Stroke Risk and Tamoxifen Therapy for Breast Cancer

Objective:

To assess the impact of Tamoxifen treatment for breast cancer on risk of stroke.

Introduction:

The authors conducted a nested case-control study of stroke after breast cancer in view of data from the NSABP B-24 and NSABP P-I trials suggesting an increased risk of stroke in women taking Tamoxifen.

Methods:

This analysis was performed on data for all women treated at a single large health maintenance organization (HMO) in Los Angeles county. The authors identified all first breast cancer cases over a 20-year period and linked these records to hospitalization data for women who possibly had strokes after their breast cancer diagnosis. case patients were members of the same HMO throughout the at-risk period, i.e. between their breast cancer diagnoses and their strokes. Patients with a subsequent primary cancer diagnosis before their stroke diagnoses, and those with thromboembolic disease other than stroke, were excluded. Strokes were confirmed by review of diagnostic information by a vascular neurologist, and other neurologic events were excluded. Strokes were classified as transient ischemie, hemorrhagic, thrombotic, embolie, or unable to classify. Two groups of cases were identified: women who had their stroke after their breast cancer diagnosis, and women who had a stroke before and had another stroke after their breast cancer diagnosis. Control subjects had invasive breast cancer and no pre- breast cancer diagnosis evidence of stroke or other thromboembolic disease. A 2:1 (controlxase) matching system, in which two control subjects were selected at random from all breast cancer patients of similar age and at similar age at the time of their breast cancer diagnosis. Information was collected on breast cancer estrogen and progesterone receptor status, reproductive history, oral contraceptive and hormone replacement therapy use, height and weight, and histories of chemotherapy use, smoking, hypertension, diabetes, and hypercholesterolemia. case patients were compared with their individually matched control subjects using univariate and multivariate conditional logistic regression methods.

Results:

* A total of 11,045 cases of breast cancer were identified, among whom 422 had possible strokes, and 179 of whom met stroke diagnostic criteria. 353 control subjects were matched.

* Almost 90% of case patients and control subjects were aged 50 years or older.

* Ischemie strokes, including transient ischemie attacks, were the most common form of stroke, occurring in 67.6% of case patients.

* Body mass index, smoking status, prevalence of history of hypercholesterolemia, and use of oral contraceptives and hormone replacement therapy, both before and after breast cancer diagnosis, did not differ between case patients and control subjects.

* Pre- and peri-menopausal women had a higher stroke risk than postmenopausal women.

* More case patients than control subjects had a history of hypertension or diabetes requiring medication.

* In a model controlling for known risk factors, Tamoxifen use was not associated with risk of stroke. case patients and control subjects did not differ with regard to dose, duration, or recency of Tamoxifen use.

* Chemotherapy was associated with an increased risk of stroke, but the magnitude of association did not vary between CMF and CAF, the most commonly used regimens. When chemotherapy regimens were considered together, the association with chemotherapy was slightly lower in women who used Tamoxifen than in those who did not.

Conclusions:

In this nested case-control study, the authors found that first stroke after breast cancer was not associated with Tamoxifen use, regardless of cumulative dose, duration, or recency of use at stroke. By contrast, stroke was associated with chemotherapy use and was more common in pre- and perimenopausal woman and in women with a history of medication-treated hypertension or diabetes.

Commentary:

Previously reported Tamoxifen vs. placebo trials for treatment of ductal carcinoma in situ or as primary prevention of breast malignancy have noted a nonstatistically significant increased incidence of strokes. In addition, literature reviews have noted an increased incidence of stroke in users of high-dose oral contraceptives and in a variety of hormone replacement therapy regimens, medications with chemical similarities to the selective estrogen receptor modulator, Tamoxifen. Although this trial is a nested case-control study and not a prospective, double-blinded, randomized comparison, the authors are to be congratulated for collecting the data of breast cancer patients and those who subsequently were diagnosed with strokes from a single HMO that has provided care to a large number of patients over two decades. The known increased incidence of thromboembolic disease associated with Tamoxifen therapy must always be considered when weighing the risks and benefits of Tamoxifen therapy for women with a history of breast cancer or DCIS, or for those seeking primary prevention. The devastating effects of a stroke could substantially outweigh any potential benefit of Tamoxifen for some patients. This analysis strongly supports no association between first stroke after breast cancer and Tamoxifen use. This information has enormous value when counseling breast cancer patients that the risk of thromboembolic disease from Tamoxifen therapy does not include an increased risk of stroke. It has also been noted in other studies that venous occlusions, such as deep vein thromboses, are more common than arterial occlusions, such as pulmonary emboli. Also of interest from this analysis is the observation that use of chemotherapy is associated with an increased incidence of stroke, reminding clinicians that this side effect must be included in the discussion with patients regarding the potential benefits of adjuvant chemotherapy.

Selected references and further reading:

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2. Caine J, Stonelake PS, Rea D, Lip GY. Coagulopathic complications in breast cancer. Cancer 2003;98:1576-86

3. Deitcher SR, Gomes MP. The risk of thromboembolic disease associated with adjuvant hormone therapy for breast cancer: a systematic review. Cancer 2004;101:439-49

4. Duggan C, Marriott K, Edwards R, Cuzick J. Inherited and acquired risk factors for venous thromboembolic disease among women taking Tamoxifen to prevent breast cancer. J Clin Oncol 2003;21:3588- 93

5. Eroglu A, Cam R, Yildiz Z, Akar N. PT G20210A, factors V G1691A, and 1299 His-Arg mutations and Tamoxifen-associated thromboembolism in patients with breast cancer. Thromb Res 2003;111:317-9

6. McDonald CC, Alexander FE, Whyte BW, Forrest AP, Stewart HJ. Cardiac and vascular morbidity in women receiving adjuvant Tamoxifen for breast cancer in a randomized trial. The Scottish Cancer Trials Breast Group. BMJ 1995;11:977-80

7. Meier CR, Jick H. Tamoxifen and risk of idiopathic venous thromboembolism. Br J Clin Pharmacol 1998;45:608-12

8. Peverill RE. Hormone therapy and venous thromboembolism. Best Pract Res Clin Endocrinol Metab 2003;17:149-64

9. Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J. Increased thromboembolic complications with concurrent Tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 1996;14:2731-7

10. Ragaz J, Coldman A. Survival impact of adjuvant Tamoxifen on competing causes of mortality in breast cancer survivors, with analysis of mortality from contralateral breast cancer, cardiovascular events, endometrial cancer, and thromboembolic episodes. J Clin Oncol 1998;16:2018-24

11. Rutqvist LE, Mattsson A. Cardiac and thromboemholic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant Tamoxifen. The Stockholm Breast Cancer Study Group. J Nad Cancer Inst 1993;85:1398-406

Geiger AM, Fischberg GM, Chen W, Bernstein L. JNC/ 2004:96; 1528- 36

Commentary by: Roger Waltzman, MD, St Vincent’s Comprehensive Cancer Center

Copyright CRC Press Dec 2004