T h e n e w e ng l a n d j o u r na l o f m e dic i n e This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. An otherwise healthy 53-year-old woman is seen for routine care after completing
treatment several months earlier for stage II estrogen-receptor–positive, HER2-posi-
tive breast cancer. The treatment consisted of lumpectomy, irradiation, adjuvant che-
motherapy (doxorubicin and cyclophosphamide followed by paclitaxel), and trastu-
zumab. Her only current medication is an aromatase inhibitor. She is amenorrheic.
She reports fatigue, hot flashes, arthralgias, and sexual difficulties and is concerned
about the risk of a recurrence. How would you follow this patient, and what would
you recommend for her symptoms?

More than 200,000 women in the United States will receive a diagnosis of invasive From the University of Michigan Compre- breast cancer in 2007.1 Improved screening and increased use of early local–regional dress reprint requests to Dr. Hayes at the treatment (surgery and irradiation) and adjuvant systemic therapy (chemotherapy, University of Michigan Comprehensive antiestrogen treatment, or trastuzumab) have been associated with a marked reduc- Cancer Center, 6312 Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, tion in mortality associated with breast cancer.1 Concerns about recurrence and the or at hayesdf@umich.edu.
long-term complications of therapy in breast-cancer survivors are increasingly com- mon and must be recognized and managed appropriately.2 N Engl J Med 2007;356:2505-13.
Copyright 2007 Massachusetts Medical Society. Referral for Genetic Counseling
A diagnosis of breast cancer is not sufficient reason by itself to perform a genetic
analysis for inherited germ-line mutations in cancer suppressor genes, such as BRCA1 and BRCA2. The risk of carrying such a gene is estimated to be less than 1% in women whose personal or family history does not suggest a high risk of familial cancer syndromes (Table 1).5 Genetic counseling is recommended for affected women who do meet these criteria, and the care of such women is beyond the scope Screening for Recurrence
The risk of recurrence relates directly to the tumor stage (the size of the tumor and
axillary lymph node status) and grade. This risk is clearly reduced by treatment, including surgery, irradiation, and systemic adjuvant therapy. Over 25% of all metas- tases occur more than 5 years after the initial diagnosis, and this percentage may be even higher among women with estrogen-receptor–positive tumors who re- n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org on June 21, 2007 . Copyright 2007 Massachusetts Medical Society. All rights T h e n e w e ng l a n d j o u r na l o f m e dic i n e ceive adjuvant endocrine treatment.6 In asymp- Local–Regional Recurrence tomatic patients, testing for tumor markers, other Screening for local recurrences in women who blood tests, and radiographic imaging are not have had breast-conserving treatment (lumpecto- recommended for routine screening to detect my and, usually, irradiation) is identical to screen- the development of metastatic disease.7 The false ing for new primary cancers in the contralateral positive rates for these tests range from 10 to breast. However, because previous surgery and 50%, resulting in needless and expensive further irradiation may alter breast-imaging findings, evaluation and anxiety on the patient’s part. Two the radiologist should be aware of the patient’s randomized trials showed no survival benefit history in this regard. No special screening (be- from intensive screening for asymptomatic meta- yond history taking and physical examination) is static disease as compared with routine clinical recommended to detect nonbreast regional re- evaluation,8,9 and one of the trials showed a de- currences (in the chest wall or regional lymph creased quality of life in the intensive-screening nodes).
group.9 These trials were conducted before the re- cent advances in diagnosis and treatment of Table 1. Criteria for Referral of a Breast-Cancer Survivor
metastatic breast cancer. However, in the absence for Genetic Counseling.*
of data showing improved survival or quality of life with early detection of metastatic disease, recommendations from professional societies re- main conservative, calling for routine clinic visits History of ovarian cancer, or a first- or second-degree relative with a history of ovarian cancer but not for any specialized testing for metastases in asymptomatic patients (Table 2).7,10-12 A first-degree relative with a history of breast cancer diag- Evaluation is indicated for patients with symp- Two or more first- or second-degree relatives with a history toms or signs suggestive of recurrence (new bone pain, dyspnea, jaundice, or neurologic symptoms), History of bilateral breast cancer or a first- or second- since treatment in these cases often provides sub- degree relative with a history of bilateral breast cancer stantial palliation and modest prolongation of sur- A male relative with a history of breast cancer vival. Patients with HER2-positive breast cancers may be at particularly high risk for brain metas- * The criteria are adapted from the Preventive Services tases, although in asymptomatic patients there is Task Force3 and the National Comprehensive Cancer no role for central nervous system screening.13 Table 2. Recommended Follow-up Care for Breast-Cancer Survivors at Average Risk for Recurrent or New Primary Cancer.*
Recurrent or New Cancer
Factors Associated with Highest Risk
Recommended Screening
* ASCO denotes American Society of Clinical Oncology, NCCN National Comprehensive Cancer Network, and USPHT U.S. Preventive Services Task Force.
† The screening recommendations for breast and ovarian cancer are different for women with an inherited BRCA1 or BRCA2 mutation or other high-risk factors (see Table 1).
n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org on June 21, 2007 . Copyright 2007 Massachusetts Medical Society. All rights Screening for New Primary Cancers
dicated (Table 2). In particular, the false positive rate for transvaginal ultrasonography in asympto- Among women with a personal history of breast matic women taking tamoxifen may be as high cancer, the risk that a tumor will develop in the as 20%, since tamoxifen can cause benign endo- contralateral breast is approximately twice the metrial thickening, polyps, and other abnormali- risk of an initial breast tumor among women ties.23 Abnormal uterine bleeding or pelvic symp- without this history, with an absolute incidence toms do require evaluation in a woman taking of approximately 0.5 to 1% per year.14 Routine tamoxifen.
annual mammographic screening is recommend- ed for early detection of new primary cancers in Common Symptoms Associated
women with a history of breast cancer, yet a popu- with Anticancer Treatments
lation survey showed that only approximately 60% Breast-cancer survivors may have several treat- of such women undergo serial mammography ment-related symptoms and toxicities (Table 3). The use of more sensitive breast-screening hormone-receptor–positive cancers are the result techniques, such as high-resolution ultrasonog- of early menopause (due to chemotherapy-induced raphy or magnetic resonance imaging (MRI), is ovarian failure or surgical or chemical ovarian controversial because they have a lower specific- ablation) or long-term antiestrogenic treatments, ity than conventional mammography, with a high including treatment with the selective estrogen- false positive rate.16 In a recent study, MRI evalu- receptor modulator (SERM) tamoxifen or one of ation of the contralateral breast at the time of the aromatase inhibitors (anastrozole, letrozole, or diagnosis detected second, mammographically exemestane). Aromatase inhibitors are now used occult breast cancers in approximately 3% of pa- at some point in most postmenopausal women tients17; it is not known whether all these can- with hormone-receptor–positive breast cancer.24 cers would have become clinically apparent. At They should not be used in women with function- present, neither MRI nor high-resolution ultraso- ing ovaries, since they may paradoxically increase nography is recommended for routine follow-up ovarian production of estrogen by enhancing the of women who have had breast cancer, unless negative hypothalamic feedback loop.25 they are considered to be at particularly high risk, Both SERMs and aromatase inhibitors inhibit as defined in Table 1.18 Although these techniques estrogen-induced cancer growth, but they have have been used to screen for cancer in the contra- different mechanisms of action and some dis- lateral breast in women whose primary cancer tinct nontumoral effects (Tables 4 and 5). SERMs was not detectable by mammography, there are have tissue-specific estrogenic and antiestrogenic no data indicating that mammography is more activities, whereas aromatase inhibitors block es- likely to miss a second cancer in these women trogen production and are therefore completely than in women whose first cancer was detected antiestrogenic.
The majority of women with breast cancer expe- Breast-cancer survivors who do not have deleteri- rience hot flashes in association with treatment.26 ous mutations in cancer-susceptibility genes do Although estrogen therapy is a highly effective not appear to be at increased treatment-indepen- treatment for hot flashes, it is generally contrain- dent risk for nonmammary cancers.19 Routine dicated in breast-cancer survivors, especially if age-appropriate screening recommendations for the women have estrogen-receptor–positive tu- colon and cervical cancers are applicable.12 Treat- mors.27-29 Randomized trials involving patients ments slightly increase the risks of some cancers, with breast cancer have shown that certain se- including angiosarcomas (after irradiation), mye- lective serotonin-reuptake inhibitors (SSRIs) and loid leukemias (after chemotherapy), and uterine the selective serotonin- and norepinephrine-reup- carcinomas (as a result of the estrogen-agonistic take inhibitor (SSNRI) venlafaxine, as well as the effects of tamoxifen).20-22 However, the incidence anticonvulsant gabapentin, reduce the frequency of these cancers is low (<1% over a period of and severity of hot flashes by approximately 50%.26 5 years), and routine screening for them is not in- One SSRI, paroxetine, may prevent the metabolic n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org on June 21, 2007 . Copyright 2007 Massachusetts Medical Society. All rights T h e n e w e ng l a n d j o u r na l o f m e dic i n e Table 3. Common Symptoms and Problems in Patients after Treatment for Breast Cancer.
Factors Associated
Symptom or Problem
with Highest Risk
Recommended Screening
Recommended Interventions*
Paroxetine (avoid if patient is receiving Dyspareunia due to Chemotherapy-induced meno- History (rule out features suggestive of persistent and progressively more se- NSAIDs Evaluate for Alzheimer’s disease or other Rule out or treat psychiatric or biologic Chemotherapy-induced meno- Bone densitometry before initiation of Adequate intake of calcium (1200–1500 mg n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org on June 21, 2007 . Copyright 2007 Massachusetts Medical Society. All rights Table 3. (Continued.)
Factors Associated
Symptom or Problem
with Highest Risk
Recommended Screening
Recommended Interventions*
Monitor left ventricular function during Appropriate medical management if present Thrombosis (deep vein, Treatment with tamoxifen Appropriate medical management if present * Representative examples of effective interventions are shown; the list is not exhaustive. SSRIs denotes selective serotonin-reuptake inhibitors, SSNRIs selective serotonin- and norepinephrine-reuptake inhibitors, and NSAIDs nonsteroidal antiinflammatory drugs.
† The FDA has not approved these drugs for this indication.
‡ Side effects or complications from these drugs are as follows: SSRIs — sweating, constipation, diarrhea, flatulence, anorexia, insomnia, somnolence, tremor, anxiety, blurred vision, loss of libido; bleeding, hyponatremia (rare), seizure (rare), mania (rare), and suicidal thoughts or behavior (rare); SSNRIs — same as above plus hypertension, hepatitis (rare); gabapentin — peripheral edema, myalgia, dizziness, hyper- activity, nystagmus, somnolence, tremor, mood disorder, fatigue, Stevens–Johnson syndrome (rare), and seizure (rare).
§ Intravaginal estradiol preparations may slightly increase systemic estrogen levels (with concern about increased risk of breast cancer recurrence).
¶ Some authorities recommend 1000 IU of vitamin D daily.
‖ Side effects or complications from bisphosphonate include esophageal irritation or ulcer; myalgias, rash; hypocalcemia, and osteonecrosis activation of tamoxifen and should not be used known popularly as chemobrain or tamoxifen brain.35 Chemotherapy has been associated with a transient decline in cognitive function, but most patients return to the same level as women Sexual dysfunction in breast-cancer survivors may who did not receive chemotherapy.36 The effects result from psychological and body-image factors of endocrine treatments are less well document- related to the diagnosis of breast cancer or its ed, but at least one small study suggests that treatment, including effects of antiestrogen ther- anastrozole causes similar changes.37 Nonhor- apy, such as dyspareunia related to vaginal dry- monal agents used to treat hot flashes, includ- ness. Intravaginal estrogenic preparations and ing the SSRIs, the SSNRIs, and gabapentin, may estradiol vaginal rings are effective in relieving contribute to cognitive difficulties.38,39 These vaginal dryness and associated symptoms, includ- symptoms should not be disregarded without ing dyspareunia and frequent urinary tract in- considering other causes of cognitive impair- fections. Randomized trials in postmenopausal ment, such as Alzheimer’s disease, especially if women without breast cancer who used the es- they occur in an older woman and are severe and trogenic ring have shown marginally increased progressive. Currently, no therapy has been prov- (though still postmenopausal) circulating levels of en effective for cognitive dysfunction, but women estradiol and estrone.31 However, there is indirect should be reassured that therapy-associated cog- evidence of systemic estrogenic effects in these nitive symptoms are rarely progressive. Given the women, which might increase the risk of breast survival benefits of antiestrogen therapy, discon- cancer recurrence.32 Although not strictly contrain- tinuation is not generally recommended for these dicated, use of intravaginal estrogen preparations, symptoms.
especially in women with estrogen-receptor– positive breast cancer who are taking aromatase Miscellaneous Symptoms inhibitors, must be used with caution and after Other common problems among women with a careful discussion of risks and benefits with the history of breast cancer include myalgias and patient. Over-the-counter nonhormonal vaginal arthralgias, depression, fatigue, and weight gain. moisturizers and lubricants appear to be modestly Recommendations for management of these symp- Long-Term Risks of Breast Cancer Treatment
Many patients report cognitive problems after Osteoporosis diagnosis and treatment of breast cancer, espe- Breast-cancer survivors who undergo an early cially during active adjuvant therapy, a condition menopause as a result of therapy or who are tak- n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org on June 21, 2007 . Copyright 2007 Massachusetts Medical Society. All rights T h e n e w e ng l a n d j o u r na l o f m e dic i n e Table 4. Effects of SERMs and Aromatase Inhibitors on Breast Cancer and Breast Tissue.
Clinical Setting
Effects on Breast Tissue
Antiestrogenic, decrease new breast cancers and recur- rent breast cancers, improve survival, palliative Aromatase inhibitors
Antiestrogenic, decrease recurrent breast cancers, Table 5. Effects of SERMs and Aromatase Inhibitors on Nonbreast Tissue.
Aromatase Inhibitors
Estrogenic or anti- Increases vaginal secretions * The effects of SERMs or aromatase inhibitors on depression or cognitive function have not been fully documented.
ing aromatase inhibitors are at increased risk for lished breast cancer. Raloxifene should not be osteoporosis and fractures.24 In contrast, post- substituted for tamoxifen in the adjuvant setting, menopausal women taking tamoxifen have a re- nor should it be used with tamoxifen, given their duced risk of osteoporosis.40 Recommendations similar effects. Moreover, because data from ran- for preventing and treating bone loss in breast- domized trials suggest that the optimal duration cancer survivors are consistent with those for of tamoxifen therapy is 5 years and that longer women without a history of breast cancer (Table use may be associated with an increased risk of 3).41 Measurement of bone mineral density is rec- recurrence,36,43 raloxifene is not recommended ommended annually or biennially for all breast- for women who have previously been treated with cancer survivors and should be performed before tamoxifen for 5 years. Neither should raloxifene the initiation of treatment with an aromatase in- be used in patients being treated with an aroma- tase inhibitor, since a randomized trial has shown Raloxifene, a SERM with pharmacologic prop- that the combination of tamoxifen and an aroma- erties similar to those of tamoxifen, is approved tase inhibitor (anastrozole) was less effective in for the prevention and treatment of osteoporosis reducing breast-cancer–related events than an but is generally not used in women with breast aromatase inhibitor alone.44 cancer. Although raloxifene and tamoxifen have Bisphosphonate therapy should be initiated if similar efficacy in the prevention of breast can- osteoporosis is present, and it should be consid- cer,42 raloxifene has not been shown to be equiv- ered in patents with osteopenia who are taking alent to tamoxifen for the treatment of estab- an aromatase inhibitor, particularly if they have n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org on June 21, 2007 . Copyright 2007 Massachusetts Medical Society. All rights other risk factors for bone loss or evidence of pro- Trastuzumab diminishes cardiac function, as de- gressive bone loss during treatment (Table 3).41 tected by echocardiography or cardiac scintigra- The early results of a randomized trial involving phy, in approximately 5% of patients during treat- women taking an aromatase inhibitor have sug- ment, but only 1% are symptomatic.50,51 Short-term gested that zoledronic acid given every 6 months, follow-up suggests that trastuzumab-induced con- as compared with delayed initiation of the drug, gestive heart failure is often reversible, but data significantly improves bone mineral density and on long-term follow-up — over the course of 5 or decreases biochemical evidence of bone turnover.45 more years — is lacking. No special monitoring However, given the potential adverse effects of is currently recommended after completion of bisphosphonates in patients with cancer, includ- these therapies, but past exposure should be kept ing osteonecrosis of the jaw, more data are need- in mind when one is evaluating a patient for symp- ed before prophylactic intravenous bisphospho- toms that might suggest congestive heart failure.
nate therapy can be routinely recommended in Venous ThromboembolismTamoxifen increases the risk of deep venous throm- bosis and cerebrovascular disease by a factor of Cardiovascular disease is a particular concern in approximately 3.40 A history of these conditions is women with breast cancer. Radiation therapy to a relative contraindication to its use. For women the left chest wall is associated with an increase who do not have such a history, the small absolute of approximately 20 to 30% in the long-term risk increase in thrombosis risk does not justify any of cardiovascular events. However, the reduction particular screening. No studies have investigated in breast-cancer recurrence and mortality due to whether antithrombotic or antiplatelet aggregation radiation therapy outweighs the risk of cardio- agents are effective in reducing the risk. Although vascular toxicity for patients in whom such ther- there are no data to support doing so, it is reason- able to suspend SERM therapy for approximately The risk of cardiovascular disease associated 2 weeks before elective surgery in order to reduce with adjuvant systemic therapies depends on the the risk of postoperative thrombosis.
particular therapy. Early menopause (before 40 years of age) has been associated with an increased risk of cardiovascular disease, raising concern about antiestrogenic therapeutic strategies for Three sets of evidence-based guidelines address- breast cancer.48 Randomized trials have suggest- ing the follow-up of patients with a history of breast ed that tamoxifen, as compared with placebo, may cancer 4,7,10 recommend periodic history taking reduce the risk of cardiovascular events. In con- and physical examination (every 4 to 6 months trast, there is concern that the profound reduction during the first year, then annually if the patient in estrogen levels induced by aromatase inhibi- is no longer receiving therapy), yearly mammo- tors may increase the risk, although early data grams, and education of the patient about symp- from the randomized trials of aromatase inhibi- toms of breast-cancer recurrence and, for patients tors include too few events to generate solid con- taking tamoxifen, signs and symptoms of uter- clusions about cardiovascular risk.24 It is prudent ine cancer. The American Society of Clinical On- for patients to follow standard guidelines for re- cology has also issued guidelines for the detec- ducing cardiovascular risk, such as engaging in tion and management of osteoporosis but not for regular moderate exercise, avoiding tobacco, and monitoring or treatment of patients for other controlling blood pressure and lipid levels.
Congestive heart failure can result from chemo- therapy with anthracyclines or from trastuzumab. The risk of anthracycline-induced congestive heart failure is directly related to the cumulative dose. In addition to preventing and controlling osteo- Even with standard cumulative doses of adjuvant porosis, bisphosphonates may reduce the risk of anthracyclines (e.g., 240 to 360 mg per square recurrent breast cancer. Two randomized trials meter of body-surface area), congestive heart fail- showed that an oral bisphosphonate, clodronate, ure occurs in approximately 0.5 to 1% of patients reduces recurrence rates and may even improve sur- during the first 1 to 5 years after treatment.49 vival, as compared with no bisphosphonate treat- n engl j med 356;24 www.nejm.org june 14, 2007 Downloaded from www.nejm.org on June 21, 2007 . Copyright 2007 Massachusetts Medical Society. All rights T h e n e w e ng l a n d j o u r na l o f m e dic i n e ment, but a third trial did not.53-55 Pending fur- new primary breast cancers, but no specific screen- ther data from trials in progress, the cost of these ing is recommended for occult metastatic disease agents and the possible risk of osteonecrosis of or rare treatment-related cancers in asymptomat- the jaw argue against their routine use in the ab- ic patients. The consequences of premature meno- pause, antiestrogen therapy, and other adjuvant The extended use of adjuvant antiestrogen therapies should be recognized and treated if in- therapy is gaining popularity. At least one ran- dicated, and estrogen therapy avoided. Medica- domized trial demonstrated a reduction in recur- tions, including SSRIs, SSNRIs, and gabapentin, rences when women with estrogen-receptor–posi- may be effective in treating hot flashes (although tive cancers were treated with a 5-year course of they have not been approved by the Food and Drug letrozole after receiving a 5-year course of tamox- Administration for this indication), and SSRIs and ifen, as compared with a 5-year course of tamoxi- SSNRIs may also alleviate depression. Sexual dys- fen alone.56 An extension of this study is examin- function can be addressed through sexual coun- ing the benefits of continuing letrozole for more seling and treatment of vaginal dryness with non- than 5 years. Since these studies involve women hormonal preparations or with cautious use of who, by definition, have a favorable prognosis, estrogen ring preparations, with the recognition the benefits must be weighed against the poten- that there is the potential for slight systemic ab- tial long-term complications of profound estrogen sorption. Bone mineral density should be assessed, adequate intake of calcium and vitamin D and regular weight-bearing exercise encouraged, and bisphosphonate treatment initiated, if indicated.
Supported by Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale.
With increased survival of patients with breast Dr. Hayes reports receiving research funding from Novartis, cancer, more breast-cancer survivors who have Pfizer, AstraZeneca, Wyeth, and GlaxoSmithKline and consult- been treated with surgery, irradiation, and adju- ing fees from Precision Therapeutics, Abraxis, American Biosci- ences, AviaraDx, Cytogen, Monogram Sciences, Siemens Medical vant systemic therapy, like the woman in the vi- Solutions Diagnostics, StemCapture, and Veridex. No other po- gnette, receive follow-up care from a primary care tential conflict of interest relevant to this article was reported.
physician. Annual mammographic screening and I thank Jennifer Griggs, Catherine Van Poznak, Sanjay Saint, Anne Schott, and Thomas Schwenk for their thoughtful reviews physical examination are warranted to screen for and comments during preparation of the manuscript.
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