Challenges in the Diagnosis and Treatment of Breast Cancer in the Elderly

This article is the first in a continuing series on cancer in older adults. The goal of this series of articles is to highlight the ways in which cancer diagnosis and management in older adults differ from cancer diagnosis and management at younger ages. Other topics that will be included in the series are cancer and aging, prostate cancer, colon cancer, hematologic malignancies, cancer screening and prevention, and palliative care and hospice.
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Introduction

Breast cancer is the second leading cause of cancer death in women, and the primary risk factor for developing breast cancer is increasing age. More than 200,000 new diagnoses of breast cancer and more than 40,000 deaths associated with breast cancer occur each year in the United States.¹ Nearly half of breast cancer diagnoses occur in women age 65 years and older, and the incidence of breast cancer increases with increasing age until the 80s. It is predicted that there will be 70.2 million people age 65 years and over by 2030.² Given the changing demographics of our nation and the world, an in-depth understanding of managing cancer in the elderly will become a critical skill for primary care physicians and oncologists alike. The management of breast cancer in older women can be challenging for a number of reasons, including concern about treatment tolerance and a lack of evidence-based data obtained in elderly women. Many older patients are not offered appropriate treatments for their cancers, and many undergo treatments that may not be appropriate for their functional status, comorbidities, and overall quality of life. Breast cancer is a major contributor to morbidity and mortality in elderly women, and improved understanding of optimal strategies for diagnosis and treatment are needed.

Goals of Care

When treating older patients with nearly any disease process, it is essential for physicians to understand the specific patient’s personal goals for medical care, his or her values, and the patient’s priorities for quality and quantity of life. This becomes especially critical as patients develop more comorbidities and have declining mental or physical function. When an elderly patient receives a diagnosis of cancer, the patient and family must understand the possibilities for cure, extension of life, and palliation. Treatment options, and their likelihood of success, must always be weighed against the risk of adverse effects and overall impact on quality of life.

Because of the complexity of cancer treatment and ongoing advances, it is important that every patient with a diagnosis of cancer be referred to an oncologist to discuss the treatment options in detail. Ideally, older patients with complex medical and social issues should be referred to a geriatric oncologist with experience in caring for elderly patients with cancer. In the case of a 50-year-old woman diagnosed with cancer with no comorbid medical problems, the direction for treatment may be obvious. However, for an 85-year-old with multiple medical problems, dementia, or physical limitations, the recommendations for care and treatment become more complex. These decisions must involve the patient and family members under the guidance of physicians who can understand and properly evaluate these complexities. Fortunately, dual-trained geriatric oncologists are becoming more common as these issues become clearer to the medical community. In addition, a shift to a multidisciplinary team approach that includes oncologists, geriatricians, pharmacists, social workers, and others may be the ideal model to improve the overall quality of cancer care in the elderly.³

Screening

The U.S. Preventive Services Task Force (USPSTF) recommends definitively for mammographic breast cancer screening until the age of 74 years. The USPSTF acknowledges that women are at increasing risk for breast cancer and mortality from breast cancer as they age. They recommend that clinicians use clinical judgment after age 75 and take into account comorbid illnesses and life expectancy when considering breast cancer screening in this population.⁴ Of course, screening for any cancer is aimed at identifying cancers early so that treatments may be performed to minimize morbidity and mortality associated with more advanced malignancy. Therefore, it is critical that older patients receive informed consent prior to mammography, understanding why mammography is being performed and what might be found. Specifically, patients should know about the possible need for biopsies or further imaging, and the potential treatments needed if a cancer is found. Some patients may decide that they do not want to undergo screening because they would not want treatment even if a cancer were found.

Breast cancer surgery is a low-risk procedure and feasible for most patients, making it reasonable to screen all women with a life expectancy of 5 years or longer. While it may not reduce overall mortality, continued screening in older women with comorbid conditions may reduce morbidity from breast cancer by identifying breast tumors before they develop into locally advanced tumors with skin invasion or ulceration, which can be quite painful to the patient. Clinical breast exam should be performed annually for all elderly women.

Pathology

Breast cancer in older women tends to be a slower and more indolent disease due to differences in biologic characteristics.5 Elderly women tend to have breast cancers with increased estrogen receptor (ER) expression, and this is associated with improved prognosis.⁶ In one series, ER expression was seen in 40% of women age 40, 60% of those age 60, and more than 70% of those age 80.⁵ ER positivity is associated with less aggressive tumor biology but also predicts benefit from endocrine therapy, which further improves outcomes.⁵ In addition, human epidermal growth factor receptor-2 (HER2) overexpression, an elevated Ki-67 proliferative marker, and aneuploidy are less common in elderly women, also all predicting improved prognosis. Of course, there are exceptions to these trends, and some older women do present with aggressive breast cancers such as those with the HER2-positive or triple-negative (ER/PR/HER2 negative) phenotypes.

Presentation of Disease

Stage of disease at presentation (Table I) is the most important prognostic factor in breast cancer and is critical to assessing risk of recurrence and planning appropriate treatment. Stage I, II, and III breast cancers are considered curable with optimal therapy, but long-term survival rates decrease with advancing stage. Five-year overall survival in elderly patients is lower at every stage than their younger counterparts. For example, 5-year overall survival for stage I breast cancer is 88% for age 67-74, 84% for age 75-84, and 50% for those age 85 and older. Importantly, these statistics represent all-cause mortality, and as patients age they have increasing mortality unrelated to their cancer.

It is sometimes difficult to tease out why mortality is increased in older patients with breast cancer. For example, is the increased mortality wholly related to noncancer causes, or is there increased breast cancer–specific mortality? If so, is that increased breast cancer–specific mortality related to undertreatment? One review of breast cancer–specific mortality in elderly patients demonstrated that women over age 75 who received less than guideline therapy had a significantly worse breast cancer–specific survival as compared to women age 65-74 who received guideline therapy or nonguideline therapy.⁷ Importantly, those women age 75 or older who received guideline therapy had similar outcomes to the younger women, even when adjusted for other prognostic factors and comorbidity. There may still be some element of selection bias in this series, but it does suggest that appropriate therapy may reduce the disparity in breast cancer survival in older women.

Stage IV breast cancer, at any age, is considered incurable, and the median survival is approximately 2 years, with 20% of women still alive at 5 years. Treatments in metastatic disease can often control disease and palliate symptoms for long periods of time. Therefore, even elderly patients with metastatic disease should see an oncologist to discuss potential treatments.

Geriatric Assessment

The percentage of patients with breast cancer with comorbid conditions increases with chronological age. Thirty-five percent of patients age 65-79 have at least two comorbid illnesses, as compared with 70% of those over 80 years of age.⁸ However, chronological age and comorbidities do not give the complete picture needed to best tailor appropriate treatment to any individual patient. Functional status including activities of daily living (ADL) and instrumental activities of daily living (IADL), cognitive function, polypharmacy, psychosocial function and support, and nutritional status should all be assessed prior to recommendation of therapy for an older patient. Patients who have excellent functioning in these areas can likely tolerate the same treatments as their counterparts who are 20 years younger.⁹ However, those elderly patients with difficulty in one or more area may have problems with treatment compliance and tolerance. There is currently no uniform process for oncologists to evaluate these issues to plan treatment for an older patient.

The Karnofsky index of performance status (KPS) and the Eastern Cooperative Oncology Group performance status (ECOG PS; Table II) scale are tools commonly used to evaluate patients’ eligibility for clinical trials. These tools are quite brief and are not specific to issues commonly seen in the elderly, making them less useful in this population.¹⁰ For example, an older patient may have a comorbidity, such as osteoarthritis, which results in a functional limitation that has nothing to do with his or her cancer diagnosis or ability to receive cancer treatment. This would cause the patient to have a lower ECOG PS score but would not reflect the overall picture of the patient. Conversely, the KPS and ECOG PS could overestimate an older patient’s overall well-being by not addressing issues such as dementia, polypharmacy, or ADL.¹⁰

A complete geriatric assessment would take into account functional status, including ADL and IADL. Functional status alone is an independent predictor of morbidity and mortality.¹¹ A list of comorbid conditions alone cannot fully address a patient’s functional status, though they remain an important component of the assessment. In one study, patients with breast cancer and three or more comorbid conditions had a 20-fold higher rate of mortality from one of those conditions than from breast cancer.¹² Polypharmacy tends to accompany comorbidities as patients age. Oncologists and primary care physicians must be continually vigilant about drug interactions, especially in older patients taking multiple medications. One dangerous example of a drug interaction in patients with cancer is warfarin and the oral chemotherapy agent capecitabine. Many older patients take warfarin, and the concurrent use of capecitabine can result in a dramatic increase in international normalized ratio, with the associated risk of bleeding.

Other critical areas of a geriatric evaluation of an elderly patient include nutrition, cognition, and psychosocial support system. Assessment of cognition becomes more and more important as persons age because of the increasing prevalence of dementia. Cognitive impairment and dementia can significantly affect a person’s ability to understand instructions regarding medications and toxicity from therapy.¹⁰ This can make it very difficult to have discussions about risks and benefits of treatment. For older patients, much more so than their younger counterparts, evaluation of social support is critical to ensuring that patients are able to navigate the sometimes complicated process of cancer treatment and its potential toxicities.

The evaluation of an older patient with cancer is an area in great need of additional information and research. Development and validation of tools for elderly patients with cancer is critical for optimizing all cancer care in older persons.¹³ Several geriatric assessment tools specifically designed for oncology patients are currently being studied to identify their role in predicting cancer treatment tolerance, toxicity, and long-term outcomes. Hopefully, there will be evidence-based data to guide the integration of these tools into cancer care in the next few years.

Treatment

Treatment for breast cancer is broadly divided into local therapy, involving surgery and/or radiation, and systemic therapy, involving chemotherapy or hormonal therapy.

Surgery and Radiation
Surgical therapy for early-stage breast cancer is considered a low-risk operation and represents the most important part of therapy. The greatest risk is from anesthesia in patients who have significant cardiopulmonary conditions.¹⁴ Occasionally, surgical therapy can be performed under local anesthesia in patients not felt to be candidates for general anesthesia. Surgical therapy should be offered to all women with early-stage breast cancer, regardless of age and comorbidities, because of the low risk of complication and the inability to cure disease without surgery.¹⁵ For patients who have an absolute contraindication to surgery, hormonal therapy alone is an option and may be able to control disease and prevent progression. While one study showed no survival benefit to surgery over hormonal therapy alone, hormonal therapy was clearly inferior to surgery in preventing local recurrences and local progression.¹⁶

In women who opt for breast-conserving surgery instead of mastectomy, or women with large tumors or bulky nodal disease, adjuvant radiation to the breast or chest wall is recommended to reduce the risk of local recurrence.

Surgery is rarely indicated in metastatic disease, unless used to palliate a nonhealing locally advanced tumor. Radiation therapy may be used in metastatic disease to control pain from bone metastases or to treat brain metastases.

In each situation, a thorough discussion of the potential risks (including those to quality of life) and benefits should be discussed with patients and their family members, allowing them to make informed decisions about their care.

Adjuvant Systemic Therapies
In addition to surgery and radiation, many women will benefit from the addition of systemic therapy, such as hormonal therapy or chemotherapy. Unlike treatment in metastatic disease, which is aimed at palliation and prolongation of life, adjuvant therapies are employed to prevent future relapses and reduce the risk of breast cancer–related death. The goal of adjuvant therapy is to eradicate micrometastatic disease so that those microscopic tumor cells will not become clinical metastases. The decision to utilize adjuvant therapy is complicated and must take into account several important factors: (1) those which predict risk of recurrence (tumor size, nodal status, grade, HER2 status, and ER positivity); (2) the likelihood of benefit of various therapies; (3) a geriatric assessment to help predict toxicity and noncancer mortality; and (4) the patient’s wishes and goals of care. One tool that can calculate the risk of relapse, mortality, and treatment benefit in cancer patients can be found at www.adjuvantonline.com. This tool enables a treating physician to enter information about age, general health status, stage, grade, and ER status, and predicts the relative benefit of different systemic therapies in that particular patient. This can help identify which treatments are most likely to reduce the risk of recurrence and mortality, and those benefits can then be weighed against the likelihood of treatment toxicities. While there are scant data on the value of adjuvant therapy in elderly patients with breast cancer, it appears that older women receive similar benefit to younger women in reducing risk of relapse, though the reduction in mortality diverges widely with increasing age.¹⁷

Adjuvant hormonal therapy. Most elderly patients with breast cancer will have hormone receptor–positive tumors, and therefore hormonal therapy represents the most important adjuvant systemic therapy in this group. Adjuvant hormonal therapies can reduce the risk of recurrence by as much as 50%.^18,19 There are two categories of oral medications for adjuvant hormonal therapy, which are usually given for 5 years. The first is the selective estrogen-receptor modulator (SERM) tamoxifen. This medication binds to ERs and acts as an estrogen antagonist in the breast. It can therefore be used in both pre- and postmenopausal women. In other tissues, it acts as an estrogen agonist, resulting in increased bone mineral density and stimulation of the endometrium. There is a small increased risk of endometrial cancer.^5,20 Other adverse effects include hot flashes, mood alteration, increased risk of venous thromboembolism, and stroke.⁵ The clotting risk clearly increases with advancing age, and caution should be taken when using tamoxifen in older women with other risk factors for clotting and cerebrovascular disease. Tamoxifen does appear to have a positive effect on the lipid profile.²¹ Studies have shown variable effects on cognitive function, and this remains controversial.

The second category is aromatase inhibitors. In postmenopausal women, the sole source of circulating estrogen is the conversion of other steroid hormones to estrogen via the enzyme aromatase, which is present in body fat, the adrenal glands, and normal breast tissue. Aromatase inhibitors were developed to inhibit this estrogen production and are now commonly used for ER–positive breast cancer in postmenopausal women with early- or late-stage disease. Aromatase inhibitors have been shown to be superior to tamoxifen in reducing the risk of recurrence in postmenopausal women with breast cancer.²² The main adverse effects of aromatase inhibitors include decreased bone mineral density, increased risk of fracture, and arthralgias. In early studies, an unfavorable effect on the lipid profile was suggested, but this has not been confirmed in placebo-controlled studies. Bisphosphonates, both oral and intravenous, have been shown to prevent the bone loss associated with aromatase inhibitor therapy and are frequently used in women who have decreased bone density at the time of diagnosis. Similar to tamoxifen, the aromatase inhibitors have an undefined effect on cognitive function, and further studies are urgently needed to better evaluate this.

Adjuvant chemotherapy. Adjuvant chemotherapy is considered for treatment of patients with a higher stage of disease, high-risk features such as HER2 positivity, or tumors that are not ER–positive, and therefore would not benefit from adjuvant hormonal therapy. Commonly used chemotherapy regimens include 4-6 cycles of doxorubicin and cyclophosphamide (AC), 4 cycles of docetaxel and cyclophosphamide (TC), or 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Studies are underway to evaluate less intensive chemotherapy regimens in elderly patients to determine whether such regimens might achieve similar reduction in mortality and disease recurrence while minimizing side effects and complications of treatment.²⁰ One such study evaluated standard chemotherapy (AC or CMF) versus oral capecitabine in women age 65 and older with breast cancer, and unfortunately capecitabine resulted in inferior cancer-related outcomes.²³ Myelosuppression, and the resulting risk of neutropenic fever, is the main acute side effect of adjuvant chemotherapy in older women. While nonhematologic toxicities such as nausea are not significantly worse in elderly patients receiving adjuvant chemotherapy for breast cancer, hematologic toxicity is clearly more prominent. This often requires more judicious use of growth factors to support white blood cell counts or hemoglobin.

One particular challenge in adjuvant chemotherapy for breast cancer is the treatment of frail elderly women, in whom very little data are available.²⁴ Studies of novel targeted drugs or nonchemotherapy agents, such as oral antidiabetic agents, are underway to identify therapies that might reduce disease recurrence and death from breast cancer while not adversely affecting quality of life for these patients.

Metastatic Disease

Unlike early-stage disease, metastatic or stage IV breast cancer is not considered curable with current therapies. The focus for these patients is on palliation of symptoms and prolongation of life with good quality. Because hormonal therapy is generally well tolerated when compared with chemotherapeutic regimens, these are first-line choices for treating patients with ER+ metastatic disease. Elderly patients diagnosed with breast cancer tend to have more ER positivity, and therefore many elderly patients can maintain a good quality of life on hormonal therapy that can extend their life from months to years.⁵

Unfortunately, nearly all patients who are treated with hormonal therapies for metastatic disease will develop resistance to these treatments. Strategies to reduce or prevent resistance to hormonal therapy are under development. Currently, cytotoxic chemotherapeutic options are considered at this time if patients desire continued therapy. These therapies typically require central venous catheter placement, time receiving therapies, and more frequent monitoring. A few oral chemotherapy regimens are available that often are more convenient for older patients who may have limited transportation or wish to avoid frequent clinic visits. Capecitabine is an oral chemotherapy that is well tolerated by patients of all ages and can result in long-lived disease control, even in those patients with a poor prognosis.²⁵ Studies have shown that when given the option, patients tend to prefer taking oral therapy, especially in the setting of palliation. However, many single-agent intravenous chemotherapies are also well tolerated. In addition, many novel molecularly-targeted agents are under development and will hopefully have fewer, or more tolerable, side effects than standard therapy.

Because many simple palliative options are available for the treatment of metastatic breast cancer, it is imperative that all patients with advanced breast cancer seek an oncology consult, no matter their function or underlying comorbidities. An in-depth discussion balancing the goals of therapy with the potential benefits will ensure that patients receive optimal therapy for their specific circumstances.

Conclusion

The increasing population of elderly patients in the United States and around the world will result in increasing numbers of older women with breast cancer, and we must understand how to optimally treat those women. Breast cancer treatment options are evolving rapidly, with novel therapies being developed every year. We must improve our ability to assess elderly patients so that these advancements will translate to better outcomes in both young and older cancer patients. An understanding of geriatric syndromes and comorbidities, as well as differences in disease biology, can improve the care of older patients with cancer. This will require further research in developing tools for evaluating elderly oncology patients to optimize their care and minimize impact on quality of life. In addition, a move toward a multidisciplinary team could be a model for improving overall quality of cancer care in the older patient. There is clearly a need for more research and more involvement in the field of geriatric oncology, including studies that focus on improving therapy for both healthy and frail elderly patients. Such research will allow us to achieve all of our goals in the treatment of older women with breast cancer: maintaining quality of life, avoiding undertreatment, and attaining maximal anticancer objectives, be that cure or palliation.

Dr. Woodruff reports no relevant financial relationships. Dr. Downey is a Pfizer advisory board member and has received research grants for a Pfizer investigator-initiated trial and a Novartis investigator-initiated trial (costs for trial implementation, IRB, data management, not for PI).

Dr. Suh is on the speaker’s bureau for Novartis.

Dr. Woodruff is a Fellow in Geriatrics at the University of Arizona, Tucson, and Dr. Downey is Assistant Professor of Clinical Medicine in the Section of Medical Oncology, with a co-appointment in the Section of Geriatrics, University of Arizona, Tucson. Dr. Suh is Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Staff in the Section of Geriatrics, The Cleveland Clinic, and Medical Director of the Geriatric Assessment Program, Euclid Hospital, Cleveland, OH.