Overview and Rationale
Although breast cancer is common in older women, guidance on optimal treatment is limited by their low enrollment in randomized clinical trials. The Surveillance Epidemiology and End Results (SEER) database shows that the median patient age for breast cancer diagnoses in the United States is 61 years.1 According to age-specific breast cancer incidence rates from SEER, approximately 42% of cases in the United States occur in women aged 65 years or older, with women aged 75 years or older representing more than 20% of these cases. The number of women aged 65 years or older in the United States is rapidly growing. The U.S. Census Bureau projects that between 2000 and 2030, the number of individuals aged 65 years or older will approximately double, from 35 to 71 million, with older women substantially outnumbering older men (approximately 70 men for every 100 women in the year 2000).2,3
Awareness of the need to identify breast cancer treatment recommendations to assure optimal, individualized treatment of older women with breast cancer is increasing. However, several obstacles to accomplishing this task exist. Functional status, social support, the presence of comorbidities, and life expectancy must be considered to maximize benefit and minimize risk for these patients. In addition, because few women older than 65 years are included in randomized clinical trials, reliable estimates of treatment efficacy and toxicity in this population are often lacking.
Excellent reviews of breast cancer in older women have been published recently.4–6 This report provides a forum for framing relevant questions on topics that impact older women with early-stage, locally advanced, and metastatic breast cancer. Areas of consensus and controversy are highlighted along with the relevant evidence. Important criteria needed to perform a geriatric assessment are included, along with discussions on the relevance of functional decline in particular organ systems and their impact on decisions relating to the use of specific therapies. Patient vignettes further highlight issues involved when evaluating and recommending treatment for individual patients.
Task force members are from NCCN member institutions, and include some members of the NCCN Breast Cancer Clinical Practice Guidelines in Oncology Panel7 (to view the most recent version of these guideline, visit the NCCN Web site at www.nccn.org) along with others with a special expertise in treating breast cancer in the older woman. A total of 18 task force members represented medical oncology, radiation oncology, surgical oncology, geriatric oncology, geriatrics, plastic surgery, and patient advocacy. All task force members were identified and invited solely by NCCN.
A formal agenda was developed by the task force chair, and individual members were assigned topics for focused didactic presentations based on high-level scientific evidence whenever possible. Substantial time was allowed for discussion after each scientific presentation. Draft versions of this report were circulated among all task force members for review and comment.
The NCCN Clinical Practice Guidelines in Oncology: Senior Adult Oncology (to view the most recent version, visit www.nccn.org) provided a means of “operationalizing” aspects of the assessment and treatment of older patients with cancer.8,9 Those guidelines served as a foundation for the task force to address some issues specific to the management of older patients with breast cancer. Table 1 provides major topics of discussion at the meeting and summarizes areas of controversy and consensus identified by participants. A common theme was the paucity of high-level evidence. Most data related to treatment of older women with breast cancer are retrospective, and virtually no data address some of these issues. The older women enrolled in available clinical trials tend to be highly selected, with few or no comorbidities, and thus may not represent the older population in general.
NCCN Task Force on Breast Cancer in the Older Woman: Discussion Topics
Defining “Older” Patients With Breast Cancer
Central issues confronting the task force were the needs 1) to identify treatment recommendations in the NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (to view the most recent version, visit www.nccn.org) that might not be suitable for “older” patients with breast cancer and 2) to determine whether a chronologic age or dividing line could be applied (e.g., ≥ 65 or ≥ 70 years) to help identify these patients. Some members of the task force recommended that “70 years or older” be used to define “older” patients. One reason for this specific cutoff point was that little or no data exist to make evidencebased decisions for these patients because they are dramatically underrepresented in breast cancer clinical trials. Therefore, they are most in need of expertdriven consensus recommendations.
However, these issues are confounded by the heterogeneous nature of older patients. Beyond chronologic age, important factors to include in evaluating an older patient with breast cancer are physiologic/ functional reserve, comorbidities, cognitive function, available social support systems, life expectancy, and risk for breast cancer mortality.
Physiologic Reserve
The term physiologic reserve describes the functional limits of a particular physiologic system when that system is exposed to a stressor; hence, a consequence of a decreased physiologic reserve is a decreased ability to adapt to stressors.10 Aging-associated changes in the heart, vasculature, lungs, kidneys, and other organ systems produce a progressive decrease in physiologic reserve independent of disease processes.11 Some physiologic changes associated with aging include decreased hepatic and renal volume and associated blood flow; decreased glomerular filtration rate; decreased bone marrow reserves; and impairment of gastrointestinal mucosal protective mechanisms.
Because cancer and its treatment are physiologic stressors, the decline in physiologic reserve associated with aging can impact tolerance to breast cancer treatment. Table 2 lists toxicities shown to have increased frequency/severity with specific cancer therapies when administered to older patients with diminished physiologic reserve in certain organ systems. The extent to which the pharmacokinetics/pharmacodynamics of chemotherapy drugs differ in older compared with younger populations was debated among members of the panel.12,18
Impact of Diminished Physiologic Reserve in Patients Treated With Specific Chemotherapeutic Agents
Comorbidities
The older population bears a greater burden of comorbidity compared with younger individuals. A population-based analysis from the National Institute on Aging/National Institutes of Health showed that hypertension, heart-related conditions, arthritis, and gastrointestinal problems were present in 42.9%, 39.1%, 34.9%, and 31.0% of the population of cancer patients aged 55 years, respectively.19 In addition, the number of comorbid conditions increased with age; approximately 10% of patients aged 55 to 64 years, 17% of patients aged 65 to 74 years, and 27% of patients aged 75 years or older were found to have 6 or more comorbidities.
Although age-related changes in physiologic reserve occur independent of comorbid conditions, the presence of one or more comorbidities can accelerate the rate of decline in physiologic reserve11,20 and may influence the severity of chemotherapy-related toxicity. Preexisting comorbidities common in elderly patients that may impact treatment decisions related to use of specific cytotoxic or endocrine agents include cardiovascular disease (e.g., congestive heart failure) and use of anthracyclines or trastuzumab;21–23 kidney dysfunction and capecitabine;16 preexisting neuropathy and taxanes;24 history of thromboembolism and tamoxifen (venous thromboembolism) or bevacizumab (arterial thromboembolism);25,26 and osteoporosis and aromatase inhibitors.27,28
Life Expectancy
Estimation of survival was identified by many task force participants as a key factor in making treatment decisions for older women with breast cancer. Data from the U.S. Centers for Disease Control and Prevention updated in 2007 indicate that, although the median life expectancy of a white woman in the United States is 80.4 years, a white woman of 65 or 75 years has a life expectancy of approximately 20.0 or 12.8 years, respectively29 (Figure 1). These values are lower for a black woman in the United States. However, comorbid conditions can have considerable impact on survival in the population aged 65 years and older.
Life expectancy by age: U.S. white women. Data from Arias E. National Vital Statistics Report: United States Life Tables, 2003. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr54/ nvsr54_14.pdf. Last accessed April 9, 2008.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 6, S4; 10.6004/jnccn.2008.2004
Figure 2 displays estimates of life expectancies of women in the United States at 65 to 85 years of age based on whether they are classified as“healthy,” “average,”or “sick.”30 Interestingly, the presence of comorbidity is shown to have the greatest impact on survival in women 65 years of age and to have progressively less effect on life expectancy for women in older age groups. This suggests that older patients may develop adaptive mechanisms to partially compensate for certain long-standing comorbidities.
Life expectancy and comorbidity. Data from Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 2000;18:1709–1717.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 6, S4; 10.6004/jnccn.2008.2004
Breast Cancer Mortality
Figure 3 shows age-specific breast cancer incidence rates in the United States from the SEER database for 1975 to 2003 for women aged 40 years and older.31 Breast cancer incidence is approximately twice as high in women aged 75 to 79 years compared with women aged 50 to 54 years. In addition, data from the U.S. National Center for Health Statistics for 2002 through 2004 show that the mortality burden from breast cancer increases with age; for example, the percentage of women in the United States aged 70 and 50 years who will die of breast cancer within 10 years is 0.9% and 0.4%, respectively.32
Trends in age-specific breast cancer incidence rates among women aged 40 years and older, 1975–2003. From Jemal A, Ward E, Thun MJ. Recent trends in breast cancer incidence rates by age and tumor characteristics among U.S. women. Breast Cancer Res 2007;9:R28; with permission.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 6, S4; 10.6004/jnccn.2008.2004
Competing causes of mortality must be evaluated in women with breast cancer to assess how likely they are to die of breast cancer than another cause.33
Associations between age-specific breast cancer mortality rates and both patient age and breast cancer stage at diagnosis are particularly relevant to the development of clinical practice guidelines. An analysis of data from SEER for approximately 400,000 patients with breast cancer diagnosed between 1973 and 2000 found that the risk for death from the disease decreased relative to the risk for death from other causes as age at diagnosis increased. However, among patients aged 70 years or older, death from breast cancer still accounted for a significant percentage of mortality, especially in patients with high-risk disease (Figure 4).34
Cause of death for white women with breast cancer aged 70 years and older after 28-year follow-up. Data from 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;96:1311–1321.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 6, S4; 10.6004/jnccn.2008.2004
A meta-analysis of data from randomized clinical trials of women with node-positive breast cancer (patients with higher-risk disease with few comorbid conditions) treated with adjuvant therapy showed that the breast cancer mortality rate in women aged 65 years and older (42%) was higher than in younger age groups (e.g., 32% in women aged ≤ 50 years and 36% in women aged 51–64 years). In this meta-analysis, the number of patients older than 65 years was limited, and the older patients had a higher disease burden than the younger patients.35
Results from a large, randomized trial of women aged 70 years and older diagnosed with low-risk disease (small, hormone receptor-positive, nodenegative breast cancer) support the conclusion that breast cancer mortality in this population is low. In this study, patients were treated with breast-conserving surgery and then randomly assigned to receive tamoxifen plus radiation therapy or tamoxifen alone. At a median follow-up of 8.2 years, 71% of patients were alive and only 2% had died of breast cancer (6% of total deaths were from breast cancer).36,37
A population-based study of 3-year mortality rates of approximately 1000 women with breast cancer identified comorbidity as a strong predictor of survival independent of age, disease stage, tumor size, treatment, race, and social/behavioral factors. Women with 3 or more particular comorbid medical problems had a 20-fold increase in non-breast cancer–related death and a 4-fold increase in all-cause mortality compared with breast cancer patients with no comorbid conditions.38
Finally, a SEER-based report of breast cancer mortality trends in the United States showed that the recent decline in breast cancer–related deaths observed for the overall population of women with breast cancer is not as significant for women aged 70 years or older compared with women younger than 70 years.39
Social Support Systems
The prevalence of women who live alone is very high among women in the United States aged 75 years or older: 50% according to data from the 2000 U.S. Census Report.2
Geriatric Assessment Tools: Evaluating the Individual “Older” Patient
Although all older patients experience an ageassociated decrease in physiologic reserve, marked differences in the rates of decline are observed among individuals. Therefore, the ability to tolerate treatment varies greatly; hence, the importance of estimating the functional reserve of the individual patient.10 Other issues also impact treatment decision-making in older patients with cancer, such as their life expectancy, whether they are likely to experience complications of cancer during their lifetime, and whether they are more likely to die with or of cancer.8,9,33
Various geriatric assessment tools are available to provide a way to estimate the “functional reserve” of a patient, identify areas where interventions may be instituted, and predict survival.8,9,33,40,41 Geriatricians use the term comprehensive geriatric assessment (CGA) to describe a multidisciplinary evaluation of a range of independent predictors of morbidity and mortality for older individuals, such as need for assistance with activities of daily living or instrumental activities of daily living, presence of comorbidities, nutritional status, level of cognition, psychosocial status, and whether polypharmacy is present.33,42
Several short screening tests for qualitatively or quantitatively evaluating specific parameters in an older patient are also part of the CGA, including the “timed up and go” test to evaluate functional status and a short memory test to evaluate mental status (Table 3).8,9,33,43 Other assessment tools include the Vulnerable Elders Survey (VES-13)41 and a system developed by the Cardiovascular Health Study group to estimate frailty,8,9,44 although neither these nor the CGA and short screening tests were designed specifically as assessment tools for cancer patients. A short, cancer-specific, primarily self-administered geriatric assessment is currently being evaluated by the Cancer and Leukemia Group B (CALGB), and a multicenter clinical trial is underway to determine which domains in the assessment are most predictive of risk for toxicity from chemotherapy among older adults with cancer.45,46
Screening Tests
Accurate estimates of the risks of both breast cancer– and non-breast cancer–specific mortality for individual patients is an extremely important component of an overall geriatric assessment, but are difficult to determine. The Charlson Comorbidity Index (CCI), based on 1-year mortality data from internal medicine patients admitted to an inpatient setting, is widely used in geriatrics and oncology. It provides an estimate of survival based on patient age and presence of specific comorbidities. The CCI has been validated in patients with breast cancer and shown to be a good predictor of survival over a 10-year period.47
Another tool includes 12 prognostic indicators, including age, male sex, certain comorbidities and behaviors, several functional measures, and a simple scoring system to estimate the 4-year mortality risk for an individual patient.48 Table 4 shows this tool with the following point system for 4-year mortality risk: 0 to 5 points: 4% or less; 6 to 9 points is 15%; 10 to 13 points is 42%; and 14 or more points is 64%.
Independent Risk Factors for 4-Year Mortality
The Adjuvant! Online program provides estimates of the 10-year risks for breast cancer–related death, death from other causes, and relapse in women with stage I, II, or IIIA breast cancer.49 The patient-specific parameters are limited to age and a comorbidity estimate. A unique feature of Adjuvant! Online is the inclusion of disease-specific parameters, such as tumor size, hormone-receptor status, tumor grade, and number of involved lymph nodes, although this program has not been specifically validated in older patients.
Specific types of organ dysfunction may be particularly important in deciding on treatment in the context of particular therapies and the specific side effects associated with them. For example, a high prevalence of renal insufficiency has been reported in older adults with cancer.50–52 Changes in renal function are often not well reflected in measurements of serum creatinine.50–52 Certain formulas for estimating individual glomerular filtration rates may provide a better assessment of renal function, although the accuracy of some of these determinations in older patients has been questioned.51,53,54 A detailed summary of aspects of these assessments relevant to the older cancer population51 and specific recommendations for adjustments in the dosing of cytotoxic agents administered to older cancer patients are provided elsewhere.50 Finally, measurement of inflammatory markers (e.g., C-reactive protein), although still investigational for cancer patients, is a potentially useful way to assess functional decline and mortality in older patients.10,55,56
Although no consensus was reached about the optimal geriatric assessment tool for evaluating an older woman with breast cancer, all task force members acknowledged the need for these tools. Advantages of the CGA are the multidisciplinary nature of the assessment and the wealth of information included in the tool, whereas the length of time and level of expertise needed to administer and evaluate the results are disadvantages to its use in the oncology setting. The opinion of task force members was that a simple 3- to 5-minute test incorporating several questions and a short performance evaluation with a simple scoring algorithm was the limit to what could be practically implemented in clinical practice. However, others expressed the view that longer, more thorough assessments may be important in critical situations, such as when deciding on the use of adjuvant therapy.
The advantage of Adjuvant! Online is that it is the only tool that can estimate both breast cancer– specific mortality and death from other causes for individual patients. Finally, several task force members anticipated an increasing role of gene array assays, such as Oncotype DX57,58 or MammaPrint,59 for providing tumor-specific information on the risks for breast cancer recurrence and breast cancer–specific mortality for older women as a supplement to the patient-specific information obtained through more standard geriatric assessments.57–59
Attitudes of Older Patients With Breast Cancer and Their Physicians
Task force members emphasized the important role of patient preference in deciding treatment for older women with breast cancer. However, few studies have explored the attitudes of these women and the psychosocial factors that influence decisionmaking. Results of a longitudinal cohort study of 563 women aged 67 years or older after surgical treatment of stage I and II breast cancer showed fewer concerns about body image and better mental health when treatment was concordant with patient preferences about appearance.60 Several studies indicated that the level of acceptance of operative procedures or chemotherapy for breast cancer did not differ among older and younger patients,61,62 although older patients were less likely to accept an improved likelihood of survival at the cost of decreased quality of life.61,62
Several studies evaluating treatment choices of older women with breast cancer found expert advice to be a key factor.62–65 In addition, results from a study of 613 pairs of women with breast cancer aged 67 years or older and their surgeons showed an association between level of physician-initiated communication and patient satisfaction with type of treatment received.66 Thus, physicians must be able to provide reasonable estimates of the risk for relapse, effect of certain treatments on relapse and mortality, and side effects associated with particular treatments when counseling older women with breast cancer; these discussions must be tailored for the individual patient.
Older women with breast cancer are more likely than their younger counterparts to be diagnosed at a later stage of disease67,68 and less likely to undergo chemotherapy67–69 or breast-conserving therapy.68,70,71 The attitudes of older patients and their physicians on breast cancer diagnosis and treatment probably contribute to the differences observed in patterns of care according to patient age. The greater emphasis on quality of life for older patients61,62 and the possible reluctance of clinicians to expose their patients to cytotoxic therapies67,72 may be partly responsible for fewer older women with breast cancer undergoing certain types of treatment. Furthermore, treatment recommended by some physicians may be influenced by evidence of a more indolent course of breast cancer tumors in older patients.67
Tumor Biology in Older Versus Younger Women With Breast Cancer
Older women have characteristic differences in the biology of breast cancer compared with younger women. Breast cancers tend to have fewer adverse prognostic features in older women. The frequency of hormone receptor–positive tumors increases with the age.67–69,73–76 In one study, women aged 50 to 64 years were less likely to have tumors that were both estrogen receptor (ER)– and progesterone receptor (PR)–positive compared with women aged 76 years or older (39.7% vs. 54.9%, respectively; P < .01), although the frequency of ER-positive tumors in these populations was not significantly different (78.6% vs. 81.3%; P = .07).67
Evaluations of ER concentrations by sucrosedensity gradient or charcoal titrations performed on tumor samples of patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 trials showed that median receptor concentration increased with patient age.77 The frequency of human epidermal growth factor receptor 2 (HER2)positive tumors is reported to be lower in populations of older patients with breast cancer compared with younger patients.67,69 Gennari et al.67 found 32.7% of elderly patients to have HER2-positive tumors, compared with 40.8% of younger patients (P < .01), and Diab et al.69 reported HER2-negative tumors in 90% and 79% of breast cancer patients aged 85 years or older and 55 to 64 years, respectively. Potential confounders of these types of analyses are the possible inaccuracies associated with the tests used to measure hormone receptor and HER2-receptor tumor status.78,79
Reports have also shown that other markers of aggressive tumors, such as tumor grade, p53 levels, and S-phase fraction, are lower in breast cancers in older patients.69 Less-aggressive histopathologic features (e.g., less lymphovascular invasion) were reported to be associated with breast cancer in older versus younger patients,80 and local recurrence rates after quadrantectomy and axillary dissection alone were found to decrease with increasing patient age.81
Some studies suggest that breast cancers are not less aggressive in older versus younger women.6,82,83 For example, in analyzing data from 2136 postmastectomy patients at a single institution who did not undergo systemic adjuvant therapy, Singh et al.83 found that among women with node-negative disease, those aged 40 to 70 years had a significantly higher distant disease-free survival rate than women older than 70 years.83 Additional studies are needed to evaluate the biologic properties of tumors in older and younger women with breast cancer and to investigate how host-related characteristics, such as age and the presence of comorbidities, influence tumor growth.
Implementation of Specific Interventions in the Older Cancer Patient: Benefits and Risks
Curative Surgery and Surgical Axillary Staging
The goals of surgery for older women with breast cancer are to 1) prevent chest wall or ipsilateral breast tumor recurrence, 2) prevent axillary recurrence, 3) prevent systemic recurrence, and 4) preserve the breast when possible and preferred by the patient. An overarching objective is to accomplish these 4 goals with minimal treatment. Minimal treatment in this context is distinguished from undertreatment and is defined as treatment that makes medical sense in the context of the patient and evidence-based treatment options.
In their landmark trial, Hughes et al.36,37 randomly assigned 636 women aged 70 years or older at diagnosis with clinical stage I (tumors ≤ 2 cm), ER-positive breast cancer to lumpectomy plus 5 years of tamoxifen or lumpectomy and whole breast irradiation plus 5 years of tamoxifen. At 8.2 years follow-up, local regional recurrence rates were approximately 1% and 7% in the arms with and without radiation therapy, respectively, and no significant differences were seen in overall or disease-free survival or need for mastectomy. Axillary recurrence was observed in only 4 patients in the tamoxifen-only group who did not undergo axillary staging, and in none of the other patient groups.
Another randomized trial showed similar results on the lack of prognostic benefit of axillary dissection in women aged 65 to 80 years with stage I breast cancer.84 Finally, results of a study of 241 consecutive patients aged 70 years or older with breast tumors 3 cm or smaller and clinically node-negative disease support the safety and accuracy of sentinel node biopsy in this population.85
Two randomized trials comparing tamoxifen alone with mastectomy plus tamoxifen for older women with operable hormone receptor-positive breast cancer showed conflicting results for overall survival. No significant difference in overall survival was observed between patient groups in one of the trials,86 whereas a significantly shorter overall survival rate was shown for patients receiving tamoxifen alone in the other trial.87 However, results from a meta-analysis of 4 studies indicated that although surgery did not significantly increase overall survival rates, patients undergoing treatment with surgery plus tamoxifen had significantly longer progression-free survival (hazard ratio, 0.65; 95% CI, 0.53–0.81; P = .0001).88
Ongoing Questions:
Questions related to the surgical treatment and evaluation of older women with breast cancer posed by the task force, for which data are limited, include:
If breast-conserving surgery is feasible in older patients with clinically positive nodes, is radiation necessary?
If a woman desires breast preservation but the tumor is 5 cm or larger, should preoperative chemotherapy or endocrine therapy be considered?
Should treatment recommendations for an older woman with a positive sentinel node differ in a woman older than 70 years? (Should this patient be treated with either axillary dissection or nodal irradiation?)
Should hormone receptor status be considered when evaluating whether to perform lumpectomy without radiation therapy? (Can the results from Hughes et al.36,37 be applied to older women with hormone receptor–negative disease?)
Is axillary staging using sentinel node biopsy useful in populations of older women with stage I, hormone receptor–positive tumors if chemotherapy is not considered an option for these patients?
The task force expressed a high level of consensus on the use of breast-conserving surgery as an option in older women with early-stage breast cancer.
Older patients who will benefit from mastectomy include those with contraindications to endocrine therapy who want to avoid radiation after breast conservation. For older patients who are very frail, nonsurgical therapy, such as endocrine therapy alone, may be a reasonable treatment option. Breast-conserving surgery without breast radiation therapy should be restricted to patients defined using the inclusion criteria from the trial of Hughes et al.36,37 The task force believes that the results of the Hughes trial36,37 cannot be generalized to support breast-conserving surgery without radiation therapy in older women with clinically positive lymph nodes or tumors that are hormone receptor-negative or larger than 2 cm.
The need to treat women with a positive sentinel node using either axillary dissection or nodal irradiation was another general area of agreement. A more controversial issue was whether a sentinel node biopsy could be considered optional in older women with small, clinical stage I, ER-positive breast tumors.
Radiation Therapy
The meta-analyses of radiotherapy trials by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed that the 5-year absolute reduction in local recurrences associated with radiation therapy after breast-conserving surgery was 22% in women younger than 50 years compared with 12% in those aged 60 to 69 years. No age-specific differences in local recurrence rates were found with postmastectomy radiation therapy. Absolute reductions of 17% and 18% were observed in the younger and older age groups, respectively.89
Hughes et al.36,37 showed that, in women aged 70 years or older with clinical stage I, ER-positive breast cancer, adding radiation therapy to breast-conserving surgery plus tamoxifen did not change the subsequent mastectomy rate, likelihood of developing distant metastases, incidence of death from breast cancer, or overall survival. Patients not undergoing radiation therapy showed an increase in the rate of local recurrence, with an absolute benefit in local recurrences of approximately 6% with radiation versus no radiation. Survival data showed that 71% of patients were alive and only 2% of deaths were attributable to breast cancer.
An evaluation was performed using the SEER tumor registry of radiation therapy after breast-conserving surgery in the community population of women aged 70 years or older with small, node-negative, ERpositive (or receptor status unknown) breast cancer.90 The 5-year risks for local recurrence in women undergoing radiation therapy and those who did not were very similar to those observed in the clinical trial of Hughes et al.36,37
However, separate analyses showed considerably higher absolute benefits of radiation therapy for women aged 66 to 69 years, those with larger tumors, and those with ER-negative tumors. Furthermore, women aged 70 to 79 years without comorbid conditions were among the patient groups most likely to benefit from radiation therapy after breast-conserving surgery, whereas the benefits of radiation therapy were substantially fewer in older women with moderate to severe comorbidity (i.e., a CCI score ≥ 2). No data are available relating to tamoxifen use in the SEER study, and this may have impacted the local recurrence rates.
A similar study using the SEER database to evaluate use of radiation therapy after breast-conserving surgery in older women (≥ 66 years) with ductal carcinoma in situ (DCIS) showed significant benefits of radiation therapy with respect to preventing local recurrence and subsequent invasive breast cancer.91
In patients undergoing breast-conserving surgery followed by radiation therapy, the addition of a “boost” to the tumor bed has been shown to reduce local failures by approximately 40%.92,93 The relative benefit seems similar across age groups. However, because older patients typically have a lower failure rate than younger patients, the magnitude of the absolute benefit of the boost is lower in the older patients.94
Two population-based studies have addressed the effectiveness of postmastectomy radiation therapy based on patient age.76,95 Data from the Canadian Breast Cancer Outcomes Unit Database were evaluated for cohorts aged 50 to 69 years and 70 years and older with a median postmastectomy follow-up of 8.3 years. On multivariate analysis, age was not an independent predictor of likelihood of local recurrence in the absence of radiation therapy. However, in patients with node-positive disease involving 4 or more lymph nodes, those aged 70 years and older showed a trend toward increased rates of local recurrence compared with those aged 50 to 69 years. Overall, patients aged 70 years and older had similar local recurrence rates to those aged 50 to 69 years.76
In an analysis of SEER data of 11,594 women aged 70 years and older treated for invasive breast cancer with mastectomy with a median follow-up of 6.2 years, significant benefit from postmastectomy radiation therapy was seen only in the group of patients with high-risk disease (i.e., low risk—T1/2, N0; high risk—T3/4 and/or N2/3).95 Issues regarding use of radiation therapy and axillary staging in an older patient with early-stage breast cancer are presented in Case Study 1.
Ongoing Questions:
What short-, intermediate-, and long-term toxicities are associated with radiation therapy in older patients?
What criteria should be considered in the decision to recommend radiation therapy for an older woman?
Because survival benefits of radiation therapy after mastectomy may not be evident for 10 to 15 years, are these benefits relevant to older patients?
Other factors influencing decisions related to radiation therapy in older women include the attitudes of patients, medical oncologists, and other referring physicians; performance status of the individual patient; and risk for local recurrence. Although the potential survival benefits of postmastectomy radiation are likely to be less relevant in older patients, other benefits of radiation therapy can include a decreased likelihood of local recurrence with increased quality of life. Finally, the potential adverse cardiovascular effects of radiation therapy, particularly when administered to the left breast, were mentioned as a factor for consideration.96
Reconstructive Surgery
Very few studies have addressed breast reconstructive surgery after mastectomy in older women. The SEER database documents that very few women aged 65 years and older undergo breast reconstruction after surgery for breast cancer.97,98 Morrow et al.97 found the percentage of patients receiving reconstruction decreased dramatically with age, with 53.0%, 36.6%, and 8.3% reconstruction rates for women aged younger than 50 years, 50 to 64 years, and 65 years and older, respectively (P < .001). Lower rates of breast reconstruction were also associated with lower income and African American ethnicity. Although many women in the study reported physician discussions of breast reconstruction, patient knowledge of the procedure was limited.
A retrospective study of 84 older women (81 were ≥ 65 years of age) who underwent breast reconstruction after mastectomy found more positive outcomes and fewer complications with autologous tissue versus implant reconstruction.99 However, all groups of the study had relatively high rates of breastsite complications, including infection.
Smoking history and obesity are critical factors that increase complication rates of reconstructive procedures, regardless of age. In addition, the presence of certain comorbidities more common in older patients, such as diabetes and hypertension, can impact decisions related to breast reconstruction. Other less-complicated alternatives to full breast reconstruction, which might be more acceptable to some older patients, include a procedure to reduce the contralateral breast100 and direct-to-implant reconstruction.101
Ongoing Questions:
Should all women, regardless of age, be offered the option of a consultation with a plastic surgeon (to become informed about breast reconstructive options, including explanations of the potential risks and benefits of the surgical procedures and their impact on cancer outcome) in the absence of medical contraindications?
Should the “functional age” threshold be lower for considering reconstructive procedures compared with breast cancer therapies that have the potential to impact disease outcome?
Are the risks associated with breast reconstructive surgery greater in older women?
The overall consensus of the task force members was that women of all age groups should be offered consultation with a reconstructive surgeon, although some participants questioned whether the risks of the procedure would ultimately outweigh the benefits for many older patients. Further investigation is required to determine if unique risks exist for older women who undergo reconstruction. Finally, several members of the task force identified a need to further investigate the attitudes of older women about breast reconstruction options.
Endocrine Therapy
Endocrine therapy is the most commonly used systemic treatment in older patients with breast cancer in both the adjuvant and metastatic settings.86,102,103 Although clinical studies of endocrine agents are limited in women aged 70 years and older, the median age of women enrolled in clinical trials of aromatase inhibitors as treatment for both early-stage, locally advanced, and metastatic breast cancer was often older than 60 years because of the eligibility requirement of postmenopausal status.104–107 Furthermore, results from the EBCTCG overview showed a decrease in risk for breast cancer recurrence and death in women aged 70 years and older with early-stage ER-positive breast cancer receiving 5 years of tamoxifen, similar to that in younger patients.108 In addition, a recent prospective cohort study of the efficacy of adjuvant tamoxifen in older women showed a 4% absolute increase in breast cancer–specific survival and an 11% absolute increase in overall survival in older women receiving tamoxifen at 5-year follow-up.103
Ongoing Questions:
Do older women with hormone receptor–positive breast cancer benefit more from endocrine therapy than younger women with the same diagnosis based on tumor biology?
Should adjuvant endocrine therapy recommendations for older women differ from those currently in NCCN guidelines for younger postmenopausal patients?
How do certain side effects of aromatase inhibitors (e.g., arthralgias, altered lipid levels, decreased bone density) and tamoxifen (e.g., venous thromboembolism and endometrial carcinoma) impact treatment tolerability and adherence in older women with breast cancer?
Areas of consensus included the benefit of endocrine therapy for older patients with hormone receptor–positive breast cancer in the adjuvant and metastatic settings, and using initial endocrine therapy with postponed use of chemotherapy to treat patients of all age groups with ER-positive metastatic disease. Several points of discussion included the increased incidence of nonaromatase inhibitor–associated arthralgias in older patients as confounders of efforts to evaluate the risk for aromatase inhibitor– induced arthralgias, and the impact of cost on the choice of endocrine therapy for older patients.109
Some issues to consider regarding use of endocrine therapy in older patients with early-stage breast cancer are presented in Case Study 1.
Chemotherapy
Adjuvant Setting:
Evidence indicates that the risk for recurrence in patients with ER-negative disease is highest in the first 5 years after diagnosis and that the likelihood of disease recurrence for patients with ERpositive disease is comparatively lower during the first 5 years. However, a reversal in this trend is seen in the subsequent 5 years, with higher recurrence rates seen for patients with ER-positive disease.110,111 This relatively lower rate of early recurrence in patients with ER-positive disease probably depends, at least partly, on the efficacy of endocrine therapy.111 Furthermore, the benefit of chemotherapy is most pronounced in the first 5 years.108,112 The early benefits of chemotherapy and endocrine therapy are appropriate considerations when deciding on adjuvant therapy for older individuals with breast cancer.
The most recently published meta-analyses of randomized trials by the EBCTCG shows that adjuvant polychemotherapy had a substantial impact on recurrence rate and breast cancer–specific mortality in women with ER-negative tumors who were younger than 50 and those 50 to 69 years of age. The absolute risk reductions in 10-year recurrence risk and breast cancer mortality are 12% and 8%, respectively, in patients younger than 50 years, and 10% and 6%, respectively, in patients aged 50 to 69 years.112 Hence, the benefits of chemotherapy in patients with ERnegative disease do not seem to be influenced by age.
Earlier EBCTCG analyses showed that the benefits of polychemotherapy, although significant, were not as marked for patients with ER-positive compared with those with ER-negative disease, and patients aged 50 to 69 years received less benefit from chemotherapy than patients younger than 50 years.108 In addition, the benefit of adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate, fluorouracil) in addition to tamoxifen therapy was considerably less pronounced in women with ER-positive disease who were 60 years or older enrolled in the NSABP B-14 and B-20 trials compared with the younger patient cohorts in these trials (Figure 5).77 In a randomized study of women 65 years or older with operable, nodepositive, mostly ER-positive breast cancer, a significant increase in disease-free survival was shown for those women who received adjuvant chemotherapy with epirubicin-based chemotherapy in addition to tamoxifen compared with women receiving tamoxifen alone, although no impact on survival was observed at a follow-up of 6 years.113
Relation between recurrence-free survival (RFS) in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 trials according to age group. For patients 60 years or older (Panel 3), RFS rate differences in the tamoxifen-treated and CMFT (cyclophosphamide, methotrexate, fluorouracil + tamoxifen)-treated groups were not significant.
From Fisher B, Jeong JH, Bryant J, et al. Treatment of lymph-node-negative, estrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Lancet 2004;364:858–868.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 6, S4; 10.6004/jnccn.2008.2004
Retrospective studies support the use of adjuvant chemotherapy in older women with ER-negative breast cancer. The results of 2 recent analyses using the SEER database found an association between use of adjuvant chemotherapy and decreased mortality in women with node-positive, ER-negative disease.114,115 A retrospective review of 4 randomized clinical trials provided evidence for benefit of intensive adjuvant chemotherapy regimens with respect to disease recurrence and breast cancer mortality in women with nodepositive breast cancer across all age groups.35 However, in this study, the impact of ER status on patient outcome was not evaluated; only approximately 35% of the patients had ER-negative disease, the group of patients aged 65 years or older had a higher average number of positive lymph nodes, and few older patients were enrolled in the trials.
An increased incidence of certain complications of chemotherapy, including cardiotoxicity and acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), has been reported in populations of older patients.21,116,117 In addition, a higher rate of treatment-related death has also been observed in older populations undergoing adjuvant chemotherapy for breast cancer,21,35 although the risk for chemotherapy-related toxicity in older women with breast cancer may depend more on the type of chemotherapy regimen than patient age.118 Some issues to consider regarding use of adjuvant chemotherapy in older patients with early-stage breast cancer are presented in Case Study 2.
Ongoing Questions:
What estimated life expectancy would be reasonable before considering chemotherapy in an older woman?
What incremental benefits would be required in older adults before the benefits of chemotherapy warrant the increased toxicity experience?
How confident are physicians that benefits of chemotherapy for 60- to 69-year-old patients translate into benefits for 70- to 100-year-old patients?
Should older patients receive lower doses of or different chemotherapy from younger patients?
The overall consensus of the task force is that the benefit-to-risk ratio of using adjuvant chemotherapy in older patients with ER-negative disease is often favorable, although other factors, such as life expectancy, impact of comorbidities, toxicities of particular agents, and personal preferences of the patient, must be considered. That the risk for recurrence of ER-negative disease is highest in the first 5 years after diagnosis further supports the usefulness of chemotherapy in many older patients with ER-negative breast cancer and justifies a life expectancy of at least 5 years as a criterion for considering chemotherapy in older patients.
Beyond absolute reduction in breast cancer recurrence or mortality, consideration of functional reserve is also important.30 Furthermore, whether dose reductions or less intensive therapies given to older patients in some studies may have diminished the observed effectiveness of chemotherapy in patients with both ER-negative and -positive disease, and whether modern, more intensive regimens would show greater efficacy in these groups of patients is unclear.
No specific adjuvant chemotherapy regimens were identified as clearly preferable, although caution in using anthracyclines, reliance on less myelosuppressive therapies, careful evaluations of renal and hepatic functions, possible benefit of weekly dosing, and early use of myeloid growth factors were mentioned as important considerations. Some underexplored areas include evaluation of the pharmacokinetics and pharmacodynamics of cytotoxic agents in older versus younger patients and the interactions of chemotherapeutic drugs with other medications in the older population.
Metastatic Setting:
Various biologic and clinical features, such as ER-negative tumor status, visceral dominant disease, and a short disease-free survival interval, have been identified as negative prognostic factors for women with metastatic breast cancer. Older age alone has not been shown to influence outcome.119 Furthermore, results from a case-control study showed no significant differences in time to disease progression and survival for women younger than 50 years, 50 to 69 years of age, and 70 years and older undergoing chemotherapy for metastatic breast cancer.120 However, women aged 70 years and older were more likely to receive lower doses of chemotherapy. Results from a randomized study of first-line combination chemotherapy (doxorubicin/paclitaxel) versus sequential single-agent chemotherapy in women (median age, 56–58 years) with metastatic breast cancer showed no differences in overall survival or quality of life between treatment arms; however, treatment-related toxicity was higher in the combination arm.119
Ongoing Question:
In the metastatic setting, is combination or sequential chemotherapy preferred for older patients?
The goals of metastatic breast cancer treatment are primarily palliative. When chemotherapy is used, sequential single agents (i.e., administering single-agent chemotherapy in tandem) are generally preferred as opposed to combination chemotherapy, because toxicity with combination regimens is likely to be more severe in the older population. In general, chemotherapy should be limited to those with hormone receptor–negative disease or those with hormone receptor–positive, endocrine therapy–refractory disease. Some members suggested that a “start low, go slow” titration to full dose could be advantageous in this setting to limit toxicity.
The preferred approach for patients with ER-positive disease is initial single-agent endocrine therapy followed sequentially with other single-agent endocrine therapy at disease progression. This strategy allows chemotherapy and its associated side effects to be delayed as long as possible. Use of HER2-targeted agents (e.g., trastuzumab, lapatinib) in older women with HER2-positive breast cancer without chemotherapy or hormone therapy may be beneficial to avoid certain treatment-related side effects.
Trastuzumab Therapy for HER2-Positive Disease:
The degree of benefit from adjuvant trastuzumab in older patients with HER2-positive disease cannot be estimated from published results because very few of these patients were enrolled in the randomized trastuzumab trials.121–125 For example, 16.0% of patients in the NSABP (B-31)/NCCTG(9831) joint analysis were aged 60 years or older, and only approximately 6% of patients were older than 65 years. Evaluation of the efficacy of trastuzumab in the metastatic setting has also been largely restricted to younger patients (e.g., mean age of patients was 54 years in both the pivotal trial of trastuzumab plus chemotherapy126 and the trial of trastuzumab monotherapy127).
Safety analyses from the NSABP B-31 study identified older age as a risk factor for trastuzumab-related cardiotoxicity.23,128,129 Increased age was identified as a risk factor for congestive heart failure (CHF) at a follow-up of 5 years (2.3% for < 50 years; 5.1% for 50–59 years; and 5.4% for ≥ 60 years; P = .03).23 In addition, use of hypertensive medications, lower baseline left ventricular ejection fraction (LVEF), and lower LVEF after treatment with doxorubicin/cyclophosphamide therapy were also identified as being significantly associated with higher rates of CHF (CHF rates with or without use of hypertensive medications were 6.8% and 3.0%, respectively; P = .02).
Ongoing Question:
Which older patients with early-stage HER2-positive breast cancer should undergo trastuzumab therapy in the adjuvant setting?
The task force agreed that the therapeutic index of adjuvant trastuzumab does not preclude adjuvant trastuzumab in most fit elderly women, given the small numbers of cardiac-related deaths observed in clinical trials and the increased risk for relapse in patients with HER2-positive disease.130 Nevertheless, the general consensus was that little evidence exists on which to base tailored recommendations for adjuvant trastuzumab in the older patient. The use of adjuvant trastuzumab is related to that of adjuvant chemotherapy, because task force participants did not advocate using trastuzumab in the absence of chemotherapy in the adjuvant setting. Some members stated that a positive HER2 tumor status in an older patient with early-stage ER-positive disease could shift the decision-making balance toward use of chemotherapy. Some issues to consider regarding use of HER2directed therapy for patients with early-stage HER2-positive breast cancer are presented in Case Study 3.
Supportive Therapies
Cancer treatment–related complications are more common in older patients with breast cancer undergoing certain types of chemotherapy regimens.21,118 Supportive care measures include therapies to minimize chemotherapy-related neutropenia and anemia. A meta-analysis of randomized studies evaluating primary prophylaxis with granulocyte-colony stimulating factors (G-CSF) versus placebo or untreated controls in patients undergoing chemotherapy indicated that G-CSF therapy was associated with decreased incidences of febrile neutropenia and early death, and a higher relative dose-intensity of chemotherapy.131 Although the decreased risk for febrile neutropenia was found to be independent of age in this meta-analysis, only the trials involving patients with lymphoma included substantial populations of older individuals.
Results of 2 population-based studies have suggested that colony-stimulating factor support during chemotherapy may increase the risk for AML/MDS in women with breast cancer132,133 (e.g., increase in absolute risk from 1.04% to 1.77%133), although results from another epidemiologic study did not support this conclusion.117 Confounding this issue is the slightly increased risk for MDS/AML observed in some studies of older women with breast cancer that has been associated with use of certain cytotoxic drug regimens.21,117,132
Treatment-related anemia is a side effect of many myelosuppressive chemotherapies. Evidence from a multivariable logistic regression model indicates that age of 65 years or older is a risk factor for development of anemia during adjuvant treatment of breast cancer.134 In addition, the volume of distribution of a cytotoxic drug may be affected by the concentration of erythrocytes, because certain agents bind to red blood cells (e.g., anthracyclines).17 However, in a randomized, placebo-controlled study of women with metastatic breast cancer, decreased overall survival was associated with erythropoietic-stimulating agent (ESA) use to maintain high hemoglobin levels.135
Use of aromatase inhibitors is also associated with loss of bone mineral density and increased risk for bone fracture. Therefore, bone health should be monitored in women undergoing this therapy and followed by appropriate interventions in women at risk for osteopenia, osteoporosis, and fracture.136,137 The use of the potent bisphosphonates is also valuable in patients with bone metastasis from breast cancer.7,136
Ongoing Questions:
What target hemoglobin level should be recommended for older patients with breast cancer?
Should transfusion or growth factor support be used preferentially to maintain this hemoglobin level?
No consensus was reached concerning optimal hemoglobin levels for older women with breast cancer. The 2009 recommendations from the NCCN Clinical Practice Guidelines in Oncology: Cancer- and Treatment-Related Anemia Panel do not support using ESAs for treating cancer-related anemia for solid tumors; short-term use of ESAs is recommended only for the treatment of anemia caused by myelosuppressive chemotherapy.138 Long-term longitudinal survivorship studies are needed to evaluate the functional and medical effects of treatments in these patients, especially on the bone marrow and heart.
Studies Involving Older Patients With Cancer
A common theme linking each of the previous topics is the paucity of data from randomized clinical trials on older patients with breast cancer. The underrepresentation of cancer patients aged 65 years and older in clinical trials has been well documented.139–141
In a retrospective study covering 1995–2002, the ages of cancer patients enrolled in registration trials submitted to the FDA for drug approval were evaluated.140
The report showed that the percentage of patients aged 65 years and older enrolled in clinical trials evaluating hormonal therapy for breast cancer closely matched the percentage of breast cancer patients aged 65 years and older in the U.S. population. However, only 6% and 15% of the patients enrolled in trials of chemotherapy in the adjuvant and advanced disease settings, respectively, were 65 years of age and older, whereas 48% of the U.S. population with breast cancer was in that age group.
A pilot study evaluating potential barriers to enrolling older women with breast cancer in clinical trials found that patients aged 65 years and older with stage II disease were as likely as their younger counterparts to accept enrollment if a trial was offered, but physicians were less likely to offer this option to older patients.72 Another putative barrier to enrolling older patients in clinical trials is limited availability of information related to potential treatment toxicities in this population.72 Nevertheless, a study evaluating the effectiveness of providing an educational intervention (involving an education seminar and distribution of educational materials) on enrollment of older patients in cooperative group clinical trials did not find an association between its implementation and increased accrual of older patients.142
Task force members agreed that active participation of older women with breast cancer in randomized clinical trials should be encouraged, the determination of causal relationships between a treatment intervention and patient outcome can only be addressed by these trials, and treatment optimization for this group of patients can only be achieved through these studies. However, strict eligibility requirements for many clinical trials, possibly resulting in inclusion of older patients with few or no comorbidities, were mentioned as a potential barrier to the usefulness of extrapolating results from these studies to the overall population of older patients. In addition, the diversity of the older population regarding functional reserve and life expectancy adds another level of complexity to the design of clinical studies that include these patients.
The need to make treatment decisions for many older breast cancer patients not well represented by clinical study populations will exist for some time. Thus, several members of the task force suggested that, in the interim, well-designed high-quality populationbased studies may be useful to address issues related to this group of patients.143,144 Although retrospective studies are limited with respect to the conclusions that can be drawn, they may be more suited to accommodating the population diversity and providing information in the short-term. Collaborative projects across clinical trials are other possibilities for evaluating the risks and benefits of a particular type of therapy in larger numbers of older breast cancer patients.130 Table 5 lists topics for potential future studies that were mentioned by task force participants.
Areas Requiring Future Study
Conclusions
Changes in functional reserve, decreased tolerance to certain cancer therapies, and an increase in competing causes of morbidity and death complicate the treatment decision-making process for older women with breast cancer. Although evidence-based guidance to help balance the benefits and risks of breast cancer treatment in older patients is limited, this population of women is large and will continue to increase for the next few decades. A great need exists to better facilitate individualized treatment based on geriatric assessment, tumor biology, clinical trial results, and the concerns and goals of the patient. Unfortunately, meaningful data to help health care providers and patients make important treatment decisions are scarce.
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