Treatment of metastatic breast cancer in older women

INTRODUCTION — Despite advances in primary and adjuvant treatment for local breast cancer, many patients will experience metastatic disease. In addition, 1 to 5 percent of women with breast cancer have metastatic disease at presentation. Although patients with metastatic breast cancer are unlikely to be cured of their disease, survival has improved over time due to improved options for treatment. As an example, compared with women treated from 1991 to 1992, those treated from 1999 to 2001 had a statistically longer survival (median, 22 versus 15 months) [1,2].

Novel treatment strategies, involving genomics-directed treatment and novel biomarkers (eg, programmed cell death ligand 1 expression for immunotherapy), are evolving. Although more information is needed regarding these approaches in the older population, they should be considered for older women with breast cancer.

This topic will address issues pertinent to systemic antitumor treatment in older women (typically defined as age >65 years) with metastatic breast cancer. General principles that guide treatment of metastatic breast cancer in all populations, as well as more extensive discussions of endocrine therapy and chemotherapy for metastatic disease, are discussed in detail elsewhere.

●(See "Overview of the approach to metastatic breast cancer".)

●(See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer".)

●(See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer".)

●(See "Assessment of cancer pain" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and "Cancer pain management with opioids: Optimizing analgesia".)

●(See "Radiation therapy for the management of painful bone metastases" and "Use of osteoclast inhibitors in early breast cancer".)

●(See "Brain metastases in breast cancer".)

●(See "Comprehensive geriatric assessment for patients with cancer".)

TREATMENT PRINCIPLES

●General principles – Regardless of age, the goals of treatment for metastatic breast cancer are to control the cancer as best as possible, while maintaining the highest functional level and quality of life as possible. We often think of it as balancing the symptoms from the cancer versus the side effects of treatment. The management principles that guide treatment of metastatic breast cancer in older women are, therefore, similar to those used to guide treatment of younger women, with few exceptions.

•Standard baseline assessment includes assessment of extent of disease, symptoms and/or organ dysfunction due to the disease, molecular and immunophenotypic testing of the cancer, and germline genetic testing (although this may be deferred until after a patient has experienced progression on initial treatment).

•Older women have poorer survival rates from metastatic breast cancer than do younger women. The factors that play into this are likely multiple, but documented variation in guideline concordance likely plays a role [3]. Although evidence-based guidelines specific to older women with metastatic breast cancer are lacking, the framework for approaching an older woman with metastatic breast cancer should be in accordance with existing guidelines.

•Endocrine therapy is almost always chosen as the initial treatment of hormone receptor-positive tumors, typically coupled with targeted treatment, as well as in those women with an unknown hormone receptor status. (See 'HER2-negative disease' below.)

•Chemotherapy should not be withheld solely on the basis of older age. Historically, older women have been less likely to receive chemotherapy despite data showing that age does not modify the survival benefit of chemotherapy for advanced disease [4-9]. In using chemotherapy in older patients, care should be taken in monitoring for toxicity, as dose adjustments are often needed [2]. One must also consider comorbid illnesses that might increase the odds of toxicity. Use of a validated model created to predict chemotherapy-related toxicity, such as the Cancer and Aging Research Group tool or the Chemotherapy Risk Assessment Scale for High-Age Patients, can be useful when weighing risks and benefits of therapy with a patient; these models give an estimated prediction of developing severe or fatal toxicity from chemotherapy (table 1 and table 2) [10,11]. (See "Systemic chemotherapy for cancer in older adults".)

•As in the treatment of younger women, older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer should receive a HER2-directed agent as part of their treatment regimen. (See 'HER2-positive disease' below.)

●Novel strategies – Treatment strategies in breast cancer are evolving, utilizing genomics and genomic assays and new markers for treatment response (eg, programmed cell death ligand 1 [PD-L1] expression on immune cells for response to PD-L1 inhibitors; germline breast cancer susceptibility gene [BRCA]1 and BRCA2 status for response to poly[ADP-ribose] polymerase inhibitors). Although reviews have been written about use of these agents in older patients [12,13], more information is needed regarding these treatments in older patients, but they represent cutting-edge strategies and are considered in appropriately selected older adults. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Metastatic disease'.)

Clinical trial participation should be offered to all patients. In general, persons over the age of 65 are underrepresented in clinical trials, and prospective data to guide treatment in this growing population are a priority [14,15]. In an analysis of breast cancer trials between 1985 and 2012, only 24 percent of participants in metastatic trials were age 65 and older; 13 percent were age 70 and older [15]. Trends showed that enrollment in trials for early-stage disease increased over time for older women, but decreased in metastatic disease. In addition, few phase I trials have been conducted to establish the safety of newer antineoplastic agents in this potentially vulnerable population [16].

HER2-NEGATIVE DISEASE

Hormone receptor-positive disease — The approach to hormone receptor-positive metastatic breast cancer is similar in all postmenopausal women regardless of age and should take into consideration the medical status and treatment preferences of the patient [17]. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer".)

Initial treatment of most cancers

Endocrine therapy — For most patients with advanced hormone receptor-positive, HER2-negative disease, endocrine therapy is administered. Indications for chemotherapy are discussed below. (See 'Rapidly progressive or endocrine therapy refractory disease' below.)

For most patients, a targeted agent is added to endocrine therapy. Endocrine therapy alone may be appropriate for patients with hormone receptor-positive disease who are unlikely to tolerate the addition of a targeted agent. (See 'Addition of targeted therapy' below.)

Our approach to selection of an endocrine agent is as follows:

●We suggest administering an aromatase inhibitor (AI) in older women because of its benefits relative to tamoxifen, as well as avoidance of the thromboembolic risks and endometrial thickening/bleeding associated with tamoxifen. However, for women at risk for bone loss, and those unable to tolerate an AI due to toxicity, tamoxifen is a reasonable alternative. There have been multiple trials evaluating the efficacy of AIs compared with tamoxifen in postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer [18]. These trials have shown superior survival outcomes with AIs when compared with tamoxifen, but much of the data are from younger postmenopausal females.

●Fulvestrant as a single agent (500 mg injection) has shown better activity than aromatase inhibition in a randomized trial, in which the median age was 63 years [19]. However, some patients may prefer oral therapy to intramuscular injection.

●Endocrine agents are typically sequenced, such that a patient may start with an AI, and upon progression, proceed with fulvestrant. After progression on fulvestrant, other endocrine agents, such as selective estrogen receptor modulators, progestational agents, etc, are considered. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Alternative front-line options'.)

Addition of targeted therapy — Several prospective, randomized clinical trials, comparing endocrine therapy alone with endocrine therapy with a targeted agent, which mechanistically works in a different way than modulating endocrine effects on the cancer cells, show that using the combination enhances the benefit compared with endocrine therapy alone. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Types of ET and targeted agents'.)

However, addition of targeted agents can add toxicity. For patients who are likely to tolerate the addition of targeted therapy, several options are available, as discussed in the sections below. Choosing between these options is similar as in younger postmenopausal women, with careful consideration of toxicities. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Preferred first-line therapy'.)

Older adult patients may be more susceptible to toxicities of certain agents. For example, older adult patients may be more susceptible to dehydration due to everolimus-related mucositis, requiring parenteral hydration earlier than a younger patient might.

For tumors with any genotype — Both cyclin-dependent kinase (CDK) 4/6 inhibitors and the mechanistic target of rapamycin (mTOR) inhibitor everolimus combine effectively with AIs. Data regarding these combinations in older women are discussed below.

●CDK 4/6 inhibition – The combination of a CDK 4/6 inhibitor and an AI appears to be effective and of comparable tolerability in older patients as in younger patients [20]. In a pooled analysis of three randomized control trials, the addition of a CDK 4/6 inhibitor to an AI improved progression-free survival (PFS), both in younger and in older adult patients [21]. The median PFS for those receiving a CDK 4/6 inhibitor and an AI versus an AI alone was 33 versus 19 months for those ≥70 years, and 27 versus 14 months for women <70 years. Grade 3 or 4 adverse events (AEs) occurred in 84 percent of those ≥70 years and in 73 percent of patients <70 years. The most common AEs leading to dose reductions or interruptions in patients ≥70 years were neutropenia, diarrhea, and increased creatinine. In particular, older adult patients should be carefully monitored for myelosuppression [22]. Regarding relative toxicities, dehydration is less of a concern with palbociclib than abemaciclib, as it is less likely to cause diarrhea. In older patients with cardiac comorbidities, especially arrhythmias, palbociclib may be a better choice than ribociclib or abemaciclib because it is less likely to cause arrhythmias. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Rationale for use of a CDK 4/6 inhibitor'.)

●mTOR inhibition – A randomized trial has demonstrated similar efficacy in older (>70 years) and younger adults for exemestane plus everolimus versus exemestane and placebo; for patients ≥70 years, hazard ratio (HR) for PFS was 0.45 (95% CI 0.30-0.68) and for patients <70 years, HR was 0.44 (95% CI 0.36-0.54) [23]. With regard to all-grade toxicity, in patients 70 years and older, versus patients younger than 70, there were numerically higher rates of decreased appetite, dyspnea, anemia, asthenia, increased creatinine, and urinary tract infection; and lower rates of stomatitis, rash, headache, nail disorders, hypercholesterolemia, and abnormal liver function tests. Rates of grade 3 and 4 toxicity were numerically higher in older adults, with the exception of stomatitis, rash, diarrhea, and headache. Importantly, after adjustment for treatment exposure, in patients 70 years and older, incidence of on-treatment deaths resulting from AEs was numerically higher in everolimus-treated patients (7.7 versus 0 percent), whereas no difference in rates was noted in patients age <70 years (1.3 versus 1.3 percent).

For tumors that have PIK3CA mutations — The alpha isoform specific phosphoinositide 3-kinase inhibitor alpelisib is approved by the US Food and Drug Administration for use with fulvestrant in hormone receptor-positive, HER2-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced breast cancer. In the phase III trial that led to the approval of alpelisib, the median age of patients was 63 years [24]. In a separate study of 51 patients ≥65 years of age, 15 patients stopped due to AEs and five patients were hospitalized due to hyperglycemia [25].

Careful consideration needs to be given to the comorbidity of diabetes/prediabetes and renal disease, particularly in older patients where diabetes is more prevalent.

Rapidly progressive or endocrine therapy refractory disease — Chemotherapy is rarely used in the first-line setting for patients with hormone receptor-positive, HER2-negative disease, but may be considered if life-threatening or rapidly progressive visceral disease with end-organ dysfunction is present.

For others, endocrine therapy, with or without the addition of a targeted agent, is appropriate. All possible endocrine therapies are used as long as there is evidence of clinical benefit with the most recent treatment. The presence of new metastatic lesions, clinical deterioration, or growth of lesions suggests a given treatment is not working. For older women with hormone receptor-positive disease that has progressed despite endocrine therapy, it is appropriate to weigh the risks and benefits of using a chemotherapeutic agent for palliative therapy. Further details regarding resistance to endocrine therapy are found elsewhere. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Resistance to treatment' and 'Chemotherapy agents with prospective data in older patients' below.)

Hormone receptor-negative (TNBC) — The approach to hormone receptor-negative metastatic breast cancer is similar, regardless of age, and should take into consideration the medical status and treatment preferences of the patient. Chemotherapy is typically used in triple-negative disease. Agents with prospective data in older patients are discussed below. (See 'Chemotherapy agents with prospective data in older patients' below.)

Select patients with programmed cell death ligand 1-positive triple-negative disease may be candidates for incorporation of an immune checkpoint inhibitor with chemotherapy. Tolerability and toxicity of immunotherapy in older patients is discussed elsewhere. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Older adult patients'.)

Special considerations

For BRCA1/2 carriers — Inhibitors of PARP may be used in breast cancer susceptibility gene (BRCA) carriers with prior exposure to chemotherapy. In the OlympiAD trial, among BRCA mutation carriers (all of whom had received an anthracycline and a taxane), olaparib improved PFS relative to chemotherapy. Although the median age in this trial was just 44 years (range, 22 to 76 years), PARP inhibitors are likely to be more tolerable than chemotherapy, even in older patients. In the olaparib group in this trial, most AEs were grade 1 or 2. The rate of grade ≥3 AEs was lower in the olaparib group than in the chemotherapy group (37 versus 51 percent, respectively). (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Patients with previous exposure to chemotherapy'.)

For HER2-low cancers — Fam-trastuzumab deruxtecan is an appropriate option for patients who have progressed on at least one prior line of chemotherapy, whose tumors have a score of 1+ on immunohistochemical [IHC] HER2 analysis; or an IHC score of 2+ with negative results on fluorescent in situ hybridization ("HER2-low"). Toxicities include neutropenia, anemia, nausea, and interstitial lung disease.

In a randomized trial in patients with metastatic HER2-low breast cancer who had received one or two previous lines of chemotherapy, fam-trastuzumab deruxtecan resulted in longer progression-free and overall survival compared to treatment with clinician's choice of chemotherapy (9.9 months versus 5.1 months respectively) [26]. Among the 114 patients ≥65 years, median PFS was 12.0 months with fam-trastuzumab deruxtecan compared with 5.6 months with chemotherapy (HR 0.47, 95% CI 0.29-0.77).

Overall, grade ≥3 toxicities occurred in 53 percent receiving fam-trastuzumab deruxtecan and 67 percent receiving chemotherapy. Overall results of this trial are discussed in more detail elsewhere. (See "Overview of the approach to metastatic breast cancer", section on 'HER2-low tumors'.)

HER2-POSITIVE DISEASE — Older women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer should be offered HER2-directed treatment. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

The role for medical therapy in women with concomitant cardiac disease is discussed separately. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Clinical guidelines'.)

Indications for chemotherapy in HER2-positive disease — Indications for chemotherapy, according to hormone receptor status, are below.

●For hormone receptor-positive disease – For older women with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive minimally symptomatic metastatic breast cancer, we often use first-line combination treatment with endocrine therapy plus HER2-targeted therapy. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Special considerations for hormone receptor-positive disease'.)

However, if their disease is rapidly progressive or symptomatic, chemotherapy plus HER2-directed therapy may be more appropriate, depending on the patient's performance status and preferences. (See 'Rapidly progressive or endocrine therapy refractory disease' above.)

●For hormone receptor-negative disease – For most patients with hormone receptor-negative, HER2-positive disease, irrespective of age, chemotherapy is typically administered concurrently with anti-HER2 therapy. Single-agent trastuzumab treatment is a less commonly used alternative for select patients (eg, a treatment-naïve patient with lower disease burden), and is discussed elsewhere. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Options irrespective of hormone receptor status'.)

Data from clinical trials are evolving rapidly. Potential chemotherapy agents to use with trastuzumab (with or without pertuzumab) treatment include the following:

●A taxane (eg, weekly paclitaxel is typically a well-tolerated choice),

●Cyclophosphamide,

●Capecitabine,

●Vinorelbine,

●A platinum salt, or

●Gemcitabine

Many of these agents do not have specific data in older women. Available data regarding these agents are discussed elsewhere, while data specifically in older patients are found below. (See "Systemic treatment for HER2-positive metastatic breast cancer" and 'Chemotherapy agents with prospective data in older patients' below.)

Data show that combinations of trastuzumab plus chemotherapy are more effective than trastuzumab alone.

For example, a prospective phase II study (EORTC 75111-10114) confirmed the benefit of adding chemotherapy to anti-HER2 therapy in older women [27]. In this study, older women with HER2-positive metastatic breast cancer, a life expectancy of more than 12 weeks, performance status of 0 to 3, and left ventricular ejection fraction 50 percent or greater were enrolled. For this trial, older was defined as:

●Age 70 or older.

●Age 65 to 69 and functional restriction, defined as limitation in at least two of eight instrumental activities of daily living (IADL), one of six activities of daily living (ADL), or a Charlson Comorbidity Index (CCI) score of more than 2.

●Age 60 to 64 and functional restriction defined as limitation in at least three of eight IADL, two of six ADL, or a CCI of more than 3.

Prior treatment with up to one line of anti-HER2 therapy (trastuzumab or lapatinib) in combination with endocrine therapy (if hormone sensitive) was allowed.

Treatment consisted of intravenous (IV) trastuzumab and IV pertuzumab with or without metronomic oral cyclophosphamide (50 mg daily without interruption). At a median follow-up of 20.7 months, among 80 patients, the addition of metronomic cyclophosphamide to trastuzumab and pertuzumab improved the six-month progression-free survival (PFS) rate (73 versus 46 percent; hazard ratio [HR] 0.65, 95% CI 0.37-1.12). Median PFS was also longer in the metronomic chemotherapy arm, 12.7 months versus 5.6 months.

In general, treatment was well tolerated. There was no grade 3 febrile neutropenia reported. Diarrhea, however, which can be debilitating in older patients [28], was reported on more than one-half of patients receiving pertuzumab.

This study also incorporated a brief geriatric assessment, the G8. More than two-thirds of participants were potentially frail according to the G8, and clinical frailty was a strong prognostic factor for overall survival (OS).

This study indicates that the addition of chemotherapy to anti-HER2 therapy improves outcomes. It also adds to the literature by (1) stressing the importance of monitoring for diarrhea in older, potentially frail patients who receive pertuzumab; (2) providing prospective data on safety and efficacy of trastuzumab emtansine in this population; and (3) confirming the important prognostic information provided by a brief geriatric assessment.

Benefit of incorporation of anti-HER2 therapy — Given the benefits of human epidermal growth factor receptor 2 (HER2)-directed treatment for metastatic breast cancer, it should be a component of treatment for HER2-positive breast cancer regardless of age. Older patients who are more frail may still benefit from anti-HER2 therapies with a less intense chemotherapy regimen. (See 'Anti-HER2 agents typically used in initial lines of therapy' below and 'Chemotherapy agents with prospective data in older patients' below.)

Anti-HER2 agents typically used in initial lines of therapy

Trastuzumab — Benefit from incorporation of trastuzumab in the treatment of older adult patients with human epidermal growth factor receptor 2 (HER2)-positive disease was shown in the RegistHER study.

This study included 209 women ages 65 years and older with HER2-positive metastatic breast cancer, approximately 50 percent of whom had hormone receptor-positive breast cancers [29]. Compared with women who did not receive trastuzumab, treatment with trastuzumab was associated with a significant improvement in PFS (median, 11.7 versus 4.6 months, respectively). However, OS was not significantly different (31.2 versus 28.5 months).

Among women receiving trastuzumab, women ages 75 years and older were more likely to receive trastuzumab monotherapy or trastuzumab plus hormonal therapy compared with younger women. In addition, women 75 years and older had a higher incidence of cardiac events (eg, angina pectoris, atrial arrhythmia, congestive heart failure, left ventricular dysfunction, myocardial infarction, pericardial effusion, and ventricular arrhythmia) compared with younger women (25 versus 7 percent).

Cardiac events were highest in patients ages 75 years and older (25.4 percent) versus ages 65 to 74 years (6.7 percent). Patients with underlying comorbidities, such as hypertension with complications and other cardiovascular diseases, were at a particularly high risk.

Pertuzumab — In a double-blind randomized trial, the addition of pertuzumab to trastuzumab and docetaxel among patients with metastatic HER2-positive breast cancer improved PFS, including among the prespecified subgroup of patients ≥65 years (HR 0.52, 95% CI 0.31-0.86) [30].

Diarrhea, fatigue, asthenia, decreased appetite, vomiting, and dysgeusia were reported more frequently in patients 65 years of age or older compared with younger patients. Neutropenia and febrile neutropenia were reported less frequently in the older age group.

Separately, pertuzumab has also shown benefit when used with endocrine therapy and trastuzumab (without chemotherapy) in hormone receptor-positive disease. In the phase II PERTAIN study, including 258 postmenopausal women with advanced hormone receptor-positive, HER2-positive breast cancer, the addition of first-line pertuzumab to trastuzumab and an aromatase inhibitor (anastrozole or letrozole) improved PFS (18.9 versus 15.8 months) [31]. One-third of the patients were ≥65 years. Side effects, particularly diarrhea, were more common with the addition of pertuzumab. In the absence of a substantial OS benefit, especially in older women, clinical judgement is required regarding whether to start pertuzumab or continue it in the face of such toxicity. Further details of this study are found elsewhere. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Special considerations for hormone receptor-positive disease'.)

Subcutaneous formulations — Subcutaneous forms of trastuzumab and pertuzumab are available, although data specifically in older patients are lacking. Further discussion is found elsewhere. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Formulations'.)

Subsequent-line anti-HER2 agents — Other targeted agents have also shown excellent outcomes in older patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, although careful attention must be paid to the toxicity profiles [32].

Antibody-drug conjugates — Antibody drug conjugates are composed of an anti-HER2 directed antibody linked with a cytotoxic chemotherapy agent.

●Ado-trastuzumab emtansine, which has shown benefit in the metastatic setting over other regimens, was evaluated in a pooled safety analysis [33]. The rate of grade 3 to 4 adverse effects was higher among older patients ≥65 years relative to those <65 years (52 versus 44 percent). An interim analysis of a randomized trial confirmed the higher rates of toxicity in patients ≥65 years, with the most frequent side effects being asthenia (30 percent), nausea (28 percent), fatigue (23 percent), and decreased appetite (22 percent) [34]. Thrombocytopenia of any grade occurred in 13 percent and hemorrhage in 24 percent of older patients (1.6 percent grade ≥ 3).

●Fam-trastuzumab deruxtecan has shown activity in heavily pretreated patients with advanced HER2-positive disease in a single-arm study in 184 patients, with median PFS of 16 months [35]. Almost one-quarter of patients in this study were ≥65 years. Toxicity considerations include neutropenia, anemia, nausea, and interstitial lung disease. Further details are discussed in detail elsewhere. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Fam-trastuzumab deruxtecan'.)

Further details regarding the efficacy and use of HER2-targeted agents are found elsewhere. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

Anti-HER2 tyrosine kinase inhibitors — Tyrosine kinase inhibitors have shown efficacy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

●Tucatinib is an oral tyrosine kinase inhibitor that improved both PFS and OS, when added to capecitabine-trastuzumab in patients with heavily pretreated HER2-positive breast cancer [36]. Approximately 20 percent of patients on HER2CLIMB were age ≥65 years, and the benefit of tucatinib was similar in older and younger patients. Trastuzumab/capecitabine/tucatinib is well tolerated in older patients, with careful dosing of the capecitabine as outlined above. (See 'Capecitabine' below and "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Tucatinib, capecitabine, and trastuzumab'.)

●Lapatinib with capecitabine was evaluated in a series of 26 older women (>65 years) with breast cancer [37]. Median PFS was seven months, which was comparable to data in younger women from other studies. The combination was well tolerated, with only one treatment discontinuation due to toxicity.

●Neratinib is a novel HER1, HER2, and HER4 tyrosine kinase inhibitor that has activity in HER2-positive breast cancer, but causes diarrhea in a majority of patients. In a study in 25 patients aged 60 or older with metastatic HER2-positive breast cancer, 36 percent had grade 3 toxicities (there were no grade 4 or 5 toxicities) [38]. Median PFS was 2.6 months and median OS was 17.4 months.

CHEMOTHERAPY AGENTS WITH PROSPECTIVE DATA IN OLDER PATIENTS — Indications for chemotherapy are discussed in other sections. (See 'Rapidly progressive or endocrine therapy refractory disease' above and 'Hormone receptor-negative (TNBC)' above and 'Indications for chemotherapy in HER2-positive disease' above.)

Clinical judgment based on the baseline health of the patient is required in deciding whether chemotherapy is appropriate, and which agent to use. Assessment of candidacy for anticancer treatments is discussed elsewhere. (See "Systemic chemotherapy for cancer in older adults" and "Systemic chemotherapy for cancer in older adults", section on 'Assessments of physical function and reserve'.)

For patients with appropriate indications, we suggest sequential single-agent therapy rather than combination chemotherapy, particularly for frail or medically unfit older patients with metastatic breast cancer [7,39-44]. However, there is no optimal or preferred sequence of agents. The choice of agent should be based on the patient's clinical status, comorbidities, and careful consideration of the agents, their schedule of administration, and specific toxicities. (See "Frailty".)

Prior treatment history, toxicities from prior treatments, and anticipated/likely toxicity of the next agent must be considered. In general, treatment with chemotherapy drugs of different classes (non-cross resistant agents) may result in a higher probability of response, especially if disease progression occurred within six months following the previously administered regimen. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Factors influencing chemotherapy choice' and "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Prior treatment and toxicities'.)

Agents that are approved for use for breast cancer and for which there is evidence of activity and toxicity specifically in older patients with metastatic breast cancer are discussed below. Although much of the data come from studies in women with human epidermal growth factor receptor 2 (HER2)-negative or unselected disease, safety data are relevant, irrespective of phenotype. We avoid anthracyclines in HER2-positive advanced disease, because of the risks of cardiotoxicity when used with trastuzumab.

Capecitabine — Capecitabine is an orally active prodrug of fluorouracil (FU) that is absorbed intact through the intestinal wall and then converted to FU in three sequential enzymatic reactions. Capecitabine is effective and well tolerated in older women with breast cancer as long as a lower initial dose (ie, 1000 mg/m² twice daily) is used [45]. This is particularly true in the setting of mild to moderate renal impairment or hyperbilirubinemia. The activity of capecitabine in older women was shown in a trial of 73 patients ≥65 years with chemotherapy-naïve metastatic breast cancer [45]. The overall response rate was 37 percent, and treatment was well tolerated, with serious (grade 3/4) diarrhea, nausea, or fatigue occurring in less than 10 percent of patients. In addition, data from one study suggest that it is as effective as single-agent taxane therapy when used in the first-line setting for metastatic disease [46]. An appropriate strategy is to begin a low dose of capecitabine for metastatic disease in the older adult patient and increase as tolerated.

Capecitabine dosed for seven days followed by seven days of rest is an alternate dosing schedule that has been investigated in advanced breast cancer [47,48] and may be more tolerable in some patients.

Taxanes — Taxanes are highly active agents in the treatment of metastatic breast cancer, even in heavily pretreated patients. Weekly paclitaxel, in particular, has a low toxicity profile, with the exception of peripheral neuropathy. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Taxanes'.)

Several studies have evaluated taxanes in older women [49-57]. In one randomized phase II study comparing weekly paclitaxel with weekly docetaxel in older patients considered unfit for every-three-week taxane therapy, the main results were [55]:

●The rate of clinical benefit (response rate plus stable disease) was better with paclitaxel compared with docetaxel (72 versus 54 percent, respectively). The difference was even more marked in patients age 70 years and older, in whom the rates of clinical benefits for paclitaxel and docetaxel were 67 and 44 percent, respectively.

●The time to progression on weekly paclitaxel was longer compared with weekly docetaxel (median, 21 versus 13 weeks, respectively).

●Weekly paclitaxel resulted in higher rates of anemia and neurotoxicity, while weekly docetaxel resulted in higher rates of edema and fatigue.

Interpretation of this study is limited by the choice of scheduling, given that docetaxel is more effectively dosed every three weeks than every week. Therefore, the observed results may not reflect improved outcomes with paclitaxel over docetaxel in the older adult population, but rather be a consequence of suboptimal dosing of docetaxel. However, for older patients, paclitaxel may be preferable because it can be given effectively on a weekly schedule, resulting in potentially less bolus toxicity.

Taxane-induced neuropathy may be particularly problematic in older adults and is discussed in detail elsewhere. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy", section on 'Taxanes'.)

Anthracyclines — Anthracyclines (doxorubicin, epirubicin, and pegylated liposomal doxorubicin) are as effective in older women with metastatic breast cancer as they are in younger women [58,59]. However, the risk of anthracycline-related cardiotoxicity and other toxicities is higher in older patients [60,61]. Given risks of cardiotoxicity particularly when used with HER2-directed therapy, we avoid anthracyclines in HER2-positive metastatic breast cancer. If an anthracycline is chosen for HER2-negative disease, we suggest a weekly schedule, if doxorubicin or epirubicin are going to be used; or use of pegylated liposomal doxorubicin (which is administered every four weeks), because of the relatively lower risk of cardiotoxicity [62]. (See "Risk and prevention of anthracycline cardiotoxicity" and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Overview of side effects of chemotherapy for early-stage breast cancer".)

For older women who will receive an anthracycline, a baseline study for the cardiac left ventricular ejection fraction (LVEF) should be obtained prior to the initiation of treatment. In addition, symptoms should be carefully monitored and LVEF reassessed with onset of symptoms or periodically during therapy. Guidelines for anthracycline monitoring in adults are discussed in more detail elsewhere. (See "Risk and prevention of anthracycline cardiotoxicity".)

For women receiving doxorubicin or epirubicin for breast cancer who appear to be benefitting from treatment, coadministration of the cardioprotectant dexrazoxane can reduce the risk of cardiotoxicity. Dexrazoxane is usually begun after a cumulative dose of 300 mg/m² of doxorubicin has been reached. There are no guidelines as to the use of dexrazoxane in women receiving epirubicin or mitoxantrone.

Evidence to support liposomal doxorubicin in older breast cancer patients comes from two studies that evaluated pegylated liposomal doxorubicin in anthracycline-naϊve patients over age 65 years or in patients who were unsuitable for standard anthracyclines [63,64]. The overall response rate was approximately 30 percent. Toxicities included hematologic toxicity, anorexia, asthenia, and stomatitis.

Vinorelbine — Several reports demonstrate that single-agent vinorelbine is active for older women with metastatic breast cancer, although neutropenia can be dose limiting [65-67]. In the largest study, 56 women ≥60 years (57 percent estrogen receptor-positive disease) were treated with vinorelbine at a dose of 30 mg/m² as a weekly infusion for 13 weeks, and then every two weeks until development of progressive disease [66]. Doses were reduced or delayed to manage toxicity. The objective response rate was 38 percent, and there were two (4 percent) complete responses. At least one episode of grade 3 to 4 granulocytopenia occurred in 45 patients (80 percent), and six developed fever in the setting of neutropenia.

There is also an every-other-week dosing schedule that is available for vinorelbine [66], which may be more tolerable for older patients.

Eribulin — Eribulin has shown activity in heavily pretreated metastatic breast cancer and is an option for the older adult patient. As examples:

●In a pooled analysis of five studies including 301 patients ≥70 years, the objective response rate was 23 percent, the median progression-free survival (PFS) was 4.8 months, and the median overall survival was 13.1 months with eribulin [68]. Grade 3 to 4 neutropenia was 0 to 49 percent. The most frequent grade 3 to 4 adverse events (AEs) among nonhematologic toxicities were fatigue (5 to 17 percent) and neurotoxicity (0 to 10 percent).

●In one small, single-institution report, the median duration of treatment with eribulin in heavily pretreated metastatic breast cancer was 16 weeks [69]. Multivariate analysis in this study showed that better performance status (hazard ratio [HR] 0.32, 95% CI 0.16-0.65) and tumor hormone receptor status (positive versus negative; HR 0.43, 95% CI 0.19-0.99) were predictive of better PFS.

●In an exploratory analysis that pooled data from two single-arm phase II studies and one open-label randomized phase III study in which patients received eribulin, the effect of age on survival and incidence of AEs was assessed. Outcomes were measured among patients <50, 50 to 59, 60 to 69, and ≥70 years [70]. Age had no statistically significant impact on OS (11.8, 12.3, 11.7, and 12.5 months, respectively) or PFS (3.5, 2.9, 3.8, and 4.0 months, respectively), and there was no overall effect of age on the incidence of AEs (including neuropathy, neutropenia, and leukopenia).

Duration of treatment — Duration of treatment with chemotherapy is similar for older patients as it is for younger patients. Typically, chemotherapy is continued until progression or poor tolerance, although for HER2-positive disease, there is also an option of maintenance therapy with HER2-directed antibodies only, after achieving "best response" on chemotherapy. This is discussed in detail elsewhere. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Optimal treatment duration of chemotherapy'.)

SUPPORTIVE CARE

Granulocyte colony-stimulating factors — Bone marrow tolerance is reduced in older adult patients, and they may be at particular risk for febrile neutropenia [71-73]. When treatment delays are required due to low absolute neutrophil counts, our first course of action is to change dose and/or schedule of the agent. If the interval of chemotherapy dosing is two weeks or greater, and it is determined that dose intensity is important to maintain disease control, then primary prophylaxis with granulocyte colony-stimulating factors (G-CSF) is considered. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Primary prophylaxis'.)

Prophylactic G-CSF in the management of older adult breast cancer patients was reviewed in a subanalysis of the NeuCup study [74]. In a subgroup analysis of 254 older adult patients (≥65 years) treated with chemotherapy with a moderately high (15 to 19 percent) or high (≥20 percent) febrile neutropenia risk, prophylactic G-CSF resulted in a significantly lower overall incidence of febrile neutropenia compared with standard practice (6 versus 24 percent). Prophylactic G-CSF was also associated with both decreased febrile neutropenia-related hospitalizations (5 versus 15 percent) and incidence of dose reductions (≥10 versus ≥15 percent).

Erythropoiesis-stimulating agents — The benefit of erythropoietin-stimulating agents (ESAs) in patients with nonhematologic malignancies appears to be restricted to those patients in whom the anemia is due to chemotherapy and is symptomatic. In addition, there is some evidence that these agents may be harmful in patients with anemia not due to chemotherapy. The risks and benefits of ESAs are discussed in detail elsewhere. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)

Osteoclast inhibition — Bisphosphonates (eg, zoledronic acid, pamidronate) or other osteoclast inhibitors (eg, denosumab) are routinely administered to patients with bone metastases, since they decrease the rate of bone complications (fractures, pain, and hypercalcemia) in women with bone metastases. A schedule of quarterly infusion is recommended [75].

However, older women should be aware of treatment-related toxicities, such as an increased risk of renal insufficiency and osteonecrosis of the jaw. Long-term administration is generally safe in older adult individuals, although patients should be monitored for renal insufficiency and hypocalcemia [76]. Long-term use (>5 years) has also been associated with an increased risk of atypical fractures (eg, subtrochanteric or femoral shaft fractures), possibly due to suppression of bone remodeling, though the absolute risk of such fractures remains low [77-80]. Selection of therapy must be personalized, taking into account the risk of toxicities, including hypocalcemia, as well as patient preferences, convenience, availability, and cost. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors" and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Medication-related osteonecrosis of the jaw in patients with cancer".)

Screening for distress — It is important to screen for distress in older patients, as they have higher levels of distress, depressive symptoms, apathy, and loneliness than do younger patients [81]. (See "Patients with cancer: Overview of the clinical features and diagnosis of psychiatric disorders".)

POTENTIAL ROLE OF SPECIALIZED ONCOGERIATRIC PROGRAMS — There is interest in developing specialized oncologic care in a geriatric care setting, sometimes referred to as oncogeriatrics.

Preliminary research comparing "usual care" for 104 patients age 70 years and older with metastatic breast cancer at a general oncology unit in the Netherlands versus treatment of 42 patients in an oncogeriatric clinic in Tampa, Florida, suggested that care in the oncogeriatric program included more local therapy, more use of chemotherapy and trastuzumab, and a greater number of lines of therapy overall [82]. Three-year overall mortality was 71 percent with standard care and 58 percent with specialized oncogeriatric care. Quality of life and functional status were not evaluated. How much of the differences in treatment are due to regional and cultural differences in approach to the disease is not known. Future, prospective, randomized studies are needed to determine the benefits of this approach.

PALLIATIVE CARE — For all patients with metastatic breast cancer, palliative care should be a part of their interdisciplinary management. Palliative care focuses on preventing and relieving suffering and on supporting the best possible quality of life for patients and their caregivers facing serious illness. (See "Benefits, services, and models of subspecialty palliative care".)

SPECIAL CONSIDERATIONS

For cancers with high TMB or MSI-H — Although rare in breast cancer, metastatic or unresectable cancers that are microsatellite high (MSI-H)/DNA mismatch-repair deficient (regardless of receptor status) may benefit from single-agent checkpoint inhibitors after progression on other treatment options. Similarly, patients with high tumor mutational burden (TMB; ≥10 mutations/megabase) unresectable or metastatic breast cancer (regardless of receptor status) may also benefit from pembrolizumab, after progression on other treatment options [83]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Single-agent checkpoint inhibitors can be well tolerated in older patients. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Older adult patients'.)

Special considerations during the COVID pandemic — The COVID-19 pandemic has increased the complexity of cancer care. Important issues in areas where viral transmission rates are high include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer".)

SUMMARY AND RECOMMENDATIONS

●Introduction – Life expectancy, functional status, and organ function are particularly important to consider when planning treatment for the older woman with metastatic breast cancer. Standard baseline assessment includes assessment of extent of disease, molecular and immunophenotypic testing, and germline genetic testing (either upon diagnosis or disease progression). (See 'treatment principles' above and "Overview of the approach to early breast cancer in older women", section on 'General health status'.)

●HER2-negative disease

•Hormone receptor-positive disease – As for younger women, for most women over the age of 65 with hormone receptor-positive metastatic breast cancer, we offer first-line endocrine therapy, with or without a targeted agent, rather than chemotherapy.

However, for those with hormone receptor-positive disease that has progressed despite endocrine therapy, or those with life-threatening or rapidly progressive visceral disease with end-organ dysfunction, it is appropriate to weigh the risks and benefits of using a chemotherapeutic agent versus pursuing best supportive care without chemotherapy. (See 'Rapidly progressive or endocrine therapy refractory disease' above.)

•Hormone receptor-negative disease – For older women with hormone receptor-negative breast cancer, chemotherapy is typically used, as for younger women. We often use a risk calculator, such as the Cancer and Aging Research Group or Chemotherapy Risk Assessment Scale for High-Age Patients toxicity tool (table 1 and table 2), to determine the risk of life-threatening toxicity from chemotherapy. (See 'Hormone receptor-negative (TNBC)' above and 'treatment principles' above.)

Those with programmed cell death ligand 1-positive triple-negative disease may benefit from the addition of immunotherapy to chemotherapy, depending on their baseline health. (See 'Hormone receptor-negative (TNBC)' above.)

•Special considerations for BRCA carriers – Patients carrying predisposing mutations of breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2) may be candidates for inhibitors of poly(ADP-ribose) polymerase.

●HER2-positive disease – For women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (irrespective of age), a HER2-directed agent is a necessary component of therapy.

•As for younger women, we generally use trastuzumab with first-line treatment, and add pertuzumab for higher-risk disease. Choice of second and subsequent lines of therapy is based on the patient's clinical status and consideration of the agents' side effect profiles and their schedule of administration. (See 'HER2-positive disease' above.)

•For older women with hormone receptor-positive, HER2-positive breast cancer that is not rapidly progressive or symptomatic, we suggest first-line combination treatment with endocrine therapy plus HER2-targeted therapy rather than chemotherapy (Grade 2B).

•However, for those with rapidly progressive or symptomatic HER2-positive disease or for those who have hormone receptor-negative, HER2-positive disease, we offer chemotherapy plus HER2-directed therapy, as would be used in younger patients, with adjustments in dose and schedule based on functional status and toxicity risk. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

●Supportive care

•When chemotherapy delays are required due to low absolute neutrophil counts, we first adjust dose and/or schedule of the agent. However, if the interval of chemotherapy dosing is ≥2 weeks, and it is determined that dose intensity is important to maintain disease control, then use of granulocyte colony-stimulating factors is considered. (See 'Granulocyte colony-stimulating factors' above.)

•Osteoclast inhibitors are often administered for bone metastases, since they decrease the rate of bone complications. Possible toxicities include renal insufficiency, hypocalcemia, and osteonecrosis of the jaw. (See 'Osteoclast inhibition' above.)

●Palliative care – Palliative care should be a part of interdisciplinary management for patients with metastatic breast cancer. (See "Benefits, services, and models of subspecialty palliative care".)