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GYNECOLOGIC ONCOLOGY

Managing Breast Cancer Survivors

Karen Jean Krag, MD

Breast cancer survivors represent a significant proportion of female patients today, and their care is by no means confined to the oncologist. These women continue to present with a full range of complaints to the primary care physician, whose role it is to assess their symptoms for associated cancer recurrence, reinforce adherence to therapy, and emphasize the value of a healthy lifestyle.

Breast cancer, either invasive or non-invasive, will be diagnosed in approximately 250,000 women in the US in 2008.1 As mortality continues to fall due to improvements in screening and treatment, there are now more than 2 million women in this country with a history of breast cancer.2 The clinicians who provide these women with ongoing care need to know the patterns of recurrence and toxicities of therapy. In addition, they must teach patients about the symptoms of recurrence, the importance of compliance with hormonal therapies, the need for continued mammographic surveillance, and the value of weight control and exercise in preventing both new primary and metastatic disease.

RECURRENCE PATTERNS

Estrogen-receptor-positive (ER+) breast cancer can recur years or decades later; in fact, 50% of recurrences manifest more than 5 years after initial treatment.3 Although the highest recurrence risk is within the first 5 years, the risk remains fairly constant from years 5 to 15, depending on the extent of the primary cancer.3 By contrast, estrogen-receptor-negative (ER-) breast cancer has a different natural history.4 The majority of these recurrences manifest within 3 years, and the vast majority within 5 years.4 These women have a much worse prognosis at diagnosis, but are much better off than those with ER+ cancer if they remain cancer-free at 5 years. The ER- tumors comprise 20% to 30% of breast cancers, and are more common in young women and black women.4

Recurrence sites also depend on cell type. Estrogen-receptor-positive breast cancer tends to recur in bone, often as the first and only site of metastatic disease. Estrogen negative cancer often recurs rapidly in visceral organs, and also has a predilection for brain metastases. Tumors positive for the HER2/neu gene can be ER+ or ER-, and account for 15% to 25% of breast cancers. They can be very virulent, often spreading to the brain. Invasive lobular cancers, which are usually ER+ and HER2/neu-, tend to spread on surfaces, and can recur as ascites, pleural effusions, or meningeal disease; they may metastasize to the pelvic organs and mimic ovarian cancer.

As metastases can occur at any time, health care professionals must always consider a history of breast cancer. Although screening with scans and blood tests has proved ineffective, a careful review of systems may warrant bone scanning, targeted blood testing, computed tomography (CT), or magnetic resonance imaging (MRI) of the brain. All women with a history of invasive cancer are at risk for distant recurrence, and metastatic disease must be included in the differential diagnosis of any complaint. Guidelines for follow-up are available through the National Comprehensive Cancer Network (www.nccn.org/default.asp).

Regional recurrences are more likely in women with more advanced disease at initial presentation. Approximately 10% to 20% of women with supraclavicular, axillary, infraclavicular, or chest wall recurrence can be cured with aggressive therapy.5 Therefore, examination of a woman with a history of breast cancer should include careful visual inspection of the skin on the chest wall and palpation of the local nodal groups.

It is difficult at times to examine the irradiated breast for ipsilateral recurrence due to induration at the radiation boost site, but further “tethering” of the skin or late development of nodularity should be investigated. Late ipsilateral recurrence is not known to worsen survival rates, but mastectomy is recommended. The role of breast MRI in monitoring is unclear, but may be useful in women with mammographically occult cancers, extremely dense breasts, or a genetic predisposition.

It is also important to elicit any changes in family history. Although most women with a positive family history are referred for BRCA testing, some patients may have cancers that predated testing, or relatives may develop cancer after the patient was diagnosed.

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PATIENT EDUCATION

Clinicians must also educate survivors about symptoms of recurrence, compliance with hormonal treatment, and the role of diet and exercise. Women should be instructed to call not only about any breast symptoms, but also about other symptoms not associated with recent activities or changes in habit. For example, aches and pains unrelated to physical activity or unusual headaches (especially upon awakening) merit evaluation. Shortness of breath, cough, and changes in appetite should also prompt a call to the physician.

Compliance with hormonal therapy is poor. Initial data from clinical trials suggested a discontinuation rate of less than 10%, but prescription plan data show that at 3 years, only 66% of women are filling their prescriptions, and far fewer take more than 80% of the prescribed dose.6 Those at highest risk for discontinuing medication include the elderly, the young, and women with depression or dementia.6 Directly addressing compliance at each visit is extremely important.

Equally important in terms of education is to emphasize the role of diet and exercise. A diagnosis of breast cancer can provide an opportunity to motivate women to embrace a healthy weight, healthy diet, and moderate exercise. Furthermore, these factors probably influence the likelihood of recurrence.

A study of almost 3,000 breast cancer survivors found that more than 9 met-hours per week of exercise—ie, anything greater than about 3 hours per week of walking, or more strenuous activity for less time—reduced the risk of death from breast cancer by 50%.7 Even walking for 1 hour per week reduced such mortality by 20%.7 Absolute benefits were in the same range as chemotherapy benefits for node-negative patients. Similar benefits were seen when exercise patterns were evaluated in 4,500 women with a history of breast cancer. Again, anything over 1 hour of walking per week reduced the risk of breast cancer mortality by almost 50%. In this study, increasing levels of exercise were associated with increasing benefit. In both studies, other-cause mortality was also prevented, and exercise was beneficial regardless of weight and diet.

The benefit of weight loss or diet is less clear. A diet high in fruits and vegetables does not appear to reduce the risk of recurrence.8 A low-fat diet alone only minimally reduces the recurrence risk overall, but is associated with a 40% risk reduction in the subset of women with ER- cancers.9 It is difficult to assess the benefit of weight loss, but it is clear that obese women have a worse prognosis than lean women.10 All survivors should be counseled about a healthy body mass index and exercise, and those with ER- tumors can be advised to consume a low-fat diet.

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TOXICITIES OF THERAPY

Long-term side effects of chemotherapy are relatively rare, but include a risk of secondary leukemia and decreased cardiac function. The latter group may be at greater risk of secondary cardiac injury, such as viral cardiomyopathy. Women treated with full axillary node dissection, especially if combined with radiation, are at risk for lymphedema; late occurrence warrants referral to physical therapy and evaluation for local recurrence.

However, most toxicities are related to hormonal treatments. For example, tamoxifen increases the risk of clotting, especially in the elderly and obese. As bedrest also significantly increases clot risk, tamoxifen should be temporarily discontinued in women hospitalized for joint replacement or other major surgeries. Tamoxifen also increases the risk of endometrial cancer, postmenopausal bleeding, fibroids, ovarian cysts, and benign polyps. There is no role for routine pelvic ultrasonography or endometrial biopsy, but any vaginal bleeding must be evaluated.

Tamoxifen does have benefits beyond decreasing the risk of breast cancer recurrence or new primary breast tumors, as it improves bone density and lowers cholesterol levels. On the other hand, it can exacerbate vasomotor instability, night sweats, and other menopausal symptoms. Affected patients should be advised to exercise regularly, and to avoid caffeine, alcohol, and stress. Venlafaxine can be helpful for severe effects, but other selective serotonin reuptake inhibitors may decrease the effectiveness of tamoxifen. Gabapentin may be beneficial as well. Hormone therapy would probably negate any tamoxifen benefits; although the estradiol vaginal ring and vaginal tablet have little systemic absorption, nonpharmacologic methods are preferred.

Most women with a history of ER+ breast cancer will be treated with an aromatase inhibitor (AI) such as anastrozole, letrozole, or exemestane. These drugs are more active than tamoxifen in preventing distant, local, and contralateral recurrence, and may be used in sequence or following a course of tamoxifen. As the AIs prevent the conversion of the adrenal hormone androstenedione to estrogen, they are only useful in postmenopausal women whose ovarian estrogen production has ceased. They should be avoided or used with great caution in women with chemotherapy-induced menopause, whose ovarian function may resume. They produce many of the same side effects as tamoxifen, but have no estrogen agonist effect—thereby conferring no clot or endometrial cancer risk, but also no cholesterol or bone mineral density (BMD) benefit. Indeed, as they decrease estrogen levels so dramatically, they actually increase the risk of osteoporosis; of women who are osteopenic when starting an AI, 50% will develop osteoporosis. Guidelines from the American Society of Clinical Oncology suggest annual BMD testing for women taking an AI; if insurance coverage is an issue, this interval can be stretched to 2 years.11 Patients should also be counseled about exercise and vitamin D/calcium supplementation. Vitamin D levels should be checked, as they may be lower in women with breast cancer. Bisphosphonates can prevent AI-induced osteoporosis, and should be initiated if the patient has osteopenia. Raloxifene is best avoided in this situation because it is related to tamoxifen, which is less effective when combined with an AI.

Arthralgia is the main toxicity associated with AIs, occurring in more than 50% of users and often leading to drug discontinuation.12 This primarily affects the hands, but other joints may ache as well. These symptoms generally begin early in the course of treatment and may worsen over time, but may respond to NSAIDs and exercise. Vitamin D supplementation is also under investigation for possible benefits. A brief “drug holiday” may also be useful. If back and hip pain develops, the possibility of recurrent breast cancer should be considered.

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CONCLUSION

With 2% of all adult women having a history of breast cancer, all clinicians must have a thorough understanding of its natural history and treatment effects. Reducing the risk of recurrence through education is also of utmost importance, as health care professionals see survivors on an ongoing basis and can reinforce recommendations about compliance and lifestyle to both reduce recurrence risk and improve overall health.

The author reports no actual or potential conflicts of interest in relation to this article.

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Karen Jean Krag, MD, is Clinical Assistant Professor, Harvard Medical School, and Medical Oncologist, Mass General/North Shore Medical Center Cancer Center, Danvers, MA.

References

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9. Chlebowski RT, Blackburn GL, Thomson CA, et al. Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst. 2006;98(24): 1767–1776.
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12. Burstein HJ. Aromatase inhibitor-associated arthralgia syndrome. Breast. 2007;16(3):223–234.

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