ABSTRACT: Although increasing age is the major risk factor for breast cancer incidence and mortality, when adjusted for disease stage, breast cancer mortality is similar among younger vs older patients. Importantly, about 90% of older women with breast cancer present with early-stage disease. The biologic characteristics of breast tumors in older patients suggest they would derive benefit from adjuvant therapy, particularly endocrine therapy, but older women are still frequently undertreated, resulting in poorer survival. Studies suggest that focusing on comorbidity rather than “chronologic age” as a surrogate for life-expectancy is a key aspect of adjuvant decision-making for older patients. Morbidity and mortality from cancer in vulnerable patients with poorer health can be accurately predicted by the Comprehensive Geriatric Assessment (CGA), which evaluates comorbidities, functional status, cognition, social support, psychological state, nutritional status, and polypharmacy. Use of the CGA and newer versions of this tool can lead to interventions that maintain function and improve quality of life in older patients with breast cancer. This article will discuss considerations regarding adjuvant therapy for older breast cancer patients with a variety of tumor types.
Breast cancer, a disease of aging, is the most common cancer in American women, and increasing age is the major risk factor for breast cancer incidence and mortality (Figure 1). Except for the very old and very young, breast cancer mortality (when stage-adjusted) is similar among older and younger patients.[2,3] Although older women are diagnosed with breast cancer at a later stage than younger women, about 90% of older women present with stage I or II disease.
The biologic characteristics of breast cancers change with increasing age; tumors in older patients are more likely to be lower grade and have lower proliferation indices, and they tend to be hormone receptor–positive, node negative, p53 negative, and HER2 negative.[5,6] There does not appear to be any difference in angiogenic markers with aging.
Major improvements in life expectancy during the second half of the 20th century have resulted in an older population that is healthier and more long-lived. Today, the estimated further life expectancy of a 65-year-old woman is about 20 additional years and for a 75-year-old woman is about 12 years. In spite of an extensive body of literature showing the benefits of adjuvant therapy in older women, especially endocrine therapy, ageism persists—and older women are frequently undertreated, resulting in poorer survival.[4,8-10] This review will focus on issues and controversies related to the use of adjuvant chemotherapy in older women; other reviews of this topic are also available.[11,12]
Comorbidity in the Older Patient With Breast Cancer
The probability of having another illness (comorbidity) increases with increasing age and is a major factor in treatment selection and likelihood of treatment-related toxicity. In one major study of 1,800 postmenopausal women with breast cancer, patient factors including diabetes, renal failure, stroke, liver disease, a previous malignant tumor, and smoking significantly predicted shortened survival even when accounting for age and breast cancer stage. In the 15% of patients who died over a 30-month period, breast cancer was the cause of death in 51%, heart disease in 17%, and previous cancers in 8%. Patients 65 to 74 years of age in this study had a median of about three comorbidities, those 75 to 84 years had a median of about four, and those 85 years and older had a median of five. In another study of 936 women 40 to 84 years of age with breast cancer, patients with three or more of seven selected comorbidities had a 20-fold higher rate of mortality from non–breast cancer causes and a four-fold higher rate of all-cause mortality compared with those without any comorbidity. A Surveillance Epidemiology and End Results (SEER)-based trial with a 28-year follow-up showed that for women 70 years and older, death from non–breast cancer causes was noted in more than 80% of those with node-negative tumors, in about 60% of those with node-positive tumors, and even in about 20% of those with metastases. Focusing on comorbidity as a surrogate for life-expectancy as opposed to “chronologic age” is a key aspect of adjuvant therapy decision-making for older patients.
The presence of comorbidities is not the only factor that is important to consider in evaluating our older patients. The Comprehensive Geriatric Assessment (CGA) includes evaluation of functional status, cognition, social support, psychological state, nutritional status, and medication (polypharmacy), in addition to comorbidities, and it can accurately predict morbidity and mortality from cancer. For older cancer patients in excellent health, CGA probably adds little to routine evaluation, but it can be of great value in vulnerable patients, for whom its use can lead to interventions that maintain function and improve quality of life. The scarcity of gerontologists and the time needed for a traditional CGA make it impractical to perform for all older patients. Shorter, validated CGA instruments are now being tested in older cancer patients and hold great promise for screening the increasing numbers of vulnerable elders with cancer who could then benefit from a more detailed CGA.[18-20] These shorter instruments are also being tested to see if they can predict which patients are at greatest risk for treatment-related toxicity. The International Society of Geriatric Oncology (SIOG) has developed useful recommendations for performing CGA.
Adjuvant Systemic Therapy:General Considerations
Selection of adjuvant chemotherapy in older patients depends on two main factors: 1) the patient’s stage and the tumor’s biologic characteristics (grade, hormone receptor, and HER2 [human epidermal growth factor receptor 2] status), and 2) the patient’s life expectancy. Historically, nonmetastatic breast cancer treatment was selected on the basis of nodal status and hormone receptor expression, and more recently by HER2 status. Clinical trials and gene microarray studies have suggested that treatment benefit is better predicted based on several defined biologic characteristics. For clinical purposes, breast cancer patients can be divided into three major subgroups: 1) hormone receptor (HR) positive (HR+) and HER2 negative; 2) HER2 positive irrespective of HR status; and 3) hormone receptor negative (HR−) and HER2 negative (“triple-negative” tumors). Estimates of recurrence and the benefits of both endocrine therapy and chemotherapy in these subgroups can be accurately made using Adjuvant! (www.adjuvantonline.com), a web-based program that can also assess the likely effects of age and comorbidity on treatment benefit. A drawback of the current version is that the program lumps all estrogen receptor (ER)-positive patients into one group and does not easily allow for estimating the benefit of trastuzumab(Drug information on trastuzumab) (Herceptin) in HER2-positive tumors. A major benefit of the program is that it accounts for life expectancy in estimating the effects of treatment.
Selection of Treatment in Older Patients With Hormone Receptor–Positive, HER2-Negative Tumors
This tumor type comprises the largest group of breast cancer patients and makes up approximately 70% or more of breast cancers in elders. Gene microarray studies suggest that these patients include two overlapping subgroups: luminal A tumors that derive a large benefit from endocrine therapy but modest, if any, benefit from chemotherapy, and luminal B tumors that derive some benefit from endocrine therapy and a substantial benefit from chemotherapy. Clinically these groups can be defined by ER and progesterone(Drug information on progesterone) receptor (PR) expression and tumor grade. For example, luminal A tumors are likely to be those with high ER and PR expression and lower tumor grade (and/or low Ki-67 expression), whereas luminal B tumors have low HR expression and are likely to be intermediate or high grade (and/or have high Ki-67 expression).
At present all patients in this group should first be considered for treatment with an aromatase inhibitor or tamoxifen(Drug information on tamoxifen) followed by an aromatase inhibitor. As a rule, patients in this group who have node-negative tumors derive little, if any, benefit from chemotherapy, although genetically based assays will likely identify a small group who will benefit. The potential added value of chemotherapy in patients with HR+/node-negative tumors and perhaps patients with minimal nodal involvement can be estimated with several gene assays including Oncotype DX and MammaPrint. Two large clinical trials testing the value of these assays and more precisely defining chemotherapy benefits when added to endocrine therapy in these patients are now in progress; these are the TAILORx trial in North America (http://www.cancer.gov/clinicaltrials/digestpage/TAILORx) and the MINDACT trial in Europe (http://www.eortc.be/services/unit/mindact/MINDACT_websiteii.asp).
There is more uncertainty regarding the role of chemotherapy in this group for patients with node-positive tumors. Data from the SEER database have suggested minimal benefit for chemotherapy in node-positive, HR-positive patients. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) meta-analysis of randomized trials in early-stage breast cancer, however, suggests that some of these patients may benefit from treatment. After 15 years of follow-up, 5 years of tamoxifen therapy in ER-positive patients reduced the annual breast cancer mortality rate by 31% irrespective of age. Of note was that about 6 months of treatment with an anthracycline-containing regimen was superior to CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil) [5-FU]) and reduced the annual breast cancer death rate by about 20% in women 50 to 69 years of age irrespective of tamoxifen use. Unfortunately, only about 1,200 patients 70 years and older were entered into trials comparing chemotherapy vs no chemotherapy, making an accurate assessment of chemotherapy effects in these older patients uncertain. It is likely that node-negative and node-positive patients with substantial comorbidity in this group will not derive any major benefit from chemotherapy.
The benefits of adjuvant chemotherapy in HR-positive patients in the EBCTCG analysis were seen only after extended follow-up, making life expectancy the key issue when considering chemotherapy for HR+/HER2-negative older patients. For patients with remaining life expectancies of 10 years or more and who have a high risk of recurrence even with endocrine therapy, use of nonanthracycline-containing regimens such as docetaxel(Drug information on docetaxel) (Taxotere) and cyclophosphamide(Drug information on cyclophosphamide) (TC) that negate the risk of cardiac toxicity should be considered. This regimen is superior to doxorubicin(Drug information on doxorubicin) and cyclophosphamide and likely CMF. For those with very high risk features such as four or more positive nodes, more aggressive taxane-containing regimens should be considered because they provide similar reductions in mortality risk in older and younger patients, though with greater toxicity in elders. Patients with HR+ tumors that involve 1–3 lymph nodes might benefit from having Oncotype DX testing, as preliminary data show that chemotherapy is of little to no value in women with low recurrence scores.[31,32]