Adjuvant Therapy of Breast Cancer in Women 70 Years of Age and Older: Tough Decisions, High Stakes
Adjuvant Therapy of Breast Cancer in Women 70 Years of Age and Older: Tough Decisions, High Stakes
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.