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Overview of the approach to early breast cancer in older women

Overview of the approach to early breast cancer in older women
Literature review current through: Sep 2023.
This topic last updated: Feb 08, 2023.

INTRODUCTION — Increasing age is the most prevalent, primary risk factor for breast cancer. Of the approximately 250,000 new cases of female breast cancer diagnosed annually in the United States, almost one-half arise in older women (typically defined as age ≥65 years, though this varies in studies).

A practical challenge to developing guidance for treatment of older women with breast cancer is that there is a wide spectrum of women in the "older" population, defined both by biological age and by functional status. A healthy, vigorous 68-year-old with a life expectancy of >20 years should receive essentially the same treatment as a 58-year-old with the same breast cancer. By contrast, an ill 88-year-old would not. These patients are often grouped together in studies of older adult patients with cancer.

Another challenge, as is broadly true in oncology, is that older patients are under-represented in clinical trials, partially due to eligibility criteria that have excluded them on the basis of age or comorbidities, and also because they have tended to be treated in centers where clinical trials were not available. As a result, there is a relative lack of evidence-based guidelines to inform the treatment of breast cancer in this population. Nevertheless, there have been clinical trials specifically for older breast cancer patients and subset analyses of trials open to all breast cancer patients, regardless of age. These results have yielded important information for treatment of older breast cancer patients.

This topic will review the available data regarding the treatment of early-stage and locally advanced breast cancer in older women [1,2]. An overview of the approach to women with newly diagnosed breast cancer and the treatment of breast cancer that applies to all women regardless of age are discussed separately.

(See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer".)

(See "Mastectomy" and "Breast-conserving therapy" and "Overview of management of the regional lymph nodes in breast cancer".)

(See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer" and "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer".)

(See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer" and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer" and "Adjuvant systemic therapy for HER2-positive breast cancer".)

(See "General principles of neoadjuvant management of breast cancer" and "Neoadjuvant therapy for patients with HER2-positive breast cancer" and "Neoadjuvant management of newly diagnosed hormone-positive breast cancer".)

TREATMENT PATTERNS — From epidemiologic data, it appears that, following a new diagnosis of breast cancer, older women often receive less aggressive treatment or less often receive guideline therapy compared with younger women worldwide [3-8]. For instance, in the largest of these studies, which included over 120,000 women, increasing age was associated with decreased rates of breast surgery, axillary surgery, and radiotherapy [7]. On the other hand, older persons more often receive upfront mastectomy and primary endocrine therapy [7].

Adjuvant chemotherapy is used less commonly in older individuals. In a population-based study of the Surveillance, Epidemiology, and End Results (SEER) database of almost 50,000 breast cancer patients, the rate of chemotherapy use for stage I or II, hormone receptor-negative, node-positive breast cancer ranged from approximately 80 percent for ages 67 to 69, down to <10 percent for those above 85 [9].

Factors that contribute to differences in treatment of the older patient — Several factors govern treatment considerations in older women. First, most Western societies with screening programs for early detection of breast cancer focus on women from age 50 (or 40, in the United States) until around age 70 (or when life expectancy is less than 10 years). As a consequence, older women are less likely to have screen-detected breast cancers. Secondly, breast cancers arising in older women are more often estrogen receptor positive, human epidermal growth factor receptor 2 negative, and lower grade. (See 'Pathologic features of the tumor' below.)

As such, tumor characteristics might also contribute to the lesser use of chemotherapy in older women compared with younger women.

Finally, there is a marked selection bias among treatment of older women that affects the interpretation of practice patterns in older patients. Thus, for instance, the group of older women in whom an Oncotype DX Recurrence Score test is ordered would be a highly select group, in which the decision on whether to recommend chemotherapy is still being made. In practical terms, that rarely includes women over age 75.

PROGNOSIS — Although a breast cancer diagnosis (particularly if early stage) may not affect the life expectancy for an older woman, population studies show that outcomes among older women with breast cancer tend to be worse than those of younger women with breast cancer.

For example, in a Surveillance, Epidemiology, and End Results (SEER) database analysis of almost 50,000 women with stage I to II breast cancer aged ≥67 years, those aged 85 to 89 years had an increased risk of dying due to breast cancer compared with those aged 67 to 69 years (hazard ratio [HR] 1.5, 95% CI 1.3-1.7) [9]. Similar findings were observed in a Dutch substudy based on the TEAM trial (adjuvant exemestane) [10]. These observations may be associated with the fact that older age was also associated with less therapy (less surgery, less radiotherapy, less chemotherapy), and those tumors also were less likely to be detected through screening mammography, which often stops in women over age 70 or 75.

An early-stage breast cancer may not affect the life expectancy of older patients. The impact of a breast cancer diagnosis on life expectancy in older adult women was addressed in a SEER-Medicare dataset that compared the survival of two groups: 66,000 women aged ≥67 years with breast cancer, and non-breast cancer controls matched for age, comorbidity, prior mammography use, and social demographics [11].

Women diagnosed with ductal carcinoma in situ (DCIS) or stage I invasive breast cancer had a lower risk of death compared with controls (HR 0.7, 95% CI 0.7-0.7 for DCIS; HR 0.8, 95% CI 0.8-0.8 for stage I breast cancer). This may be because healthier women were still undergoing mammographic breast cancer screening. Cardiovascular disease was the most common cause of death in these women.

Women diagnosed with stage II disease or higher had an increased risk of death compared with controls (HR 1.1, 95% CI 1.0-1.2), regardless of age. However, among women aged ≥80 years diagnosed with stage II breast cancer, cardiovascular disease was still the most common cause of death.

For women with stage III or IV breast cancer, breast cancer was the most common cause of death.

In a separate study of women with breast cancer and median follow-up of 4.7 years, the proportion of deaths from breast cancer decreased as age increased. Of all deaths, the percentage of breast cancer deaths was 70 percent among women aged 50 to 69 years; 57 percent among those aged 70 to 74 years; 47 percent among those aged 75 to 79 years, and 39 percent for those aged ≥80 years [12]. Thus, a sizeable proportion or older patients die from causes other than breast cancer.

Impact of comorbidity — Comorbidity is characterized as the number and effect of an individual's other physical and psychological diseases in addition to the condition for which he or she is seeking treatment [13]. The presence of comorbidity is independently associated with decreased life expectancy and plays a major role in determining survival in older patients with cancer. For women with breast cancer, life expectancy is almost halved in the presence of comorbidity, such as a prior myocardial infarction [14].

Comorbid conditions that impose functional limitations are associated with higher mortality (from both breast cancer and non-breast-cancer causes), particularly if they are expected to worsen over time (eg, diabetes with end-organ damage, steroid- or oxygen-dependent chronic obstructive pulmonary disease, or dementia) [15-17]. In one study of over 64,000 women with breast cancer (median age 75), the adjusted HR of death (from all causes) increased as the severity of comorbidity increased (measured using the Charlson Comorbidity Index Score [18,19]); compared with patients with no comorbidity, the risk of death increased with increasing comorbidity level [15]:

Index comorbidity score 1 – HR 1.45 (95% CI 1.41-1.48)

Index comorbidity score 2 – HR 2.12 (95% CI 2.05-2.20)

Index comorbidity score ≥3 – HR 3.19 (95% CI 3.06-3.32)

These data emphasize the importance of comorbidity on overall prognosis among older women with breast cancer. The presence and severity of comorbidity must be considered in weighing the risks and benefits of what we do to treat breast cancer in these patients. Among women who are older and have a severe comorbidity, the threshold risk for treatment may be higher.

The impact of comorbidity was evaluated in two large retrospective studies. In one study [20], the benefit of chemotherapy was absent in cases of significant comorbidity [20], but still present in another similar study [21]. This type of retrospective, nonrandomized analyses are however prone to selection bias, making strong conclusions on the impact of frailty on chemotherapy uncertain.

ASSESSMENT OF BREAST CANCER IN THE OLDER PATIENT

General health status — Treatment considerations should be individualized based on general prognostic tumor-related markers (biology and extent of disease), global health status (providing information on life expectancy and treatment tolerance), and patient preference, but not on chronological age per se. Care must be taken to avoid "overtreating" older patients with adjuvant therapies if they are more likely to die from other causes prior to a possible breast cancer recurrence. (See 'Impact of comorbidity' above.)

An online tool called ePrognosis estimates life expectancy based on medical history and has been validated for use among women with early stage breast cancer [22]. By providing an estimate of noncancer mortality risk, the ePrognosis tool can help frame treatment decisions, especially for adjuvant chemotherapy. The Cancer and Aging Research Group-Breast Cancer (CARG-BC) was developed to predict toxicity from chemotherapy specifically in older adults with early breast cancer (calculator 1) [23]. (See "Systemic chemotherapy for cancer in older adults", section on 'Breast cancer'.)

Patients over age 70 with breast cancer may be screened for geriatric syndromes using a brief tool. (See "Comprehensive geriatric assessment for patients with cancer", section on 'Pre-CGA screening tools'.)

Based on the results of the screening, a comprehensive geriatric assessment (CGA) may help clinicians develop a coordinated plan for breast cancer treatment. CGA involves the assessment of important age-related domains such as functionality, cognition, depression, nutrition, comorbidity, polypharmacy, and social situation. Guidelines recommend that CGA be included in baseline assessment of all older patients with cancer [24]. (See "Comprehensive geriatric assessment for patients with cancer".)

Pathologic features of the tumor — The optimal approach to the older patient with breast cancer depends on the tumor extent (stage) and subtype. In general, breast cancers that occur in older women are more often in an advanced stage, more likely to be hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative, and have more indolent features compared with those that arise in younger women [25-30]. Also, when looking at the distribution of molecular subtypes by PAM50 according to age [31], luminal A and B tumors are more common, while the more aggressive subtypes (basal-like and HER2-enriched) are less common in older women compared with younger women.

However, it should also be acknowledged that all biologic subtypes occur in all age categories.

SURGICAL MANAGEMENT — The typical treatment approach to healthy older women with newly diagnosed, non-metastatic breast cancer includes surgery for removal of the cancer from the breast. However, decisions on axillary assessment, radiation, and systemic therapy may be altered in older versus younger women, based on tumor biology, extent of disease, general health status, and patients' wishes. A comprehensive geriatric assessment (CGA) can help assess general health status and should be included to guide treatment decisions in the older adult patient. (See "Comprehensive geriatric assessment for patients with cancer".)

Breast surgery — Assessment for whether a patient is a good candidate for surgery includes review of life expectancy, comorbidities, and frailty. (See 'General health status' above and "Comprehensive geriatric assessment for patients with cancer".)

In medically fit older women, standard breast cancer surgery options should be offered, given morbidity and mortality benefits. One study of perioperative outcomes among older cancer patients, about one-half of which were women with breast cancer, confirmed particularly low postsurgical complication rates (18.9 percent) and average hospital stays (median, three days) for older breast cancer patients [32].

Most older women choose breast conservation surgery over mastectomy [33]. In addition, breast-conserving surgery results in less disability in older women [34]. (See "Mastectomy" and "Breast-conserving therapy", section on 'Older adults'.)

Patients with tumors that cannot be treated by breast-conserving surgery (eg, cT4, multifocal tumors, etc) are best treated by mastectomy. Although mastectomy is also appropriate for patients with large, unifocal cancers deemed unsuitable for breast-conserving surgery, preoperative (neoadjuvant) systemic therapy can be offered to some patients, especially if they are interested in breast-conserving therapy [35]. For patients with hormone receptor-positive disease who are not initially candidates for surgery based on the extent of their disease, neoadjuvant endocrine therapy may allow for a less aggressive surgery to be performed at a later date. This issue is discussed elsewhere. (See "General principles of neoadjuvant management of breast cancer".)

Surgery versus endocrine therapy alone for hormone receptor-positive disease — We favor surgery rather than primary endocrine therapy for women with hormone receptor-positive breast cancer because surgical resection reduces the risk of a local recurrence and its associated morbidity. Moreover, breast surgery is well tolerated in older women and, in cases where general anesthesia is contraindicated, it can even be done under local anesthesia.

Our preference for surgery as the primary treatment is supported by multiple trials and a 2006 meta-analysis, which compared surgery (alone or followed by tamoxifen) with tamoxifen as the sole treatment for newly diagnosed breast cancer [36,37]. Compared with tamoxifen alone:

There was an improvement in progression-free survival favoring surgery alone (hazard ratio [HR] 0.55, 95% CI 0.39-0.77) or surgery plus tamoxifen (HR 0.65, 95% CI 0.53-0.81).

There was no statistically significant difference in overall survival (OS) for surgery alone (HR 0.98, 95% CI 0.74-1.30); however, there was a trend toward an improvement in OS with surgery plus tamoxifen (HR 0.86, 95% CI 0.73-1.00).

However, two trials with extended follow-up not included in the 2006 meta-analysis, as well as an epidemiologic study, did not confirm the positive impact of surgery on OS [21,38,39]. In conclusion, we recommend upfront surgery, which has low rates of morbidity, for management of local breast cancer in fit, older patients. Surgery may be delayed for specific individual reasons, where women are pursuing primary endocrine therapy in order to downsize the tumor and allow for less extensive surgery.

Management of the axilla — Older women may not require axillary lymph node surgery, particularly those with a clinically negative axilla and hormone receptor-positive cancers that will be treated with endocrine therapy. Further discussion is found elsewhere. (See "Overview of management of the regional lymph nodes in breast cancer", section on 'Select older patients with small hormone receptor-positive tumors'.)

In a retrospective cohort study of over 2100 patients aged 75 or older, 1467 were considered eligible for axillary staging, of whom 258 (17 percent) had incomplete axillary staging [40]. Age, comorbidities, and patient preferences were the main reasons for omission of complete axillary staging. The 10-year axillary recurrence rate in patients with incomplete axillary staging was 5.2 percent, and the OS was comparable between patients with or without complete axillary staging.

ADJUVANT SYSTEMIC THERAPY

Chemotherapy

Risks and benefits — Data suggest that older adult women receiving adjuvant chemotherapy can experience a survival benefit from treatment [41-43], but may be more prone to experiencing toxicities. Patients with triple-negative or human epidermal growth factor receptor 2 (HER2)-positive tumors, or those with more advanced disease, will derive greater benefit from adjuvant chemotherapy than patients with hormone-sensitive, HER2-negative breast cancer.

Evaluation of general health status through comprehensive geriatric assessment (CGA) allows clinicians to estimate residual life expectancy (independent of the cancer) and to predict potential chemotherapy toxicity. Also, patients' wishes, after being informed on the pros and cons of chemotherapy, are very important to take into account. (See 'General health status' above.)

As an example of observed benefits, in a study of patients ≥70 years with estrogen receptor (ER)-positive, node-positive breast cancer, and comorbidities, among 592 patients included in a matched analysis, receipt of chemotherapy was associated with improved survival (hazard ratio [HR] 0.67, 95% CI 0.48-0.98), after adjustment for potential confounding factors [42]. Separately, in a study from the Surveillance, Epidemiology, and End Results (SEER) cancer registries including over 5000 women age 65 and older with hormone receptor-negative, non-metastatic breast cancer, adjuvant chemotherapy was associated with a mortality reduction of approximately 15 percent on multivariate analysis [43]. The most pronounced benefits were experienced by those with involved lymph nodes or other high-risk features, including poor differentiation or larger tumor size. Finally, in a retrospective study discussed above, chemotherapy did not benefit those with significant comorbidity [20]. (See 'Impact of comorbidity' above.)

While in general, healthy older women can tolerate standard breast cancer treatments, they may be at increased risk for toxicity including short-term (eg, drug-induced) mortality when using the same chemotherapy regimens as younger women [44-46]. For instance, a large Medicare study demonstrated that patients aged >65 years have more than double the risk of being hospitalized for chemotherapy-related reasons compared with the younger ones, despite frequent use of prophylactic granulocyte colony-stimulating factors (G-CSF), as well as a small, short-term mortality risk [46]. In a real-world population in the United States, a SEER database analysis showed that 2.9 percent of early breast cancer patients ≥65 years old died within one year after the start of chemotherapy [45]. Even in a clinical trial setting, in which various adjuvant chemotherapy regimens were evaluated, the incidence of treatment-related mortality was higher with increasing age: 0.2 percent for age 50 years or less, 0.7 percent for age 51 to 64 years, and 1.5 percent for age 65 years or older (p <0.001) [44].

Tools to predict benefit — The results from the PREDICT tool may be used as a starting point for overall survival (OS) estimates with and without chemotherapy, with the knowledge that older women were included in model building.

PREDICT was developed using a cohort of women with early breast cancer in the United Kingdom (UK), with 32 percent of the exploratory cohort being >65 years old. The model was validated with another UK cohort that included 32 percent older women as well. The model incorporates mode of detection, HER2 status, and Ki67 level. PREDICT calculates OS at 5, 10, and 15 years. A Dutch study assessed the validity of PREDICT by testing the FOCUS cohort of the Netherlands. Information related to 2012 patients with a median age of 75 years was entered into the model, and survival outcomes were compared with outcomes available in their municipal population registries. The study revealed that PREDICT estimated 5-year OS adequately (1.7 percent prediction difference), while the 10-year OS prediction was overestimated (4.5 percent difference) [47,48]. One weakness of this model is the lack of input regarding comorbidity. When PREDICT was evaluated factoring in comorbidities of women in the FOCUS cohort, PREDICT underestimated 5-year OS in women without comorbidity (-3.7 percent), while overestimating survival in women with ≥4 comorbidities (11.8 percent) [48].

For patients with hormone receptor-positive breast cancer, where there is a question about whether or not chemotherapy will add enough benefit to justify the toxicity, gene expression profiles can be helpful. (See "Prognostic and predictive factors in early, non-metastatic breast cancer", section on 'Receptor status' and "Deciding when to use adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer".)

Several data on the use of Oncotype DX Recurrence Score (RS) are available focusing on the older population [49-51]. After menopause, there is a slight increase in low-risk RS, but the ≥70-year-old population still contains a significant proportion of intermediate-risk patients and a small group of high-risk patients, the latter group probably having most benefit from adjuvant chemotherapy [52]. Use of the RS is discussed in detail elsewhere, including special considerations for women with intermediate values. (See "Deciding when to use adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer", section on 'Validation in node-negative, HR-positive disease'.)

Tools to predict chemotherapy toxicity — Ongoing work has identified prognostic scoring systems that may be predictors of treatment-related toxicities, including the Cancer and Aging Research Group (CARG) [53], the CARG-Breast Cancer (CARG-BC) score [23], and Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) [54] scores. These are discussed elsewhere. (See "Systemic chemotherapy for cancer in older adults", section on 'Models predicting chemotherapy toxicity and early death'.)

HER2-negative disease

Preference for standard chemotherapy regimens — For older adult women for whom chemotherapy will be offered, we prefer standard chemotherapy regimens, such as docetaxel and cyclophosphamide (TC), or, for fit women with higher-risk disease, anthracycline-taxane regimens. Data regarding these regimens in human epidermal growth factor receptor 2 (HER2)-negative breast cancer in the general population are discussed elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Choosing a regimen'.)

The older regimen, cyclophosphamide, methotrexate, and fluorouracil (CMF), may be considered in those who have contraindications both to anthracyclines and taxanes. Other nonstandard regimens have either been associated with worsened toxicities and/or efficacy among older adults.

For example, in a randomized trial (Cancer and Leukemia Group B [CALGB] 49907) of 633 women aged 65 years or older with stage I to IIIB breast cancer, patients who were randomly assigned to capecitabine, the nonstandard treatment arm, were twice as likely to have a relapse and almost twice as likely to die as patients who were randomly assigned to standard chemotherapy (either cyclophosphamide plus doxorubicin [AC] or CMF) [55]. Specifically, the three-year relapse-free survival (RFS) with capecitabine versus standard chemotherapy was 68 versus 85 percent (HR 2.09, 95% CI 1.38-3.17), and the OS rate was 86 versus 91 percent (HR 1.85, 95% CI 1.11-3.08). At 10 years, rates of RFS continued to be inferior with capecitabine (50 versus 56 percent with chemotherapy), as were OS rates (56 and 62 percent, respectively) [56]. Of the patients who received capecitabine, 34 percent had at least one grade 3 or 4 adverse event, versus 60 percent of those receiving AC and 70 percent of patients receiving CMF. Most of the severe toxicities in the standard chemotherapy arms were hematologic. A nonhematologic grade 3 or 4 adverse event occurred in 33 percent of patients who received capecitabine, 25 percent of those who received AC, and 41 percent of those who received CMF. The most common of these were fatigue and gastrointestinal symptoms, which occurred more frequently with CMF than the other regimens. Despite these toxicities, 80 percent of patients receiving capecitabine, 92 percent of those receiving AC, and 62 percent of those receiving CMF received all planned cycles of treatment. Further discussion on anthracycline-containing regimens, as well as CMF, is found below. (See 'Anthracycline-based treatment for fit patients with high-risk disease' below and 'Other regimens' below.)

These results are in line with the ICE trial, which failed to demonstrate a benefit with the nonstandard adjuvant regimen of capecitabine relative to placebo, among women receiving adjuvant treatment with the third-generation bisphosphonate ibandronate [57]. In this trial, 1380 women aged 65 years or older with node-positive or high-risk, node-negative breast cancer were randomly assigned to ibandronate with or without capecitabine. All subjects were considered to be unsuitable candidates for standard chemotherapy. Subjects with hormone-sensitive disease also received endocrine therapy. At three years, there was no statistical difference for the primary endpoint of disease-free survival (DFS) with the addition of capecitabine (85 versus 84 percent) or at five years (79 versus 75 percent).

In a separate large, prospective, randomized trial (n = 601), weekly docetaxel, the nonstandard treatment arm, was compared with standard CMF in older patients and found to be not superior to CMF while having more toxicity [58]. Specifically, differences in DFS and OS for docetaxel versus CMF were not statistically significant. Hematologic toxicity, mucositis, and nausea were worse with CMF; quality of life (QOL) and specific adverse events including allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, and cardiac and skin toxicity were worse with docetaxel.

Together, these data suggest that standard combination regimens are efficacious in older adult patients, with acceptable toxicity for many such patients.

Anthracycline-based treatment for fit patients with high-risk disease — For fit, older adult patients with normal baseline cardiac function (by echocardiogram or equivalent) and no serious underlying cardiovascular disease, with high-risk breast cancers (eg, node-positive tumors, larger tumors, triple negative tumors >1 cm), we typically use a regimen such as dose-dense doxorubicin and cyclophosphamide concurrently, followed by paclitaxel (AC-T). This is based on the positive benefits of these regimens on breast cancer outcomes compared with older-generation regimens (ie, CMF) [59,60]. However, it should be acknowledged that most of the "standard" anthracycline-taxane combinations have only been studied in younger or selected fit, older patients [61]. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer".)

Classical anthracycline-taxane regimens can be used for medically fit older patients, but the benefit of treatment must be balanced by the increased risks of (anthracycline-based) chemotherapy, including increased hematologic toxicity, heart damage [44,62,63], and short-term (eg, drug-induced) mortality, that are found in older patients. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Results from the CALGB 40101 trial serve as an example of both the benefits and risks of anthracycline-based treatment. In this CALGB trial, four or six cycles of either paclitaxel (T), administered weekly or biweekly, versus AC were compared in approximately 3800 lower-risk patients of all ages [64]. T performed worse than AC (HR for OS of 1.27, favoring AC), but noninferiority was not demonstrated. The estimated absolute advantage of AC at five years was 3 percent for recurrence-free survival (91 versus 88 percent) and 1 percent for OS (95 versus 94 percent). As expected, the incidence of any grade 3 or higher hematologic toxicity was higher among those receiving AC than T (eg, grade ≥3 neutropenia occurred in 26 to 33 percent in the AC arms, versus 3 percent in the T arms). By contrast, neuropathy was more common in the T than the AC arms (approximately 6 to 13 versus <1 percent), though older age was not an independent risk factor [65]. Cardiac toxicity was infrequent in both groups, although two cardiac deaths occurred among patients receiving AC. Seven patients, all receiving AC, developed acute myelogenous leukemia or myelodysplastic syndrome.

Risks of anthracyclines in older patients were also evaluated in a study using the SEER-Medicare database that included 43,338 women aged 66 to 80 with stage I to III breast cancer with no history of pre-existing heart failure [62]. Over 4700 women received an anthracycline-containing chemotherapy regimen, while almost 4000 received a non-anthracycline-containing regimen; 34,705 women received no chemotherapy. At a median follow-up of 56 months, the following heart failure rates for women aged 66 to 70 years were reported at 5 and 10 years:

For women treated with anthracyclines: 19 and 38 percent, respectively

For women treated without an anthracycline: 18 and 33 percent, respectively

For women not treated with chemotherapy: 15 and 29 percent, respectively

Analyses indicated an interaction between age and adjuvant anthracycline treatment, and suggested that anthracycline increases the risk of heart failure as far out as 10 years later. The absolute numbers of heart failure are quite high in this study, probably related to the administrative coding system in the United States, but the relative increase in the anthracycline arm likely reflects a relevant long-term risk.

For women aged 71 to 80 years, there were no statistically significant differences between the three groups in rates of congestive heart failure.

Besides age, other baseline characteristics associated with the development of heart failure included hypertension, diabetes, coronary artery disease, and being a Black person. Recommended maximum doses based upon the presence of risk factors have been described [66]. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Docetaxel/cyclophosphamide in others — For lower-risk cancers (eg, those with node-negative, hormone receptor-positive tumors; or node-negative, triple-negative tumors, particularly those >1 cm), or for patients in whom the oncologist/patient wants to avoid the risks associated with anthracyclines, TC is an appropriate regimen.

Preference for TC is based on one randomized trial showing that four cycles of TC result in a higher DFS and OS compared with AC among women with stage I to III breast cancer (16 percent of whom were 65 years or older) [67]. In this study, there was a marked DFS and OS benefit for TC compared with AC, and benefit was also seen in the ≥65-year-old population, while toxicity was acceptable (though prophylactic G-CSF is necessary because of high rates of febrile neutropenia with this regimen when used without G-CSF [68]).

There have been subsequent studies on TC specifically in the older population, with acceptable toxicity rates, and >90 percent being able to complete the four cycles [69,70]. When the impact of TC on QOL and geriatric assessment was measured consecutively, clinical frailty and QOL seemed to decline somewhat at three months, but fully recovered at one year [70].

Subsequent clinical trials have compared TC versus anthracycline-taxane regimens. For example, joint analysis of the ABC Trials compared TC chemotherapy versus an anthracycline-, cyclophosphamide-, and taxane-based regimen in over 4000 women receiving adjuvant therapy for HER2-negative breast cancer, approximately 30 percent of whom were ≥60 years [71]. Although overall, TC was inferior to the anthracycline- and taxane-based regimen in regards to four-year invasive DFS, anthracycline-based therapy did not meaningfully improve outcomes in ER-positive breast cancers or in triple-negative, lymph node-negative patients (figure 1). Given the risk-benefit ratio of adjuvant chemotherapy, we recommend four cycles of TC in older women needing adjuvant chemotherapy, but six cycles of TC can also be considered in cases of high-risk features and acceptable tolerance. Further discussion of the ABC trials is found elsewhere. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Acceptable alternatives to anthracycline-based treatment'.)

Other regimens — In general, if adjuvant chemotherapy is given to older patients, classical regimens (like docetaxel-cyclophosphamide, or in selected patients, a sequential anthracycline-taxane regimen with optimal supportive care) are generally preferred, while other regimens such as CMF might be reserved for specific situations. For the patient who is unlikely to tolerate concurrent multiagent chemotherapy, it is reasonable to offer a sequential single-agent therapy (eg, docetaxel followed by cyclophosphamide, each for four cycles; or doxorubicin, followed by paclitaxel, followed by cyclophosphamide, each for four cycles). It should be acknowledged that the latter is the only sequential single-agent regimen that has been formally studied [72]).

The old, standard regimen of CMF can be a reasonable option in patients with contraindication for anthracyclines and taxanes (eg, a patient with cardiac risk factors who is intolerant of steroids due to poorly controlled diabetes or other reasons). CMF with oral cyclophosphamide is deemed the more effective of the CMF regimens [73], but the intravenous (IV) formulation is often more practical (eg, because the patient does not tolerate pills or because low blood counts and treatment delays require use of growth factors). If the IV regimen is used, every-three-week administration with peg-filgrastim for hematologic support is an appropriate option, reducing clinic visits compared with other IV schedules. CMF is, however, associated with a higher risk of serious (grade 3) toxicity, including hematologic and mucosal toxicity in women aged ≥65 years compared with younger women [74,75]. Moreover, CMF has been replaced by anthracyclines and/or taxane regimens because of superior efficacy in the general population. Data regarding CMF, AC, and single-agent capecitabine are discussed above. (See 'Preference for standard chemotherapy regimens' above.)

Support for sequential single-agent dosing of standard chemotherapy regimens comes from CALGB 9741, a trial of approximately 2000 patients randomly assigned to receive adjuvant chemotherapy with ACT in one of four ways: as sequential single agents (A then T then C) given every three weeks; sequential single agents given every two weeks with growth factor support; concurrent AC followed by T, given every three weeks; or concurrent AC followed by T given every two weeks, with growth factor support [72]. In this trial, dose density improved disease-free recurrence, but there was no difference in either DFS or OS between the concurrent and sequential schedules. Grade 3 or greater emesis was more common for the concurrent regimens than for the sequential regimens (7 versus 3 percent). Severe neutropenia was less frequent in patients who received the dose-dense regimens.

Extrapolating from the metastatic setting, weekly paclitaxel has activity in breast cancer and may be an option for the patient who is unlikely to tolerate multiple chemotherapy agents. In general, this is a less preferred option to either concurrent or sequential multiagent chemotherapy regimens. (See 'Anthracycline-based treatment for fit patients with high-risk disease' above and "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Taxanes'.)

HER2-positive disease

Benefits of combination of HER2-directed therapy and chemotherapy — For older women with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer who have undergone surgery, we recommend adjuvant trastuzumab plus chemotherapy.

Addition of trastuzumab improves survival and diminishes recurrence risk compared with chemotherapy alone and is tolerated in older patients [76]. In a systematic review of prospective randomized trials with available data on the use of adjuvant trastuzumab in patients aged >60 years, a 47 percent relative risk reduction was observed in older adult patients receiving trastuzumab compared with chemotherapy alone (HR 0.53, 95% CI 0.36-0.77). Cardiac events occurred in 5 percent of older patients receiving trastuzumab.

There are insufficient data to recommend adjuvant trastuzumab without chemotherapy in early breast cancer, but data are emerging. One Japanese randomized phase II study compared standard adjuvant chemotherapy plus trastuzumab with adjuvant trastuzumab alone. This study included 275 patients, with median age 73.5 years [77,78]. With 4.1 years' median follow-up, single-agent trastuzumab was not noninferior to standard trastuzumab plus chemotherapy. The study did show more toxicity and worse QOL during chemotherapy, but, by three years after randomization, QOL differences were the same between groups.

Choice of chemotherapy — For higher-risk fit patients (eg, those with involved nodes, or larger tumors) who are candidates for adjuvant chemotherapy, an anthracycline-taxane regimen can be offered, but the same issues of increased toxicity as described above are present for the majority of older patients. Cardiac toxicity is a particular issue since both anthracyclines and trastuzumab can affect the heart [79]. The classical anthracycline-taxane-trastuzumab combinations have been studied mainly in young, fit patients, and only fewer than 1000 of 20,000 study participants in the pivotal trials were aged >60 years. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Incidence'.)

Taxane-anti-HER2 combinations without anthracyclines are attractive for older patients. The regimen of docetaxel, carboplatin, and trastuzumab (TCH) is an option, but patients above age 70 were excluded from the BCIRG01 study, and hematologic toxicity with a high-dose carboplatin and docetaxel combination is a major concern, so we avoid this regimen for many older patients.

As an alternative, one study observed hardly any metastatic relapse in >400 low-risk women treated with paclitaxel and trastuzumab [80], similar to results from a single-arm study with TC and trastuzumab [81]. Although these two latter taxane-trastuzumab combinations have been investigated only in the general population in lower-risk tumors, they are very attractive for the older population in general, and we use these regimens also in older women with higher-risk, HER2-positive early breast cancer because of the favorable benefit versus risk relationship.

Approach to incorporation of HER2-directed therapy

We recommend that patients who have undergone surgery for early human epidermal growth factor receptor 2 (HER2)-positive breast cancer receive HER2-directed therapy as part of their adjuvant treatment.

It should be acknowledged that a significant proportion of older patients with HER2-positive early breast cancer do not receive trastuzumab [82], and that congestive heart failure occurs more frequently with versus without trastuzumab: 29 percent in ≥66-year-old trastuzumab users versus 19 percent in non-trastuzumab users [83]. Despite the higher risk of cardiotoxicity, cardiac monitoring according to guidelines, which recommend checking the ejection fraction every three months during trastuzumab treatment, are less often followed in older patients: one study reported that only 36 percent of older patients receiving trastuzumab were monitored according to guidelines [84].

Concerning trastuzumab duration, as is the case for younger women in whom trastuzumab is recommended, one year of adjuvant trastuzumab should be administered in the older patient, and most are able to complete this without complication [85]. However, shorter than a one-year duration of trastuzumab can be an option to decrease cardiac risk, although conflicting results about the impact on relapse risk do not allow use of a shorter duration as a standard. (See "Adjuvant systemic therapy for HER2-positive breast cancer".)

Adjuvant pertuzumab added to trastuzumab and chemotherapy is an option based on the Aphinity trial, but only 13 percent of patients were ≥65 years of age in Aphinity. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Dual anti-HER2 therapy in high-risk disease'.)

The absolute benefit of pertuzumab addition in terms of decreased invasive DFS was rather minor, and pertuzumab-associated diarrhea may be more debilitating for older than younger persons. Moreover, Aphinity evaluated pertuzumab only in combination with trastuzumab and a classical anthracycline-taxane or TCH regimen, which are feasible only in a minority of older patients. The addition of pertuzumab and trastuzumab in combination with paclitaxel alone, or TC, is investigational.

Neratinib has shown a statistically significant DFS benefit following adjuvant trastuzumab in the ExteNET trial [86]. However, its main side effect of diarrhea puts older patients at particular risk of dehydration, and the recommended upfront prescription for antidiarrheals carries risk for constipation. Additional data to define risks and benefits in older patients are needed, and if neratinib is used, careful monitoring is required. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Dual anti-HER2 therapy in high-risk disease'.)

The neoadjuvant approach has been less frequently used in older women with HER2-positive early breast cancer in the past because of concerns of toxicity. However, there is an increasing trend to use neoadjuvant systemic therapy in this setting since the adjuvant systemic part can be escalated or de-escalated depending on the response at surgery. The main difficulty is to select a chemotherapy partner for the neoadjuvant systemic therapy part. There are no prospective trials specifically available for the older population, so our approach is to extrapolate the data from the adjuvant setting, as discussed above. (See 'Choice of chemotherapy' above.)

For women with HER2-positive disease who have been treated with neoadjuvant therapy and have residual disease at the time of surgery, adjuvant trastuzumab emtansine (T-DM1) reduces recurrences relative to trastuzumab by approximately one-half [87]. However, T-DM1 is associated with increased toxicities (eg, thrombocytopenia, peripheral neuropathy, fatigue) and treatment discontinuation relative to trastuzumab, and fewer than 10 percent of women evaluated in the KATHERINE trial were ≥65 years old. We therefore offer T-DM1 to fit, older women with appropriate indications, but toxicity needs to be monitored. These data are discussed in detail elsewhere. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Residual disease'.)

Endocrine therapy for hormone receptor-positive disease — According to guidelines, adjuvant endocrine therapy should be offered to all women with ER-positive breast tumors >0.5 cm, regardless of age, provided they are candidates for medical therapy. We prefer to administer an aromatase inhibitor (AI) in older women because of its benefits in the adjuvant setting compared with tamoxifen, as well as avoidance of the thromboembolic risks and endometrial thickening/bleeding associated with tamoxifen. However, for women at risk for cardiovascular complications or bone loss, and those unable to tolerate an AI due to toxicity, tamoxifen is a reasonable alternative. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer".)

Tamoxifen improves breast cancer outcomes compared with observation alone, including 10-year risks of recurrence (23 versus 44 percent, respectively) and breast cancer-specific mortality (20 versus 37 percent) [88], and this benefit seems maintained in older women [1]. In the 2010 Early Breast Cancer Trialists' Group (EBCTCG) meta-analysis, adjuvant treatment with tamoxifen versus an AI was also evaluated [89]. Treatment with an AI for five years resulted in trends toward reduced recurrences compared with tamoxifen in women aged 60 to 69 years (12 versus 14 percent; relative risk [RR] 0.80) and in women aged 70 years or older (14 versus 17 percent; RR 0.78). Thus, compared with tamoxifen, AIs are slightly superior for reducing relapse risk in older women.

As in younger women, the optimal duration of endocrine therapy use is not clear. A minimum duration of five years of endocrine therapy should be prescribed for most older women. However, longer durations up to 10 years might be appropriate in selected patients, especially those with higher-risk tumor features (eg, nodal involvement, higher tumor grade). The issue of duration of treatment is discussed separately. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Duration of endocrine treatment'.)

Adjunctive systemic treatments — There is growing interest in the use of bisphosphonates in the adjuvant setting with two aims: reducing the relapse risk, and decreasing the risk of therapy-induced osteoporotic fractures (with age being the most important risk factor for osteoporosis). Decision making regarding adjuvant bisphosphonates follows the same approach in older women with breast cancer as for younger women. As renal function declines with age, and the dose of zoledronic acid needs to be adapted to renal function, specific attention to this issue is needed in older persons. (See "Use of osteoclast inhibitors in early breast cancer", section on 'Postmenopausal women'.)

ADJUVANT RADIATION — Radiation therapy (RT) is generally well tolerated and the cosmetic results are excellent, even in older women [90]. In general, however, studies show that the risk of a local recurrence is lower in older women, and the benefits of RT following breast conservation surgery decline with age [91,92]. Therefore, some older women may prefer to avoid adjuvant RT, particularly those with small, estrogen receptor-positive breast cancer and no evidence of nodal disease who agree to take endocrine therapy. Large, randomized trials (eg, Cancer and Leukemia Group B [CALGB] 9343 and PRIME-II) have suggested that omission of RT in this subset is an acceptable strategy [93,94], assuming that endocrine therapy is administered. These data are discussed in detail elsewhere. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Possible omission of RT for select ER-positive, HER2-negative cancers'.)

Patients who prefer not to proceed with adjuvant RT should be counseled that they may have a slightly higher risk of an in-breast cancer recurrence compared with those who undergo RT. Similar to the adjuvant chemotherapy discussion, general life expectancy also plays a role in the true benefit of adjuvant RT; in frail patients with higher-risk tumors, adjuvant RT will provide little, if any, benefit. (See "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer".)

NONSURGICAL CANDIDATES — We suggest the following approach to the treatment of older women who are not appropriate surgical candidates:

For patients with hormone receptor-positive disease who are not initially candidates for surgery based on the extent of their disease, neoadjuvant endocrine therapy may allow for resectability at a later point. (See "General principles of neoadjuvant management of breast cancer" and "Neoadjuvant management of newly diagnosed hormone-positive breast cancer".)

For patients who refuse surgery and those patients who, on the basis of preferences or comorbidities that limit life expectancy, are not likely ever to be surgical candidates, our approach is based on the primary tumor features. For details, see below. (See 'Indications for systemic therapy' below.)

In general, for women with a limited life expectancy (due to comorbidities) and those who wish to avoid treatment-related toxicity, we proceed with supportive care and referral for palliative care services. (See "Primary palliative care".)

Indications for systemic therapy

Hormone receptor-positive breast cancer — Patients with hormone-positive disease who are not surgical candidates are offered primary endocrine therapy. For those who are candidates, we prefer surgery, as discussed above. (See 'Surgery versus endocrine therapy alone for hormone receptor-positive disease' above.)

There are no randomized trials in women who did not undergo primary surgery comparing endocrine therapy with more aggressive treatment (ie, chemotherapy) or with observation, nor are there prospective studies evaluating tamoxifen versus an aromatase inhibitor (AI) in this population. However, based on the incremental benefits of an AI on survival outcomes compared with tamoxifen when administered in the metastatic and adjuvant setting for women with postmenopausal breast cancer, we prefer an AI. Tamoxifen is a reasonable alternative in women who do not tolerate an AI.

Most data on the role of primary endocrine therapy come from retrospective studies. As examples:

In one series, 104 women with early-stage breast cancer who were unwilling or unfit to undergo surgery opted for endocrine therapy (without surgery) and received letrozole (2.5 mg daily) [95]. The median age of patients was 83 years (range, 53 to 98 years). The reasons given for pursuing primary endocrine treatment were frailty (46 percent), comorbidities (29 percent), patient preference (16 percent), and older age (9 percent). Treatment with letrozole resulted in [95]:

An overall response rate of 82 percent with median time to initial response of 4 months (range, 2 to 24 months) and median time to best response of nine months (range, 3 to 50 months). The median overall survival was 51 months (range, 4 to 103 months).

A 12 percent incidence of fractures during treatment, most commonly involving the femur or wrist.

Treatment cessation due to disease progression in 18 percent. During a median follow-up of 56 months, 42 patients (40 percent) died, though only 12 (29 percent) died of breast cancer.

In another retrospective study, 184 women received tamoxifen or an AI rather than surgery due to comorbidities (35 percent), age (15 percent), and patient choice (40 percent) [96]. The mean age of patients was 84 years (range, 75 to 89 years). Fifty percent had T2-sized cancers and 22 percent had node involvement. With a mean follow-up time of 2.6 years, the main findings were:

Observed times to response and progression were similar in those receiving tamoxifen or an AI.

Endocrine therapy resulted in an initial response rate of 58 percent and stable disease in 11 percent.

Although 65 percent died during follow-up, only 14 percent died of breast cancer.

Triple-negative breast cancer — For asymptomatic nonsurgical candidates with triple-negative localized disease, we observe without systemic treatment, although a short course of radiotherapy can be considered to avoid/treat local symptoms. Also, chemotherapy can be considered when the tumor is causing local symptoms or when symptoms or cancer-related problems are expected in the near future. In such cases, we offered single-agent chemotherapy using an approach similar to the treatment of women with metastatic breast cancer (eg, capecitabine or paclitaxel weekly). (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Initial chemotherapy'.)

HER2-positive breast cancer — For asymptomatic nonsurgical candidates with human epidermal growth factor receptor 2 (HER2)-positive localized disease, we observe without systemic treatment, although a short course of radiotherapy can be considered to avoid/treat local symptoms. HER2-directed therapy can also be considered when the tumor is causing local symptoms or when symptoms or cancer-related problems are expected in the near future. In such cases, we offer anti-HER2 therapy with single-agent chemotherapy (or potentially with endocrine therapy, for hormone receptor-positive disease), using an approach similar to the treatment of women with HER2-positive metastatic breast cancer. (See "Systemic treatment for HER2-positive metastatic breast cancer" and "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Special considerations for hormone receptor-positive disease'.)

Primary RT — We typically do not administer radiation therapy (RT) as the sole treatment of breast cancer in medically frail patients, although it can be considered if surgery and systemic therapy are not feasible, and local problems are present or expected.

There are only limited data on the role of RT as primary treatment (without surgery), and no randomized trials have been performed. The available data suggest that long-term results following primary RT are inferior to surgery [97,98]. As an example, in a study of 514 women, women who underwent primary RT had lower 5- and 10-year survivals compared with women who underwent lumpectomy (68 and 43 percent versus 85 and 75 percent, respectively) [97].

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Treatment of early-stage, hormone-responsive breast cancer in postmenopausal women (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Breast cancer is a major health concern in the older population. Older women often are treated less aggressively than younger women, which may contribute to inferior outcomes seen in this population. On the other hand, overtreatment should be avoided if a patient is more likely to die from other causes prior to a possible breast cancer recurrence. (See 'Impact of comorbidity' above and 'Introduction' above and 'Treatment patterns' above.)

Treatment considerations should be individualized based on general prognostic tumor-related markers (biology and extent of disease), global health status (providing information on life expectancy and treatment tolerance), and patient preference, but not on chronological age per se. Patients over age 70 with breast cancer may be screened for geriatric syndromes using a brief tool. Based on the results of the screening, a comprehensive geriatric assessment (CGA) may help clinicians develop a coordinated plan for breast cancer treatment. (See 'General health status' above and "Comprehensive geriatric assessment for patients with cancer".)

For older women with newly diagnosed, non-metastatic breast cancer who are appropriate surgical candidates, we recommend surgical resection (Grade 1B).

For patients with hormone receptor-positive disease who are not initially candidates for surgery based on the extent of their disease, neoadjuvant endocrine therapy may allow for less aggressive surgery to be performed at a later date. This issue is discussed elsewhere. (See "General principles of neoadjuvant management of breast cancer" and "Neoadjuvant management of newly diagnosed hormone-positive breast cancer".)

For patients with hormone receptor-positive, small (<2 cm) tumors and a clinically negative axilla who will receive adjuvant endocrine therapy, both axillary surgery and breast radiation may be able to be avoided, without an adverse effect on survival. Decision making should occur in a multidisciplinary setting. These issues are discussed elsewhere. (See "Overview of management of the regional lymph nodes in breast cancer", section on 'Select older patients with small hormone receptor-positive tumors' and "Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer", section on 'Possible omission of RT for select ER-positive, HER2-negative cancers'.)

Adjuvant chemotherapy may be needed in some patients, with choice of regimen influenced by tumor biology, tumor extent, and patient preference, as in the general population. However, general health status as assessed by CGA also affects treatment decisions. (See 'Adjuvant systemic therapy' above and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Regimen selection and administration' and "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Choice of chemotherapy'.)

For patients ≥65 years old treated for early, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, indications for chemotherapy are influenced by tumor receptor status, tumor extent, and patient preference, as in the general population, and are discussed elsewhere. However, general health status as assessed by CGA also affects treatment decisions. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Indications for treatment' and 'General health status' above.)

If chemotherapy is deemed appropriate, for most patients ≥65 years treated for early, HER2-negative breast cancer, we suggest four cycles of docetaxel and cyclophosphamide (TC) over other chemotherapy regimens (Grade 2C). However, for fit patients with higher-risk disease (eg, node-positive disease; T3 tumors; triple negative tumors, especially those >1 cm), an anthracycline- and taxane-based regimen may be preferred. Some contributors also consider six cycles of TC for higher-risk, hormone receptor-positive, HER2-negative disease.

For the patient who is unlikely to tolerate concurrent multiagent chemotherapy, it is reasonable to offer sequential single-agent chemotherapy (eg, doxorubicin, followed by paclitaxel, followed by cyclophosphamide, each for four cycles).

For most women ≥65 years old with HER2-overexpressing breast cancer who have undergone surgery, we recommend adjuvant trastuzumab plus chemotherapy rather than chemotherapy alone (Grade 1B). We also suggest it over trastuzumab alone (Grade 2C).

Regarding choice of chemotherapy with the anti-HER2 therapy, for most such patients, we suggest a non-anthracycline-based regimen over an anthracycline-based regimen (Grade 2C), with a choice between such regimens driven by the patient's general health status and tumor risk features. However, for fit patients with higher-risk disease (eg, node-positive disease, T3 tumors, or hormone receptor-negative tumors >1 cm), an anthracycline- and taxane-based regimen may be preferred.

For women with early breast cancer who are not candidates for surgery (including those who decline surgery), we take the patient's tumor characteristics and the presence of local symptoms into consideration in our approach, recognizing that alternative strategies may also be appropriate, in the setting of limited data (see 'Nonsurgical candidates' above):

For nonsurgical candidates with HER2-negative, hormone receptor-positive breast cancer, we suggest primary endocrine therapy, rather than chemotherapy or observation (Grade 2C). (See 'Surgery versus endocrine therapy alone for hormone receptor-positive disease' above.)

For asymptomatic nonsurgical candidates with triple-negative or HER2-positive localized disease, we suggest observation rather than active treatment (Grade 2C), reserving treatment for situations in which the tumor is causing local symptoms, is metastatic and symptomatic, or in which cancer-related problems are expected in the near future. (See "Systemic treatment for HER2-positive metastatic breast cancer".)

Medically frail women with a limited life expectancy and those who wish to avoid treatment and the associated risk of toxicity should be offered supportive care and a referral for palliative care services. (See 'Primary RT' above and "Primary palliative care".)

  1. Wildiers H, Kunkler I, Biganzoli L, et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology. Lancet Oncol 2007; 8:1101.
  2. Biganzoli L, Wildiers H, Oakman C, et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol 2012; 13:e148.
  3. Wyld L, Garg DK, Kumar ID, et al. Stage and treatment variation with age in postmenopausal women with breast cancer: compliance with guidelines. Br J Cancer 2004; 90:1486.
  4. Enger SM, Thwin SS, Buist DS, et al. Breast cancer treatment of older women in integrated health care settings. J Clin Oncol 2006; 24:4377.
  5. Lavelle K, Todd C, Moran A, et al. Non-standard management of breast cancer increases with age in the UK: a population based cohort of women > or =65 years. Br J Cancer 2007; 96:1197.
  6. Cyr A, Gillanders WE, Aft RL, et al. Breast cancer in elderly women (≥ 80 years): variation in standard of care? J Surg Oncol 2011; 103:201.
  7. Bastiaannet E, Liefers GJ, de Craen AJ, et al. Breast cancer in elderly compared to younger patients in the Netherlands: stage at diagnosis, treatment and survival in 127,805 unselected patients. Breast Cancer Res Treat 2010; 124:801.
  8. Lavelle K, Sowerbutts AM, Bundred N, et al. Is lack of surgery for older breast cancer patients in the UK explained by patient choice or poor health? A prospective cohort study. Br J Cancer 2014; 110:573.
  9. Schonberg MA, Marcantonio ER, Li D, et al. Breast cancer among the oldest old: tumor characteristics, treatment choices, and survival. J Clin Oncol 2010; 28:2038.
  10. van de Water W, Markopoulos C, van de Velde CJ, et al. Association between age at diagnosis and disease-specific mortality among postmenopausal women with hormone receptor-positive breast cancer. JAMA 2012; 307:590.
  11. Schonberg MA, Marcantonio ER, Ngo L, et al. Causes of death and relative survival of older women after a breast cancer diagnosis. J Clin Oncol 2011; 29:1570.
  12. Ali AM, Greenberg D, Wishart GC, Pharoah P. Patient and tumour characteristics, management, and age-specific survival in women with breast cancer in the East of England. Br J Cancer 2011; 104:564.
  13. Extermann M, Aapro M. Assessment of the older cancer patient. Hematol Oncol Clin North Am 2000; 14:63.
  14. Extermann M, Balducci L, Lyman GH. What threshold for adjuvant therapy in older breast cancer patients? J Clin Oncol 2000; 18:1709.
  15. Patnaik JL, Byers T, Diguiseppi C, et al. The influence of comorbidities on overall survival among older women diagnosed with breast cancer. J Natl Cancer Inst 2011; 103:1101.
  16. Vaeth PA, Satariano WA, Ragland DR. Limiting comorbid conditions and breast cancer stage at diagnosis. J Gerontol A Biol Sci Med Sci 2000; 55:M593.
  17. Fleming ST, Sabatino SA, Kimmick G, et al. Developing a claim-based version of the ACE-27 comorbidity index: a comparison with medical record review. Med Care 2011; 49:752.
  18. Clough-Gorr KM, Stuck AE, Thwin SS, Silliman RA. Older breast cancer survivors: geriatric assessment domains are associated with poor tolerance of treatment adverse effects and predict mortality over 7 years of follow-up. J Clin Oncol 2010; 28:380.
  19. Clough-Gorr KM, Thwin SS, Stuck AE, Silliman RA. Examining five- and ten-year survival in older women with breast cancer using cancer-specific geriatric assessment. Eur J Cancer 2012; 48:805.
  20. Kimmick GG, Li X, Fleming ST, et al. Risk of cancer death by comorbidity severity and use of adjuvant chemotherapy among women with locoregional breast cancer. J Geriatr Oncol 2018; 9:214.
  21. de Glas NA, Jonker JM, Bastiaannet E, et al. Impact of omission of surgery on survival of older patients with breast cancer. Br J Surg 2014; 101:1397.
  22. Kimmick GG, Major B, Clapp J, et al. Using ePrognosis to estimate 2-year all-cause mortality in older women with breast cancer: Cancer and Leukemia Group B (CALGB) 49907 and 369901 (Alliance A151503). Breast Cancer Res Treat 2017; 163:391.
  23. Magnuson A, Sedrak MS, Gross CP, et al. Development and Validation of a Risk Tool for Predicting Severe Toxicity in Older Adults Receiving Chemotherapy for Early-Stage Breast Cancer. J Clin Oncol 2021; 39:608.
  24. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Older adult oncology. Version 1.2019 http://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/senior.pdf (Accessed on July 10, 2019).
  25. Gennari R, Curigliano G, Rotmensz N, et al. Breast carcinoma in elderly women: features of disease presentation, choice of local and systemic treatments compared with younger postmenopasual patients. Cancer 2004; 101:1302.
  26. Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst 2000; 92:550.
  27. Pierga JY, Girre V, Laurence V, et al. Characteristics and outcome of 1755 operable breast cancers in women over 70 years of age. Breast 2004; 13:369.
  28. Rodrigues NA, Dillon D, Carter D, et al. Differences in the pathologic and molecular features of intraductal breast carcinoma between younger and older women. Cancer 2003; 97:1393.
  29. Malik MK, Tartter PI, Belfer R. Undertreated breast cancer in the elderly. J Cancer Epidemiol 2013; 2013:893104.
  30. Van Belle V, Van Calster B, Brouckaert O, et al. Qualitative assessment of the progesterone receptor and HER2 improves the Nottingham Prognostic Index up to 5 years after breast cancer diagnosis. J Clin Oncol 2010; 28:4129.
  31. Jenkins EO, Deal AM, Anders CK, et al. Age-specific changes in intrinsic breast cancer subtypes: a focus on older women. Oncologist 2014; 19:1076.
  32. PACE participants, Audisio RA, Pope D, et al. Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help. A SIOG surgical task force prospective study. Crit Rev Oncol Hematol 2008; 65:156.
  33. Sandison AJ, Gold DM, Wright P, Jones PA. Breast conservation or mastectomy: treatment choice of women aged 70 years and older. Br J Surg 1996; 83:994.
  34. Sweeney C, Schmitz KH, Lazovich D, et al. Functional limitations in elderly female cancer survivors. J Natl Cancer Inst 2006; 98:521.
  35. Mano M, Fraser G, McIlroy P, et al. Locally advanced breast cancer in octogenarian women. Breast Cancer Res Treat 2005; 89:81.
  36. Hind D, Wyld L, Beverley CB, Reed MW. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev 2006; :CD004272.
  37. Hind D, Wyld L, Reed MW. Surgery, with or without tamoxifen, vs tamoxifen alone for older women with operable breast cancer: cochrane review. Br J Cancer 2007; 96:1025.
  38. Chakrabarti J, Kenny FS, Syed BM, et al. A randomised trial of mastectomy only versus tamoxifen for treating elderly patients with operable primary breast cancer-final results at 20-year follow-up. Crit Rev Oncol Hematol 2011; 78:260.
  39. Johnston SJ, Kenny FS, Syed BM, et al. A randomised trial of primary tamoxifen versus mastectomy plus adjuvant tamoxifen in fit elderly women with invasive breast carcinoma of high oestrogen receptor content: long-term results at 20 years of follow-up. Ann Oncol 2012; 23:2296.
  40. Poodt IGM, Schipper RJ, Vugts G, et al. The rationale for and long-term outcome of incomplete axillary staging in elderly women with primary breast cancer. Eur J Surg Oncol 2018; 44:1714.
  41. Crozier JA, Pezzi TA, Hodge C, et al. Addition of chemotherapy to local therapy in women aged 70 years or older with triple-negative breast cancer: a propensity-matched analysis. Lancet Oncol 2020; 21:1611.
  42. Tamirisa N, Lin H, Shen Y, et al. Association of Chemotherapy With Survival in Elderly Patients With Multiple Comorbidities and Estrogen Receptor-Positive, Node-Positive Breast Cancer. JAMA Oncol 2020; 6:1548.
  43. Elkin EB, Hurria A, Mitra N, et al. Adjuvant chemotherapy and survival in older women with hormone receptor-negative breast cancer: assessing outcome in a population-based, observational cohort. J Clin Oncol 2006; 24:2757.
  44. Muss HB, Woolf S, Berry D, et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 2005; 293:1073.
  45. Rosenstock AS, Lei X, Tripathy D, et al. Short-term mortality in older patients treated with adjuvant chemotherapy for early-stage breast cancer. Breast Cancer Res Treat 2016; 157:339.
  46. Barcenas CH, Niu J, Zhang N, et al. Risk of hospitalization according to chemotherapy regimen in early-stage breast cancer. J Clin Oncol 2014; 32:2010.
  47. Wishart GC, Azzato EM, Greenberg DC, et al. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res 2010; 12:R1.
  48. de Glas NA, Bastiaannet E, Engels CC, et al. Validity of the online PREDICT tool in older patients with breast cancer: a population-based study. Br J Cancer 2016; 114:395.
  49. Kizy S, Altman AM, Marmor S, et al. 21-gene recurrence score testing in the older population with estrogen receptor-positive breast cancer. J Geriatr Oncol 2019; 10:322.
  50. Wu SG, Zhang WW, Wang J, et al. 21-Gene Recurrence Score Assay and Outcomes of Adjuvant Radiotherapy in Elderly Women With Early-Stage Breast Cancer After Breast-Conserving Surgery. Front Oncol 2019; 9:1.
  51. Ruiz R, Namuche F, Morante Z, et al. Age's importance in early breast cancer: Oncotype Dx results in patients ≤40 years. Cancer Res 2018; 79S: SABCS #P3-08-16.
  52. Swain SM, Nunes R, Yoshizawa C, et al. Quantitative Gene Expression by Recurrence Score in ER-Positive Breast Cancer, by Age. Adv Ther 2015; 32:1222.
  53. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 2011; 29:3457.
  54. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer 2012; 118:3377.
  55. Muss HB, Berry DA, Cirrincione CT, et al. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 2009; 360:2055.
  56. Muss HB, Polley MC, Berry DA, et al. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol 2019; 37:2338.
  57. von Minckwitz G, Reimer T, Potenberg J, et al. The phase III ICE study: Adjuvant Ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer. Cancer Res 2015; 75S: SABCS #S3-04.
  58. Perrone F, Nuzzo F, Di Rella F, et al. Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial. Ann Oncol 2015; 26:675.
  59. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687.
  60. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012; 379:432.
  61. Decoster L, Van Puyvelde K, Mohile S, et al. Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations†. Ann Oncol 2015; 26:288.
  62. Pinder MC, Duan Z, Goodwin JS, et al. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 2007; 25:3808.
  63. Loibl S, von Minckwitz G, Harbeck N, et al. Clinical feasibility of (neo)adjuvant taxane-based chemotherapy in older patients: analysis of >4,500 patients from four German randomized breast cancer trials. Breast Cancer Res 2008; 10:R77.
  64. Shulman LN, Berry DA, Cirrincione CT, et al. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol 2014; 32:2311.
  65. Barginear M, Dueck AC, Allred JB, et al. Age and the Risk of Paclitaxel-Induced Neuropathy in Women with Early-Stage Breast Cancer (Alliance A151411): Results from 1,881 Patients from Cancer and Leukemia Group B (CALGB) 40101. Oncologist 2019; 24:617.
  66. Ryberg M, Nielsen D, Cortese G, et al. New insight into epirubicin cardiac toxicity: competing risks analysis of 1097 breast cancer patients. J Natl Cancer Inst 2008; 100:1058.
  67. Jones S, Holmes FA, O'Shaughnessy J, et al. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol 2009; 27:1177.
  68. Do T, Medhekar R, Bhat R, et al. The risk of febrile neutropenia and need for G-CSF primary prophylaxis with the docetaxel and cyclophosphamide regimen in early-stage breast cancer patients: a meta-analysis. Breast Cancer Res Treat 2015; 153:591.
  69. Freyer G, Campone M, Peron J, et al. Adjuvant docetaxel/cyclophosphamide in breast cancer patients over the age of 70: results of an observational study. Crit Rev Oncol Hematol 2011; 80:466.
  70. Brouwers B, Hatse S, Dal Lago L, et al. The impact of adjuvant chemotherapy in older breast cancer patients on clinical and biological aging parameters. Oncotarget 2016; 7:29977.
  71. Blum JL, Flynn PJ, Yothers G, et al. Anthracyclines in Early Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol 2017; 35:2647.
  72. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003; 21:1431.
  73. Lindeman GJ, Boyages J, Driessen C, Langlands AO. Intravenous or oral adjuvant CMF for node-positive breast cancer. Aust N Z J Surg 1992; 62:556.
  74. Crivellari D, Bonetti M, Castiglione-Gertsch M, et al. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII. J Clin Oncol 2000; 18:1412.
  75. De Maio E, Gravina A, Pacilio C, et al. Compliance and toxicity of adjuvant CMF in elderly breast cancer patients: a single-center experience. BMC Cancer 2005; 5:30.
  76. Brollo J, Curigliano G, Disalvatore D, et al. Adjuvant trastuzumab in elderly with HER-2 positive breast cancer: a systematic review of randomized controlled trials. Cancer Treat Rev 2013; 39:44.
  77. Sawaki M, Taira N, Uemura Y, et al. Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. J Clin Oncol 2020; 38:3743.
  78. Taira N, Sawaki M, Uemura Y, et al. Health-Related Quality of Life With Trastuzumab Monotherapy Versus Trastuzumab Plus Standard Chemotherapy as Adjuvant Therapy in Older Patients With HER2-Positive Breast Cancer. J Clin Oncol 2021; 39:2452.
  79. Shenoy C, Klem I, Crowley AL, et al. Cardiovascular complications of breast cancer therapy in older adults. Oncologist 2011; 16:1138.
  80. Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015; 372:134.
  81. Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol 2013; 14:1121.
  82. Reeder-Hayes K, Peacock Hinton S, Meng K, et al. Disparities in Use of Human Epidermal Growth Hormone Receptor 2-Targeted Therapy for Early-Stage Breast Cancer. J Clin Oncol 2016; 34:2003.
  83. Chavez-MacGregor M, Zhang N, Buchholz TA, et al. Trastuzumab-related cardiotoxicity among older patients with breast cancer. J Clin Oncol 2013; 31:4222.
  84. Chavez-MacGregor M, Niu J, Zhang N, et al. Cardiac Monitoring During Adjuvant Trastuzumab-Based Chemotherapy Among Older Patients With Breast Cancer. J Clin Oncol 2015; 33:2176.
  85. Vaz-Luis I, Keating NL, Lin NU, et al. Duration and toxicity of adjuvant trastuzumab in older patients with early-stage breast cancer: a population-based study. J Clin Oncol 2014; 32:927.
  86. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18:1688.
  87. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N Engl J Med 2019; 380:617.
  88. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011; 378:771.
  89. Dowsett M, Cuzick J, Ingle J, et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28:509.
  90. Deutsch M. Radiotherapy after lumpectomy for breast cancer in very old women. Am J Clin Oncol 2002; 25:48.
  91. Veronesi U, Luini A, Del Vecchio M, et al. Radiotherapy after breast-preserving surgery in women with localized cancer of the breast. N Engl J Med 1993; 328:1587.
  92. Smith BD, Gross CP, Smith GL, et al. Effectiveness of radiation therapy for older women with early breast cancer. J Natl Cancer Inst 2006; 98:681.
  93. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343. J Clin Oncol 2013; 31:2382.
  94. Kunkler IH, Williams LJ, Jack WJ, et al. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol 2015; 16:266.
  95. Balakrishnan A, Ravichandran D. Early operable breast cancer in elderly women treated with an aromatase inhibitor letrozole as sole therapy. Br J Cancer 2011; 105:1825.
  96. Wink CJ, Woensdregt K, Nieuwenhuijzen GA, et al. Hormone treatment without surgery for patients aged 75 years or older with operable breast cancer. Ann Surg Oncol 2012; 19:1185.
  97. Calle R, Pilleron JP, Schlienger P, Vilcoq JR. Conservative management of operable breast cancer: ten years experience at the Foundation Curie. Cancer 1978; 42:2045.
  98. Weissberg JB, Prosnitz LR. Treatment of early breast cancer with primary radiation therapy: rationale, results, and techniques. Bull N Y Acad Med 1982; 58:203.
Topic 757 Version 58.0

References

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