Breast Cancer Survivorship
Paula Rosenblatt, Ikumi Suzuki, Angela DeRidder, and Nilam Patel
The National Cancer Institute (NCI) defines a cancer survivor as the individual from the “time of diagnosis until the end of life” (1). With a 5-year breast cancer survival rate of 90%, issues of survivorship should be discussed at the start of the treatment (2). Issues such as fertility preservation, risk of cardiac toxicity, neuropathy, and lymphedema should be assessed prior to starting surgery, chemotherapy, and radiation therapy as treatment will leave permanent effects. As the National Comprehensive Cancer Network (NCCN) states, surviving cancer can have a large “impact on health, physical and mental states, health behaviors, professional and personal identity, sexuality, and financial standing” of the individual (3). The Institute of Medicine suggests that there should be standards for survivorship care that address prevention of recurrent and new cancer, surveillance of spread, assessment of late effects, intervention for consequences of cancer and its treatment, coordination of care between primary physician and specialists, and development of survivorship plans to delineate these roles, educate, and communicate with the survivor (3). The American Cancer Society (ACS) and the American Society of Clinical Oncology (ASCO) jointly published guidelines based on the previously noted goals and completed a systematic review of the literature to examine the evidence for the practice of survivorship (4). A panel of experts convened to discuss consensus recommendations when evidence-based literature was not available.
Combining the NCCN, ACS, and ASCO guidelines, this chapter reviews breast cancer survivorship as it relates to:
1. Surveillance for breast cancer recurrence
2. Screening for secondary primary cancers
3. Assessment, management, and interventions of physical and psychosocial long-term and late effects including:
Cognitive impairment and fatigue
Distress, depression, anxiety, and sleep disorders
Lymphedema, musculoskeletal health, and bone health
Neuropathy and pain
Infertility, premature menopause, and sexual health
Body image and health promotion
4. Survivorship care planning and coordination
SURVEILLANCE FOR BREAST CANCER RECURRENCE
Recurrence of breast cancer is a major fear for survivors. All breast cancer patients should be educated on symptoms of local, regional, and distant recurrence and encouraged to seek medical attention at any concern. Palpation of new masses, nipple discharge, change in skin and breast contours, axillary/clavicular/cervical lymphadenopathy, localized bone pain, nausea, weight loss, and headaches should prompt full workup. While there are strong recommendations from ASCO against the use of routine laboratory tests, tumor markers, and systemic imaging in patients treated with curative intent, the importance of routine follow-up and physical exams for signs of recurrence cannot be overstated (5).
We recommend breast cancer survivors have a thorough history and physical exam every 3 to 6 months for the first 3 years, every 6 to 12 months for years 4 and 5, and annually after the fifth year (6). While systemic imaging is not recommended in routine breast cancer follow-up, breast-specific imaging remains important for detecting an in-breast recurrence or new primary breast cancer.
After breast conservation surgery, we recommend a mammogram at 4 to 6 months after completion of radiation and then annually unless specific mammographic findings require earlier follow-up (6).
Routine addition of contrast enhanced breast MRI for screening after diagnosis of breast cancer remains controversial and should be based on the risk of second cancer and concerning features (extremely dense breast tissue or occult breast cancer on initial mammography) that would make mammography alone insufficient.
A lifetime risk of breast cancer greater than 20% to 25%, personal or first degree family history of high penetrance deleterious mutation (BRCA mutation/Li–Fraumeni/Cowden syndrome), and history of chest radiation therapy qualifies a patient for MRI surveillance for breast cancer (7).
While official recommendations remain indeterminate for patients with dense breasts and previous abnormal biopsies of atypical ductal hyperplasia/lobular carcinoma in-situ (ADH/LCIS), the use of MRI can be considered as recent data suggests lifetime risk exceeding 30% for ADH (7,8). A discussion of the increased sensitivity of MRI and the high false positive rates needs to occur prior to the test being performed.
SCREENING FOR SECOND PRIMARY CANCER
Routine screening for endometrial cancer with annual gynecologic exams is recommended for postmenopausal patients on selective estrogen-receptor modulators (SERMs) (tamoxifen) (4,10). While in the absence of symptoms routine endometrial imaging or endometrial biopsies are not recommended, new onset bleeding should prompt a complete workup (10).
Enhanced screening for second primaries for patients with hereditary genetic syndromes, such as the hereditary breast and ovarian cancers, Lynch syndrome, Li–Fraumeni, hereditary diffuse gastric cancer, and Cowden syndrome, should be guided by recommendations from the NCCN (11). As previously discussed in Chapter 9, a thorough review of family history and referral for genetic counseling and testing is important for patients with concerning family histories. Extended gene panels using next generation testing now identify medium/intermediate penetrance genes as well. The most appropriate management for many of these genes is still unknown (12).
Myelodysplastic syndrome and leukemia are a known rare sequela of chemotherapy and radiation. Alkylating agents (cyclophosphamide) and topoisomerase targeting drugs (anthracyclines) are the most frequently implicated and are used in many adjuvant breast cancer regimens (13).
A review of over 20,000 patients with early-stage breast cancer treated between 1998 and 2007 found a marrow neoplasm cumulative incidence rate of 0.48% and a rate of 0.54 per 1,000 person years for patients treated with surgery/chemotherapy/radiation as compared to 0.16 for those treated with surgery alone. The hazard ratio for all three modalities was 7.6 (95% CIs [1.6, 35.8]; P = .01). Among patients who developed acute leukemia, two thirds had complex cytogenetics. While the breast cancer stage, race, and tumor characteristics were not significantly different in those who developed marrow neoplasm versus those without, patients with marrow neoplasms were significantly older (13). While there is no recommendation for routine testing with a complete blood count, incidentally discovered cytopenias or symptoms such as infections/fatigue/bruising/bleeding should prompt workup (4).
ASSESSMENT AND MANAGEMENT OF PHYSICAL AND PSYCHOSOCIAL LONG-TERM AND LATE EFFECTS
Anthracyclines, monoclonal antibodies, left breast radiation (especially when the internal mammary lymph nodes are targeted), hormonal therapy with aromatase inhibitors (AIs), and early menopause have been associated with varying degrees of cardiovascular effects and cardiac toxicity (4). Preexisting cardiac disease and risk stratification should be taken into consideration prior to initiating therapies.
Medical management of cardiac toxicities involves prompt referral to cardiology when abnormalities are detected and treatment with beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and lipid lowering agents as appropriate.
ASCO and ACS have no specific long-term follow-up recommendations in the follow-up of asymptomatic breast cancer patients treated with adjuvant chemotherapy. They recommend patients receive education of possible cardiac symptoms, smoking cessation, diet, exercise, and monitoring of periodic lipid levels per the U.S. Preventive Services Task Force recommendations (4).
Chronic/late-onset anthracycline-induced cardiac toxicity presents within a few months to decades after the last dose of chemotherapy and progresses from an asymptomatic cardiomyopathy to overt heart failure. The cause of the cardiac toxicity is still unclear, but the primary mechanism is likely related to oxidative stress and damage to myocytes (14,15).
A study of older breast cancer patients who received anthracycline-based chemotherapy compared to no chemotherapy demonstrated hazard ratios for cardiomyopathy, CHF, and heart disease of 2.48 (95% CIs [2.10, 2.93]), 1.38 (95% CIs [1.25, 1.52]), and 1.35 (95% CIs [1.26, 1.44]), respectively (16).
The strongest risk factor for the development of cardiac toxicity is the lifetime cumulative dose of anthracycline. The risk of cardiac toxicity increases sharply after 400 to 450 mg/m2 for doxorubicin although with substantial individual variation (17).
A baseline pretreatment transthoracic echocardiogram (echo) or multigated acquisition (MUGA) scan should be performed prior to administration of anthracycline-based chemotherapy. In the adjuvant setting, concurrent and posttreatment heart function assessments are not usually necessary in the low-risk patient. However, we often check an echo within 1 year of completion of anthracycline in patients with one or more cardiac risk factors (age >65 years, cumulative doxorubicin dose of 300 mg/m2, underlying cardiovascular disease, and low-normal left ventricular ejection fraction (LVEF) of 50%–54%) (3). Mortality due to anthracycline cardiac toxicity has improved with the use of drugs for heart failure such as ACE inhibitors and beta-blockers.
Dexrazoxane is a chelating agent that has a cardioprotective effect when treating with high-dose anthracyclines (18). However, there is a theoretical risk of decreasing the efficacy of anthracycline treatment with the chelator. Therefore, dexrazoxane is not recommended for breast cancer patients who are undergoing potentially curative/adjuvant treatment with anthracycline-based regimens. For patients with metastatic disease receiving higher cumulative doses of doxorubicin, dexrazoxane should be added after initial doses exceed 300 mg/m2. Routine assessment of ejection fraction should occur after 250 to 300 mg/m2 and again between 400 and 450 mg/m2. Once a dose of 500 mg/m2 is reached, monitoring of ejection fraction should be completed every 50 mg/m2. A decline in ejection fraction of less than the lower limit of normal or the clinical development of heart failure are indications for stopping the chemotherapy. Epirubicin is an anthracycline also used in the treatment of breast cancer with the maximum cumulative dose limit at 900 mg/m2 (18).
HER2 Directed Therapy
As opposed to anthracyclines, the cardiac toxicity of HER2 targeted monoclonal antibodies (trastuzumab and pertuzumab) usually presents as a reversible, dose-independent, asymptomatic decrease in LVEF. It is considered a “Type II” cardiac toxicity as there is a loss of contractility, but no myocyte destruction (19).
Concern regarding trastuzumab’s cardiac toxicity was noted early in its history. A black box warning of cardiac toxicity was placed on the drug after the large phase III trial for metastatic breast cancer found an incidence of heart failure of 27% when combined with anthracycline and 13% when combined with paclitaxel, compared to 8% in patients treated without trastuzumab (20). Follow-up clinical studies that excluded patients with preexisting decreased ejection fraction showed significantly less cardiac toxicity.
In the BCIRG006 adjuvant trial, a sustained subclinical loss of mean LVEF (>10% relative decline) was noted in 18.6% of study participants in the anthracycline/docetaxel/trastuzumab arm, 9.4% in the docetaxel/carboplatin/trastuzumab arm, and 11.2% in the anthracycline/docetaxel arm, while the rate of clinical heart failure was low; 2%, 0.4%, and 0.7%, respectively (21).
A meta-analysis of nearly 12,000 patients receiving trastuzumab showed that the overall incidence of cardiac toxicity resulting in congestive heart failure was 2.5% compared to 0.4% of controls (RR 5.11; P < .00001) (22).
As described in Chapters 5 and 6, pertuzumab is a second monoclonal antibody that targets HER2 and is used in combination with trastuzumab in the neoadjuvant and metastatic setting (25). TRYPHAENA was a phase II neoadjuvant study that evaluated the cardiac safety of this medication. The rate of decreased LVEF ranged from 2.6% to 5.6% and symptomatic congestive heart failure from 0% to 2.7% (25). The nonanthracycline regimen of docetaxel/carboplatin/trastuzumab/pertuzumab had the lowest incidence of cardiac dysfunction with the highest pathologic complete response rate (25).
When used in the neoadjuvant setting, the package insert recommends cardiac monitoring every 6 weeks. If a drop in LVEF to <45% or an absolute decrease of 10 points with a LVEF of 45% to 49% is noted the drug is withheld. Reassessment should occur within 3 weeks and the medications can be resumed when the LVEF >49% (26).
In the metastatic setting, trastuzumab, pertuzumab, and ado-trastuzumab emtansine HER2 targeted agents are utilized for treatment. These drugs can cause asymptomatic declines in the LVEF and rare symptomatic heart failure.
In the metastatic setting, cardiac assessment every 3 months is appropriate with a guideline to hold therapy for ado-trastuzumab, if LVEF falls to less than 40% or if 40% to 45% with more than a 10-point decrease from baseline, while for pertuzumab + trastuzumab, to hold treatment if LVEF is below 45% or 45% to 49% and more than a 10-point drop from baseline (27,28).
Lapatinib, an oral, reversible, tyrosine kinase epidermal growth factor receptor (EGFR) (ERBB1) and HER2 inhibitor, is approved for treatment of advanced breast cancer. A pooled analysis of 3,689 patients enrolled in clinical trials with lapatinib showed low levels of cardiac toxicity for lapatinib; cardiac events were usually asymptomatic reversible declines in LVEF with similar rates for patients who were exposed versus not to anthracyclines or trastuzumab in the past (29). See the summary of cardiac monitoring recommendations for HER2 agents in Box 11.1.
Older radiotherapy techniques for breast cancer involved significant doses of radiation to the heart. A meta-analysis from the Early Breast Cancer Trialists Collaborative Group (EBCTCG) of 40 trials found that while radiotherapy decreased the annual mortality rate from breast cancer, there was significant increase in the annual mortality rate from other causes (21% increase) that was largely attributable to cardiac and vascular events (30). The spectrum of radiation-related cardiac disease includes myocardial damage and coronary artery disease when mediastinal radiation is used (31). SEER Medicare analyses have demonstrated that the risk of cardiac death is not elevated for women treated since 1990 (32). This improvement could be related to improved techniques or possibly decreased targeting of the internal mammary lymph nodes. While current breast radiotherapy doses to the heart are significantly less, there is no entirely safe dose and the effects of radiation to the heart are dose-dependent (33).
Box 11.1 Cardiac Monitoring Recommendations for HER2 Directed Agents
• Pretreatment and serial echo or multigated acquisition (MUGA) study at approximately every 3 month intervals (26).
• Follow cardiac function with the same test and do not switch from MUGA to echo and vice versa in the same patient.
• If the LVEF falls >15 points from baseline or ≥10 points and below the institutional limits of normal, hold HER2 directed therapy for 4 weeks and repeat cardiac imaging.
• If the LVEF returns to normal, HER2 therapy can be reinitiated; otherwise, repeat cardiac imaging in 4 weeks.
• Any symptoms of CHF (increased dyspnea on exertion, edema, weight gain, new murmur) should prompt an immediate evaluation for cardiac toxicity.
• HER2 directed agents are discontinued for the development of clinical heart failure.
• Cardiac toxicity is more frequent and severe when trastuzumab is used in combination with anthracyclines; thus, in practice they are not given concurrently. It is unclear if one potentiates the effects of the other or if each has an independent mechanism (23).
Source: From Ref. (23). Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol. 2008;26(8):1231–1238.
Cognitive Impairment and Fatigue
Seventy-five percent of breast cancer patients report decline of cognitive function during their treatment and 35% report continuing impairment after treatment ends (34–36). The presence of treatable and contributing factors of cognitive impairment such as depression, insomnia, substance abuse, medication effects, and causes of fatigue should be evaluated (3,4). However, often no distinct cause can be identified and the patient is assumed to have cognitive impairment related to treatment.
“Chemo brain” is a lay term given to this phenomenon and it can be a source of fear and anxiety for those patients about to embark on cancer treatment (37). These subtle yet significant effects on cognitive functioning can have a large impact on quality of life (37,38).
Breast cancer patients appear to be particularly susceptible to cognitive deficits for numerous reasons including effects of cancer itself, emotional stress of the diagnosis, and the sequelae of chemotherapy and hormone therapy. Multiple studies have confirmed objective evidence of cognitive decline after chemotherapy (37–39). Analyses using a battery of neuropsychological tests have shown deficits in various cognitive domains including visuospatial ability, executive function, information processing speed, and verbal and visual memory (40,41). Most of these deficits were small to moderate but consistent throughout different studies looking at effects of adjuvant chemotherapy on neurocognitive function. Studies with brain imaging in breast cancer patients who have received chemotherapy show structural changes reflective of treatment effects (42,43). The exact timing and duration of the impairment is still unclear (41). Risk factors for cognitive impairment include older age; cyclophosphamide, methotrexate, and fluorouracil (CMF) regimen; and lower cognitive reserve (44,45).
In addition to cytotoxic agents, breast cancer patients with hormone-receptor-positive breast cancer receive adjuvant hormonal therapy. Tamoxifen has been found to have a negative impact on cognitive function (39). Along the same principles, AIs, which are known to cause estrogen-deprived states, have also been shown to cause mild cognitive impairment when compared to tamoxifen; however, the role of these agents in posttreatment cognitive dysfunction has not been well established (46,47).
As health care providers for breast cancer survivors, understanding the possibility of cognitive dysfunction and its effect on quality of life and function in society is essential.
• The clinical validation that posttreatment cognitive dysfunction is a real entity and reassurance to the patient that the cognitive effects are not progressive and have not been associated with progression to dementia helps ease many patients’ concerns.
• Neuropsychological testing, occupational therapy, and speech therapy has been helpful for some patients in developing coping techniques.
• Encouragement of physical activity, meditation, mindfulness stress reduction, limitation of alcohol, and promotion of good sleep hygiene may benefit cancer-associated cognitive dysfunction (3).
Fatigue is very common in cancer patients treated with radiation and chemotherapy, and some patients experience longer lasting symptoms causing disruptions in quality of life and increased distress. The NCCN defines cancer-related fatigue as the “a distressing persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.” Fatigue can be exacerbated by medications, anemia, nutritional deficiency, thyroid dysfunction, adrenal insufficiency, cardiac or pulmonary dysfunction, pain, deconditioning, depression, and insomnia; these entities should be evaluated based on history (3,4).
DISTRESS, DEPRESSION, ANXIETY, AND SLEEP DISORDERS
Distress is the “multifactorial unpleasant emotional experience of a psychological (ie, cognitive, behavioral, emotional), social, and or spiritual nature that may interfere with the ability to cope effectively with cancer and/or its physical symptoms, and its treatment.” Breast cancer patients may be uniquely susceptible to depression, anxiety, and resultant distress due to decreased estrogen levels secondary to hormone therapy and chemotherapy (48). Estrogen has been shown to have antidepressive effects, and treatment for breast cancer can lead to an estrogen-deprived state (48). It is important to routinely assess breast cancer survivors for distress and mental health disorders and offer appropriate counseling, treatments, and referrals as necessary.
We recommend the use of the distress thermometer, Patient Health Questionnaire-9 or -12, or the General Anxiety Disorder 7 item scale; validated screening tools for distress, depression, and anxiety; these should be implemented regularly. Identification of substance abuse is also important as it can exacerbate any mental illness (49–51). NCCN also recommends screening for panic disorder, posttraumatic stress disorder, and suicidal ideations (3).
In collaboration with their primary care physicians, breast cancer survivors should undergo routine assessments for signs and symptoms of insomnia, depression, anxiety, and distress. For those at higher risk, a more thorough assessment may be needed. To ensure appropriate and timely management, there should be a low threshold to refer these patients to mental health professionals for evaluation and management. Counseling, mindful meditation, hope therapy, and making meaningful interventions have helped many breast cancer survivors (52). Other times, pharmacologic assistance may be needed as well.
Major depressive disorder (MDD) was found to have a prevalence of 22% among breast cancer survivors and only 11.6% in the general cancer population (4). The rate of depression in breast cancer (4.5%–46%) is higher than rates in most other cancer types, behind only oropharyngeal (22%–57%) and pancreatic cancers (33%–50%) (53). In the first year after diagnosis patients are at the highest risk for MDD, especially for younger patients and those who have received chemotherapy (48). These high rates of depression may be due to a multitude of factors including body image issues, physical effects of treatment, loss of sexual function, ongoing fatigue, and perpetual concern about recurrence.
Anxiety rates are also very high in breast cancer patients. One large cohort study found pure anxiety symptoms in 14.7% and mixed anxiety/depression in 10.8% of patients (54). Despite the high rates of depression and anxiety among breast cancer patients, dedicated studies on management of these patients are lacking. Pharmacotherapy and psychotherapy are the mainstay of treatment for mild to moderate depression and anxiety. Studies that included patients with breast cancer have shown selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and mirtazapine to be effective treatment.
Patients should be counseled on the expected side effects and the multiple weeks it takes for SSRIs and SNRIs to become effective. A review of the side effects may be helpful in treating concomitant problems the patient may face (insomnia, appetite issues, pains, hot flashes). Short-term use of benzodiazepines in cases of anxiety may be necessary but long-term use should be limited.
For those taking tamoxifen, the antidepressive medications duloxetine, sertraline, fluvoxamine, paroxetine, fluoxetine, and bupropion may inhibit metabolism of tamoxifen to its active metabolites via the cytochrome P450 2D6 enzymes, leading to a decrease in therapeutic effect of tamoxifen. In this situation, alternative antidepressants should be considered if possible (55).
Sleep disorders are prominent in cancer patients and may contribute to cognitive impairment, fatigue, and depression. Treating contributing factors such as pain, hot flashes, sleep apnea, and activating medications are important steps in addressing sleep disorders. Review of sleep hygiene, exercise times, caffeine consumption, and meditation techniques may help regulate sleep. Cognitive behavior therapy is also recommended. Pharmacologic agents can be used short term, but most recommend limited exposure.
LYMPHEDEMA, MUSCULOSKELETAL PAIN, AND BONE HEALTH
Musculoskeletal symptoms are commonly reported in patients who are undergoing or have undergone treatment for breast cancer. Twenty-five to sixty percent of breast cancer patients experience chronic pain as a result of their treatments (56). Surgery may cause chest wall pain and difficulties in movement of the upper extremity on the side of surgery.