2301 E D I T O R I A L Pregnancy after Breast Carcinoma The Ultimate Medical Challenge Hervy E. Averette, M.D.1 Ramin Mirhashemi, M.D.1 Frederick L. Moffat, M.D.2 1 Division of Gynecologic Oncology, University of Miami, School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida. 2 Division of Surgical Oncology, University of Miami, School of Medicine, Sylvester Comprehensive Cancer Center, Miami, Florida. he report by Velentgas et al.1 in this issue of Cancer addresses an important issue in the management of premenopausal breast carcinoma survivors. This subgroup of patients frequently has questions and concerns regarding future childbearing, in particular the plausibility of fertility after systemic chemotherapy and the risk of recurrence and overall survival due to pregnancy. The authors in this study concluded that pregnancy after breast carcinoma does not appear to have an adverse effect on survival. In addition, they state that the rate of miscarriages among women who become pregnant after breast carcinoma is higher than expected. It is difficult to ignore the strong body of evidence linking reproductive history to breast carcinoma. The risk of developing breast carcinoma decreases by 25% for each year that menarche is delayed and the relative risk is 0.73 for those women whose natural menopause occurs before age 45 years compared with those women whose natural menopause occurs between the ages of 45–54 years.2 In contrast, multiparity, young age at first pregnancy, and history of breastfeeding all appear to create a protective effect on breast carcinoma risk. In addition, surgical castration (oophorectomy) has been reported to reduce the risk of breast carcinoma in animals and humans.3 Women who undergo oophorectomy before the age of 35 years have a 50% reduction in the risk of breast carcinoma. The common link between these protective factors appears to be the cumulative lifetime exposure to estrogen. This correlation has contributed strongly to the belief that hormonal milieu is a factor for the development and possible progression of breast carcinoma. One of the most profound hormonal changes in a woman’s lifetime is pregnancy. There have been many studies evaluating the prognosis of patients diagnosed with breast carcinoma during pregnancy and when matched for age and stage of disease, patients with breast carcinoma during pregnancy have the same prognosis as nonpregnant patients. The immunologic effects of pregnancy on breast carcinoma also are a topic of discussion. According to data first collected in Utah and T See referenced original article on pages 2424 –32. Address for reprints: Hervy E. Averette, M.D., Division of Gynecologic Oncology, University of Miami, School of Medicine, Sylvester Comprehensive Cancer Center, 1475 N.W. 12th Avenue, D-52, Miami, FL 33136. Received March 5, 1999; accepted March 8, 1999. © 1999 American Cancer Society 2302 CANCER June 1, 1999 / Volume 85 / Number 11 later confirmed in New York, there may be an immunization against breast carcinoma that occurs during pregnancy.4 The “fetal antigen hypothesis” suggests the possibility that breast carcinoma cells and fetal cells share common antigens. During pregnancy, a woman develops a form of isoimmunization that in turn protects her against breast carcinoma.5 This theory may be applicable to patients with a history of breast carcinoma. According to this hypothesis, fetal antigens during pregnancy can elicit a strong memory response from the immune system (primed from previous exposure to breast carcinoma cells), with the generation of a specific cellular and humoral response. As a result, subclinical micrometastases are kept in check by the immune system. The current study by Velentgas et al. is particularly timely because it comes at a time when American women are opting for later childbirth and the incidence of breast carcinoma continues to rise in all age groups. Approximately 25% of women will develop breast carcinoma in their premenopausal years and still may wish to bear children. The concern with subsequent pregnancy after breast carcinoma treatment is that of dormant micrometastases stimulated by gestational systemic hormones. This concern was addressed in a 1994 study from cancer centers in five countries.6 They noted that survival proportionately was better with a longer interval between pregnancy and breast carcinoma diagnosis (up to 4 years). Because the detrimental effect of pregnancy was reported up to 4 years after treatment for breast carcinoma, this study supports the promotional influence of gestational hormones on existent, but subclinical, disease. Although the promotional effect of pregnancy is suggested in this particular study, to our knowledge there are seven published reports implying that subsequent pregnancy after breast carcinoma is safe when corrected for stage of the tumor.7-13 There certainly are some limitations to the current study by Velentgas et al. as well as other published reports. To our knowledge, with the exception of two Scandinavian studies, all the reports regarding this topic are retrospective series with cases retrieved based on memory of the treating physician, review of hospital records, and/or interview with family members. The number of reported pregnancies after breast carcinoma is fairly small when compared with the estimated number of young breast carcinoma survivors who may become pregnant. Furthermore, the potential for selection bias in these retrospective studies is enormous. A form of bias termed “healthy mother effect” may occur because patients who give birth have to survive at least until the delivery and may be more likely to be free of disease at the time of pregnancy. Data regarding how many pregnancies have occurred in breast carcinoma survivors are vague because many result in unrecognized spontaneous abortion or unreported induced abortion. The potential for these biases has been acknowledged appropriately in the study by Velentgas et al. The interval between breast carcinoma diagnosis and pregnancy also is an important factor and needs to be addressed further. It is difficult to analyze the effect that the interval between treatment and pregnancy has on overall prognosis because women who defer pregnancy for many years also are those who have remained disease free for longer periods and in general have less aggressive malignancies and better prognoses. Clark and Reid found that those patients who became pregnant within 6 months of treatment had a 5-year survival rate of 54% compared with a 5-year survival rate of 78% for patients who waited 6 months to 2 years.14 In contrast, Mignot et al. found no statistical difference in outcome between patients who conceived within 6 months of treatment versus those who had conceived later.15 Recurrence rates for breast carcinoma are highest during the first 2 years after treatment; therefore, it may be prudent to defer pregnancy until 2 years after the completion of therapy. Thus, the importance of timing correlates more with the breast carcinoma prognosis than with any other effect that pregnancy may have on prognosis. Another question of interest is whether interrupting the pregnancy will affect prognosis. Clark and Reid noted that those patients who had a therapeutic or spontaneous abortion had lower survival rates when compared with those patients who continued their pregnancy to term.14 However, to our knowledge the majority of reports regarding this topic conclude that abortion appears to have no favorable influence on outcome and should not be recommended, at least for patients with limited (lymph node negative) disease.16 Many patients with Stage I or Stage II breast carcinoma are treated with adjuvant chemotherapy. The complex issue of chemotherapy-induced ovarian failure is another important predicament facing young breast carcinoma survivors. A discussion of this topic is beyond the scope of this editorial, but suffice it to say that the use of alkylating or alkylating-like agents are correlated strongly with premature menopause and poor ovarian function. Velentgas et al. observed a higher rate of spontaneous abortions in their study group compared with a control group of patients without breast carcinoma (24% vs. 18%). Their findings are consistent with the literature in other human malignancies. Mulvihill et al. reported on 40 women who had a total of 59 pregnancies after treatment for Hodgkin lymphoma, the majority of whom had un- 2303 dergone chemotherapy as part of their treatment.17 They noted a significantly higher spontaneous abortion rate compared with the general population. They concluded that this could be due to defects in hormonal factors that normally maintain gestation, presumably secondary to chemotherapy-induced ovarian dysfunction. In their discussion Velentgas et al. point out that the proportion of women who had undergone adjuvant chemotherapy or radiation therapy did not appear to differ among the women who had miscarriages and the women with other pregnancy outcomes.1 However, this does not explain the higher miscarriage rate in their population compared with the general population. Furthermore, they state that . 50% of the women who miscarried after breast carcinoma also delivered at least 1 live-born infant.1 This statement is misleading due to the lack of data clarifying whether the aforementioned group of patients received adjuvant chemotherapy and/or radiation therapy. To understand better the etiology of the higher rate of spontaneous abortions in breast carcinoma survivors, one would need to perform serum studies of hormone levels during the first and second trimesters of pregnancy. Some women, aware of the risk of chemotherapyinduced ovarian failure, have elected to maintain fertility potential via assisted reproductive techniques. The advancements in the field of cryopreservation of patients’ oocytes and donor eggs have provided these patients with new options. However, there is very little known regarding the consequences of hormonal hyperstimulation of in vitro fertilization in breast carcinoma survivors, and further studies need to be done. The ethical questions raised concerning this technology also are significant and are a topic of discussion. We commend the work of Velentgas et al. and their in-depth statistical analysis. Their findings are consistent with those of other groups. The effect of pregnancy on survival after successful treatment of breast carcinoma has been studied by enough investigators and with adequate numbers to allow the formation of reasonable conclusions. First, pregnancy does not appear to affect adversely the prognosis of patients with Stage I or Stage II breast carcinoma. To our knowledge the majority of studies show no difference in the overall and 5-year survival rates of patients who become pregnant after breast carcinoma. In addition, neither the number of pregnancies, termination versus term pregnancies, nor the interval between breast carcinoma treatment and subsequent pregnancy appear to alter patient outcome. Second, the decision to conceive should be based on the prognosis of the particular patient based on tumor type and stage, not on the effect the pregnancy may have on the breast carcinoma. Third, women who are diagnosed with Stage IV disease with a 5-year survival rate of 0 –15% should not consider conception. Patients with Stage III disease should consider deferring pregnancy for at least 5 years after treatment. Finally, patients with recurrent Stage I or Stage II tumors should not contemplate conception because of the intensity of treatment and the poor prognosis associated with their diagnosis. Fourth, the potential for chemotherapy-induced ovarian failure secondary to adjuvant treatment with alkylating agents may lead to infertility. Women with Stage I or Stage II tumors and a good prognosis may be candidates for assisted reproductive techniques, but the consequences of hormonal hyperstimulation may be adverse and need to be studied further. Fifth, there may be a higher rate of spontaneous abortion in breast carcinoma survivors. This observation may be due to the effect of adjuvant chemotherapy and/or radiation therapy on ovarian function. Finally, the decision to conceive after treatment for breast carcinoma is a complicated one. It involves the consideration of many factors, some medically related and others psychologically related. Thorough counseling by a physician, oncology nurses, psychologists, and other patients who have dealt with this issue may be of utmost importance when a breast carcinoma survivor considers pregnancy. REFERENCES 1. Velentgas P, Daling JR, Malone KE, Weiss NS, Williams MA, Self SG, et al. Pregnancy after breast carcinoma: outcomes and influence on mortality. Cancer 1999;85:2424 –32. 2. Harris JR, Morrow M, Bonadonna G. Cancer of the breast. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: principles of oncology. 4th edition. Philadelphia: J.B. Lippincott, 1993:1264 –332. 3. Kelsey JL, Berkowitz GS. Breast cancer epidemiology. Cancer Res 1988;48:5615–23. 4. Janerich DT, Thompson WD, Mineau GP. Maternal pattern of reproduction and risk of breast cancer in daughters: results from the Utah population database. J Natl Cancer Inst 1994;86:1634 –9. 5. Surbone A, Petrek J. Pregnancy after breast cancer. The relationship of pregnancy to breast cancer development and progression. 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