB, et al: Barriers to clinical trial participation by older women with breast cancer. J Clin Oncol 21:2268-2275, 2003.
81. Lara PN Jr, Higdon R, Lim N, et al: Prospective evaluation of cancer clinical trial accrual patterns: Identifying potential barriers to enrollment. J Clin Oncol 19:1728-1733, 2001.
82. Siminoff LA, Zhang A, Saunders Sturm CM, et al: Referral of breast cancer patients to medical oncologists after initial surgical management [see comments]. Med Care 38:696-704, 2000.
83. Kemeny M, Muss HB, Kornblith AB, et al: Barriers to participation of older women with breast cancer in clinical trials (abstract 2371). Proc Am Soc Clin Oncol 19:602a, 2000.
84. Kornblith AB, Kemeny M, Peterson BL, et al: Survey of oncologists' perceptions of barriers to accrual of older patients with breast carcinoma to clinical trials. Cancer 95:989-996, 2002.
85. 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 96:1311-1321, 2004.