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Tamoxifen as Systemic Treatment of Advanced Breast Cancer during Pregnancy—Case Report and Literature Review
Gynecologic Oncology 80, 405– 408 (2001) doi:10.1006/gyno.2000.6080, available online at http://www.idealibrary.com on
CASE REPORT Tamoxifen as Systemic Treatment of Advanced Breast Cancer during Pregnancy—Case Report and Literature Review R. J. Isaacs,* W. Hunter,† and K. Clark‡ *Department of Medical Oncology, †Department of Pediatrics, and ‡Department of Obstetrics and Gynecology, Palmerston North Hospital, Palmerston North, New Zealand Received July 31, 2000; published online January 31, 2001
CASE HISTORY
Background. When patients with metastatic breast cancer become pregnant, management is complicated by the potential harms of drug treatment to the fetus and by the potential effects of the pregnancy on the cancer. Chemotherapy is considered optimal systemic anti-cancer therapy from the second trimester, while tamoxifen has been considered inappropriate due to concerns over possible teratogenesis and lack of efficacy. Case. We report a patient who became pregnant concurrent with the identification of metastatic breast cancer and who elected to continue her pregnancy with tamoxifen as sole systemic anticancer therapy. The pregnancy was difficult, but a normal child was delivered and the mother responded to subsequent hormone manipulation. The putative teratogenic effects of tamoxifen and the mechanisms underlying tamoxifen resistance in this setting are discussed. Conclusions. The use of tamoxifen in pregnancy is complex, but is not necessarily associated with fetal harm and may be considered a therapeutic option in selected cases. © 2001 Academic Press
INTRODUCTION
A 38-year-old woman (JA) presented with a right breast lump in 1996, managed surgically by wide local excision and axillary dissection, with histology showing a 3-cm, grade II infiltrating ductal carcinoma with 1/16 nodes involved by metastatic carcinoma. The tumor was estrogen receptor positive (90% of cells strongly positive) and progesterone receptor negative, with no c-erbB2 amplification. JA received four cycles of adjuvant chemotherapy with 60 mg/m 2 of doxorubicin and 600 mg/m 2 of cyclophosphamide, followed by radiotherapy to the right breast only (50 Gy in 25 fractions with a 10 ␥-Gy electron boost to the tumor in 5 fractions). Adjuvant tamoxifen was also recommended, but declined by the patient. In March 1998, JA represented with a short history of mid-back and rib pain. CT scan confirmed widespread lytic bone metastases and multiple small pulmonary metastases, including three 1.5-cm pulmonary metastases at the left base, as well as a small left pleural effusion. CXR demonstrated the left basal metastases and effusion. JA was treated with radiotherapy to T10 –L1, where there was marked lytic disease, receiving 20 Gy in five fractions, and she was commenced on 20 mg of tamoxifen daily. Her back pain improved, but 2 weeks later JA represented with a progressive history of morning nausea and vomiting, with pregnancy confirmed by HCG levels and ultrasound showed a viable 8-week fetus. Extensive discussions over potential management options were held. JA was extremely reluctant to consider chemotherapy at this stage and elected to continue her pregnancy with tamoxifen as sole systemic anti-cancer treatment. Staging CT scan of the chest was repeated with pelvic shielding 5 weeks after tamoxifen was begun, showing an objective partial response in the lung metastases on bidimensional measurements, with no significant change in the lytic bone lesions after this short interval. CXR at 14 weeks gesta-
A case is presented of a 38-year-old woman who became pregnant concurrent with the identification of metastatic breast cancer and who was subsequently managed with tamoxifen as sole systemic anti-cancer therapy during pregnancy. The cancer was stable until the third trimester when there was disease progression, but a normal baby was delivered at 31 weeks gestation and the child has achieved normal growth and development milestones to 2 years of age, while the mother survived for 23 months after delivery. This case raises important questions about the implications of using tamoxifen for advanced breast cancer during pregnancy. These issues are discussed and the relevant literature is reviewed. 405
0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
406
ISAACS, HUNTER, AND CLARK
tion (14/40) was again normal, indicating a maintained response. Amniocentesis at 16/40 revealed a normal fetal karyotype. Serial ultrasound scans throughout the pregnancy were normal. JA elected to continue with her pregnancy and remained well until 25/40 when she developed progressive lethargy, bone pain, and weight loss, associated with a partial fourth right lumbar nerve root weakness and an incomplete right facial nerve palsy. JA was delivered at 31/40 by lower segment cesarean section due to her deteriorating performance status. During the procedure no palpable liver, nodal, or other intraperitoneal metastases were detected. Tubal ligation was performed, but the ovaries were left in situ. A healthy male fetus weighing 1940 g (75th centile) was delivered from a breech presentation with Apgar scores of 8/10 at 1 min and 10/10 at 5 min. Preauricular skin tags were present, with no other malformations apparent. The baby required treatment for moderate hyaline membrane disease with nasal CPAP from Day 2 until Day 6 of life, with a maximum oxygen requirement of 50% FiO 2. On Day 8 a presumptive diagnosis of necrotizing enterocolitis was made, but the baby recovered rapidly with antibiotics and total parenteral nutrition. The baby tolerated oral feeds from Day 19, with supplemental iron initially, but was well enough to be discharged on Day 42 weighing 2840 g. At 24 months of age the baby remains well, physical examination is normal, and his developmental progress is normal for his corrected age. Three weeks postpartum JA remained unwell with lethargy, weight loss, and bone pain. Repeat CT scan confirmed marked progression of lytic bone metastases from the scan at 13/40, along with minimal progression of pulmonary metastases. CA 15-3 was mildly elevated at 81.6 IU/L (normal ⬍35). JA received palliative radiotherapy to the right hemipelvis and elected to proceed with a therapeutic trial of 160 mg/day of Megostat with 90 mg of IV Pamidronate monthly. She responded symptomatically, with resolution of her right leg weakness and facial nerve palsy, while CA 15-3 levels normalized and there was sclerosis of the nonirradiated bone metastases on plain X-ray. JA remained well until 15 months after delivery, when her disease progressed in bone and pleura. Her disease then sequentially failed to respond to an LHRH analog, anthracycline-based and then taxane chemotherapy, and she died 23 months after delivery. DISCUSSION The case reported here is the first, to our knowledge, of a successful pregnancy while the mother has continued to take tamoxifen as sole systemic therapy for metastatic breast cancer throughout pregnancy, with the child at 2 years of age showing no adverse effects of pregnancy-long exposure to tamoxifen. Management of this patient required identification of risks not only to the mother, but also to the child from both the metastatic breast cancer and its treatment. There is limited
published information on these issues, particularly on the risks of tamoxifen during pregnancy. Relevant publications and the implications of this case are discussed below. The Risks to the Pregnant Mother from Metastatic Breast Cancer It had previously been held that breast cancer diagnosed in pregnancy carried a worse prognosis, but this appears to relate primarily to the diagnosis of more advanced disease [1]. When pregnant patients with breast cancer are matched for age and stage with nonpregnant patients, survival is similar [2, 3], indicating that the pregnancy itself does not compromise prognosis. The Risks to the Fetus from Metastatic Breast Cancer Certain malignancies including melanoma, lymphoma, leukemia, and hepatocellular carcinoma have been described as rarely metastasizing to the fetus [4]. There have been occasional reports of placental metastasis with breast cancer [4], but no reports of fetal involvement with this malignancy [5]. The Risks to the Fetus from Breast Cancer Treatment Following the positive results not only of the Overview studies of tamoxifen use as adjuvant treatment of young women [6], but also of the NSABP-P1 study in breast cancer prevention [7], an increasing number of premenopausal women, some of whom may have metastatic disease, are likely to be taking tamoxifen when they become pregnant. The use of tamoxifen during pregnancy has previously been discouraged owing to concerns about potential teratogenic effects and the risks of disease progression [1, 8]. The case for induction of teratogenesis by tamoxifen, however, mainly relies on indirect evidence from animal work [9 –12], with only anecdotal reports of abnormalities in humans. Epithelial changes similar to those seen with diethylstilbestrol have been reported in mice exposed to tamoxifen in the neonatal period [10]. Stilbestrol teratogenicity in humans occurs predominantly in female offspring with an increased incidence of genital tract abnormalities, including delayed malignancy, while in males with prenatal exposure to exogenous estrogens no significant increase in either urogenital tract abnormalities or malignancy has been reported [13]. Other rodent studies have described a condition called “kinky ribs” on exposure to tamoxifen [12], while some have suggested a link to intrauterine growth retardation [11]. The effects of tamoxifen on aspects of development, however, appear to be species-specific [14]. Direct evidence for teratogenesis in humans is very limited, with only isolated reports of rare forms of fetal abnormality associated with tamoxifen use [15, 16], in which no causal link has been established. In view both of the paucity of evidence demonstrating significant risk from tamoxifen and of the early evidence of clinical response, JA elected to continue with this drug as her sole anti-cancer medication.
407
CASE REPORT
JA elected not to proceed with chemotherapy during the first trimester, as this form of treatment has been associated with teratogenic effects [17], particularly when anti-metabolites such as methotrexate are used [3]. From the second trimester on, however, chemotherapy is generally advised as optimal systemic therapy for pregnant women with breast cancer [3, 8, 18]. Chemotherapy does not appear to significantly increase the risks of fetal malformation at this stage of pregnancy [3], although some studies report a higher rate of fetal loss, growth retardation, and premature birth [19, 20]. A recent study of 24 patients treated after the second trimester with fluorouracil (1000 mg/m 2), doxorubicin (50 mg/m 2), and cyclophosphamide (500 mg/m 2) demonstrated an average gestational age of 38 weeks, with normal Apgar scores, birthweights, and immediate postpartum health in all cases [18]. Nevertheless, JA remained reluctant to consider chemotherapy throughout her pregnancy. Radiotherapy can cause fetal loss [15], with doses of ⬎0.1 Gy to the fetus being associated with various detrimental effects [21]. Assessment of the radiotherapy fields used for JA indicated that the fetus was exposed to 0.17 Gy and fortunately at 2 years of age the child continues to show no evidence of toxicity. Pregnancy had not been diagnosed at the time of treatment in this case, but ideally radiotherapy should be given with caution and special shielding used to minimize the dose to the fetus [21]. Radiological monitoring of disease activity is also difficult in pregnancy owing to concerns over radiation exposure to the fetus. While magnetic resonance imaging appears to be safe in pregnancy [22, 23] and may have enabled earlier treatment of progressive disease, this modality was not readily available for our patient at the time of this pregnancy. Potential Mechanisms for Disease Progression during the Third Trimester This woman’s cancer showed initial evidence of response to tamoxifen and the disease appeared to remain static until the third trimester, when it progressed both symptomatically and on blood testing. While estriol levels increase during pregnancy, suggesting that the estrogen receptors (ERs) may have been saturated in the third trimester to account for disease progression, tamoxifen has been shown to be as effective in premenopausal women, with their much higher estrogen levels, as in postmenopausal women [6]. This suggests that it is the high receptor affinity of the 4-hydroxy metabolite of tamoxifen, rather than the concentration of hormone or drug, which defines response in this setting. An alternative explanation for disease progression may be the ratio of ER isoforms. Recently two forms of ER, -␣ and -, have been identified. Regulation of expression of these subtypes is apparently independent [24], with protein levels of ER- increased in tamoxifen resistance [25]. Overall ER expression appears to be down-regulated in early pregnancy and
does not appear to increase until term, when the ratio of ER- to ER-␣ appears to increase dramatically in human uterine smooth muscle [26]. While ER expression in breast cancer cells during pregnancy has not been reported, if similar changes were induced by the physiological changes of pregnancy they might then contribute to the functional tamoxifen resistance seen in this case. CONCLUSIONS This case illustrates the difficulties of managing the pregnant woman with advanced breast cancer. While chemotherapy remains the preferred systemic treatment option from the second trimester, tamoxifen may stabilize hormone-responsive disease until the fetus is viable in women with estrogenreceptor-positive tumors who are reluctant to consider cytotoxic chemotherapy. Furthermore, this case demonstrates that tamoxifen exposure throughout pregnancy is not necessarily associated with significant fetal abnormality. The survival of the mother also did not appear to have been compromised by the use of tamoxifen during pregnancy, as she achieved the median survival of women with bone-predominant metastatic breast cancer. Indeed, her disease later proved to be resistant to chemotherapy following a further response to hormonal manipulation. ACKNOWLEDGMENTS We thank Professor Adrian Harris and Dr. Lisa Williams for their critical review of the manuscript.
REFERENCES 1. Harris J, Morrow M, Norton L. Malignant tumors of the breast. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and practice of oncology, 5th ed, vol 2. Philadelphia–New York, Lippincott–Raven, 1997; 1557– 616. 2. Petrek JA. Breast cancer during pregnancy. Cancer 74(1 suppl): 1994; 518 –27. 3. Shapiro CL, Mayer RJ. Breast cancer during pregnancy. Adv Oncol 1992;8(3):25–9. 4. Dildy GAd, Moise KJ Jr, Carpenter RJ, Jr, Klima T. Maternal malignancy metastatic to the products of conception: a review. Obstet Gynecol Surv 1989;44(7):535– 40. 5. Dipaola RS, Goodin S, Ratzell M, Florczyk M, Karp G, Ravikumar TS. Chemotherapy for metastatic melanoma during pregnancy. Gynecol Oncol 1997;66(3):526 –30. 6. Group EBCTC. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451– 67. 7. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90(18):1371– 88. 8. Jordan VC. The role of tamoxifen in the treatment and prevention of breast cancer. Curr Probl Cancer 1992;16(3):129 –76. 9. Hilakivi-Clarke L, Cho E, Onojafe I, Liao J, Clarke R. Maternal exposure
408
10. 11.
12.
13.
14.
15.
16. 17.
ISAACS, HUNTER, AND CLARK
to tamoxifen during pregnancy increases carcinogen-induced mammary tumorigenesis among female rat offspring. Clin Cancer Res 2000;6: 305– 8. Sweet DL Jr, Kinzie J. Consequences of radiotherapy and antineoplastic therapy for the fetus. J Reprod Med 1976;17(4):241– 6. Sadek S, Bell SC. The effects of the antihormones RU486 and tamoxifen on fetoplacental development and placental bed vascularisation in the rat: a model for intrauterine fetal growth retardation. Br J Obstet Gynaecol 1996;103(7):630 – 41. Furr BJ, Valcaccia B, Challis JR. The effects of Nolvadex (tamoxifen citrate; ICI 46,474) on pregnancy in rabbits. J Reprod Fertil 1976;48(2): 367–9. Mittendorf R. Teratogen update: carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero. Teratology 1995; 51(6):435– 45. Halakivi-Clarke L, Cho E, Onojafe I, Liao DJ, Clarke R. Maternal exposure to tamoxifen during pregnancy increases carcinogen-induced mammary tumorigenesis among female rat offspring. Clin Cancer Res 2000; 6(1):305– 8. Cullins SL, Pridjian G, Sutherland CM. Goldenhar’s syndrome associated with tamoxifen given to the mother during gestation [letter]. JAMA 1994;271(24):1905– 6. Tewari K, Bonebrake RG, Asrat T, Shanberg AM. Ambiguous genitalia in infant exposed to tamoxifen in utero [letter]. Lancet 350(9072):183, 1997. Buekers TE, Lallas TA. Chemotherapy in pregnancy. Obstet Gynecol Clin North Am 1998;25(2):323–9.
18. Berry DL, Theriault RL, Holmes FA, Paris VM, Booser DJ, Singletary SE, Buzdar, AU, Hortobagyi GN. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999;17(3): 855– 61. 19. Willemse PH, van der Sijde R, Sleijfer DT. Combination chemotherapy and radiation for stage IV breast cancer during pregnancy. Gynecol Oncol 1990;36(2):281– 4. 20. Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Burke B, Sutcliffe SB, Koren G. Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 1992;166(3):781–7. 21. Mayr NA, Wen BC, Saw CB. Radiation therapy during pregnancy. Obstet Gynecol Clin North Am 1998;25(2):301–21. 22. Kanal E. Pregnancy and the safety of magnetic resonance imaging. MRI Clin North Am 1994;2(2):309 –17. 23. Beers GJ. Biological effects of weak electromagnetic fields from 0 Hz to 200 MHz: a survey of the literature with special emphasis on possible magnetic resonance effects. Magn Reson Imaging 1989;7(3):309 –31. 24. Jones PS, Parrott E, White IN. Activation of transcription by estrogen receptor alpha and beta is cell type- and promoter-dependent. J Biol Chem 1999;274(45):32008 –14. 25. Speirs V, Malone C, Walton DS, Kerin MJ, Atkin SL. Increased expression of estrogen receptor beta mRNA in tamoxifen- resistant breast cancer patients. Cancer Res 1999;59(21):5421– 4. 26. Wu JJ. Increased expression of estrogen receptor beta in human uterine smooth muscle at term. Eur J Endocrinol 2000;142(1):92–9.
CASE REPORT Tamoxifen as Systemic Treatment of Advanced Breast Cancer during Pregnancy—Case Report and Literature Review R. J. Isaacs,* W. Hunter,† and K. Clark‡ *Department of Medical Oncology, †Department of Pediatrics, and ‡Department of Obstetrics and Gynecology, Palmerston North Hospital, Palmerston North, New Zealand Received July 31, 2000; published online January 31, 2001
CASE HISTORY
Background. When patients with metastatic breast cancer become pregnant, management is complicated by the potential harms of drug treatment to the fetus and by the potential effects of the pregnancy on the cancer. Chemotherapy is considered optimal systemic anti-cancer therapy from the second trimester, while tamoxifen has been considered inappropriate due to concerns over possible teratogenesis and lack of efficacy. Case. We report a patient who became pregnant concurrent with the identification of metastatic breast cancer and who elected to continue her pregnancy with tamoxifen as sole systemic anticancer therapy. The pregnancy was difficult, but a normal child was delivered and the mother responded to subsequent hormone manipulation. The putative teratogenic effects of tamoxifen and the mechanisms underlying tamoxifen resistance in this setting are discussed. Conclusions. The use of tamoxifen in pregnancy is complex, but is not necessarily associated with fetal harm and may be considered a therapeutic option in selected cases. © 2001 Academic Press
INTRODUCTION
A 38-year-old woman (JA) presented with a right breast lump in 1996, managed surgically by wide local excision and axillary dissection, with histology showing a 3-cm, grade II infiltrating ductal carcinoma with 1/16 nodes involved by metastatic carcinoma. The tumor was estrogen receptor positive (90% of cells strongly positive) and progesterone receptor negative, with no c-erbB2 amplification. JA received four cycles of adjuvant chemotherapy with 60 mg/m 2 of doxorubicin and 600 mg/m 2 of cyclophosphamide, followed by radiotherapy to the right breast only (50 Gy in 25 fractions with a 10 ␥-Gy electron boost to the tumor in 5 fractions). Adjuvant tamoxifen was also recommended, but declined by the patient. In March 1998, JA represented with a short history of mid-back and rib pain. CT scan confirmed widespread lytic bone metastases and multiple small pulmonary metastases, including three 1.5-cm pulmonary metastases at the left base, as well as a small left pleural effusion. CXR demonstrated the left basal metastases and effusion. JA was treated with radiotherapy to T10 –L1, where there was marked lytic disease, receiving 20 Gy in five fractions, and she was commenced on 20 mg of tamoxifen daily. Her back pain improved, but 2 weeks later JA represented with a progressive history of morning nausea and vomiting, with pregnancy confirmed by HCG levels and ultrasound showed a viable 8-week fetus. Extensive discussions over potential management options were held. JA was extremely reluctant to consider chemotherapy at this stage and elected to continue her pregnancy with tamoxifen as sole systemic anti-cancer treatment. Staging CT scan of the chest was repeated with pelvic shielding 5 weeks after tamoxifen was begun, showing an objective partial response in the lung metastases on bidimensional measurements, with no significant change in the lytic bone lesions after this short interval. CXR at 14 weeks gesta-
A case is presented of a 38-year-old woman who became pregnant concurrent with the identification of metastatic breast cancer and who was subsequently managed with tamoxifen as sole systemic anti-cancer therapy during pregnancy. The cancer was stable until the third trimester when there was disease progression, but a normal baby was delivered at 31 weeks gestation and the child has achieved normal growth and development milestones to 2 years of age, while the mother survived for 23 months after delivery. This case raises important questions about the implications of using tamoxifen for advanced breast cancer during pregnancy. These issues are discussed and the relevant literature is reviewed. 405
0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
406
ISAACS, HUNTER, AND CLARK
tion (14/40) was again normal, indicating a maintained response. Amniocentesis at 16/40 revealed a normal fetal karyotype. Serial ultrasound scans throughout the pregnancy were normal. JA elected to continue with her pregnancy and remained well until 25/40 when she developed progressive lethargy, bone pain, and weight loss, associated with a partial fourth right lumbar nerve root weakness and an incomplete right facial nerve palsy. JA was delivered at 31/40 by lower segment cesarean section due to her deteriorating performance status. During the procedure no palpable liver, nodal, or other intraperitoneal metastases were detected. Tubal ligation was performed, but the ovaries were left in situ. A healthy male fetus weighing 1940 g (75th centile) was delivered from a breech presentation with Apgar scores of 8/10 at 1 min and 10/10 at 5 min. Preauricular skin tags were present, with no other malformations apparent. The baby required treatment for moderate hyaline membrane disease with nasal CPAP from Day 2 until Day 6 of life, with a maximum oxygen requirement of 50% FiO 2. On Day 8 a presumptive diagnosis of necrotizing enterocolitis was made, but the baby recovered rapidly with antibiotics and total parenteral nutrition. The baby tolerated oral feeds from Day 19, with supplemental iron initially, but was well enough to be discharged on Day 42 weighing 2840 g. At 24 months of age the baby remains well, physical examination is normal, and his developmental progress is normal for his corrected age. Three weeks postpartum JA remained unwell with lethargy, weight loss, and bone pain. Repeat CT scan confirmed marked progression of lytic bone metastases from the scan at 13/40, along with minimal progression of pulmonary metastases. CA 15-3 was mildly elevated at 81.6 IU/L (normal ⬍35). JA received palliative radiotherapy to the right hemipelvis and elected to proceed with a therapeutic trial of 160 mg/day of Megostat with 90 mg of IV Pamidronate monthly. She responded symptomatically, with resolution of her right leg weakness and facial nerve palsy, while CA 15-3 levels normalized and there was sclerosis of the nonirradiated bone metastases on plain X-ray. JA remained well until 15 months after delivery, when her disease progressed in bone and pleura. Her disease then sequentially failed to respond to an LHRH analog, anthracycline-based and then taxane chemotherapy, and she died 23 months after delivery. DISCUSSION The case reported here is the first, to our knowledge, of a successful pregnancy while the mother has continued to take tamoxifen as sole systemic therapy for metastatic breast cancer throughout pregnancy, with the child at 2 years of age showing no adverse effects of pregnancy-long exposure to tamoxifen. Management of this patient required identification of risks not only to the mother, but also to the child from both the metastatic breast cancer and its treatment. There is limited
published information on these issues, particularly on the risks of tamoxifen during pregnancy. Relevant publications and the implications of this case are discussed below. The Risks to the Pregnant Mother from Metastatic Breast Cancer It had previously been held that breast cancer diagnosed in pregnancy carried a worse prognosis, but this appears to relate primarily to the diagnosis of more advanced disease [1]. When pregnant patients with breast cancer are matched for age and stage with nonpregnant patients, survival is similar [2, 3], indicating that the pregnancy itself does not compromise prognosis. The Risks to the Fetus from Metastatic Breast Cancer Certain malignancies including melanoma, lymphoma, leukemia, and hepatocellular carcinoma have been described as rarely metastasizing to the fetus [4]. There have been occasional reports of placental metastasis with breast cancer [4], but no reports of fetal involvement with this malignancy [5]. The Risks to the Fetus from Breast Cancer Treatment Following the positive results not only of the Overview studies of tamoxifen use as adjuvant treatment of young women [6], but also of the NSABP-P1 study in breast cancer prevention [7], an increasing number of premenopausal women, some of whom may have metastatic disease, are likely to be taking tamoxifen when they become pregnant. The use of tamoxifen during pregnancy has previously been discouraged owing to concerns about potential teratogenic effects and the risks of disease progression [1, 8]. The case for induction of teratogenesis by tamoxifen, however, mainly relies on indirect evidence from animal work [9 –12], with only anecdotal reports of abnormalities in humans. Epithelial changes similar to those seen with diethylstilbestrol have been reported in mice exposed to tamoxifen in the neonatal period [10]. Stilbestrol teratogenicity in humans occurs predominantly in female offspring with an increased incidence of genital tract abnormalities, including delayed malignancy, while in males with prenatal exposure to exogenous estrogens no significant increase in either urogenital tract abnormalities or malignancy has been reported [13]. Other rodent studies have described a condition called “kinky ribs” on exposure to tamoxifen [12], while some have suggested a link to intrauterine growth retardation [11]. The effects of tamoxifen on aspects of development, however, appear to be species-specific [14]. Direct evidence for teratogenesis in humans is very limited, with only isolated reports of rare forms of fetal abnormality associated with tamoxifen use [15, 16], in which no causal link has been established. In view both of the paucity of evidence demonstrating significant risk from tamoxifen and of the early evidence of clinical response, JA elected to continue with this drug as her sole anti-cancer medication.
407
CASE REPORT
JA elected not to proceed with chemotherapy during the first trimester, as this form of treatment has been associated with teratogenic effects [17], particularly when anti-metabolites such as methotrexate are used [3]. From the second trimester on, however, chemotherapy is generally advised as optimal systemic therapy for pregnant women with breast cancer [3, 8, 18]. Chemotherapy does not appear to significantly increase the risks of fetal malformation at this stage of pregnancy [3], although some studies report a higher rate of fetal loss, growth retardation, and premature birth [19, 20]. A recent study of 24 patients treated after the second trimester with fluorouracil (1000 mg/m 2), doxorubicin (50 mg/m 2), and cyclophosphamide (500 mg/m 2) demonstrated an average gestational age of 38 weeks, with normal Apgar scores, birthweights, and immediate postpartum health in all cases [18]. Nevertheless, JA remained reluctant to consider chemotherapy throughout her pregnancy. Radiotherapy can cause fetal loss [15], with doses of ⬎0.1 Gy to the fetus being associated with various detrimental effects [21]. Assessment of the radiotherapy fields used for JA indicated that the fetus was exposed to 0.17 Gy and fortunately at 2 years of age the child continues to show no evidence of toxicity. Pregnancy had not been diagnosed at the time of treatment in this case, but ideally radiotherapy should be given with caution and special shielding used to minimize the dose to the fetus [21]. Radiological monitoring of disease activity is also difficult in pregnancy owing to concerns over radiation exposure to the fetus. While magnetic resonance imaging appears to be safe in pregnancy [22, 23] and may have enabled earlier treatment of progressive disease, this modality was not readily available for our patient at the time of this pregnancy. Potential Mechanisms for Disease Progression during the Third Trimester This woman’s cancer showed initial evidence of response to tamoxifen and the disease appeared to remain static until the third trimester, when it progressed both symptomatically and on blood testing. While estriol levels increase during pregnancy, suggesting that the estrogen receptors (ERs) may have been saturated in the third trimester to account for disease progression, tamoxifen has been shown to be as effective in premenopausal women, with their much higher estrogen levels, as in postmenopausal women [6]. This suggests that it is the high receptor affinity of the 4-hydroxy metabolite of tamoxifen, rather than the concentration of hormone or drug, which defines response in this setting. An alternative explanation for disease progression may be the ratio of ER isoforms. Recently two forms of ER, -␣ and -, have been identified. Regulation of expression of these subtypes is apparently independent [24], with protein levels of ER- increased in tamoxifen resistance [25]. Overall ER expression appears to be down-regulated in early pregnancy and
does not appear to increase until term, when the ratio of ER- to ER-␣ appears to increase dramatically in human uterine smooth muscle [26]. While ER expression in breast cancer cells during pregnancy has not been reported, if similar changes were induced by the physiological changes of pregnancy they might then contribute to the functional tamoxifen resistance seen in this case. CONCLUSIONS This case illustrates the difficulties of managing the pregnant woman with advanced breast cancer. While chemotherapy remains the preferred systemic treatment option from the second trimester, tamoxifen may stabilize hormone-responsive disease until the fetus is viable in women with estrogenreceptor-positive tumors who are reluctant to consider cytotoxic chemotherapy. Furthermore, this case demonstrates that tamoxifen exposure throughout pregnancy is not necessarily associated with significant fetal abnormality. The survival of the mother also did not appear to have been compromised by the use of tamoxifen during pregnancy, as she achieved the median survival of women with bone-predominant metastatic breast cancer. Indeed, her disease later proved to be resistant to chemotherapy following a further response to hormonal manipulation. ACKNOWLEDGMENTS We thank Professor Adrian Harris and Dr. Lisa Williams for their critical review of the manuscript.
REFERENCES 1. Harris J, Morrow M, Norton L. Malignant tumors of the breast. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and practice of oncology, 5th ed, vol 2. Philadelphia–New York, Lippincott–Raven, 1997; 1557– 616. 2. Petrek JA. Breast cancer during pregnancy. Cancer 74(1 suppl): 1994; 518 –27. 3. Shapiro CL, Mayer RJ. Breast cancer during pregnancy. Adv Oncol 1992;8(3):25–9. 4. Dildy GAd, Moise KJ Jr, Carpenter RJ, Jr, Klima T. Maternal malignancy metastatic to the products of conception: a review. Obstet Gynecol Surv 1989;44(7):535– 40. 5. Dipaola RS, Goodin S, Ratzell M, Florczyk M, Karp G, Ravikumar TS. Chemotherapy for metastatic melanoma during pregnancy. Gynecol Oncol 1997;66(3):526 –30. 6. Group EBCTC. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451– 67. 7. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90(18):1371– 88. 8. Jordan VC. The role of tamoxifen in the treatment and prevention of breast cancer. Curr Probl Cancer 1992;16(3):129 –76. 9. Hilakivi-Clarke L, Cho E, Onojafe I, Liao J, Clarke R. Maternal exposure
408
10. 11.
12.
13.
14.
15.
16. 17.
ISAACS, HUNTER, AND CLARK
to tamoxifen during pregnancy increases carcinogen-induced mammary tumorigenesis among female rat offspring. Clin Cancer Res 2000;6: 305– 8. Sweet DL Jr, Kinzie J. Consequences of radiotherapy and antineoplastic therapy for the fetus. J Reprod Med 1976;17(4):241– 6. Sadek S, Bell SC. The effects of the antihormones RU486 and tamoxifen on fetoplacental development and placental bed vascularisation in the rat: a model for intrauterine fetal growth retardation. Br J Obstet Gynaecol 1996;103(7):630 – 41. Furr BJ, Valcaccia B, Challis JR. The effects of Nolvadex (tamoxifen citrate; ICI 46,474) on pregnancy in rabbits. J Reprod Fertil 1976;48(2): 367–9. Mittendorf R. Teratogen update: carcinogenesis and teratogenesis associated with exposure to diethylstilbestrol (DES) in utero. Teratology 1995; 51(6):435– 45. Halakivi-Clarke L, Cho E, Onojafe I, Liao DJ, Clarke R. Maternal exposure to tamoxifen during pregnancy increases carcinogen-induced mammary tumorigenesis among female rat offspring. Clin Cancer Res 2000; 6(1):305– 8. Cullins SL, Pridjian G, Sutherland CM. Goldenhar’s syndrome associated with tamoxifen given to the mother during gestation [letter]. JAMA 1994;271(24):1905– 6. Tewari K, Bonebrake RG, Asrat T, Shanberg AM. Ambiguous genitalia in infant exposed to tamoxifen in utero [letter]. Lancet 350(9072):183, 1997. Buekers TE, Lallas TA. Chemotherapy in pregnancy. Obstet Gynecol Clin North Am 1998;25(2):323–9.
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