HT AND BREAST CANCER

Putting the WHI report on breast cancer in perspective

By Leon Speroff, MD

A large body of literature suggests that tumors in hormone users are better-differentiated and of lower grade and stage, with better outcomes. The contrary findings from WHI may reflect the older age of the participants and a need to discontinue HT 2 weeks before mammography in women aged 65 and older with dense breasts.

The Women's Health Initiative (WHI) updated report on breast cancer in the canceled estrogen-progestin arm of the clinical trial was based on an average follow-up of 5.6 years with a maximum of 8.6 years.¹ The total number of breast cancers in the 16,608 postmenopausal women in the trial reached 349 invasive and 84 in situ cases as of July 2002. An increase in the treated group began to emerge in the third year (Table 1).

TABLE 1
Invasive breast cancer

Invasive breast cancer was increased, 199 cases in the treated group and 150 in the placebo group; hazard ratio 1.24 (1.01–1.54). However, in situ cancer was only slightly increased (47 cases in the treated group and 37 in the placebo group), a difference that did not achieve statistical significance! Analysis of the invasive breast cancers only in adherent participants, acknowledging the high drop out rate in the study, did not change the results.

The breast cancers in the treated group were slightly larger, with more positive nodes and less localized disease. There were no differences in histology, distribution of estrogen receptor-positive and progesterone receptor-positive cancers, or tumor grade (Table 2).

TABLE 2
Characteristics of the invasive breast cancers

WHI vs. case–control studies

Thus far, this is the best report to emerge from the WHI. It is crisply written, with an appropriate discussion confined to the data. The analysis was completed after central adjudication of the breast cancer diagnoses and took into consideration adherence to therapy. Very effective randomization is apparent in the nearly identical characteristics, including breast cancer risk factors, of the participants comparing the treated group with the placebo group.

The increase in breast cancer was based upon the increase in invasive cases; however, "accounting for the sequential monitoring gives an adjusted 95% CI of 0.97 to 1.59." This adjustment is the Bonferroni correction for multiple analysis. What does it mean when the adjustment causes a loss of statistical significance? Frankly, it is difficult for me to translate this into clinical application. I think Paul McDonough expressed it best when he considered the WHI and said that the statistical results are somewhere between the reported nominal numbers and the reduced numbers after adjustment.² If that is the case, is the conclusion clinically meaningful? Regardless, we have to deal with the fact that the WHI, clinicians, and epidemiologists have decided the results are clinically meaningful.

TABLE 3
Abnormal mammography findings

The WHI detected no differences in the histologic types of breast cancer (about 67% ductal, 11% lobular, and the rest mixed), disagreeing with case–control studies suggesting that estrogen-progestin therapy is associated with mainly an increase in invasive lobular tumors.³ How does this correlate with national statistics that indicate a rise in lobular tumors and an unchanging incidence of ductal cancers?⁴

The results indicate that the tumors are more advanced in stage than previously reported in case– control and cohort studies. The authors point out in their discussion that the results (both the invasive breast cancers and the mammography findings) are consistent with stimulation of growth in established breast cancers (supported by no statistical difference in in situ tumors), but at the same time, a delay in diagnosis. This certainly challenges the idea that hormone users have better outcomes because of earlier detection. The WHI suggests that this disagreement could be because of a difference in mammography use in the observational studies. However, even in studies that have examined tumor characteristics and outcome in users and non-users who used mammography equally, lower stage and grade of disease and a better outcome is seen in hormone users. In addition, a prospective cohort study found little impact of hormone use on mammography specificity.⁵ In contrast to many reports in the literature, the WHI investigators say their results suggest that invasive breast cancers diagnosed in women who use hormone therapy may have a worse prognosis, basing this conclusion on the differences observed in tumor size and spread of disease.

HT and mammography

The mammography findings are very important, suggesting that the greater rate of abnormal mammograms in women treated with estrogen-progestin represents an unwanted and expensive effect of hormone therapy. Nearly 5,000 of the 8,506 women in the treated group were unblinded because of vaginal bleeding. Is it possible that this unblinding introduced diagnostic bias into the mammography findings? The WHI investigators believe this is unlikely because mammography findings were managed by the participants' local clinicians, separately from the WHI study reports. However, what influence is there on interpretation when the patient reports to her clinician that she is experiencing vaginal bleeding? Surely the clinician, knowing the patient is a WHI participant, would conclude that she is receiving hormonal treatment.

Does hormone therapy impair mammographic screening? The literature is mixed on this question. A review of seven studies concluded that six of them indicated decreased mammographic sensitivity in hormone users, with a slight increase in false-positive recalls.⁶ A French study found a lower incidence of interval cancers in nonusers, but a prospective American study concluded that recall rates were essentially the same in hormone users and nonusers, and that hormone therapy rarely causes a diagnostic dilemma.^7,8 Overall, studies have suggested a decrease in mammographic sensitivity with little impact on specificity (false-negative recall rates).

The studies are based on small numbers of interval cancers, and it is uncertain how real or how large this effect is because of the difficulty in controlling for confounding factors (for example, age, age at menopause, and time since menopause). If the effectiveness of breast cancer screening is reduced by postmenopausal hormone therapy, one would expect an adverse impact on breast cancer mortality. Instead, a study that indicated a reduction in mammographic sensitivity also reported smaller, more differentiated (Grade 1) tumors among the users compared with the nonusers,⁹ and most of the studies that have examined breast cancer mortality rates in women who have used postmenopausal hormone therapy have documented improved survival rates.^10-20 Evidence indicates that hormone users develop smaller, better-differentiated (lower-grade) tumors, evidence that is consistent with effects on pre-existing tumors, and that surveillance/detection bias is not the only explanation for better survival.^21-26 Lower-grade tumors are present even when there is no difference in the prevalence of mammography in hormone users versus nonusers, or when the data are adjusted for the method of detection.^17,19,26

An analysis of the breast cancers in our own institution revealed that more tumors in hormone users were detected by screening mammography, but when assessing outcomes in all cancers detected by mammography, hormone users had more ductal in situ tumors, more node-negative cancers, smaller tumors, and less invasive disease; and thus better survival rates.²⁷ By now, it is well-recognized that the participants in the WHI represent an older postmenopausal population (average age 63 and an average of 18 years since menopause). This older population is more likely to have pre-existing occult tumors that would become detectable quickly after hormonal stimulation. Is it possible that the WHI results reflect this older population, which might have occult tumors that are, in fact, larger and more prone to respond to hormonal stimulation than tumors in younger women?

Women with a greater mammographic breast density have a higher risk of breast cancer, and about 25% of women on estrogen-progestin therapy have an increase in their breast density. However, it is not certain that the short-term increase in density with hormone therapy changes an individual's risk of breast cancer. The increase in breast density associated with postmenopausal hormone therapy appears to be a transient, reversible change that is inconsistent with a persistent effect on cellular proliferation. After discontinuing hormone therapy, breast density rapidly decreases.^28-30 In a retrospective analysis, regression of hormone-induced abnormalities was found to occur within 2 weeks of cessation of treatment.³⁰ In the 12 patients who exhibited no change after discontinuing therapy, eight were biopsied after ultrasonography, revealing one cancer and one case of atypical hyperplasia. Bigger and better studies of this approach are needed, but it suggests the following clinical recommendation. The older a postmenopausal patient is, the greater the risk of developing an increase in breast density with hormone therapy. Therefore, there is good reason to recommend discontinuing hormone therapy for 2 weeks prior to mammography in women older than age 65 who have dense breasts. In younger women who are recalled for a suspicious or difficult-to-read mammogram, it would be worthwhile to discontinue hormone treatment for 2 weeks prior to repeat evaluation.

Conclusion

There may be a small increase in breast cancers with estrogen-progestin therapy or the treatment may stimulate growth of pre- existing tumors. I don't believe it is appropriate to discard the large body of literature indicating that tumors in hormone users are better-differentiated, lower-grade and stage disease, with better outcomes. The contrary finding in the WHI may reflect the older age of its participants. The challenge is to identify the reasons for the disagreement between the WHI and the previous literature. It is too simplistic to just accept the WHI because it is a randomized, clinical trial. We have already learned that the WHI has limitations that make it inappropriate to apply its conclusions to all postmenopausal women.

REFERENCES

1. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. The Women's Health Initiative Randomized Trial. JAMA. 2003;289:3243-3253.

2. McDonough PG. The randomized world is not without its imperfections: reflections on the Women's Health Initiative Study. Fertil Steril. 2002;78:951-956.

3. Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of breast cancer. JAMA. 2003;289:3254-3263.

4. Li CI, Anderson BO, Daling JR, et al. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003;289:1421-1424.

5. Carney PA, Miglioretti DL, Yankaskas BC, et al. Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med. 2003;138:168-175.

6. Banks E. Hormone replacement therapy and the sensitivity and specificity of breast cancer screening: a review. J Med Screen. 2001;8:29-34.

7. Seradour B, Esteve J, Heid P, et al. Hormone replacement therapy and screening mammography: analysis of the results in the Bouches du Rhône programme. J Med Screen. 1999;6:99-102.

8. Moy L, Slanetz PJ, Yeh ED, et al. Hormone replacement therapy rarely complicates or alters interpretation on screening mammography: a prospective analysis. Radiology. 2000;217:446. abstract nr 1004.

9. Sendag F, Terek M, Ozsener S, et al. Mammographic density changes during different postmenopausal hormone replacement therapies. Fertil Steril. 2001;76:445-450.

10. Bergkvist L, Adami HO, Persson I, et al. Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. Am J Epidemiol. 1989;130:221-227.

11. Hunt K, Vessey M, McPherson K. Mortality in a cohort of long-term users of hormone replacement therapy: an updated analysis. Br J Obstet Gynaecol. 1990;97:1080-1086.

12. Henderson BE, Paganini-Hill A, Ross RK. Decreased mortality in users of estrogen replacement therapy. Arch Intern Med. 1991;151:75-78.

13. Persson I, Yuen J, Bergkvist L, et al. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy—long-term follow-up of a Swedish cohort. Int J Cancer. 1996;67:327-332.

14. Willis DB, Calle EE, Miracle-McMahill HL, et al. Estrogen replacement therapy and risk of fatal breast cancer in a prospective cohort of postmenopausal women in the United States. Cancer Causes Control. 1996;7:449-457.

15. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. 1997;336:1769-1775.

16. Sellers TA, Mink PJ, Cerhan JR, et al. The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med. 1997;127:973-980.

17. Schairer C, Gail M, Byrne C, et al. Estrogen replacement therapy and breast cancer survival in a large screening study. J Natl Cancer Inst. 1999;91:264-270.

18. Fowble B, Hanlon A, Freedman G, et al. Postmenopausal hormone replacement therapy: effect on diagnosis and outcome in early-stage invasive breast cancer treated with conservative surgery and radiation. J Clin Oncol. 1999;17:1680-1688.

19. Jernstrom H, Frenander J, Ferno M, et al. Hormone replacement therapy before breast cancer diagnosis significantly reduces the overall death rate compared with never-use among 984 breast cancer patients. Br J Cancer. 1999;80:1453-1458.

20. Nanda K, Bastian LA, Schulz K. Hormone replacement therapy and the risk of death from breast cancer: a systematic review. Am J Obstet Gynecol. 2002;186:325-334.

21. Bonnier P, Romain S, Giacalone PL, et al. Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstet Gynecol. 1995;85:11-17.

22. Magnusson C, Holmberg L, Norden T, et al. Prognostic characteristics in breast cancers after hormone replacement therapy. Breast Cancer Res Treat. 1996;38:325-334.

23. Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol. 1998;16:3115-3120.

24. O'Connor IF, Shembekar MV, Shousha S. Breast carcinoma developing in patients on hormone replacement therapy: a histological and immunohistological study. J Clin Pathol. 1998;51:935-938.

25. Salmon RJ, Ansquer Y, Asselain B, et al. Clinical and biological characteristics of breast cancers in post-menopausal women receiving hormone replacement therapy for menopause. Oncol Rep. 1999;6:699-703.

26. Bilimoria MM, Winchester DJ, Sener SF, et al. Estrogen replacement therapy and breast cancer: analysis of age of onset and tumor characteristics. Ann Surg Oncol. 1999;6:200-207.

27. Cheek J, Lacy J, Toth-Fejel S, et al. The impact of hormone replacement therapy on the detection and stage of breast cancer. Arch Surg. 2002;137:1015-1019.

28. Rutter CM, Mandelson MT, Laya MB, et al. Changes in breast density associated with initiation, discontinuation, and continuing use of hormone replacement therapy. JAMA. 2001;285:171-176.

29. Berkowitz JE, Gatewood OM, Goldblum LE, et al. Hormonal replacement therapy: mammographic manifestations. Radiology. 1990;174:199-201.

30. Harvey JA, Pinkerton JV, Herman CR. Short-term cessation of hormone replacement therapy and improvement of mammographic specificity. J Natl Cancer Inst. 1997;89:1623-1625.

Dr. Speroff is Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Ore.

Leon Speroff. Putting the WHI report on breast cancer into perspective.

Contemporary Ob/Gyn

Aug. 1, 2003;48:69-76.