Late Breast Cancer Survivorship: Side Effects and Care Recommendations

Abstract

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology, to patients seen in their own clinical practice.

CASE PRESENTATION

Eight years ago, at age 54 years, an otherwise healthy premenopausal woman was diagnosed with clinical T3N0M0, estrogen receptor– and progesterone receptor–positive, human epidermal growth factor receptor 2–negative, Nottingham grade 1 (of 3) invasive ductal carcinoma with 20% Ki67. She received neoadjuvant chemotherapy with 12 doses of once weekly paclitaxel 80 mg/m² followed by four doses of dose-dense (once ever 2 weeks) doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²). Subsequently, she underwent a right-sided simple mastectomy and sentinel lymph node biopsy, which revealed multiple foci of invasive cancer in the breast. The largest tumor focus measured 2.2 cm in maximum dimension, and one of five sentinel nodes contained a micrometastasis (residual tumor burden class-II). She received postmastectomy radiation and ultimately opted for a contralateral mastectomy the following year despite genetic testing that did not reveal a cancer-predisposing genetic mutation. She received 2.5 years of tamoxifen before switching to letrozole because of severe hot flashes. The patient became amenorrheic during and after chemotherapy, and postchemotherapy, her estradiol levels were consistently in the postmenopausal range. At the time of switching to letrozole, her bone mineral density was normal.

Now, after nearly 5 years of letrozole, she is 62 years old, and her only symptoms are mild fatigue and musculoskeletal pain in her hands and lower back. During a routine annual visit to medical oncology for physical examination and assessment of endocrine therapy toxicities, her blood pressure was 150/86, her weight was 82 kg, and her body mass index was 30 kg/m². A review of her medical record reveals that, within the prior year (at her primary care provider's office), she had a normal fasting glucose level, a negative Cologuard test, and the following fasting lipid panel: total cholesterol of 237 mg/dL, HDL of 41 mg/dL, LDL of 175 mg/dL, and triglyceride of 107 mg/dL. Her last pap smear was negative for intraepithelial lesion or malignancy a year ago. Her only medications are letrozole 2.5 mg once daily, 1,000 IU of ergocalciferol once daily, and ibuprofen 400 mg up to three times per day as needed for joint pain. Physical examination does not reveal any abnormalities that are concerning for new or recurrent breast cancer, nor any signs of congestive heart failure.

CHALLENGES IN DIAGNOSIS AND MANAGEMENT

Breast cancer is the most common noncutaneous malignancy in women worldwide.¹ As a result of improvements in early diagnostics and treatment options, more than four out of five patients are alive 10 years after a nonmetastatic invasive breast cancer diagnosis.² There are now nearly 4 million breast cancer survivors in the United States, and this number is projected to be close to 5 million by 2030.³ Multiple population-based studies have identified non–breast cancer–related conditions, especially cardiovascular diseases, as important causes of mortality in breast cancer survivors.^4-7 This may be in part because risk factors for cardiovascular disease, such as hypertension, diabetes, and obesity, are slightly more prevalent among women with breast cancer (even before any oncologic therapy) than among those without breast cancer.⁷ Breast cancer treatments, including cardiotoxic chemotherapies and endocrine therapies, as well as left-sided radiation, can themselves also increase the risk of cardiovascular disease.^8-10 In addition, breast cancer survivors face an elevated risk of osteoporosis, anxiety/depression, and second primary cancers secondary to breast cancer-directed therapy.^11-14 Therefore, optimal health care for breast cancer survivors should not only assess for breast cancer recurrence and address symptoms related to oncologic therapies, but also should include screening and prevention strategies for conditions such as hypertension, diabetes, coronary artery disease, cerebrovascular disease, new nonbreast cancers, osteoporosis, anxiety, and depression (Fig 1).

FIG 1.

Key components of care for breast cancer survivors. CV, cardiovascular; DEXA, dual energy x-ray absorptiometry.

Cardiovascular Risk Factors

Cardiovascular diseases and breast cancer share several common risk factors: obesity, metabolic syndrome, age, diet, and lack of physical activity. In addition, certain breast cancer therapies, including anthracycline-based chemotherapies, anti–human epidermal growth factor receptor 2 therapies, and endocrine therapies, are associated with various cardiovascular toxicities, including asymptomatic left ventricular dysfunction, overt heart failure, hypertension, arrhythmias, myocardial ischemia, valvular disease, thromboembolic disease, pulmonary hypertension, and pericarditis.^9,10 In the companion by Kwan et al¹⁵ to this article, the authors report higher cumulative incidences of hypertension and diabetes, but a lower cumulative incidence of dyslipidemia, in 14,942 breast cancer survivors diagnosed from 2005 to 2013 at Kaiser Permanente Northern California compared with 74,702 matched controls.

The hypertension- and diabetes-related findings of this study are consistent with prior studies showing that these cardiovascular risk factors (and also obesity, which predisposes to these) increase in prevalence after receipt of breast cancer treatment.^16-19 This is important because hypertension and diabetes are potentially modifiable risk factors that could impair both oncologic and cardiovascular outcomes. Hypertension is known to be particularly common among breast cancer survivors of African descent, contributing to racial disparities in morbidity and mortality.^19,20 Although the absolute difference found by Kwan et al¹⁵ in cumulative incidence rates of hypertension between women 2 years after breast cancer and controls was only 2% (10.9% v 8.9%), these incidence rates are not trivial, and underscore the importance of blood pressure monitoring and management in the breast cancer survivors. Furthermore, even this 2% difference could translate into meaningful differences in long-term risk of coronary artery disease, renal disease, and stroke.

Similarly, although the absolute differences in cumulative incidence rates of diabetes found by Kwan et al¹⁵ between cancer survivors and controls were small at various time points (2.1% v 1.7% at 2 years, 4.9% v 4.4% at 5 years, and 9.3% v 8.8% at 10 years), the rates themselves were not low, highlighting the importance of screening for diabetes in cancer survivors. Systemic breast cancer therapies, such as chemotherapy and endocrine therapy, may contribute to the elevated risk of diabetes in breast cancer survivors.^21-23 This is particularly problematic because diabetes mellitus diagnosed before or after a breast cancer diagnosis is linked to poorer overall survival.^24,25

The finding by Kwan et al¹⁵ that breast cancer survivors were less likely to develop dyslipidemia than controls (cumulative incidence 23.7% v 27.0%, respectively at 10 years) was interesting in light of other studies suggesting that certain breast cancer therapies may be associated with adverse effects on lipids; for example, aromatase inhibitor therapy,^26,27 chemotherapy,²⁸ and chemotherapy-induced premature ovarian failure.²⁹ The findings by Kwon et al are encouraging for breast cancer survivors and could in part reflect efforts among survivors to eat healthfully, which may result in a reduction of dietary cholesterol intake.

Obesity influences both breast cancer and cardiovascular outcomes among breast cancer survivors: both excess weight at the time of a breast cancer diagnosis and gaining weight postdiagnosis are associated with increased risks of breast cancer recurrence and death.¹⁷ Patients treated with chemotherapy are more likely to gain weight than patients receiving locoregional therapies only, likely due primarily to sustained reductions in physical activity and resulting metabolic changes.^30,31 This weight gain tends to be sarcopenic obesity, meaning weight gain in the presence of lean tissue loss or absence of lean tissue gain.³⁰ Women also often gain weight while taking 5-10 years of adjuvant endocrine therapy.³² Thus, weight loss interventions, such as that studied in the recently fully accrued BWEL trial, will be important to improve our understanding of optimal survivorship care (ClinicalTrials.gov identifier: NCT02750826).

Survivorship visits, when patients are far enough from the cancer therapies that they are emotionally ready to expand their health focus to other conditions, may be an optimal venue for discussion of the importance of screening for and management of cardiovascular risk factors to reduce the risk of future cardiovascular events and improve survival.^16,33,34 Part of cancer survivorship care should include educating breast cancer survivors, especially prior recipients of anthracycline (which can cause late congestive heart failure³⁵) regarding symptoms of cardiac dysfunction (eg, shortness of breath, orthopnea, chest pain, leg swelling, fatigue, and deteriorating endurance). Such symptoms may require additional cardiac testing such as echocardiogram and cardiac biomarker testing.³⁶ Counseling about healthy lifestyle should include information about the benefits of regular physical activity, resistance training, healthy dietary practices, weight reduction (if overweight), and smoking cessation. The American Cancer Society/American Society of Clinical Oncology (ASCO) breast cancer survivorship guidelines recommend monitoring lipid panel according to the US Preventive Services Task Force (USPSTF) recommendations.³⁷ In addition, the ASCO guidelines for the prevention and monitoring of cardiac dysfunction in survivors of adult cancers recommend regular evaluation and management of cardiovascular risk factors such as smoking, hypertension, diabetes, dyslipidemia, and obesity in patients previously treated with cardiotoxic cancer therapies.³⁶ Unfortunately, limited data are available from randomized trials to demonstrate that screening and aggressive management of cardiovascular risk factors improve long-term cardiac outcomes in breast cancer survivors. Therefore, our current practice is to follow USPSTF guidelines (Table 1) for most survivors, although some survivors may warrant more intensive testing. Additional emphasis shall be given to minority populations, including African Americans, considering cardiovascular risk factors are more prevalent in this groups.

TABLE 1.

Recommendations for Cardiovascular Risk Factor Screening According to US Preventive Services Task Force

Second Primary Cancers

Breast cancer survivors are also at risk of developing subsequent nonbreast primary cancers, including (but not limited to) uterine, colorectal, lung, ovarian, and thyroid carcinomas, as well as sarcoma and nonlymphocytic leukemia.^12,13 The risk of specific nonbreast primaries in breast cancer survivors is related to genetic predisposition, shared risk factors such as obesity, estrogen exposure, and environmental exposure, and oncologic treatment toxicities.^12,13 The ASCO breast cancer guidelines recommend continuing with age-appropriate cancer screening (eg, screening for cervical, colon, and breast cancer) as recommended for the general population.³⁷ Table 2 provides recommendations pertaining to cancer screening for the general population, which we also apply to breast cancer survivors who do not carry a known cancer-predisposing genetic mutation. Routine endometrial ultrasonography and/or biopsy is not recommended. However, women on tamoxifen should have annual gynecologic assessment and careful evaluation of any abnormal uterine bleeding; such symptoms would prompt a more specific workup.⁴⁵ Pathogenic mutation carriers should have additional screening on the basis of the risks based on individual mutation.⁵¹ Knowledge of hereditary cancer is rapidly evolving; therefore, it is essential to periodically update the family history of breast cancer survivors and institute additional interventions as needed.^51,52

TABLE 2.

Recommendations Related to Screening Breast Cancer Survivors for Second Cancers

Osteoporosis

Various breast cancer treatments (eg, aromatase inhibitors, therapeutic ovarian suppression, and chemotherapy-induced early menopause) predispose women to osteopenia and osteoporosis. Therefore, postmenopausal breast cancer survivors are at an elevated risk for clinical fractures.¹¹ Antiresorptive therapies such as bisphosphonates and denosumab can prevent and treat osteoporosis and osteopenia, and bisphosphonate therapy can also reduce risk of breast cancer recurrence.^53,54 Therefore, adjuvant bisphosphonate therapy is often considered for 3-5 years for these postmenopausal women and those receiving ovarian function suppression. After that treatment (as well as earlier in those who do not opt to receive adjuvant bone strengthener despite receipt of bone-thinning aromatase inhibitor and/or ovarian function suppression-based therapy), dual energy x-ray absorptiometry scans every 2 years may help to guide bone-directed therapy.

Other Health Problems

Breast cancer survivors often also suffer other health problems, including fatigue, cognitive impairment, and emotional distress.^37,55 Therefore, the ASCO breast cancer survivorship guidelines recommend screening for these conditions, and this may be particularly important for those at highest risk including those who are very young, those with a history of prior psychiatric illness, and those with fewer financial resources.³⁷

SUGGESTED APPROACHES TO MANAGEMENT

Optimal survivorship care begins at the time of breast cancer diagnosis and ideally includes a strong, communicative partnership between oncology and primary care. After all planned surgery, chemotherapy, and radiation are complete (even if adjuvant endocrine therapy continues), care will eventually fully (or nearly fully) transition from oncology to primary care. This transition may be a multiyear process, depending on risk of recurrence, patient and provider preferences and values, and access and communication issues. Discussions between oncologists and primary care providers with case presentations and continuing education sessions may play a role in facilitating excellent care throughout the survivorship period. In addition, a survivorship care plan summarizing treatment received, future treatment plans (if any), symptoms of recurrence to watch for, and potential future health risks can be helpful to patients. More than 5 years after a breast cancer diagnosis, much of cancer survivorship care is focused on counseling about other health risks including cardiovascular issues, second cancers, and bone thinning. Key components of long-term survivorship care also include discussions about the beneficial impact of physical activity on overall and breast cancer-related mortality,^56,57 body composition, physical function, psychologic outcomes, and quality of life.^57-60 Assessment for and management of hypertension, diabetes, dyslipidemia, and obesity are ideally the purview of primary care, as are age-appropriate screenings for second cancers (eg, colonoscopy, lung cancer screening, and pap smear), but it is important for oncologists who are engaged in the care of long-term survivors to also be familiar with (and able to discuss) relevant national guidelines including from USPSTF. Mutation-specific prophylactic interventions and screenings should be offered to patients who carry a pathogenic germline mutation.⁵¹

CLINICAL CHOICES

In the aforementioned clinical scenario, a portion of the patient's visit was spent discussing the pros and cons of extended adjuvant endocrine therapy. She ultimately decided to stop her letrozole and transition her care entirely to her primary care provider. A dual energy x-ray absorptiometry scan was ordered for the following year, and she was encouraged to discuss the possible initiation of antihypertensive medication with her primary care provider. In addition, her medical oncologist explained the importance of following recommendations for diabetes screening, cholesterol monitoring and management, and weight reduction. She had no symptoms of congestive heart failure; so, no echocardiogram was ordered (given that neither the National Comprehensive Cancer Network nor ASCO recommends late echocardiography in asymptomatic patients after receipt of a cumulative dose of 240 mg/m² of doxorubicin).^37,52 However, she was encouraged to increase her aerobic activity to at least 150 minutes per week and to incorporate strength or resistance training two or three times per week. A healthy diet was discussed, including a recommendation to eat more fresh fruits, vegetables, and unrefined carbohydrates, and to minimize refined carbohydrates, saturated fat, and red meats.^37,52 She was offered referrals to both nutrition and exercise physiology. Although her cervical cancer screening will end at age 65 years, she was advised to continue colon cancer screening, for which she prefers to use Cologuard, a DNA-based colorectal cancer screening test, every 3 years. Her oncologist sent a note to her primary care provider to summarize her prior oncologic treatments, future health risks, recommendations for care, and plan for full transition of survivorship care to her primary care physician going forward. No additional routine visits were planned in medical oncology after this visit; however, this patient was encouraged to return to medical oncologist if symptoms or signs of recurrent breast cancer developed in the future.

AUTHOR CONTRIBUTIONS

Conception and design: Elizabeth J. Cathcart-Rake, Kathryn J. Ruddy

Data analysis and interpretation: Nusrat Jahan

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Late Breast Cancer Survivorship: Side Effects and Care Recommendations

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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