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© 2001 American Society for Clinical Oncology
Too Early to Say That Pregnancy Has an Antitumor Effect on Breast CancerNew York, NY To the Editor:The article by Gelber et al1 in the March 15, 2001, issue of the Journal of Clinical Oncology confirms that subsequent pregnancy in breast cancer survivors does not negatively affect the prognosis of the underlying disease. Indeed, this should be the message we convey to our young patients, whose desire for pregnancy after breast cancer is particularly understandable after they have faced such a dreadful disease.2,3 However, I wish to comment on the authors’ conclusion that the superior survival "may merely reflect a healthy patient selection bias, but is also consistent with an antitumor effect of the pregnancy." While the healthy mother effect is well understood since the publication of a recent countrywide study from Finland,4 the statement that pregnancy has an antitumor effect is at the present time unsupported by available data. Indeed, the authors themselves do not offer any evidence that this may be true. On the contrary, epidemiologic, laboratory, and clinical data support a strong influence of hormones on breast cancer. The role of reproductive history is well known and considered important in risk-assessment models.5 Other epidemiologic variables, such as ethnic differences in breast cancer incidence, may be explained by factors affecting the levels of circulating estrogens.6 Laboratory data indicate that both initiation and promotion of breast cancer are influenced by estrogens7 and that autocrine and paracrine factors are also mediated by estrogens in hormone-sensitive breast cancer.8,9 Oophorectomy reduces the risk of breast cancer in animals and in women,10 and it has been used successfully in the treatment of metastatic breast cancer since the 19th century.11 The efficacy of hormonal manipulations on breast cancer has been demonstrated in the early12 and in the advanced settings13 for hormone receptor–positive breast cancers, and there are at least anecdotal reports even in estrogen receptor–negative cases. Other data in support of an influence of estrogens on breast cancer are more controversial2,3: pregnancy seems to have a dual effect on breast cancer, ie, there may be a transient increase in incidence in the years following a pregnancy, which is later superseded by a long-term protective effect. Whether chemotherapy-induced amenorrhea plays a positive role in the survival of treated patients in the adjuvant setting is highly debated. Whether estrogen replacement therapy has any deleterious effect on established breast cancer is presently being studied. Estriol—the preponderant estrogen in pregnancy—is a weaker estrogen than estradiol, but it is difficult to speculate on why and how this particular estrogen would have a specific antitumor effect. The authors themselves state that "there may be a biologic beneficial effect that is unexplained."1 In conclusion, no antitumor effect of pregnancy has yet been demonstrated, and only a prospective study may shed light on this very important issue. One such study, funded by the Army Breast Cancer Research Program, is ongoing at Memorial Sloan-Kettering Cancer Center in New York, NY, and at other institutions; it has accrued approximately 600 young premenopausal women diagnosed with early breast cancer (J.A. Petrek, verbal communication, April 2001). The aim is to assess and follow all variables related to fertility, including the rate of attempted and achieved pregnancies, as well as their true outcome. For now, it is appropriate to reassure those patients who desire to attempt a natural pregnancy and possibly to caution those who may need to undergo extensive fertility treatments, the effects of which on breast cancer are as yet unknown. Our patients’ autonomy will be best served by admitting to them that we do not yet fully understand why the survival of patients who have a full-term pregnancy after breast cancer seems to be improved. REFERENCES
1.
Gelber S, Coates AS, Goldhirsh A, et al: Effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer. J Clin Oncol 19: 1671-1675, 2001 2. Surbone A, Petrek JA: Childbearing issues in breast carcinoma survivors. Cancer 79: 1271-1278, 1997[Medline] 3. Surbone A, Petrek JA: Pregnancy after breast cancer: The relationship of pregnancy to breast cancer development and progression. Crit Rev Oncol Hematol 27: 169-178, 1998[Medline] 4. Sankila R, Heinavaara S, Hakulinen T: Survival of breast cancer patients after subsequent term pregnancy: "Healthy mother effect." Am J Obstet Gynecol 170: 818-823, 1994[Medline]
5.
Gail MH, Brinton LA, Byar DP, et al: Projecting individual probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81: 1879-1886, 1989 6. Setchell KDR, Zimmer-Nechemias L, Cai J, et al: Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet 350: 23-27, 1997[Medline]
7.
Henderson BE, Ross R, Bernstein L: Estrogens as a cause of human cancer: The Richard and Hinda Rosenthal Foundation award lecture. Cancer Res 48: 246-253, 1988 8. Lippman ME, Dickson RB, Gelmann EP, et al: Growth regulation of human breast carcinoma occurs through regulated growth factor secretion. J Cell Biochem 35: 1-16, 1987[Medline] 9. Osborne CK, Arteaga CL: Autocrine and paracrine growth regulation of breast cancer: Clinical implications. Breast Can Res Treat 15: 3-11, 1990 10. MacMahon B: Reproduction and cancer of the breast. Cancer 71: 3185-3188, 1993[Medline] 11. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment. Lancet 2:104-107, 162-165, 1896 12. Early Breast Cancer Trialist Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339: 71-85, 1992[Medline] 13. Harris JR, Morrow M, Bonadonna G: Cancer of the breast, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles of Oncology (ed 4). Philadelphia, PA, J.B. Lippincott Co, 1993, pp 1264-1332
Response
International Breast Cancer Study Group Statistical Center, Dana-Farber Cancer Institute, Boston, MA In Reply:We thank Dr Surbone for her thoughtful remarks. Two issues that she mentions should be discussed further. One is the methodologic issue that even prospective studies such as the Memorial Sloan-Kettering project will not be able to ascertain the effect of pregnancy on outcome in the absence of a randomized clinical trial framework. Nevertheless, these registry studies, including a prospective study being conducted jointly by the Dana-Farber Cancer Institute and the International Breast Cancer Study Group, will contribute to our understanding of the factors that influence outcome. The second issue is that pregnancy is not only associated with endocrine events. There are several other postulated antitumor effects of pregnancy, including angiogenesis1 and immunolologic2 factors. In addition, there is some evidence of tumor suppression during pregnancy.3 These arguments are controversial, but they should be mentioned within this context for completeness. The important message of our work, as well as that of others, has come through: women who wish to become pregnant following the diagnosis of breast cancer can be reassured. REFERENCES 1. Smith SK: Angiogenesis and implantation. Hum Reprod 6: 59-66, 2000 (suppl) 2. Grasso G, Massai L, Migliaccio P, et al: Plasma anti-viral activity and interferon-gamma production by super-antigen-stimulated lymphocytes during normal human pregnancy. Am J Reprod Immunol 45: 217-225, 2001 3. Zumoff B: Hormonal profiles in women with breast cancer. Obstet Gynecol Clin North Am 21: 751-772, 1994[Medline]
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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