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Tamoxifen for Patients With Estrogen Receptor–Negative Breast Cancer

From the National Cancer Institute, Bethesda, MD.

Address reprint requests to Sandra M. Swain, MD, Cancer Therapeutics Branch, National Naval Medical Center, 8901 Wisconsin Ave, Bldg 8, Rm 5101, Bethesda, MD 20889-5105; email: swains{at}mail.nih.gov

	INTRODUCTION

TOP INTRODUCTION INCIDENCE REFERENCES

 
CLEARLY, THE administration of tamoxifen in the adjuvant setting has resulted in prolonged survival in thousands of women with estrogen receptor (ER)–positive breast cancer.¹ This includes a benefit in not only those women who are node-positive but also node-negative and pre- and postmenopausal. In addition, tamoxifen has been shown to benefit women with ductal carcinoma-in-situ by causing a decrease in invasive and noninvasive breast cancer.² Even earlier in the spectrum of breast cancer, the National Surgical Adjuvant Breast and Bowel Project (NSABP) P1 prevention trial found a reduction in the incidence of ER-positive breast cancer in women at risk of developing breast cancer.³ The question that has been central to practicing physicians has been whether tamoxifen should be given to women who have breast cancer that is ER-negative. There are several different issues to consider. Why would one use tamoxifen in this setting? There are several answers to this question, which include the increased survival from primary breast cancer, the prevention of a contralateral breast cancer, and also the agonist activity on bone and potentially other sites. The first section of this article deals with mechanisms of action in tamoxifen, the second, with whether survival is increased in women with ER-negative tumors, the third, with decreasing contralateral cancers. Finally, there is a discussion of the agonist side effects of tamoxifen that could potentially benefit the patient.

	INCIDENCE

TOP INTRODUCTION INCIDENCE REFERENCES

 
There is a much higher percentage of patients with ER-negative tumors in younger age groups (K.C. Chu, personal communication, April 2001). However, the incidence is much lower in the younger age groups, so the absolute numbers of ER-negative cancers are not large overall. A recent study evaluating the estrogen/progesterone receptor phenotypes has led to the suggestion that breast cancer is two diseases, with early-onset and late-onset variants.⁴ The premenopausal women were more likely to be ER-negative and progesterone receptor (PR)–negative, and the postmenopausal women tended to be ER-positive and PR-positive. These results indicate that the number of women in the ER-negative category is fairly small overall and could be the reason that definitive results are not available regarding the efficacy of tamoxifen.

A subset of patients that is increasing in size with the advent of early detection by screening mammography is the group of patients with tumors less than 1 cm in size. Patients who are ER-positive in this group are usually treated with tamoxifen, on the basis of the NSABP P1 prevention trial for prevention of contralateral breast cancer (CBC).

OUTCOME
An analysis of patients with tumors of 1 cm or smaller with negative nodes was done that combined several NSABP studies.⁵ There were 235 patients with ER-negative tumors and 1,024 with ER-positive tumors. The size of the tumors in the ER-negative population was 6 to 10 mm in 85%, with 60% of the tumors 10 mm in size. The 8-year relapse-free survival rate (second primary cancers and deaths were censored) of women with ER-negative tumors treated with surgery alone was 81%, compared with 90% in those patients treated with chemotherapy and surgery (P = .06). Survival rates were 93% and 91%, respectively (P = .65). Fifty percent of the deaths in these patients were attributed to breast cancer, and 50% were attributed to other causes. The conclusion from this analysis was that the use of chemotherapy and/or tamoxifen should be considered for the treatment of women with ER-negative or ER-positive tumors 1 cm and no axillary lymph node metastases. Other series have reported relapse-free survival rates ranging from 83% to 100% in patients with tumors 1 cm in size with negative nodes.⁵

The National Institute of Health consensus statement from November 2000 concludes that women with tumors of any size and ER-positive status should be given tamoxifen.⁶ It also states that, if tumors are ER-negative, adjuvant chemotherapy should be individualized and tamoxifen treatment should not be given.

TAMOXIFEN: MECHANISM OF ACTION
Tamoxifen is a selective ER modulator that acts as a partial estrogen antagonist in the breast and an agonist in other tissues.⁷ The antagonist activity occurs through inhibition of the ER in breast tissue. Tamoxifen acts as an agonist in humans, as evidenced by the increased incidence of endometrial cancer, the stabilization of bone mineral density, the decrease in total cholesterol, and the increase in incidence of thromboembolic disease.

There are several issues regarding the ER status of tumors. One issue includes quality control and how accurate the measurement of ER is by each laboratory. The immunohistochemical assays must also be done with positive controls, and this is not usually reported. There are data that report a high false-negative rate with immunohistochemistry (IHC).⁸ Unpublished data show that the results of 15% to 20% of IHC analyses performed in the United States and Europe are reported as ER-negative when they are actually ER-positive (C. Allred, personal communication, April 2001). Also, because many of the tumor specimens are very small, the samples may be inadequate to determine ER. Because tumors are heterogeneous and not all breast cancer cells express ER, the positive cells may be missed. A carefully performed study of almost 2,000 patients found that IHC was superior to the ligand-binding assay because of ease of use and, most importantly, its equivalent predictive value for response to adjuvant tamoxifen treatment.⁹ The results of this study found that as few as 1% to 10% of weakly positive cells were adequate to confer an improvement in disease-free and overall survival in women treated with tamoxifen. Therefore, a small number of cells positive for ER may be adequate to predict a response to hormonal therapy, but many laboratories may report the results as negative.

Second, there are currently two known ERs, ER-alpha (ER-) and ER-beta (ER-ß).¹⁰ It has been shown that 4-OH tamoxifen has partial agonist/antagonist activity through ER- but a pure antagonistic effect through ER-ß.¹¹ A small study of 47 unselected invasive breast cancer patients reported the results of the presence of ER- and ER-ß by IHC.¹² Interesting results were obtained Thirty patients (64%) were positive for ER-, and 33 (76%) were positive for ER-ß. Of the 17 ER-–negative cases, eight (47%) were ER-ß–positive. When these cases were tested by biochemical assay for ER, five of eight were positive for ER. A second part of the study was the evaluation of 118 women treated with adjuvant tamoxifen. ER-ß expression of greater than 10% was associated with an increase in survival. Conclusions from these studies are that a high percentage of women were thought to have ER-negative tumors but were positive for ER-ß. Second, the presence of ER-ß was associated with an increase in survival rates in women treated with adjuvant tamoxifen.

Another study also looked at ER- and ER-ß in 92 cases of primary breast cancer by both IHC and mRNA in situ hybridization.¹³ They found that 24% of ER-–negative tumors expressed ER-ß and that 22% of tumors that were negative for both ER- and PR were positive for ER-ß. The tumors that were positive for ER-ß were associated with low histologic grade, negative axillary nodes, and low S-phase fraction, indicating that they may be less aggressive and more responsive to hormonal therapy interventions.

As molecular profiling of tumors becomes more sophisticated, it is probable that tumors will be classified into subtypes, one of which will be their response to treatments such as tamoxifen. Exciting work in this area has evaluated gene expression patterns using cDNA microarrays in patient tumor specimens and has delineated gene expression clusters.¹⁴ These included four groups: ER-positive or luminal-like, ER-negative or basal-like, erbB2-positive, and normal breast. Tumors that were ER-negative were either basal-like or erbB2-positive. These studies are the beginnings of the reclassification of breast cancer more specifically by gene expression patterns.

There are several other hypothetical mechanisms of action of tamoxifen that may not be related to action through the ER on the basis of basic laboratory studies. These include a biologic response activity with a modulation by inhibition of natural killer activity,¹⁵ inhibition of protein kinase C,¹⁶ a decrease in insulin-like growth factor levels,¹⁷ and antiangiogenic activity.¹⁸

It is not out of the question that a tumor that has been reported to be ER-negative is actually ER-positive and/or hormonally responsive. Although there are other mechanisms of action proposed for tamoxifen that might lead to activity, it is unlikely that these are clinically relevant. This is supported by the most recent data from the Overview, which did not show an increase in survival for women whose tumors were ER-negative and treated with tamoxifen.

CLINICAL DATA WITH TAMOXIFEN IN ER-NEGATIVE TUMORS
The 1998 Overview of tamoxifen for early breast cancer included 8,000 women with ER-poor breast tumors, half of whom were treated with tamoxifen.¹ The proportional recurrence reduction with the administration of tamoxifen was 10% (SD, 4%; 2P = .007; 95% confidence interval, 2% to 17%). There was no evidence of a trend toward a benefit with longer tamoxifen treatment. The proportional mortality reduction was 6% (SD, 4%; not significant) with no trend toward an increased benefit with longer duration. There were 2,000 women with ER-poor, PR-poor tumors who had no benefit from tamoxifen in this group (1% [SD, 7%]). There were 602 women with ER-poor, PR-positive tumors. In this group there was a recurrence reduction of 23% (SD, 12%; 2P = .05), and mortality reduction was 9% (SD, 14%; not significant). In women over 50 years of age, there was a 16% (SD, 5%) recurrence reduction and a 12% (SD, 5%) mortality reduction. The proportional reduction in contralateral breast cancer was 29% (SD, 15%). The conclusions from this Overview were that the overall effects of tamoxifen were, at best, small and that this was an issue for further research.

The updated Overview analysis was presented in preliminary form in Oxford in September 2000 and included 12,000 women with ER-negative tumors, half of whom were treated with tamoxifen (R. Peto, personal communication, September 2000). In general, the results did not support a benefit of tamoxifen in women with ER-poor disease. Two trials specifically and prospectively posed the question: does tamoxifen benefit the woman with an ER-negative breast tumor? These trials were NSABP B-23 and Southwest Oncology Group 8897 (Intergroup 102). Neither trial showed a benefit for tamoxifen in this situation, and both were included in the September Overview described above.

NSABP B-23 included 2,008 patients with ER-negative, node-negative tumors randomized either to cyclophosphamide/doxorubicin with tamoxifen or placebo or to cyclophosphamide/methotrexate/fluorouracil with tamoxifen or placebo.¹⁹ There were no differences in relapse-free nor overall survival in women treated with tamoxifen. The 5-year survival rates for both groups were 90%, with similar outcomes in women aged 49 years or younger and women 50 or older. There were 18 contralateral breast cancer patients in the tamoxifen-treated group and 19 in the placebo group. The conclusion was that there was neither benefit nor harm to the addition of tamoxifen. Specifically, premenopausal women did not have a survival decrease with the addition of tamoxifen.

Southwest Oncology Group 8897 compared cyclophosphamide, methotrexate, and fluorouracil to cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen in high-risk, node-negative breast cancer patients.²⁰ In postmenopausal women, the over- all survival rate was 88% in both chemotherapy and chemotherapy-plus-tamoxifen groups. In premenopausal women, there was a significant detriment to survival in the women treated with chemotherapy and tamoxifen compared with chemotherapy alone (89% v 94%, P = .04). These results are similar to those of NSABP B-09, in which survival was decreased in premenopausal women treated with tamoxifen and chemotherapy.²¹

The data available at the current time do not support a survival benefit with the administration of tamoxifen to women with ER-negative breast cancer. If tamoxifen were to be given, it would most likely be to decrease contralateral breast cancer or to incur the beneficial agonistic effects.

TAMOXIFEN AND CONTRALATERAL BREAST CANCER
The most recent Oxford Overview did not have evidence of a significant reduction in CBC with the use of tamoxifen in patients with ER-negative tumors. However, it must be noted that the cases of CBC were small, with approximately 150 cases each in the tamoxifen and the control group. Therefore, it cannot be said conclusively from these worldwide data that tamoxifen does not prevent CBC in women with ER-poor disease.

A review of CBC presented information from 18 trials in which CBC incidence was reported.²² Conclusions from this review include that longer durations of tamoxifen use reduced the incidence of CBC and that the incidence of CBC was greater in node-negative compared with node-positive patients. The hypothesis for the latter conclusion is that patients with node-negative disease had longer follow-up as a result of longer survival and lower recurrence rates.

Specific ER information regarding CBC in women who have primary breast tumors that are ER-negative is sparse. Most of the reported trials do not report the ER status of the first and second primary tumor. Two publications specifically address the ER results of CBC (Table 1).^23,24 The first study evaluated ER by the ligand binding assay. The results in 28 patients indicated high concordance of ER results in the primary tumor with the CBC regardless of whether it was synchronous or metachronous. The two discordant cases were in patients whose primary tumors were ER-negative and contralateral cancers were ER-positive at 34 fmol/mg/protein and 18 fmol/mg/protein. The second study evaluated 28 patients with CBCs with lower levels of concordance of 68% and 78%. This report did not include information as to whether the tumors were ER-positive or ER-negative. Therefore, the ER status of the first primary tumor may not predict the ER status of the CBC. Much more information needs to be evaluated at the current time, both from available databases and from prospective studies, to answer this question.

TAMOXIFEN AS AN AGONIST
Tamoxifen has been shown to decrease total cholesterol and low-density lipoprotein with no change in high-density lipoprotein.²⁶ It is postulated that tamoxifen may reduce the incidence of atherosclerotic heart disease, on the basis of these findings. However, this is not proven at the current time. Also, tamoxifen stabilizes bone density in postmenopausal women.²⁷ This is not the case for premenopausal women, in whom bone density may be decreased.²⁸ It is not recommended that women with a history of breast cancer receive estrogen replacement therapy. Therefore, the potential cardiovascular benefits and positive effects on bone density of tamoxifen in postmenopausal women may make tamoxifen administration a reasonable approach in some patients. However, there are effective treatments, which have proven effects in large numbers of patients, that include the statins and bisphosphonates, which should be the first choices.

DISCUSSION
There are no conclusive data on survival or CBC to support treatment with tamoxifen in women with ER-negative breast cancer. Treatment with tamoxifen in these patients is not recommended at this time. However, there are fewer events in these patients than there are in women with ER-positive disease. Therefore, more data are needed to definitively state that tamoxifen does not benefit women with ER-negative disease.

One caveat is that there are substantial numbers of women who may actually be ER-positive and either have a false-negative result as a result of poor quality control of the assay or the presence of ER-ß that is not detectable by current methods. Therefore, it is imperative to have ER measured by a reputable laboratory.

	REFERENCES

TOP INTRODUCTION INCIDENCE REFERENCES

 
1. Tamoxifen for early breast cancer: An overview of the randomized trials—Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:1451-1467, 1998

2. Fisher B, Dignam J, Wolmark N, et al: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353: 1993-2000, 1999[Medline]

3. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371-1388, 1998[Abstract/Free Full Text]

4. Anderson WF, Chu KC, Chatterjee N, et al: Tumor variants by hormone receptor expression in white patients with node-negative breast cancer from the surveillance, epidemiology, and end results database. J Clin Oncol 19: 18-27, 2001[Abstract/Free Full Text]

5. Fisher B, Dignam J, Tan-Chiu E, et al: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93: 112-120, 2001[Abstract/Free Full Text]

6. Adjuvant Therapy for Breast Cancer. National Institutes of Health Consensus Development Conference Statement, November 1-3, 2000. Available at: http://odp.od.nih.gov/consensus/cons/114/114_intro.htm (accessed April 2001)

7. Jordan VC: Long-term adjuvant tamoxifen therapy for breast cancer. Breast Cancer Res Treat 15: 125-136, 1990[Medline]

8. Rhodes A, Jasani B, Barnes DM, et al: Reliability of immunohistochemical demonstration of estrogen receptors in routine practice: Interlaboratory variance in the sensitivity of detection and evaluation of scoring systems. J Clin Pathol 53: 125-130, 2000[Abstract/Free Full Text]

9. Harvey JM, Clark GM, Osborne CK, et al: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17: 1474-1481, 1999[Abstract/Free Full Text]

10. Elledge RM, Fuqua SAW Estrogen and progesterone receptors, in Harris JR (ed)Diseases of the Breast (ed 2). Philadelphia, PA, Lippincott, Williams & Wilkins, 2000, pp 471-488

11. Barkhem T, Carlsson B, Nilsson Y, et al: Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists. Mol Pharmacol 54: 105-112, 1998[Abstract/Free Full Text]

12. Mann S, Laucirica R, Carlson N, et al: Estrogen receptor beta expression in invasive breast cancer. Hum Pathol 32: 113-118, 2001[Medline]

13. Jarvinen TA, Pelto-Huikko M, Holli K, et al: Estrogen receptor beta is coexpressed with ER alpha and PR and associated with nodal status, grade, and proliferation rate in breast cancer. Am J Pathol 156: 29-35, 2000[Abstract/Free Full Text]

14. Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406: 747-752, 2000[Medline]

15. Berry J, Green BJ, Matheson DS: Modulation of natural killer cell activity by tamoxifen in stage I post-menopausal breast cancer. Eur J Cancer Clin Oncol 23: 517-520, 1987[Medline]

16. Gundimeda U, Chen Z, Gopalakrishna R: Tamoxifen modulates protein kinase C via oxidative stress in estrogen receptor-negative breast cancer cells. J Biol Chem 271: 13504-13514, 1996[Abstract/Free Full Text]

17. Pollak M, Costantino J, Polychronakos C, et al: Effect of tamoxifen on serum insulin-like growth factor-I levels of stage I breast cancer patients. J Natl Cancer Inst 82: 1693-1697, 1990[Abstract/Free Full Text]

18. Gagliardi A, Collins DC: Inhibition of angiogenesis by antiestrogens. Cancer Res 53: 533-535, 1993[Abstract/Free Full Text]

19. Fisher B, Anderson S, Tan-Chiu E, et al: Tamoxifen and chromotherapy for axillary node-negative, estrogen receptor–negative breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 19: 931-942, 2001[Abstract/Free Full Text]

20. Hutchins L, Green S, Ravdin P, et al: CMF versus CAF ± tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: Update of tamoxifen results. Breast Cancer Res Treat 57: 25, 1999 (abstr)

21. Fisher B, Redmond C, Brown A, et al: Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med 305: 1-6, 1981[Abstract]

22. O’Regan R, Jordan VC, Gradishar WJ: Tamoxifen and contralateral breast cancer , in American College of Surgeons Collective Reviews, Elsevier Science Inc, 1999, pp 678-683

23. Hahnel R, rer Nat D, Twaddle E: The relationship between estrogen receptors in primary and secondary breast carcinomas and in sequential primary breast carcinomas. Breast Cancer Res Treat 5: 155-163, 1985[Medline]

24. Gogas J, Markopoulos CH, Skandalakis P, et al: Bilateral breast cancer. Am Surg 59: 733-735, 1993[Medline]

25. Narod SA, Brunet J, Ghadirian P, et al: Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Lancet 356: 1876-1881, 2000[Medline]

26. Love RR, Wiebe DA, Newcomb PA: Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 115: 860-864, 1991

27. Love RR, Mazess RB, Borden HS: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326: 852-856, 1992[Abstract]

28. Powles RJ, Hickish TF, Kanis JA, et al: Effect of tamoxifen on bone density measured by dual-energy x-ray absorptiometer in healthy premenopausal and postmenopausal women. J Clin Oncol 14: 78-84, 1996[Abstract]

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