Breast Cancer During Pregnancy: Page 2 of 2
Breast Cancer During Pregnancy: Page 2 of 2
The control of local and systemic disease is the treatment goal for both the pregnant and nonpregnant breast cancer patient. Treatment strategies are similar for both pregnant and nonpregnant breast cancer patients, although the impact of such decisions on the fetus and on the outcome of pregnancy must be considered in the pregnant patient.
Mastectomy with axillary lymph node dissection can be performed with minimal risk to the developing fetus or the continuation of the pregnancy.[37-39] From a registry of 5,405 surgeries performed in pregnant patients, Mazze and Kallen concluded that the incidence of congenital malformations and stillbirths did not increase in women who underwent surgery while pregnant. They did note, however, an increase in the incidence of low- and very low-birthweight infants thought to be secondary to prematurity and intrauterine growth retardation. They also noted an increase in the incidence of infants born alive but who died within 168 hours (the majority of these infants were in the very low-birthweight category).
No particular type of anesthesia or surgery was associated with an increased incidence of adverse reproductive outcomes in this study. The authors suggested that the underlying illness that necessitated the surgery may have contributed to these adverse outcomes.
Duncan et al did not find an increase in congenital anomalies when they compared 2,565 pregnant women who underwent surgery to pregnant controls who did not have surgery. Thus, if the procedure is clinically indicated, the pregnant breast cancer patient can undergo definitive surgery for the malignancy with minimal risk to the fetus, but both the obstetric team and the anesthetist should be involved in the decision to proceed with surgery.
Breast-conserving surgery (lumpectomy or quadrantectomy) with axillary lymph node dissection is technically feasible in the pregnant breast cancer patient. However, the radiation therapy required to complete local therapy for the breast is contraindicated during pregnancy, secondary to the risks associated with fetal exposure to radiation. A therapeutic course of 5,000 cGy to the breast could result in a first-trimester fetal dose of 10 to 15 cGy or a third-trimester dose as high as 200 cGy, with the higher dose resulting from the greater proximity of the near-term fetus to the radiation field.
Data collected from the Hiroshima-Nagasaki atomic bomb detonations showed that an air dose of 1 to 9 cGy during weeks 6 to 11 of pregnancy resulted in an 11% incidence of microcephaly and mental retardation in the children, compared to a 4% incidence in the control group.
Therefore, breast-conserving surgery could be an option for a patient who presents in her third trimester or for a patient whose later stage of disease at presentation warrants the use of neoadjuvant chemotherapy prior to surgery such that the surgery would be performed later in the pregnancy or even postpartum. In the prospective cohort of breast cancer patients followed at M. D. Anderson Cancer Center, the majority had a modified radical mastectomy (18 of 22) with only 2 undergoing segmental resection with postpartum radiation therapy.
The indications for systemic therapy in the pregnant breast cancer patient are similar to those in the nonpregnant patient; ie, all women with node-positive and many with node-negative breast cancer are candidates. Little information exists regarding the pharmacokinetics of the individual cytotoxic agents in the pregnant patient.
A number of physiologic changes during pregnancy, including alterations in renal and hepatic function, increases in plasma volume, and the "third space" of the amniotic sac, may influence the pharmacology of antineoplastic drugs. There are no prospective studies that have reported in utero drug concentrations and/or fetal tissue drug levels. Although the placenta is thought to be a significant barrier to drug penetration, one case was reported of measurable tissue levels of anthracycline in a stillborn whose mother had received doxorubicin shortly before delivery.
The information on the effects of antineoplastic drugs administered during pregnancy has been derived largely from case reports, small case series, and collected reviews. In a review of 217 cases of pregnant women treated with chemotherapy between 1983 and 1995 for a variety of malignancies, 18 newborns had congenital abnormalities, 2 had chromosomal abnormalities, 4 were stillborn, and 15 spontaneous abortions occurred.
The majority of stillborn infants and infants with chromosomal or congenital abnormalities had mothers who were given chemotherapy in the first trimester. Among the 14 pregnant breast cancer patients treated with a variety of systemic therapies, including 1 treated with hormonal therapy, there were 2 spontaneous abortions, 1 stillborn infant, and 3 infants born with congenital abnormalities of varying severities. Of the live-born infants with no congenital abnormalities (n = 8), 1 infant had intrauterine growth retardation and 3 were born prematurely.
First-Trimester Therapy: Doll et al reviewed a total of 139 cases of chemotherapy during the first trimester of pregnancy for a variety of malignancies and reported a 17% incidence of fetal malformations. The incidence of fetal malformations for the 150 women given chemotherapy during their second or third trimesters of pregnancy was 1.3%. Of 20 pregnant breast cancer patients treated with systemic chemotherapy who had been identified through a nationwide retrospective survey in France, there were 2 spontaneous abortions (both treated with chemotherapy in their first trimester), 1 stillbirth, and 17 live births; 1 infant died at age 8 days without apparent etiology. Thus, the period of exposure to chemotherapy is critical, with exposure during the first trimester of pregnancy—the period of organogenesis—carrying the greatest risk.
Second- and Third-Trimester Therapy: The only prospective cohort of pregnant breast cancer patients treated with systemic therapy during their second and/or third trimester did not report any congenital malformations, stillbirths, or spontaneous abortions. The 24 women in this study were treated during the second and third trimesters with FAC (fluorouracil [5-FU], 1,000 mg/m2 intravenously [IV]; doxorubicin [Adriamycin], 50 mg/m2 continuous infusion over 72 hours; and cyclophosphamide [Cytoxan, Neosar], 500 mg/m2 IV) for a median of four cycles. Berry et al concluded that chemotherapy could be administered during the second and third trimesters with minimal complications.
The only antepartum maternal complications noted were the hospitalization of one patient for diarrhea and suspected (but unconfirmed) pyelonephritis that resolved with symptomatic and supportive care, and one patient with a history of deep-vein thrombosis in the calf who developed another thrombus in the same calf and required hospitalization for intravenous heparin. There are no published reports on the use of taxanes in the treatment of breast cancer during pregnancy, and therefore, their use cannot be recommended at this time.
Hormonal Agents: In the series by Ebert et al, one infant exposed to tamoxifen (Nolvadex) during all three trimesters was born at 26 weeks’ gestation with Goldenhar’s syndrome. The use of hormonal agents such as selective estrogen-receptor modulators (SERMs) or aromatase inhibitors cannot be recommended, as they could interfere with the hormonal milieu of a normal pregnancy.
Other Agents: Most of the published literature does not recommend the use of methotrexate in the management of breast cancer during pregnancy, because it is an abortifactant and causes severe fetal malformations when given in the first trimester.[45,47] Many of the cytotoxic drugs, especially the alkylating agents, are known or thought to be excreted in breast milk. Therefore, women receiving systemic chemotherapy should be cautioned against breastfeeding while receiving chemotherapy. Caution should also be exercised with regard to the use of antiemetics chosen for women receiving chemotherapy for breast cancer during pregnancy, because antiemetics vary with regard to their safety profile in pregnant or nursing women.
As previously mentioned, local breast irradiation required for the completion of breast-conserving treatment is contraindicated in pregnancy because of the risks associated with fetal exposure to radiation. If breast cancer is diagnosed in the third trimester and breast-conserving therapy is a treatment option, breast irradiation may be delayed until after delivery. In addition, women who require neoadjuvant therapy for locally advanced breast cancer may postpone surgery until later in their pregnancy or after the birth of their child, making breast-conserving surgery an option.
Although in the past it was believed that the termination of pregnancy improved survival in pregnant women with breast cancer, a number of reported case series do not support this hypothesis.[49,50] For example, in a series of 24 pregnant breast cancer patients treated with radical mastectomy, survival did not improve in those who had aborted their pregnancy. Some studies have suggested that pregnant women who terminate their pregnancies may actually have decreased survival, compared with those who continue their pregnancies.[51,52]
However, these results must be interpreted with caution as they may be biased. Because they are based on retrospective case reviews, these findings cannot account for the possibility that abortion was more likely to be recommended to those with more advanced disease or poorer prognostic features. In addition, such individuals would be more likely to have decreased survival regardless of whether they terminated their pregnancy.
The decision to continue or terminate the pregnancy must be made by a woman who has been fully informed of the evidence, or lack thereof, regarding termination of pregnancy and survival in this unique group of breast cancer patients. In cases of known or suspected fetal teratogenesis or when the health of the mother is in jeopardy, termination of pregnancy may be an appropriate medical recommendation.
The majority of relevant case reviews and case series reported in the literature have concentrated on the frequency of spontaneous abortion and congenital malformations in infants exposed to chemotherapy in utero. Few studies have actually examined the potential complications that may arise during labor and delivery when the mother is receiving chemotherapy. In a review of 14 cases of pregnancy during breast cancer compiled by Ebert et al, 3 of 8 live-born children without congenital anomalies were premature, and 1 of the full-term deliveries was born with intrauterine growth retardation.
Of the 17 live births among 20 women in a French retrospective cohort of pregnant breast cancer patients, 1 newborn died 8 days after birth without any apparent etiology, 2 had transient respiratory distress likely related to prematurity, and 1 had intrauterine growth retardation. One woman was anemic at the time of delivery (hemoglobin value = 9.5 g/dL), and one child had transient leukopenia with normal hemoglobin and platelet counts. The mean gestational age at delivery in the French series was 34.7 weeks.
In a case-control study by Zemlickis et al, women with breast cancer during pregnancy were significantly more likely to have a premature infant, and their infants had a statistically lower mean birthweight, compared to controls. These differences persisted even when an adjustment was made for gestational age.
Finally, in the prospective cohort of 24 pregnant breast cancer patients reported by Berry et al, the median gestational age at delivery was 38 weeks, with 3 women delivering prematurely, 1 as a consequence of preeclampsia and 2 with idiopathic premature labor. Among the infants born to this cohort, 1 had hyaline membrane disease secondary to prematurity but recovered without complications, 2 required oxygen support for transient tachypnea of the newborn (both having resolution of their symptoms within 48 hours), 1 had transient leukopenia without infectious sequelae, having been exposed to chemotherapy 2 days before delivery, and 1 had a birthweight lower than the 10th percentile for gestational age.
It is difficult to draw conclusions based on these studies since all but one are retrospective in nature, but a lower-than-average gestational age was a fairly consistent finding in all the above studies.
There are few published reports on the long-term effects of in utero chemotherapy exposure on the subsequent mental and physical health of exposed infants. In the French case series of pregnant breast cancer patients, all 16 live infants were reported to have reached normal developmental milestones. The prospective cohort of Berry et al did not report any known developmental abnormalities in the children. After 50 live births recorded to pregnant women undergoing chemotherapy for acute leukemia, there was normal growth and development and no evidence of malignancy in any of the 7 children who received long-term follow-up (up to 17 years). The results of the aforementioned studies must be interpreted with caution, however, as formal developmental testing was not performed on these children.
Aviles and Niz reported a series of 20 children exposed to chemotherapy in utero for treatment of maternal leukemia. Only 17 of these children received long-term follow-up; 1 was stillborn and 2 died in infancy—1 from septicemia at 21 days of age and 1 from gastroenteritis at 90 days of age. Of the remaining 17 children with follow-up to 22 years, there appeared to be no long-term sequelae as a result of this chemotherapeutic exposure.
In this study, the children were followed quite closely with physical examinations and blood counts every 3 months for the first 2 years of life and every 6 months thereafter. The children underwent a complete neurologic evaluation and had formal intelligence testing twice (3 years apart). Based on these limited data, one can cautiously conclude that exposure to chemotherapy for the treatment of maternal breast cancer in utero does not appear to affect the normal development of children so exposed.
Women with a history of breast cancer during pregnancy should be followed as per the guidelines published by the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) for women treated for primary breast cancer.[56,57]
Impact of Pregnancy on Recurrence and Survival
Although initially breast cancer during pregnancy was thought to be associated with a poorer prognosis, numerous case-control series have suggested that when matched for age and stage at presentation, there is no significant difference in survival between women with pregnancy-associated breast cancer and nonpregnant breast cancer patients.[28,33,58,59] There are, however, other case-control studies in which pregnancy-associated breast cancer was reported to decrease survival, compared to controls matched for stage.
The majority of studies have concluded that women who become pregnant after successful treatment for breast cancer do not worsen their prognosis with respect to their cancer.[49,61-65] Other studies interpret the available data more cautiously and conclude that the effect of subsequent pregnancy on breast cancer prognosis is unclear.
Breast cancer coincident with pregnancy is a relatively rare clinical situation that may become more frequent in the industrialized world as more women delay childbearing. The preferred surgical option for women with breast cancer during pregnancy—modified radical mastectomy—can be accomplished with minimal fetal risk. Although it may be possible to perform breast-conserving surgery, the radiation therapy required to complete local therapy to the breast must be delayed until after delivery because of concern regarding fetal radiation exposure.
The majority of information concerning the systemic therapy of breast cancer during pregnancy consists of case series and case-control studies. Nevertheless, data from one prospective cohort of pregnant women treated with FAC chemotherapy support the premise that breast cancer can be treated during the second and third trimesters with minimal complications.
There are no data to support the use of taxanes or hormonal therapy to treat pregnant breast cancer patients. Methotrexate should not be used during pregnancy, as it is an abortifacient and can cause severe congenital abnormalities if administered in the first trimester. Pregnancy termination does not appear to improve survival, but situations in which maternal health is in jeopardy or fetal anomalies are known or suspected may make this a medical option to be considered.
1. Reis LAG, Hankey BF, Miller BA, et al: Cancer Statistics Review 1973-1988. Bethesda, Md, National Cancer Institute, NIH publication 91-2789, III.39, 1991.
2. White TT: Prognosis of breast cancer for pregnant and nursing women: Analysis of 1,413 cases. Surg Gynecol Obstet 100:661-666, 1955.
3. Saunders CM, Baum M: Breast cancer and pregnancy: A review. J R Soc Med 86:162-165, 1993.
4. Anderson JM: Mammary cancers and pregnancy. BMJ 1:1124-1127, 1979.
5. Wallack MK, Wolf JA Jr, Bedwinek J, et al: Gestational carcinoma of the female breast. Curr Probl Cancer 7:1-58, 1983.
6. Crosby CH, Barclay THC: Carcinoma of the breast: Surgical management of patients with special conditions. Cancer 28:1628-1636, 1971.
7. Anderson BO, Petrek JA, Byrd DR, et al: Pregnancy influences breast cancer stage at diagnosis in women 30 years of age and younger. Ann Surg Oncol 3:204-211, 1996.
8. Noyes RD, Spanos WJ Jr, Montague ED: Breast cancer in women aged 30 and under. Cancer 49:1302-1307, 1982.
9. Ventura SJ: First births to older mothers, 1970-86. Am J Public Health 79:1675-1677, 1989.
10. Kelsey JL, Berkowitz GS: Breast cancer epidemiology. Cancer Res 48:5615-5623, 1988.
11. King RM, Welch JS, Martin JK Jr, et al: Carcinoma of the breast associated with pregnancy. Surg Gynecol Obstet 160:228-232, 1985.
12. Byrd BF Jr, Bayer DS, Robertson JC, et al: Treatment of breast tumors associated with pregnancy and lactation. Ann Surg 155:940-947, 1962.
13. Bunker ML, Peters MV: Breast cancer associated with pregnancy and lactation. Am J Obstet Gynecol 85:312-319, 1963.
14. Westberg SV: Prognosis of breast cancer for pregnant and nursing women. Acta Obstet Gynecol Scand 25 (suppl 4):1-239, 1946.
15. Max MH, Klamer TW: Pregnancy and breast cancer. South Med J 76:1088-1090, 1983.
16. Liberman L, Giess CS, Dershaw DD, et al: Imaging of pregnancy-associated breast cancer. Radiology 191:245-248, 1994.
17. Samuels TH, Liu F-F, Yaffe M, et al: Gestational breast cancer. Can Assoc Radiol J 49:172-180, 1998.
18. Mattison DR, Angtuaco T: Magnetic resonance imaging in prenatal diagnosis. Clin Obstet Gynecol 31:353-389, 1988.
19. Kirkinen P, Partanen K, Vainio P, et al: MRI in obstetrics: A supplementary method for ultrasonography. Ann Med 28:131-136, 1996.
20. Bottles K, Taylor RN: Diagnosis of breast masses in pregnant and lactating women by aspiration cytology. Obstet Gynecol 66(suppl):76-78, 1985.
21. Gupta RK: The diagnostic impact of aspiration cytodiagnosis of breast masses in association with pregnancy and lactation with an emphasis on clinical decision making. The Breast Journal 3:131-134, 1997.
22. Gupta RK, McHutchinson AGR, Dowle CS, et al: Fine-needle aspiration cytodiagnosis of breast masses in pregnant and lactating women and its impact on management. Diagn Cytopathol 9:156-159, 1993.
23. Schackmuth EM, Harlow CL, Norton LW: Milk fistula: A complication after core breast biopsy. Am J Roentgenol 161:961-962, 1993.
24. Collins J, Liao S, Wile A: Surgical management of breast masses in pregnant women. J Reprod Med 40:785-788, 1995.
25. Tobon H, Horowitz LF: Breast cancer during pregnancy. Breast Dis 6:127-134, 1993.
26. Jackisch C, Schwenkhagen A, Louwen F, et al: Breast cancer in pregnancy (abstract 228). Proc Am Soc Clin Oncol 14:132, 1995.
27. Ishida T, Yokoe T, Kasumi F, et al: Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation: Analysis of case-control study in Japan. Jpn J Cancer Res 83:1143-1149, 1992.
28. Bonnier P, Romain S, Dilhuydy JM, et al: Influence of pregnancy on the outcome of breast cancer: A case-control study. Int J Cancer 72:720-727, 1997.
29. Berry DL, Theriault RL, Holmes FA, et al: Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 17:855-861, 1999.
30. Elledge RM, Ciocca DR, Langone G, et al: Estrogen receptor, progesterone receptor, and HER-2/neu protein in breast cancers from pregnant patients. Cancer 71:2499-2506, 1993.
31. Johannsson O, Loman N, Borg A, et al: Pregnancy-associated breast cancer in BRCA1 and BRCA2 germ-line mutation carriers. Lancet 352:1359-1360, 1998.
32. Shen T, Vortmeyer AO, Zhuang Z, et al: High frequency of allelic loss of BRCA2 gene in pregnancy-associated breast cancer. J Natl Cancer Inst 91:1686-1687, 1999.
33. Zemlickis D, Lishner M, Degendorfer P, et al: Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 166:781-787, 1992.
34. Petrek JA, Dukoff R, Rogatko A: Prognosis of pregnancy-associated breast cancer. Cancer 67:869-872, 1991.
35. Baker J, Ali A, Grock MW, et al: Bone scanning in patients with breast carcinoma. Clin Nucl Med 12:519-524, 1987.
36. Harbert JC: Efficacy of bone and liver scanning in malignant disease: Facts and opinions, in: Harbert JC (ed): Nuclear Medicine Annual. New York, Raven Press, 1982.
37. Mazze RI, Kallen B: Reproductive outcome after anesthesia and operation during pregnancy: A registry of 5405 cases. Am J Obstet Gynecol 161:1178-1185, 1989.
38. Pedersen H, Finster M: Anesthetic risk in the pregnant surgical patient. Anesthesiology 51:439-451, 1979.
39. Gianopoulos JG: Establishing the criteria for anesthesia and other precautions for surgery during pregnancy. Surg Clin North Am 75:33-45, 1995.
40. Duncan PG, Pope WDB, Cohen MM, et al: Fetal risk of anesthesia and surgery during pregnancy. Anesthesiology 64:790-794, 1986.
41. Brent RL: The effect of embryonic and fetal exposure to x-ray, microwaves, and ultrasound: Counseling the pregnant and non-pregnant patient about these risks. Semin Oncol 16:347-368, 1989.
42. Petrek JA: Breast cancer during pregnancy. Cancer 74:518-527, 1994.
43. Miller RW, Mulvihill JJ: Small head size after atomic radiation. Teratology 14:355-358, 1976.
44. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of randomized trials. Lancet 352:930-942, 1998.
45. Doll DC, Ringenberg S, Yarbro JW: Antineoplastic agents and pregnancy. Semin Oncol 16:337-346, 1989.
46. Karp GI, von Oeyen P, Valone F, et al: Doxorubicin in pregnancy: Possible transplacental passage. Cancer Treat Rep 67:773-777, 1983.
47. Ebert U, Loffler H, Kirch W: Cytotoxic therapy and pregnancy. Pharmacol Ther 74:207-220, 1997.
48. Giacalone P-L, Laffargue F, Benos P: Chemotherapy for breast carcinoma during pregnancy. Cancer 86:2266-2272, 1999.
49. Holleb AI, Farrow JH: The relation of carcinoma of the breast and pregnancy in 283 patients. Surg Gynecol Obstet 115:65-71, 1962.
50. Nugent P, O’Connell TX: Breast cancer and pregnancy. Arch Surg 120:1221-1224, 1985.
51. Clark RM, Chua T: Breast cancer and pregnancy: The ultimate challenge. Clin Oncol 1:11-18, 1989.
52. Deemarsky LJ, Neishtadt EL: Breast cancer and pregnancy. Breast 7:17-21, 1981.
53. Gemignani ML, Petrek JA, Borgen PI: Breast cancer and pregnancy. Surg Clin North Am 79:1157-1169, 1999.
54. Reynoso EE, Shepherd FA, Messner HA, et al: Acute leukemia during pregnancy: The Toronto Leukemia Study Group experience with long-term follow-up of children exposed in utero to chemotherapeutic agents. J Clin Oncol 5:1098-1106, 1987.
55. Aviles A, Niz J: Long-term follow-up of children born to mothers with acute leukemia during pregnancy. Med Pediatr Oncol 16:3-6, 1988.
56. American Society of Clinical Oncology: Recommended breast cancer surveillance guidelines. J Clin Oncol 15:2149-2156, 1997.
57. NCCN Breast Cancer Practice Guidelines Panel: Update: NCCN Practice Guidelines for the Treatment of Breast Cancer. Oncology 13(11A):187-212, 1999.
58. Lethaby AE, O’Neill MA, Mason BH, et al: Overall survival from breast cancer in women pregnant or lactating at or after diagnosis. Int J Cancer 67:751-755, 1996.
59. Ezzat A, Raja MA, Berry J, et al: Impact of pregnancy on non-metastatic breast cancer: A case control study. Clin Oncol 8:367-370, 1996.
60. Tretli S, Kvalheim G, Thoresen S, et al: Survival of breast cancer patients diagnosed during pregnancy or lactation. Br J Cancer 58:382-384, 1988.
61. Sutton R, Buzdar AU, Hortobagyi GN: Pregnancy and offspring after adjuvant chemotherapy in breast cancer patients. Cancer 65:847-850, 1990.
62. Mignot L, Morvan F, Sarrazin D, et al: Breast carcinoma and subsequent pregnancy (abstract). Proc Am Soc Clin Oncol 5:57, 1986.
63. Peters MV: The effect of pregnancy in breast cancer, in Forrest APM, Kunkler PB (eds): Prognostic Factors in Breast Cancer, pp 65-80. Baltimore, Williams & Wilkins, 1968.
64. Cooper DR, Butterfield J: Pregnancy subsequent to mastectomy for cancer of the breast. Ann Surg 171:429-433, 1970.
65. Velentgas P, Daling JR, Malone KE, et al: Pregnancy after breast carcinoma: Outcomes and influence on mortality. Cancer 85:2424-2432, 1999.