Triple-negative breast cancer, which affects about 10% of older women with breast cancer, represents a major treatment challenge in this population. Treatment decisions for these patients can best be made based on geriatric assessment, estimated life expectancy, whether the treatment goal is prolonged survival or palliation, the potential benefits and toxicities of a specific treatment, and the patient’s personal goals for treatment. Treatment outcomes for healthy older and younger women are similar, but great challenges exist in managing the vulnerable and frail patient. The cornerstone of therapy for early-stage triple-negative breast cancer is local therapy (surgery and radiation) and, for most patients, adjuvant chemotherapy. In the management of metastatic triple-negative breast cancer, all therapy is palliative and chemotherapy is the treatment of choice. Since all treatment modalities in older patients—especially chemotherapy—can affect physical and mental function, a geriatric assessment is key in selecting the most appropriate treatment strategy. Many older patients (older than 70 years) are poor candidates for state-of-the-art therapy, and some who have substantial comorbidities not related to breast cancer may opt for palliative and hospice care. In this review, we will discuss the role of geriatric assessment, alternative treatment modalities for older women with triple-negative breast cancer, and other special considerations for this patient population.
Breast cancer is the leading cancer diagnosis among women in the United States, accounting for approximately one in three cancers, and it is the second leading cause of cancer-related death in women. Based on data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, the median age at breast cancer diagnosis for women in the United States is 62 years, and among patients with breast cancer the average age at death is 68 years. Since the second half of the 20th century, major improvements in public health and advances in medical care have led to significant increases in life expectancy in the United States, with the female population aged 65 years and older expected to grow from 26.4 million in 2015 to an estimated 46.2 million in 2050. This 80% increase will result in an absolute increase in the number of older women with breast cancer.
Triple-negative breast cancer represents a distinct phenotype of breast cancer characterized by rapid tumor growth, a relapse rate that peaks in the first 2 to 3 years after diagnosis, and an increased incidence in African-American and Hispanic populations. While increasing age is generally associated with a decreasing incidence of triple-negative breast cancer, in one SEER study (N = 57,483), triple-negative breast cancer was diagnosed in approximately 10% of breast cancer patients over 65 years of age. In another registry-based study of 771 patients with stages I to III triple-negative breast cancer, 159 (21%) were 65 years of age and older. Notably, in the latter study, patients older than 65 were significantly less likely to receive chemotherapy (61% of patients over 75 years of age did not receive chemotherapy, compared with 5% of patients younger than 64 years; P < .001), and 12% of patients in this older age group were not evaluated by an oncologist. Regardless of cancer type, the management of older patients with cancer is characterized by less treatment compared with younger patients; in breast cancer, this conservative approach has been shown to result in poorer breast cancer–specific survival in older patients compared with younger ones.
Genetic subtyping has shown that triple-negative breast cancer is associated with the basal-like subtype, which occurs less frequently in older patients. In a cohort of 3,947 patients with triple-negative breast cancer, molecular subtyping as determined by the PAM50 breast cancer gene expression assay showed that the basal-like subtype was found in 44% of patients aged 21 to 39 years, in 22% of patients aged 50 to 59 years, and in 9% of patients aged 70 to 93 years. In the group with triple-negative breast cancer, after controlling for subtype, treatment, tumor size, nodal status, and grade, age had no impact on either disease-free or overall survival.
The treatment of triple-negative breast cancer is challenging, given that chemotherapy is the only available systemic therapy for these patients. Since chemotherapy can be associated with severe toxicity, management challenges with this breast cancer subtype are even greater in older patients, who may also have a greater incidence of comorbid illness, use of multiple medications, and preexisting functional loss, such that treatment-related toxicity may dramatically alter their daily function and quality of life. In this review, we provide recommendations for the care of older patients with triple-negative breast cancer, including assessment of functional status, estimation of toxicity risk and survival, and management approaches to consider for older patients with early or metastatic disease.
A key characteristic of the aging process is a cumulative decline in the function of multiple physiologic systems. This results in decreased organ function reserve, as well as comorbidity, frailty, and limited ability to tolerate stressors such as infections or chemotherapy. These declines and resultant physiologic deficits occur at varying rates in different individuals and organ systems, so that there may be vast differences in life expectancy, functional status, and health status among patients of identical chronologic ages. Geriatric assessment is a multidimensional interdisciplinary evaluation that can be used to identify patient-related health problems by summarizing key features of an older adult’s physical function as well as information about polypharmacy, comorbidities, nutritional status, cognitive status, and psychosocial status. Many deficits uncovered by geriatric assessment are not detected on routine clinical evaluation. In one large study, one or more geriatric assessment–identified deficits were found in 69% of patients with a normal Karnofsky Performance Status score. The identified deficits included polypharmacy, impairments in cognitive function, and impairments in instrumental activities of daily living. In another study, only 10% of older cancer patients with geriatric assessment–identified falls had appropriate clinician documentation in their medical records, and even fewer (6%) had referrals for evidence-based interventions for fall prevention. Identifying these deficits is particularly important because they are independent predictors of poor survival outcomes that could potentially attenuate the benefit of chemotherapy in older women with triple-negative breast cancer.
Regardless of their particular diagnosis, most breast cancer patients who develop recurrence do so within 2 to 3 years after the initial diagnosis. Accurate estimation of life expectancy is essential in selecting treatment for older adults with cancer, especially for frail patients for whom the potential survival benefit of adjuvant chemotherapy may be nullified by competing medical comorbidities. Several validated online tools are available that enable accurate estimates to be made, and which may incorporate geriatric assessment variables in addition to demographic and clinical data (eg, https://eprognosis.ucsf.edu/calculators).
Not only is the geriatric assessment a valuable instrument for predicting the potential benefits of chemotherapy, but it can also be used to assess the potential toxicities of chemotherapy. In a pivotal study of 500 patients, geriatric assessment–identified deficits—including falls and hearing impairment, but not Karnofsky Performance Status scores—were shown to predict the risk of grades 3 and 4 chemotherapy toxicity.[13,14] This validated model and others are available online (Table 1). The geriatric assessment can also identify deficits for which targeted evidence-informed interventions are available that can improve outcomes. In a classic study, cancer patients randomized postoperatively to three home visits and five telephone contacts by an advanced practice nurse survived significantly longer than patients randomized to usual care (mortality rates in the whole cohort, 22% vs 28%). The major benefit was among those with more advanced cancer stage (2-year survival, 67% vs 40% favoring the intervention group). Since then, other studies have shown that geriatric assessment interventions can lead to improvement in quality of life and may help with chemotherapy decision making.[17-19]
Four Key Steps in Making Treatment Decisions for Older Patients With Triple-Negative Breast Cancer
Following initial screening and preferably a geriatric assessment, management of the older patient with triple-negative breast cancer can be broken down into four steps:
• First, determine whether the medical goal of treatment is to improve the chance for cure (the goal of treatment in the adjuvant setting) or palliation, and convey this information to the patient and family.
• Second, query the patient as to what is important to her and what her goals are for being treated. The patient and family may not always agree on these goals, and it is critical that discord be resolved early.
• Third, using geriatric assessment–based data and appropriate tools and models, including estimates of life expectancy for the individual patient, calculate the risks and benefits of treatment.
• Last, present these risks-and-benefits data to the patient and family using shared decision making and in language that they can understand, to finalize the plan for care.
Management of Early-Stage Triple-Negative Breast Cancer
For the majority of older women with triple-negative breast cancer, core biopsy will establish a definitive diagnosis, and for most of these patients management should be similar to that of younger women. Breast conservation should be offered when appropriate, with the goal of no ink on the tumor margin. Sentinel node sampling has replaced axillary dissection for a clinically negative axilla and in patients with one to two positive sentinel nodes and a clinically negative axilla; further axillary dissection is unnecessary for patients who will receive locoregional irradiation. For patients with positive sentinel nodes, axillary radiotherapy represents an appropriate alternative to axillary lymph node dissection.[21,23] Recently there has been interest in the use of accelerated partial breast irradiation as an alternative to whole-breast radiotherapy, but the suitability of the former approach in women with triple-negative breast cancer is uncertain.[24,25]
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