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Abstract

Breast cancer is a disease of aging and the incidence of breast cancer increases dramatically with increasing age. In spite of major advances in prevention, screening and treatment approximately 40,000 Americans still die of metastatic breast cancer every year – the majority being women aged 65 years and older. Metastatic breast cancer remains incurable regardless of age and the goals of treatment are to reduce symptoms when present and to provide the patient with the best quality of life for as long as possible. Cornerstones of treatment to control metastases include endocrine therapy, chemotherapy and radiation therapy. Supportive care that includes psychosocial support and treatment of pain is also a key component of management. This review focuses on the issues related to the care of older women with metastatic breast cancer.

Keywords

age aged breast cancer chemotherapy elderly endocrine therapy treatment

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Release date: 3 July 2012; Expiration date: 3 July 2013

Learning objectives

Upon completion of this activity participants should be able to:

Analyze the clinical presentation of metastatic breast cancer

Develop effective practice patterns for endocrine therapy in cases of metastatic breast cancer

Evaluate the use of chemotherapy for metastatic breast cancer among older women

Assess ancillary therapy for older women with metastatic breast cancer

Breast cancer is the most common cancer in women accounting for 23% of all female cancer and 14% of cancer deaths globally [1]. In the USA in 2010, there were estimated to be 1,529,560 new cancer cases and 549,490 cancer deaths. Of these, 209,060 were new cases of breast cancer and resulted in 40,230 deaths. Breast cancer is also a disease of aging with an incidence rate of 82.2 new patients per 100,000 in women aged less than 65 years versus 403.8 per 100,000 for those aged 65 years and older [101]. The average age at diagnosis is currently 61 years and the average age at death is 68 years. Approximately 5% of these new breast cancer patients present with metastases when their breast cancer is first discovered, but the vast majority of patients who develop metastases do so months to years after their initial diagnosis and treatment. In affluent nations most women with breast cancer will survive without recurrence and mortality rates for breast cancer continue to improve. However, the loss of 40,000 women yearly to breast cancer in the US has remained relatively constant and the majority of these patients are aged 65 years and older.

Although many men and women aged 65 years and older are healthy and have long life expectancies, they are considered to be the aging population by the National Institutes of Aging, the major federal agency providing grant funding for aging research. Medicare eligibility in the USA also begins for most at 65 years of age and until recently, social security benefits began at this age. This has led medical and health-policy researchers to consider individuals aged 65 years and older as the aging population. Irrespective of the patient's age, once breast cancer metastasizes it is incurable. Data from the Surveillance, Epidemiology and End Results project of the National Cancer Institute for patients diagnosed between 1999 and 2005 indicate that approximately 25% of all patients diagnosed with metastatic (stage IV) breast cancer survive for 5 years, including 25% of white and 16% of African–American patients. However, only approximately 10% of these patients remain alive at 10 years [101]. These data suggest that a substantial number of breast cancer survivors in the USA have metastases. Key demographic data related to metastatic breast cancer are presented in Box 1. The majority of patients with metastases will be treated. Endocrine therapy and most supportive therapies are usually devoid of major side effects and are well tolerated by most patients. Chemotherapy can be associated with substantial toxicity and may initially compound symptoms related to metastases; if effective in causing tumor reduction, however, its benefits will usually exceed its toxicity. This review will address the management of older women with metastatic breast cancer.

The natural history of metastatic breast cancer

Metastatic breast cancer can involve any organ and the myriad of treatment options available frequently make management challenging. Approximately a third of patients with metastatic breast cancer present with a local or regional recurrence involving lymph nodes and/or the chest wall. Over time, 75% of these patients develop metastases to other organs. The initial clinical presentation of metastases as well as the frequency noted at autopsy is presented in Table 1 [2,3]. The autopsy data are compelling and show that breast cancer can spread to any organ. However, most symptoms arise from the involvement of bone, lung and pleura or liver and brain. In addition, the breast cancer phenotype can predict the likely site of metastases and the tempo of the metastatic disease. For instance, patients with endocrine receptor-positive tumors are more likely to develop bone metastases [4], and endocrine receptor positivity predicts a longer clinical course [5]. Patients with breast cancers that are estrogen and progesterone negative (hormone-receptor negative) and HER-2 negative (‘triple negative’) are more likely to have lung metastases and a shorter clinical course [6]. Within each phenotype, having a longer time from initial diagnosis to the development of metastases (‘disease-free interval’), having bone or soft tissue as opposed to liver or lung metastases and having fewer sites of metastases are all associated with longer survival [7]. Adding to the complexity of management is the observation that the phenotype of the cancer cells in the metastases can differ from the initial phenotype found in the breast at diagnosis in approximately 30% of patients [8]. This has led to the increased use of biopsy of metastatic sites to determine if there have been changes in hormone receptor or HER-2 status, which could dramatically effect treatment selection.

Table 1.

Organ involvement of metastatic breast cancer.

Site	Initial presentation (%)	Autopsy (%)
Bone	40–75	44–71
Lung	5–15	59–79
Pleura	5–15	23–51
Liver	3–10	56-65
Brain	<5	9–20
Pericardium	<5	19–21
Intestine	<5	18
Adrenal glands	<5	31–49

Data taken from [4,5].

Box 1.

Key demographic data for metastatic breast cancer.

2.5 million breast cancer survivors in the USA

40,000 breast cancer deaths per year in the USA

5% of patients have metastases at the time of diagnosis

75–80% of breast cancer patients who develop metastasis will die from breast cancer by 5 years and 90% by 10 years

5-year survival is better for whites (20–25%) than African–Americans (16%)

Approach to the older patient with metastatic breast cancer

The older adult population possesses sufficient variability in physical, cognitive, biologic and psychosocial function such that chronological age cannot be used to clearly define this group. As such, age alone should not be used as the basis for treatment decisions in older adults. However, increasing age is a surrogate for increasing comorbidity and loss of function, key factors that relate to treatment choice. Thus, for older patients, it is important to customize therapy based on individual patient characteristics, function, symptoms and, if there is extensive comorbidity, life expectancy. In addition to controlling symptoms, the approach to older women with metastatic breast cancer can be conceptualized to involve three other major steps: a determination of the patients other major illnesses (comorbidity), a measure of functional status and the patient's preferences for therapy.

Comorbidity

When considering potentially toxic therapy in older women with metastatic breast cancer, an important consideration is to determine which, if any, comorbid condition is most likely to impact treatment toxicity. Although the diagnosis of metastatic breast cancer understandably causes concern because it is an incurable disease, in older adults it may be the patient's other comorbidities that are more important in affecting function and quality of life. Even in the metastatic setting, approximately 20% of patients aged 70 years and older die of nonbreast cancer causes [9]. For those older patients with substantial comorbidity, working closely with the patient's primary care physician or geriatrician will maximize the benefits of care.

Functional status

Traditionally, the Karnofsky (KPS) and Eastern Cooperative Oncology Group (ECOG) performance status have been used by oncologists to assess the functional status of cancer patients. The KPS score ranges from 100 (normal function) to zero (death) with scores of 80 and above indicating normal activity. The ECOG scoring ranges from zero (normal function) to five (death) and scores of 0–1 indicate excellent performance status. These tools, which are limited to simple numeric scales that define the patient's symptoms and activity levels, although helpful, are limited in value and do not accurately assess the function of older cancer patients [10]. Geriatricians have used the comprehensive geriatric assessment (CGA) to obtain a measure of an older patient's functional, cognitive, emotional, nutritional, social and psychological status. The CGA also includes a review of the patient's comorbid medical conditions, functional status and medications (Table 2) . Several studies have demonstrated the ability of the CGA to predict survival, chemotherapy toxicity, postoperative morbidity and mortality in older patients [11,12]. For example, a model derived from clinical characteristics and selected elements from the CGA allows clinicians to predict severe toxicity from chemotherapy [11]; those patients predicted to be at high risk for severe toxicity may benefit from treatment with lower doses of chemotherapy or foregoing chemotherapy.

Table 2.

Domains evaluated in a geriatric assessment.

Domain	What is measured?
Functional status	Activities of daily living and instrumental activities of daily living – must be able to do these to live independently
Comorbidity	Number of any coexisting illnesses in addition to cancer
Psychological state	Assessment of anxiety and depression
Social support	Availability of social support
Nutritional status	BMI
Cognition	Measure of cognitive function
Medications	Number and type of medications: potential interactions

Geriatricians assess function by determining the ability of older adults to perform activities of daily living such as bathing, dressing and toileting and instrumental activities of daily living such as shopping and financial and medication management. In a study of 363 older cancer patients, 13% of those with good performance status (up and out of bed more than 50% of the time) had two or more comorbid conditions and 9.3 and 37.7% had limitations in activities of daily living and instrumental activities of daily living, respectively [13]. The performance of a CGA is time consuming and may take several hours. Moreover, geriatricians are in short supply. The recent development of shorter instruments that take approximately 30 min to complete and are mostly self-administered should help bring the capability of carrying out a geriatric assessment to busy oncologists and primary care physicians [14].

Patient preference

When discussing the risks and benefits of therapy, it is important to consider a patient's values and preferences. This is particularly important given that the potential benefits of therapy may be overshadowed by toxicity and quality of life issues. Furthermore, it is important to clarify the goals of therapy, provide realistic expectations and set appropriate end points for discontinuation of therapy. Providing patients and families with precise details about the potential for toxicity as well as the costs of therapy is essential. In one classic study of 226 patients who had limited life expectancy, almost all would accept a low-burden treatment, but 74 and 89% would decline a treatment that resulted in severe functional impairment or cognitive impairment, respectively [15].

Selecting therapy & predicting toxicity

Owing to the under-representation of elderly patients in clinical trials, there is less information regarding the potential risks and benefits associated with treatment as compared with younger patients [16]. Although age should not limit access to cancer treatment, the older population of patients is more likely to have comorbidities that may reduce the tolerability of anticancer treatment and increase the risk of adverse events [17]. As metastatic breast cancer is not curable, the main treatment goal is to maintain quality of life, prolong survival and minimize symptoms from disease [18]. Since treatment is primarily palliative, significant toxicity should be avoided.

Physiological changes that accompany aging have an impact on the pharmacology of anticancer therapy [19], and these age-related changes can affect drug dosing and tolerance of treatment. A decrease in renal function is often seen with aging and can impact the clearance of chemotherapy [20]. The serum, creatinine, used in younger adults to estimate renal function, is a poor indicator of renal function in older adults owing to a decrease in muscle mass with aging [21]. A decline in hepatic mass and cytochrome p450 potentially alters the metabolism of many drug therapies [22], and alterations in gastric motility and secretions can also affect drug absorption from oral medications [23]. With increasing age, body composition also changes with an increase in body fat and a decrease in total body water. These changes increase the volume of distribution of drugs that are lipid or water soluble, therefore augmenting the actual drug levels achieved [20]. Many physiological changes occur with aging that alter the pharmacokinetics and pharmacodynamics of numerous drugs. The extent of these changes varies among older patients and requires careful attention when determining treatment. The elderly patient is also more likely than the younger patient to be taking medications that may have adverse interactions with anticancer drugs leading to an increased risk in potential toxicity [24].

Approximately three-quarters of older patients have metastases that have arisen from endocrine receptor-positive tumors and are best treated with endocrine therapies until there is clear evidence of refractoriness to endocrine treatment. These patients, as well as those who were initially endocrine-receptor negative, are then candidates for chemotherapy. Once the decision for starting chemotherapy is made, patients with reasonably good organ function, metastases that are not rapidly progressing and those with moderate or absent symptoms are best treated with single-agent sequential chemotherapy [22]. It is uncertain whether there is an optimal sequence of treatment for either endocrine therapy or chemotherapy, but, especially for chemotherapy, starting with less toxic therapies first is the best strategy. Combination chemotherapy is superior to single-agent therapy for achieving a higher response rate and for controlling breast cancer for a longer time interval (progression-free survival), but does not lead to convincing improvement in survival [25]. It is more toxic, but should be considered for patients with rapidly progressing tumors where even modest progression would be life-threatening. For patients with tumors that are HER-2 positive, anti-HER-2-directed therapy (e.g., trastuzumab and lapatinib), in addition to either endocrine therapy (in endocrine receptor-positive patients) [26] or chemotherapy, can substantially improve response to treatment and the duration of the response [27].

Endocrine therapy

Owing to its favorable side-effect profile and the fact that most of these agents can be given orally, endocrine treatment should be the treatment of choice for women with hormone receptor-positive tumors (i.e., the estrogen and/or progesterone receptor is positive) who do not have life-threatening metastases [18]. In general, patients with endocrine receptor-positive metastatic tumors should be treated with endocrine therapy until disease progression and when it is clear that the tumor is refractory to further endocrine treatment. The biological basis of endocrine therapy is to block or reduce the ability of circulating estrogen to stimulate tumor growth and spread. Even very old patients have circulating levels of estradiol that are sufficient to stimulate tumor growth. The proportion of estrogen receptor-positive breast cancers increases with increasing age and is considered a more favorable tumor biology since hormone receptor-positive tumors tend to grow more slowly and frequently respond to endocrine therapy [28]. Significant treatment benefits with endocrine therapy have been shown in the elderly patient population [29]. The main choices for initial treatment are aromatase inhibitors (AIs) or tamoxifen. In large randomized trials, AIs have been shown to be as, or more, effective than tamoxifen in the metastatic setting [29]. Unlike tamoxifen, AIs are not associated with an increased risk of venous thromboembolism or endometrial cancer, but can cause severe arthralgia and myalgia in up to one-third of patients [30]. Although there is an increased risk for osteoporosis and fracture with long-term use, osteoporosis is less problematic in the metastatic setting owing to shortened life expectancy [30]. Fracture risk assessment and concurrent treatment of osteoporosis is important to limit this risk. In addition, patients who have bone metastasis will be on bisphosphonates or denosumab that also decrease the amount of overall bone loss [31]. Patients with an initial response to endocrine therapy can frequently benefit from subsequent treatment with another endocrine agent after relapse [32]. The cognitive effect of endocrine treatment is a concern, especially in older adults, but should not preclude a trial of endocrine therapy, particularly in the metastatic setting given less long-term health concerns. More trials are needed to determine the extent of any cognitive decline that may relate to treatment, its impact on quality of life and possible reversibility after treatment [33].

There is no optimal sequence of agents, but starting with an AI or tamoxifen will provide the best strategy for most patients. For those patients who develop metastases while taking an AI in the adjuvant setting, initial endocrine therapy should consist of tamoxifen; for those taking tamoxifen, an AI should be the first choice. Optimal use of endocrine therapy is achieved by using agents sequentially until metastases progress. Patients who have discontinued a previously used endocrine more than a year prior to tumor progression can be retreated with the same agent and may respond again [18]. Those who develop metastases on an AI or tamoxifen can be treated with the alternate agent, respectively, and those with metastases resistant to both tamoxifen and an AI can be treated with a different AI or fulvestrant, a selective estrogen receptor downregulator [18]. Patients with very slow-growing tumors refractory to these agents can be further treated with progestins (e.g., megestrol acetate among others), estradiol and even glucocorticoids. Using endocrine therapy until metastases are convincingly refractory to hormonal therapy allows for a delay in chemotherapy and maintenance of the highest quality of life. A list of endocrine therapies and their potential toxicities are listed in Table 3 .

Table 3.

Endocrine therapy and chemotherapy.

Therapies commonly used in metastatic breast cancer treatment	Geriatric considerations
Hormonal agents
SERMs such as tamoxifen and toremifene	Increased risk of endometrial cancer, but with preservation of bone mineral density
Estrogen-deprivation therapy, including aromatase inhibitors such as anastrozole, exemestane and letrozole	Can worsen osteoporosis and concurrent treatment for osteoporosis and evaluation of falls risk encouraged
Chemotherapy
Single agents
Anthracyclines, such as doxorubicin, epirubicin, idarubicin and the anthraquinone, mitoxantrone	Careful cardiac monitoring is required with the use of doxorubicin due to cardiotoxicity
Antitubulin agents such as taxanes, epothilones and eribulin	Fatigue and neuropathy frequently reported that has been treatment limiting
Vinca-alkaloids, such as vinorelbine	Frequent neutropenia and constipation among most important toxicities
Fluoropyrimidines, such as 5-FU and capecitabine	5-FU has a decreased clearance in elderly and the standard dose of capecitabine is not feasible due to lethal toxicity (diarrhea) and requires reduced dosing. Oral capecitabine available
Combination regimens
Cyclophosphamide, methotrexate and 5-FU, known as CMF	Modified schedule of CMF for elderly with absolute dose calculated on basis of renal function
Targeted therapies
Trastuzumab	Careful cardiac monitoring, particularly in the setting of prior cardiac disease or diabetes
Lapatinib	Monitor carefully for diarrhea
Bevacizumab	Worsened hypertension and proteinuria noted in the elderly

5-FU: 5-fluorouracil; CMF: Cyclophosphamide, methotrexate and fluorouracil; SERM: Selective estrogen receptor modulator.

Approximately 30–60% of older patients treated with first-line endocrine therapy for metastases have a ‘response’, which is defined as at least a 30% reduction in the diameter of the tumor [34] and is frequently associated with a dramatic improvement in symptoms. Moreover, approximately 20–30% of patients have no change in tumor size for at least 24 weeks and, in those patients with minimal or no symptoms, this stabilization of tumor growth can maintain a clinical benefit [35]. The response to endocrine therapy generally lasts for 6–12 months and is likely to be longer for patients with longer times from their initial diagnosis of breast cancer to the time when metastases were first discovered (the ‘disease-free interval’). Patients who have only bone or soft tissue (e.g., skin and lymph nodes) metastases and a lesser number of metastatic sites are also likely to have a higher response rate and a longer duration of response [7]. After tumor progression on initial treatment, subsequent response rates and durations of response are approximately half that for initial therapy [36].

Patients with lytic bone metastasis should be treated with bone resorption inhibitory drugs (e.g., bisphosphonates or denosumab) regardless of age. Bisphosphonates are effective at preventing skeletal-related events (SREs), bone pain and hypercalcemia [37]. Recent studies have shown that denosumab (a specific inhibitor of receptor activator of NF-κB ligand) is superior to bisphosphonates in delaying or preventing SREs in patients with breast cancer metastatic to bone [37].

Chemotherapy

The use of chemotherapy for metastatic breast cancer should be considered for older women with the possible exception of frail patients. Chemotherapy is the treatment of choice for women whose tumors are hormone-receptor negative or endocrine refractory [18]. No randomized trial has compared chemotherapy with best supportive care. Since the risk of toxicity is higher for chemotherapy than endocrine therapy and can result in decreased function and quality of life, palliative measures without chemotherapy may still be a reasonable choice for elderly, unfit patients who are asymptomatic and have a low burden of disease [38]. However, fit women older than 70 years of age have similar response rates, duration of response and overall survival with chemotherapy as their younger counterparts [39]. Sequential treatment with single agents as opposed to using several agents at the same time (poly- or combination chemotherapy) is generally preferred for the elderly cancer patient, given the potential reduction in the risk of toxicity. Combination therapy has shown improved response rates and time to progression, but also higher toxicity without an overall improvement in survival [25,40]. In circumstances that require urgent reduction in tumor burden, combination chemotherapy is preferred.

The specific choice of a particular chemotherapy drug depends on the individual patient characteristics, physician and patient preferences and drug availability [18]. Many retrospective and small Phase I and II studies of chemotherapy have been published, but these studies have known limitations and likely suffer from inclusion bias given that the included patients are a relatively healthy subset of the elderly population. In most of these trials, eligibility criteria have required normal or good performance status and adequate hematologic, liver and renal function, leading to exclusion of sicker and less functional patients [41]. A few large, randomized controlled trials exist that explore different chemotherapy regimens for the treatment of metastatic breast cancer in the elderly patient. One retrospective cohort study in older women with breast cancer showed that chemotherapy improved median survival and reduced the hazard of death by 39% [42]. In another randomized study of chemotherapy in older postmenopausal women with metastatic breast cancer, older women tolerated chemotherapy well and epirubicin (an anthracycline) was superior to gemcitabine in improving overall survival [43]. Newer trials have shown that the oral agent capecitabine is a relatively safe and effective treatment for elderly breast cancer patients [44]. Weekly paclitaxel has also been studied as first-line chemotherapy in elders and is highly effective, but is associated with a 15% occurrence of serious toxicities [45]. Eribulin, another new agent, has also been shown to be effective in elders with metastases [46].

There is no optimal sequence of single chemotherapy agents and starting with the least toxic agent first is a good strategy. In general, single-agent treatments are associated with response rates of approximately 20–60% when used as first-line treatments and, like endocrine therapy, subsequent therapies tend to only be approximately half as effective as the previous treatment, although exceptions are common. Initial responses tend to last for approximately 6 months and, similar to endocrine therapy, some patients may have prolonged periods of tumor stabilization.

Anti-HER-2 & targeted therapy

The HER-2 protein is a unique and useful target for drug therapy. HER-2 is overexpressed in the tumor cells of 15–25% of all breast cancer patients [47], but is less frequently present with increasing age [28]. Increased HER-2 expression correlates with a poor prognosis in untreated patients [48], but more recently and with the advent of anti-HER2 targeted therapy, outcomes have dramatically improved for patients in the metastatic setting treated with anti-HER-2 agents. In patients with HER-2 overexpressing metastatic breast cancer, the addition of trastuzumab (Herceptin®, Genentech, CA, USA) to first-line chemotherapy has improved survival compared with chemotherapy alone [49]. Elderly patients have been shown to tolerate trastuzumab well, but careful management is necessary as there is an increased risk of trastuzumab-induced heart failure with increasing age [50], a risk that may be related more to the prevalence of comorbidities than to age alone [51]. Patients with a history of cardiac disease and diabetes appear to be at the highest risk for developing cardio toxicity and require close cardiac monitoring [52]. Trastuzumab used as monotherapy can also be very effective and, except for cardiac risk, is associated with only minimal toxicity [53]. Lapatinib, another anti-HER-2-directed small molecule can also increase response rates and duration of response when added to chemotherapy; its rate-limiting toxicity is diarrhea [54].

In patients with HER-2-negative metastatic breast cancer, the efficacy of first-line chemotherapy has improved by combining the anti-VEGF monoclonal antibody, bevacizumab, with chemotherapy [55]. Several randomized controlled trials have shown an improvement in both response rate and progression-free survival when bevacizumab is combined with chemotherapy as compared with chemotherapy alone. Bevacizumab treatment is tolerable and effective in elderly patients [56,57]. In one trial, patients greater than 70 years of age had an increase in hypertension and proteinuria when compared with younger patients, but these toxicities were mild and did not preclude the use of bevacizumab in the older, more vulnerable population [56]. Although the elderly (>70 years of age) were at higher risk of developing hypertension as the result of bevacizumab therapy, baseline hypertension prior to therapy did not predict the presence or severity of elevated blood pressure [56]. A subset analysis of elderly subjects in the AVADO trial also showed improved progression-free survival with acceptable tolerability in an older population [57]. However, since survival benefits have not been demonstrated for the addition of bevacizumab to chemotherapy, this agent is currently not approved for use in metastatic breast cancer in the US (currently only used in clinical trials). Numerous other targeted agents are currently being investigated in clinical trials, but none have, as yet, become an established part of treatment in this setting.

Predicting chemotherapy toxicity

Since the response to chemotherapy in the fit elderly patient has been shown to be similar to their younger counterparts [39], a major issue in the elderly is trying to predict who is most likely to experience toxicity. This is of critical importance as all treatment is palliative in this setting and the primary goal of treatment is to control or delay symptoms. As mentioned previously, the use of performance status measures (e.g., KPS or ECOG performance status) do not address the heterogeneity in the aging process [11], and are only marginally related to functional status [10]. In an initial prospective study, an increase in chemotherapy-related toxicity was associated with increased diastolic blood pressure, bone marrow invasion by tumor, published toxicity of the chemotherapy regimen itself (MAX2) and elevated lactate dehydrogenase [58]. The MAX2 index that was developed in this pilot study has subsequently been shown to be an effective predictive tool for specific chemotherapy regimens and helps to allow a comparison of toxicities across several programs [59]. Another predictive model has recently been developed that incorporates age, laboratory values and geriatric assessment parameters for determining risk for major chemotherapy-related toxicity that stratifies patients into low (30%), intermediate (52%) or high risk (83%) for chemotherapy toxicity [12]. Tools such as the Chemotherapy Risk Assessment Scale for High-Age Patients score calculator that stratifies patients into four toxicity risk categories according to treatment and clinical variables are now available [60]. These estimates of toxicity can provide additional information when determining the risk and benefit of treatment in elderly individuals. Although these models and tools are still under development and require further validation, they are likely to become a routine part of the evaluation of elderly cancer patients.

Radiation therapy in the metastatic setting

Radiation therapy is used to palliate localized, symptomatic sites of metastatic breast cancer. Timing of treatment is best coordinated with multidisciplinary care providers, and the overall approach is highly individualized. The location of the metastatic site, disease-free interval, tempo of progression, extent of symptoms and patient performance status are all important considerations [61]. If the site in question is the first documented location of metastatic disease, a biopsy to confirm the diagnosis and hormone receptor and HER-2 expression may be useful prior to irradiation.

Bone metastasis

Radiotherapy has been successfully used for decades to palliate localized bone pain from metastatic cancer. Bone is the most common site of metastatic involvement, and there may be a unique subset of metastatic breast patients who have an indolent pattern of bone-only metastasis [4]. However, bone metastases are not always indolent. The pattern of breast cancer metastasis varies with subtype, with bone-only disease in the range of 20–30% [62]. The performance status and overall tempo of the disease may impact on the selection of the radiation fractionation schedule, since more protracted treatment tends to offer more durable palliation [63]. Imaging studies (typically plain x-rays, bone scan, CT scan, MRI scan or PET/CT scan) and a detailed history and physical exam must be reviewed in tandem to identify the sites requiring treatment. For a given patient, there may be multiple radiologic bone abnormalities, and the reported symptomatic/painful sites and those elicited on physical exam are a crucial element in the identification of sites requiring therapy. Careful attention to weight-bearing bones may also reveal sites of metastatic involvement where prompt treatment may help prevent a pathologic fracture.

There are numerous randomized trials comparing external-beam dose (fractionation) schedules for palliation of bone metastasis [64]. The number of treatments (fractions) can range from one to 20 and is dependent on the goals and potential toxicities of treatment. The overall response rate and complete response rate for pain relief are not significantly different among the various fractionation schemes; however, the likelihood of retreatment after using a single fraction setting is 2.5-fold higher than the multiple fraction setting. Thus, fractionated treatment schemes may be more appropriate for patients with an excellent performance status and indolent disease. A recent evidence-based guideline concludes that external-beam radiotherapy continues to be the mainstay for the treatment of pain and/or prevention of the morbidity caused by bone metastases [65]. Older patients tolerate radiation to bone metastases and should be offered such treatment when appropriate. Pain relief is seen in the vast majority of patients. Overall, approximately 60% of patients get an excellent response to therapy and in 25%, there is a complete resolution of bone pain. For patients with metastasis involving vertebral bodies with compression fracture, there may also be a role for vertebroplasty/kyphoplasty [66].

In carefully selected patients with multiple sites of symptomatic bone metastasis, intravenous administration of bone-seeking radio-nuclides (the radiopharmaceuticals ⁸⁹Sr and ⁵³Sm) has been associated with major improvements in pain [67]. Decisions regarding radiopharmaceutical therapy must be made in collaboration with medical oncology, as the breast cancer population has often been heavily treated with chemotherapy, which may increase the risk of bone marrow suppression for radionuclide therapy.

CNS metastases

Over the course of their illness, brain metastases develop in as many as a third of all patients with metastatic breast cancer [68]. Furthermore, as the efficacy of new systemic agents continues to increase, the incidence of brain metastasis in breast cancer patients may grow as the ‘blood–brain barrier’ prevents many chemotherapy agents from crossing into the brain to destroy cancer cells. There is a wide spectrum of clinical presentation with CNS involvement, from an asymptomatic solitary brain metastasis in a patient who is free of disease elsewhere, and where tumors are found incidentally when imaging is performed for other purposes, to the ‘bed-bound’ patient with severe headache, nausea, loss of motor function and/or seizures. The options for treatment also span a wide spectrum, from neurosurgical resection with adjuvant radiation, radiosurgery alone (focused treatment to the tumor alone), whole-brain radiation alone or combinations of the above [68]. For a single brain metastasis (‘oligometastatic’ brain metastasis) in patients with good performance status, radiosurgery alone may provide excellent tumor shrinkage with fewer late effects than irradiating the whole brain [69,70].

For multiple brain metastasis, whole-brain radiation may be an appropriate option and usually requires ten daily treatments (fractions) [71]. For elderly patients with a poor performance status and who have a very poor prognosis (weeks to months), a shorter fractionation schedule may be appropriate [72]. It may also be appropriate to consider supportive care with steroids, antiepileptic agents and supportive care, as determined by the wishes of the patient and family. As newer conformal techniques for CNS radiation have developed (‘Cyberknife,’ ‘Gammaknife’ and linac-based radiosurgery), the level of complexity in patterns of care has grown [73]. Appropriateness criteria and evidence-based guidelines have been developed and provide a useful framework in multidisciplinary management [74,75]. The available evidence suggests no age-related downside to effectiveness and toxicity and older patients should be considered for such treatments. In addition, chemotherapy and, less frequently, endocrine therapy may be useful in treating brain metastases.

The spread of cancer to the coverings of the brain and spinal cord (leptomeningeal metastases) occurs in a small proportion of breast cancer patients. Most of these patients are treated with chemotherapy that is administered into the spinal fluid. The outcome is usually dismal with average survivals of only a few months. Radiation therapy can be used in selected patients in addition to chemotherapy or alone to palliate symptoms, particularly when there are cranial nerve palsies associated with base of skull involvement [76].

Spinal cord compression

Compression of the spinal cord by breast cancer occurs in a small percentage of patients with metastatic breast cancer, almost all of whom have bone metastases. This dreaded complication, if not treated within hours to days, can result in paralysis and can further compromise function. The clinical presentation includes back pain in almost all patients, followed by leg weakness and accompanying sensory and autonomic dysfunction. While the approach is individualized, randomized data support consideration of surgical decompression followed by external-beam radiation [77]. Older patients should be considered for such treatment although the risks of surgery must be carefully weighed in the older frail patient.

Ancillary therapies

Surgical removal of the primary tumor in a patient with metastases

In the USA, only a small proportion of women (~5%) present with metastatic breast cancer at the same time that the primary breast cancer is detected, a presentation that is more common in older women [102]. A major controversy in the management of these patients is whether to remove the primary lesion. One hypothesis why such surgery may be helpful is that an uncontrolled primary lesion may continue to seed the systemic circulation with malignant cells resulting in more metastases and poorer outcomes. Older data suggest no survival advantage for removing the primary tumor, but several recent retrospective studies suggest that some patients with metastatic breast cancer may derive a survival benefit from surgical resection [78]. However, these recent studies have likely been biased by patient characteristics in the surgical group that portend a better prognosis, such as younger age, smaller tumors and fewer metastatic sites, and it is unclear whether the beneficial results of surgery are the result of more favorable patient selection. Randomized controlled trials are forthcoming. At present, and irrespective of age, surgery should only be considered if quality of life is likely to be improved by resection of the primary lesion.

Reducing complications of bone metastasis

In addition to systemic treatment and radiation therapy, bisphosphonates (e.g., pamidronate) can be effective in preventing and resolving complications of skeletal metastases such as pain and fracture. Monthly intravenous zolendronic acid has been the mainstay of treatment and can substantially reduce complications [79]. The receptor activator for the NF-κB ligand inhibitor denosumab, a recently approved human monoclonal antibody for use in women with metastatic breast cancer, inhibits osteoclast activity and reduces bone resorption. Desnosumab is administered subcutaneously and has been shown to be superior to zolendronic acid in delaying or preventing pathologic fracture, radiation or surgery to bone and spinal cord compression [38]. Both these agents can cause osteonecrosis of the jaw and require close monitoring and dental supervision. In addition, renal insufficiency has been reported in patients taking zoledronic acid. Gastroesophageal reflux is a bothersome side effect of bisphosphonates. Barring these complications, however, both are generally well tolerated and should be considered for older women with bone metastases.

Pain control

Pain from metastatic breast cancer is most commonly due to bone metastases, but is also the result of tumor growth in other organ sites and is best managed using a multimodality approach [80]. The first step in management includes taking a thorough history detailing the characteristics of the pain including location, severity, relationship to activity and effect on function. The National Comprehensive Cancer Network clinical practice guidelines recommend opioid analgesics as the mainstay of therapy. These can be used for both nociceptive and neuropathic pain. Opioid analgesics should be used cautiously in older adults who may be more susceptible to their side effects. Decreased organ function and changes in body composition can result in higher serum levels and can predispose the patient to drug accumulation [81]. For these reasons, the selection of an appropriate agent is crucial. In addition, starting with low doses and titrating can help to prevent some untoward reactions such as confusion. Patients with concerns should be reassured that the risk of addiction in older adults is low [82]. Constipation remains a troublesome side effect and is best treated with an adequate bowel regimen. Ancillary agents, such as steroids and antidepressants, may be helpful in selected patients and should be considered in specific situations.

Nutrition

Unintentional weight loss is a poor prognostic factor in older adults and is of particular concern in older cancer patients [83]. Even small amounts of weight loss (e.g., 5% of body weight) are important and serve as an indicator of poor nutrition and a significant reduction in muscle mass. Simple assessment tools such as the Mini Nutritional Assessment can be used to screen and detect at-risk patients [84]. Meeting nutritional requirements in the population can be challenging since cancer-associated anorexia and chemotherapy-induced nausea and vomiting are prevalent. Some simple strategies involve adequate treatment of nausea using as-needed or scheduled antiemetics if necessary and the use of oral nutritional supplements. Having a dietician as part of the healthcare team is a critical component in addressing the nutritional needs of older cancer patients. Enteral and intravenous alimentation should be avoided in most patients with metastatic cancer irrespective of age; such interventions are unlikely to improve survival and can be associated with major complications [85]. Furthermore, cancer-associated cachexia is complex and can be difficult to treat even with adequate nutrition [86].

Palliative care & hospice

Several studies have shown that hospice and palliative-care interventions are associated with improved quality of life and survival in cancer patients [87]. The use of a structured palliative-care program can lead to improved quality of life and survival in patients with metastatic cancer, including patients receiving chemotherapy [87]. Hospice care should be considered for patients when further cancer therapy is considered futile. Enrolling patients in a hospice early may improve survival and leads to improved support for patients and families [88].

Conclusion

Caring for metastatic breast cancer in older adults remains a challenging endeavor. However, many tools are available to improve quality of life by controlling cancer and its resultant symptoms. The general approach to the patient with metastatic breast cancer is shown in Figure 1 and includes assessment of patient-related, cancer-specific and therapy issues. Physicians, nurses, patients and families must all recognize that the goals of care in the metastatic setting are controlling disease and maximizing quality of life.

Figure 1.

Assessment of patient-related, cancer-specific and therapy issues.

Future perspective

Major advances in the treatment of metastatic breast cancer have been modest irrespective of age and only continued research can result in major improvements. We are in an unprecedented era of scientific advancement and it is likely that new and more effective treatments will evolve. Nonetheless, these authors believe that it will be a long time before metastatic breast cancer becomes a curable disease for the majority of effected individuals. The number of older Americans with cancer, including breast cancer, will continue to increase in the next decade resulting in increasing challenges to an already stressed and broken healthcare system. Training primary care physicians, oncologists and geriatricians to provide optimal care for older women with metastatic breast cancer will remain a challenge, but a challenge we should be able to overcome. At present, an increasing number of educational programs are being developed and implemented with a goal of training cancer specialists of all types in geriatric care. In addition, the future will likely bring to the healthcare team validated assessment tools that will accurately predict survival, response to treatment and treatment-related toxicity. To succeed we must continue to develop healthcare teams that work together and focus on quality of life, maintenance of function and controlling metastases for all older women with metastatic breast cancer.

Executive summary

Background

The incidence of breast cancer increases dramatically with increasing age.

The majority of women who die of breast cancer are aged 65 years and older.

The natural history of breast cancer

Metastatic breast cancer is incurable.

Metastases can involve any organ.

Only approximately 25% of women with metastatic breast cancer survive for 5 years and only 10% survive for 10 years.

Approach to the older patient with metastatic breast cancer

The goals of treatment are to maximize quality of life and control the cancer growth for as long as possible.

Approximately 20% of older patients with metastatic breast cancer die of nonbreast cancer-related causes.

Geriatric assessment should be a component of care for older women with metastatic breast cancer.

Selecting therapy and predicting toxicity

Older women with metastatic breast cancer should be considered for endocrine therapy if their breast cancer is hormone-receptor positive.

Older women with metastatic breast cancer that is refractory to endocrine treatment or that is hormone-receptor negative should be considered for chemotherapy.

Palliative care & hospice

Palliative care should be integrated into treatment programs for patients on systemic therapies who have major symptoms.

Conclusions

Optimal care is provided by a team of healthcare professionals.

Footnotes

CME Author

Charles P Vega, Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA

Disclosure: Charles P Vega has disclosed no relevant financial relationships.

Authors and Disclosures

Trevor Jolly, Division of Hematology and Oncology, Department of Medicine, University of North Carolina – Chapel Hill, Chapel Hill, NC, USA

Disclosure: Trevor Jolly has disclosed no relevant financial relationships.

Grant R Williams, University of North Carolina – Chapel Hill, Chapel Hill, NC, USA

Disclosure: Grant R Williams has disclosed no relevant financial relationships.

Ellen Jones, University of North Carolina –Chapel Hill, Chapel Hill, NC, USA

Disclosure: Ellen Jones has disclosed no relevant financial relationships.

Hyman B Muss, University of North Carolina – Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

Disclosure: Hyman B Muss has disclosed no relevant financial relationships.

Editor

Elisa Manzotti, Publisher, Future Science Group

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

Treatment of metastatic breast cancer in women aged 65 years and older

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Treatment of Metastatic Breast Cancer in Women Aged 65 Years and Older

Abstract

Keywords

The natural history of metastatic breast cancer

Approach to the older patient with metastatic breast cancer

Comorbidity

Functional status

Patient preference

Selecting therapy & predicting toxicity

Endocrine therapy

Chemotherapy

Anti-HER-2 & targeted therapy

Predicting chemotherapy toxicity

Radiation therapy in the metastatic setting

Bone metastasis

CNS metastases

Spinal cord compression

Ancillary therapies

Surgical removal of the primary tumor in a patient with metastases

Reducing complications of bone metastasis

Pain control

Nutrition

Palliative care & hospice

Conclusion

Future perspective

Footnotes

Treatment of metastatic breast cancer in women aged 65 years and older

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