- Email: [email protected]
Chemotherapy with Taxanes in Breast Cancer During Pregnancy: Case Report and Review of the Literature
case
report
Chemotherapy with Taxanes in Breast Cancer During Pregnancy: Case Report and Review of the Literature Vinaya Potluri,1 David Lewis,2 Gary V. Burton1 Abstract Two patients with breast cancer received docetaxel-containing chemotherapy as adjuvant or neoadjuvant therapy during pregnancy. The first pregnant patient began neoadjuvant therapy with doxorubicin/cyclophosphamide at 14 weeks of gestation. After 4 cycles of doxorubicin/cyclophosphamide and surgery, she received adjuvant docetaxel for 4 cycles. The second patient began neoadjvuant therapy with doxorubicin/docetaxel at 14 weeks of gestation and received 6 cycles. The fetus of the first patient had hydrocephalus on ultrasound at 17 weeks of gestation (before docetaxel therapy) that persisted on serial follow-up ultrasounds and spontaneously regressed over several months after delivery. No fetal malformations were detected in the second fetus. These 2 cases add to the existing data on the use of taxanes during pregnancy. Although the data are limited with case reports, pregnant patients with cancer can be treated with chemotherapy including taxanes during the second and third trimesters without significant risks to the fetus. Taxanes should not be excluded, if indicated, in pregnant patients with cancer. Clinical Breast Cancer, Vol. 7, No. 2, 167-170, 2006 Key words: Cyclophosphamide, Docetaxel, Doxorubicin
Introduction Cancer is the second leading cause of death in the age group between 20 years and 39 years and complicates 1 in 1000 pregnancies.1 By definition, pregnancy-associated cancer includes cancers detected during gestation and immediately after delivery. The common cancers occurring during pregnancy include breast, cervical, lymphoma, melanoma, and leukemia.2 Breast cancer is the most common tumor diagnosed during pregnancy, with the incidence averaging 1 in 3000 pregnancies.3 The frequency of breast cancer diagnosis during pregnancy might be increasing because women today delay childbearing until later in life. The physiologic changes that occur in pregnancy present specific challenges for the detection and management of cancer during pregnancy. Chemotherapy during pregnancy is a challenging problem and an ethical dilemma. There are many case reports and 1Department of Medicine 2Department of Obstetrics and Gynecology Louisiana State University Health Sciences Center Shreveport Submitted: Dec 13, 2005; Revised: Jan 30, 2006; Accepted: Feb 28, 2006 Address for correspondence: Gary V. Burton, MD, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130 Fax: 318-813-1004; e-mail: [email protected]
retrospective series reporting on the pregnancy outcomes of systemic chemotherapy administered during pregnancies, including regimens containing cyclophosphamide, doxorubicin, 5-fluorouracil (5-FU), and epirubicin.4,5 There is, however, limited information on the use and risk of taxane therapy during pregnancy. There have been 5 reports describing the outcomes of 5 patients receiving paclitaxel during pregnancy (2 in breast cancer and 3 in ovarian cancer)6-10 and only 1 report using docetaxel in a patient with breast cancer during pregnancy.11 We describe the outcomes of 2 additional patients who received docetaxel for breast cancer during pregnancy, with 1 child having a minor but probably unrelated birth defect.
Case Reports Case 1 A 29-year-old woman (gravida 5, para 4) was diagnosed in 2003 with stage IIIA breast cancer at 12 weeks of gestation. The tumor was 85 mm and nonfixed, and axillary lymph nodes were matted and fixed, measuring 35 mm. Biopsy was performed, and pathology was consistent with grade III infiltrating ductal carcinoma. Estrogen and progesterone receptors were positive (42% and 51%), and HER2/neu was positive for overexpression by fluorescence in situ hybridization. The patient began neoadjuvant chemotherapy at 14 weeks
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Breast Cancer June 2006 • 167
Taxanes for Breast Cancer During Pregnancy of gestation with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks for 4 cycles. The patient had a fetal ultrasound at 17 weeks of gestation that revealed hydrocephalus (dilated lateral and third ventricle). The patient was closely monitored with serial fetal ultrasounds. She underwent a modified radical mastectomy and axillary node dissection at 24 weeks of gestation. The pathologic staging revealed the residual tumor to be 68 mm, and 8 of 11 lymph nodes were positive for tumor. She received 4 cycles of adjuvant docetaxel (75 mg/m2) every 2 weeks between weeks 26 and 32 of gestation. She delivered at 34 weeks, with the infant having mild hydrocephalus, which regressed spontaneously over several months. The patient received radiation therapy followed by adjuvant hormonal therapy. The child’s development has been normal at 28 months.
Case 2 A 38-year-old woman (gravida 2, para 1) was diagnosed in 2005 with stage IIIA breast cancer at 10 weeks of gestation. The tumor measured 63 mm, and the axillary lymph nodes were matted and measured 45 mm. Biopsy results demonstrated poorly differentiated infiltrating ductal carcinoma with estrogen and progesterone receptor positivity (46% and 15%) and HER2/neu negativity by fluorescence in situ hybridization. She began neoadjuvant chemotherapy at 14 weeks of gestation with doxorubicin (60 mg/m2) and docetaxel (75 mg/m2) every 3 weeks for 6 cycles (standard neoadjuvant regimen at Louisiana State University at that time). Fetal ultrasound monitoring demonstrated normal intrauterine growth and development. The patient developed preeclampsia and underwent caesarian delivery at 35 weeks of gestation. The infant was healthy with no detectable malformations. The patient underwent a modified radical mastectomy and axillary node dissection 10 days after delivery. The pathologic specimen had small foci of residual carcinoma with dystrophic calcification, and 13 of 19 lymph nodes were involved. The patient received adjuvant radiation therapy followed by adjuvant hormonal therapy. Development of the infant has been normal at 9 months.
Discussion Breast cancer during pregnancy is likely to be more advanced (because of diagnostic delay)12 with axillary node involvement (56%-67% reported),13 higher incidence of HER2/neu overexpression (reports ranging from 28% to 58%),13-15 and higher incidence of estrogen receptor negativity (54%-80%) compared with age-matched controls.13,15 Mammography with abdominal shielding can be safely performed during pregnancy.16 Mammograms, however, can be difficult to interpret during pregnancy because of physiologic breast changes; therefore, any suspicious breast lesion should be tested by biopsy.17 Breast biopsy during pregnancy can be performed safely by fine needle aspiration, core needle biopsy, or surgical excision. Fine needle aspiration is preferred, because there is a risk of milk fistula associated with core needle biopsy.18
168 • Clinical Breast Cancer June 2006
Breast cancer during pregnancy was previously considered to have a poor prognosis.19 However, most of the recent literature suggests that stage-specific survival for pregnant patients with breast cancer is similar to survival for women who are not pregnant.20,21 The treatment of breast cancer in pregnant patients should not be delayed, and patients should receive the best standard treatment without modification. Breast cancer treatment is multimodality therapy with surgery, systemic chemotherapy, radiation, and hormone therapy. Radiation therapy and hormone therapy with tamoxifen are contraindicated during pregnancy because of potential fetal injury or death. These can usually be delayed until after delivery without affecting patient outcome.22-24 Surgery and chemotherapy have been used during pregnancy without harm to the mother or fetus.4,5 Therapeutic abortion is a patient option; however, optimum cancer therapy can usually be provided after the first trimester without having a deleterious effect on the health of the mother or the child, and there are data suggesting survival is not altered with therapeutic abortion.20,25 The majority of available chemotherapeutic agents (Food and Drug Administration Class D) are considered to have an undefined or definite evidence of fetal risk. More than 2500 agents have been reported to be teratogenic in animal models, although clear evidence of toxicity in the human fetus is available only for a few. Maghfoor and Doll’s review of the literature (updated in 2001) on patients treated with chemotherapy during pregnancy reported that 15% of pregnancies exposed to chemotherapy during the first trimester resulted in fetal malformation, whereas 1.4% exposed during the latter 2 trimesters resulted in fetal malformation.26 Exposure within 1 week of conception can cause spontaneous abortion or have no effect on the fetus. Therefore, chemotherapy should be delayed until the second and third trimester to minimize fetal malformation risk. There are multiple case reports and retrospective series reporting on the management of breast cancer during pregnancy. The M. D. Anderson Cancer Center experience is the only prospective study reported in the literature. Patients at M. D. Anderson Cancer Center were treated with a standardized protocol by a multidisciplinary breast cancer group with surgery and adjuvant or neoadjuvant chemotherapy.4 In an update of this experience, 39 women received 5-FU/doxorubicin/cyclophosphamide chemotherapy for a median of 4 cycles during the second and third trimesters with no reported spontaneous abortions, stillbirths, or fetal anomalies.27 A retrospective London series reported on 28 patients during an 18-year period from 5 hospitals.5 Sixteen of 28 patients received doxorubicin/cyclophosphamide or cyclophosphamide/epirubicin and chemotherapy. Twelve of 28 patients received cyclophosphamide/methotrexate/5-FU. One patient was treated during the first trimester with cyclophosphamide/methotrexate/5-FU and had a spontaneous abortion. All other patients were treated after the first trimester, and no congenital anomalies, spontaneous abortions, or deaths were reported.
Vinaya Potluri et al In women with estrogen receptor–negative, lymph node– positive tumors, there are data to support the addition of a taxane to their chemotherapy regimen.28-30 Data on sequential, dose-dense, adjuvant chemotherapy with doxorubicin/ paclitaxel/cyclophosphamide in patients with * 4 ipsilateral axillary lymph nodes appear promising.31 However, the data in pregnant patients with these regimens are limited. In animal models, docetaxel and paclitaxel have been shown to be toxic to the embryo and fetus during organogenesis. Embryotoxic and fetotoxic effects were characterized by increased intrauterine deaths, decreased fetal weight, and delayed fetal ossification.32,33 There are 3 case reports of patients with breast cancer treated with taxanes. One patient received paclitaxel/epirubicin from 14 weeks to 32 weeks of gestation with no maternal or fetal complications.9 A second patient with bilateral breast cancer received weekly paclitaxel from 20 weeks of gestation and delivered a normal baby.10 A third patient received docetaxel for a rapidly progressive metastatic breast cancer immediately after the first trimester.11 She received 3 cycles of therapy between 23 weeks and 30 weeks of gestation, and a healthy infant was delivered at 32 weeks; the child’s development was normal at 2 years. Treatment with paclitaxel was also reported in 3 patients with ovarian cancer in combination with carboplatin or cisplatin during pregnancy without report of fetal malformation.6-8 Trastuzumab is a useful adjuvant therapy for metastatic HER2/neu–overexpressing breast cancer. HER2 expression is high in embryonic tissues. Animal studies have demonstrated placental transfer without harm to the fetus.34 There is only 1 case report on the use of trastuzumab in pregnancy.35 The patient had received adjuvant trastuzumab for 5 months and was found to be pregnant at 23 weeks of gestation. Ultrasound revealed anhydramnios and a small urinary bladder. Amniotic fluid slowly increased after trastuzumab withdrawal, and the infant had no abnormalities at delivery. Endocrine therapy is delayed until the end of pregnancy, because tamoxifen has been shown to be teratogenic in animal studies as well as in humans. Tamoxifen has been associated with fetal anomalies, including craniofacial defects as well as rare abnormalities like Goldenhar’s syndrome (oculoauriculovertebral dysplasia) and ambiguous genitalia.23,24
Conclusion Although breast cancer detected during pregnancy tends to be of advanced stage and more often hormone receptor negative, the prognosis is similar to that of patients who are not pregnant when matched for age and disease stage. Chemotherapy has been safely administered to pregnant patients after 14 weeks of gestation (ie, after the completion of organogenesis) without significant risk to the fetus or patient. The addition of taxanes to cyclophosphamide and an anthracycline for adjuvant therapy reduces the risk of breast cancer. Chemotherapy including taxanes should be considered for treatment of pregnant women when indi-
cated. This limited experience with 8 patients (case reports) suggests pregnant patients with cancer can be treated with taxane-containing chemotherapy during the second and third trimesters without significant risk to the fetus. A multidisciplinary approach for the management of pregnant patients with breast cancer allows for continuation of pregnancy without maternal health compromise or fetal risk.
References 1. Antonelli NM, Dotters DJ, Katz VL, et al. Cancer in pregnancy: a review of the literature. Part I-II. Obstet Gynecol Surv 1996; 51:125-142. 2. Smith LH, Dalrymple JL, Leiserowitz GS, et al. Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997. Am J Obstet Gynecol 2001; 184:1504. 3. Donegan WL. Breast carcinoma and pregnancy. In: Donegan WL, Spratt JS, eds. Cancer of the Breast. 4th ed. Philadelphia, PA: Saunders; 1995:732-741. 4. Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999; 17:855. 5. Ring AE, Smith IE, Jones A, et al. Chemotherapy for breast cancer during pregnancy: an 18 year experience from five London teaching hospitals. J Clin Oncol 2005; 23:4192-4197. 6. Sood AK, Shahin MS, Sorosky JI. Paclitaxel and platinum chemotherapy for ovarian carcinoma during pregnancy. Gynecol Oncol 2002; 83:599-600. 7. Mendez LE, Mueller A, Salom E, et al. Paclitaxel and carboplatin chemotherapy administered during pregnancy for advanced epithelial ovarian cancer. Obstet Gynecol 2003; 5:1200-1202. 8. Ferrandina G, Distefano M, Testa A, et al. Management of an advanced ovarian cancer at 15 weeks of gestation: case report and literature review. Gynecol Oncol 2005; 97:693-696. 9. Gadducci A, Cosio S, Fanucchi A, et al. Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and review of the literature. Anticancer Res 2003; 23:5225-5230. 10. Gonzalez-Angulo AM, Walters RS, Carpenter RF Jr, et al. Paclitaxel chemotherapy in a pregnant patient with bilateral breast cancer. Clin Breast Cancer 2004; 5:317-319. 11. De Santis M, Lucchese A, De Carolis S, et al. Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel. Eur J Cancer Care (Engl) 2000; 9:235. 12. Petrek J. Breast cancer and pregnancy. In: Harris JR, Lippman ME, Morrow M, eds. Diseases of the Breast. Philadelphia: Lippincott-Raven; 1996:883. 13. Middleton LP, Amin M, Gwyn K, et al. Breast carcinoma in pregnant women: assessment of clinicopathologic and immunohistochemical features. Cancer 2003; 98:1055-1060. 14. Aziz S, Pervez S, Khan S, et al. Case control study of novel prognostic markers and disease outcome in pregnancy/lactation-associated breast carcinoma. Pathol Res Pract 2003; 199:15-21. 15. Elledge RM, Ciocca DR, Langone G, et al. Estrogen receptor, progesterone receptor, and HER-2/neu protein in breast cancers from pregnant patients. Cancer 1993; 71:2499-2506. 16. Nicklas AH, Baker ME. Imaging strategies in the pregnant cancer patient. Semin Oncol 2000; 27:623-632. 17. Ahn BY, Kim HH, Moon WK, et al. Pregnancy- and lactation-associated breast cancer: mammographic and sonographic findings. J Ultrasound Med 2003; 22:491-497. 18. Schackmuth EM, Harlow CL, Norton LW. Milk fistula: a complication after core breast biopsy. Am J Roentgenol 1993; 161:961. 19. White TT. Carcinoma of the breast and pregnancy; analysis of 920 cases collected from the literature and 22 new cases. Ann Surg 1954; 139:9-18. 20. Zemlickis D, Lishner M, Degendorfer P, et al. Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 1992; 166:781-787. 21. Merkel DH. Pregnancy and breast cancer. Semin Surg Oncol 1996; 12:370-375. 22. Mayr NA, Wen BC, Saw CB. Radiation therapy during pregnancy. Obstet Gynecol Clin North Am 1998; 25:301-321. 23. Tewari K, Bonebrake RG, Asrat T, et al. Ambiguous genitalia in infant exposed to tamoxifen in utero. Lancet 1997; 350:183.
Clinical Breast Cancer June 2006 • 169
Taxanes for Breast Abbreviated Title Cancer During Pregnancy 24. Cullins SL, Pridjian G, Sutherland CM. Goldenhar’s syndrome associated with tamoxifen given to the mother during gestation. JAMA 1994; 271:1905-1906. 25. King RM, Welch JS, Martin JK Jr, et al. Carcinoma of the breast associated with pregnancy. Surg Gynecol Obstet 1985; 160:228-232. 26. Maghfoor I, Doll DC. Chemotherapy in pregnancy. In: Perry MC, ed. The Chemotherapy Source Book. 3rd ed. Philadelphia: Lippincott Williams &Wilkins; 2001:537. 27. Gwyn K, Theriault R, Sahin A, et al. Treatment of breast cancer (Br Ca) during pregnancy (Pg) using a standard protocol: update of the M.D. Anderson experience. Proc Am Soc Clin Oncol 2001; 20:18b (Abstract #1821). 28. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for nodepositive breast cancer. N Engl J Med 2005; 352:2302-2313. 29. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003; 21:976-983.
170 • Clinical Breast Cancer June 2006
30. Mamounas EP, Bryant J, Lembersky C, et al. Paclitaxel (T) following (AC) as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B 28. Proc Am Soc Clin Oncol 2003; 22:4 (Abstract #12). 31. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dosedense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741 [published erratum in J Clin Oncol 2003; 21:2226]. J Clin Oncol 2003; 21:1431-1439. 32. USP DI®. Drug Information for the Health Care Professional. 26th ed; 2006. 33. Kai S, Kohmura H, Hiraiwa, et al. Reproductive and developmental toxicity studies of paclitaxel. (II)--Intravenous administration to rats during the fetal organogenesis. J Toxicol Sci 1994; 19(suppl 1):69-91. 34. Leslie KK. Chemotherapy and pregnancy. Clin Obstet Gynecol 2002; 45:153-164. 35. Watson WJ. Herceptin (trastuzumab) therapy during pregnancy. Obstet Gynecol 2005; 105:642-643.
report
Chemotherapy with Taxanes in Breast Cancer During Pregnancy: Case Report and Review of the Literature Vinaya Potluri,1 David Lewis,2 Gary V. Burton1 Abstract Two patients with breast cancer received docetaxel-containing chemotherapy as adjuvant or neoadjuvant therapy during pregnancy. The first pregnant patient began neoadjuvant therapy with doxorubicin/cyclophosphamide at 14 weeks of gestation. After 4 cycles of doxorubicin/cyclophosphamide and surgery, she received adjuvant docetaxel for 4 cycles. The second patient began neoadjvuant therapy with doxorubicin/docetaxel at 14 weeks of gestation and received 6 cycles. The fetus of the first patient had hydrocephalus on ultrasound at 17 weeks of gestation (before docetaxel therapy) that persisted on serial follow-up ultrasounds and spontaneously regressed over several months after delivery. No fetal malformations were detected in the second fetus. These 2 cases add to the existing data on the use of taxanes during pregnancy. Although the data are limited with case reports, pregnant patients with cancer can be treated with chemotherapy including taxanes during the second and third trimesters without significant risks to the fetus. Taxanes should not be excluded, if indicated, in pregnant patients with cancer. Clinical Breast Cancer, Vol. 7, No. 2, 167-170, 2006 Key words: Cyclophosphamide, Docetaxel, Doxorubicin
Introduction Cancer is the second leading cause of death in the age group between 20 years and 39 years and complicates 1 in 1000 pregnancies.1 By definition, pregnancy-associated cancer includes cancers detected during gestation and immediately after delivery. The common cancers occurring during pregnancy include breast, cervical, lymphoma, melanoma, and leukemia.2 Breast cancer is the most common tumor diagnosed during pregnancy, with the incidence averaging 1 in 3000 pregnancies.3 The frequency of breast cancer diagnosis during pregnancy might be increasing because women today delay childbearing until later in life. The physiologic changes that occur in pregnancy present specific challenges for the detection and management of cancer during pregnancy. Chemotherapy during pregnancy is a challenging problem and an ethical dilemma. There are many case reports and 1Department of Medicine 2Department of Obstetrics and Gynecology Louisiana State University Health Sciences Center Shreveport Submitted: Dec 13, 2005; Revised: Jan 30, 2006; Accepted: Feb 28, 2006 Address for correspondence: Gary V. Burton, MD, Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA 71130 Fax: 318-813-1004; e-mail: [email protected]
retrospective series reporting on the pregnancy outcomes of systemic chemotherapy administered during pregnancies, including regimens containing cyclophosphamide, doxorubicin, 5-fluorouracil (5-FU), and epirubicin.4,5 There is, however, limited information on the use and risk of taxane therapy during pregnancy. There have been 5 reports describing the outcomes of 5 patients receiving paclitaxel during pregnancy (2 in breast cancer and 3 in ovarian cancer)6-10 and only 1 report using docetaxel in a patient with breast cancer during pregnancy.11 We describe the outcomes of 2 additional patients who received docetaxel for breast cancer during pregnancy, with 1 child having a minor but probably unrelated birth defect.
Case Reports Case 1 A 29-year-old woman (gravida 5, para 4) was diagnosed in 2003 with stage IIIA breast cancer at 12 weeks of gestation. The tumor was 85 mm and nonfixed, and axillary lymph nodes were matted and fixed, measuring 35 mm. Biopsy was performed, and pathology was consistent with grade III infiltrating ductal carcinoma. Estrogen and progesterone receptors were positive (42% and 51%), and HER2/neu was positive for overexpression by fluorescence in situ hybridization. The patient began neoadjuvant chemotherapy at 14 weeks
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1526-8209, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Breast Cancer June 2006 • 167
Taxanes for Breast Cancer During Pregnancy of gestation with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks for 4 cycles. The patient had a fetal ultrasound at 17 weeks of gestation that revealed hydrocephalus (dilated lateral and third ventricle). The patient was closely monitored with serial fetal ultrasounds. She underwent a modified radical mastectomy and axillary node dissection at 24 weeks of gestation. The pathologic staging revealed the residual tumor to be 68 mm, and 8 of 11 lymph nodes were positive for tumor. She received 4 cycles of adjuvant docetaxel (75 mg/m2) every 2 weeks between weeks 26 and 32 of gestation. She delivered at 34 weeks, with the infant having mild hydrocephalus, which regressed spontaneously over several months. The patient received radiation therapy followed by adjuvant hormonal therapy. The child’s development has been normal at 28 months.
Case 2 A 38-year-old woman (gravida 2, para 1) was diagnosed in 2005 with stage IIIA breast cancer at 10 weeks of gestation. The tumor measured 63 mm, and the axillary lymph nodes were matted and measured 45 mm. Biopsy results demonstrated poorly differentiated infiltrating ductal carcinoma with estrogen and progesterone receptor positivity (46% and 15%) and HER2/neu negativity by fluorescence in situ hybridization. She began neoadjuvant chemotherapy at 14 weeks of gestation with doxorubicin (60 mg/m2) and docetaxel (75 mg/m2) every 3 weeks for 6 cycles (standard neoadjuvant regimen at Louisiana State University at that time). Fetal ultrasound monitoring demonstrated normal intrauterine growth and development. The patient developed preeclampsia and underwent caesarian delivery at 35 weeks of gestation. The infant was healthy with no detectable malformations. The patient underwent a modified radical mastectomy and axillary node dissection 10 days after delivery. The pathologic specimen had small foci of residual carcinoma with dystrophic calcification, and 13 of 19 lymph nodes were involved. The patient received adjuvant radiation therapy followed by adjuvant hormonal therapy. Development of the infant has been normal at 9 months.
Discussion Breast cancer during pregnancy is likely to be more advanced (because of diagnostic delay)12 with axillary node involvement (56%-67% reported),13 higher incidence of HER2/neu overexpression (reports ranging from 28% to 58%),13-15 and higher incidence of estrogen receptor negativity (54%-80%) compared with age-matched controls.13,15 Mammography with abdominal shielding can be safely performed during pregnancy.16 Mammograms, however, can be difficult to interpret during pregnancy because of physiologic breast changes; therefore, any suspicious breast lesion should be tested by biopsy.17 Breast biopsy during pregnancy can be performed safely by fine needle aspiration, core needle biopsy, or surgical excision. Fine needle aspiration is preferred, because there is a risk of milk fistula associated with core needle biopsy.18
168 • Clinical Breast Cancer June 2006
Breast cancer during pregnancy was previously considered to have a poor prognosis.19 However, most of the recent literature suggests that stage-specific survival for pregnant patients with breast cancer is similar to survival for women who are not pregnant.20,21 The treatment of breast cancer in pregnant patients should not be delayed, and patients should receive the best standard treatment without modification. Breast cancer treatment is multimodality therapy with surgery, systemic chemotherapy, radiation, and hormone therapy. Radiation therapy and hormone therapy with tamoxifen are contraindicated during pregnancy because of potential fetal injury or death. These can usually be delayed until after delivery without affecting patient outcome.22-24 Surgery and chemotherapy have been used during pregnancy without harm to the mother or fetus.4,5 Therapeutic abortion is a patient option; however, optimum cancer therapy can usually be provided after the first trimester without having a deleterious effect on the health of the mother or the child, and there are data suggesting survival is not altered with therapeutic abortion.20,25 The majority of available chemotherapeutic agents (Food and Drug Administration Class D) are considered to have an undefined or definite evidence of fetal risk. More than 2500 agents have been reported to be teratogenic in animal models, although clear evidence of toxicity in the human fetus is available only for a few. Maghfoor and Doll’s review of the literature (updated in 2001) on patients treated with chemotherapy during pregnancy reported that 15% of pregnancies exposed to chemotherapy during the first trimester resulted in fetal malformation, whereas 1.4% exposed during the latter 2 trimesters resulted in fetal malformation.26 Exposure within 1 week of conception can cause spontaneous abortion or have no effect on the fetus. Therefore, chemotherapy should be delayed until the second and third trimester to minimize fetal malformation risk. There are multiple case reports and retrospective series reporting on the management of breast cancer during pregnancy. The M. D. Anderson Cancer Center experience is the only prospective study reported in the literature. Patients at M. D. Anderson Cancer Center were treated with a standardized protocol by a multidisciplinary breast cancer group with surgery and adjuvant or neoadjuvant chemotherapy.4 In an update of this experience, 39 women received 5-FU/doxorubicin/cyclophosphamide chemotherapy for a median of 4 cycles during the second and third trimesters with no reported spontaneous abortions, stillbirths, or fetal anomalies.27 A retrospective London series reported on 28 patients during an 18-year period from 5 hospitals.5 Sixteen of 28 patients received doxorubicin/cyclophosphamide or cyclophosphamide/epirubicin and chemotherapy. Twelve of 28 patients received cyclophosphamide/methotrexate/5-FU. One patient was treated during the first trimester with cyclophosphamide/methotrexate/5-FU and had a spontaneous abortion. All other patients were treated after the first trimester, and no congenital anomalies, spontaneous abortions, or deaths were reported.
Vinaya Potluri et al In women with estrogen receptor–negative, lymph node– positive tumors, there are data to support the addition of a taxane to their chemotherapy regimen.28-30 Data on sequential, dose-dense, adjuvant chemotherapy with doxorubicin/ paclitaxel/cyclophosphamide in patients with * 4 ipsilateral axillary lymph nodes appear promising.31 However, the data in pregnant patients with these regimens are limited. In animal models, docetaxel and paclitaxel have been shown to be toxic to the embryo and fetus during organogenesis. Embryotoxic and fetotoxic effects were characterized by increased intrauterine deaths, decreased fetal weight, and delayed fetal ossification.32,33 There are 3 case reports of patients with breast cancer treated with taxanes. One patient received paclitaxel/epirubicin from 14 weeks to 32 weeks of gestation with no maternal or fetal complications.9 A second patient with bilateral breast cancer received weekly paclitaxel from 20 weeks of gestation and delivered a normal baby.10 A third patient received docetaxel for a rapidly progressive metastatic breast cancer immediately after the first trimester.11 She received 3 cycles of therapy between 23 weeks and 30 weeks of gestation, and a healthy infant was delivered at 32 weeks; the child’s development was normal at 2 years. Treatment with paclitaxel was also reported in 3 patients with ovarian cancer in combination with carboplatin or cisplatin during pregnancy without report of fetal malformation.6-8 Trastuzumab is a useful adjuvant therapy for metastatic HER2/neu–overexpressing breast cancer. HER2 expression is high in embryonic tissues. Animal studies have demonstrated placental transfer without harm to the fetus.34 There is only 1 case report on the use of trastuzumab in pregnancy.35 The patient had received adjuvant trastuzumab for 5 months and was found to be pregnant at 23 weeks of gestation. Ultrasound revealed anhydramnios and a small urinary bladder. Amniotic fluid slowly increased after trastuzumab withdrawal, and the infant had no abnormalities at delivery. Endocrine therapy is delayed until the end of pregnancy, because tamoxifen has been shown to be teratogenic in animal studies as well as in humans. Tamoxifen has been associated with fetal anomalies, including craniofacial defects as well as rare abnormalities like Goldenhar’s syndrome (oculoauriculovertebral dysplasia) and ambiguous genitalia.23,24
Conclusion Although breast cancer detected during pregnancy tends to be of advanced stage and more often hormone receptor negative, the prognosis is similar to that of patients who are not pregnant when matched for age and disease stage. Chemotherapy has been safely administered to pregnant patients after 14 weeks of gestation (ie, after the completion of organogenesis) without significant risk to the fetus or patient. The addition of taxanes to cyclophosphamide and an anthracycline for adjuvant therapy reduces the risk of breast cancer. Chemotherapy including taxanes should be considered for treatment of pregnant women when indi-
cated. This limited experience with 8 patients (case reports) suggests pregnant patients with cancer can be treated with taxane-containing chemotherapy during the second and third trimesters without significant risk to the fetus. A multidisciplinary approach for the management of pregnant patients with breast cancer allows for continuation of pregnancy without maternal health compromise or fetal risk.
References 1. Antonelli NM, Dotters DJ, Katz VL, et al. Cancer in pregnancy: a review of the literature. Part I-II. Obstet Gynecol Surv 1996; 51:125-142. 2. Smith LH, Dalrymple JL, Leiserowitz GS, et al. Obstetrical deliveries associated with maternal malignancy in California, 1992 through 1997. Am J Obstet Gynecol 2001; 184:1504. 3. Donegan WL. Breast carcinoma and pregnancy. In: Donegan WL, Spratt JS, eds. Cancer of the Breast. 4th ed. Philadelphia, PA: Saunders; 1995:732-741. 4. Berry DL, Theriault RL, Holmes FA, et al. Management of breast cancer during pregnancy using a standardized protocol. J Clin Oncol 1999; 17:855. 5. Ring AE, Smith IE, Jones A, et al. Chemotherapy for breast cancer during pregnancy: an 18 year experience from five London teaching hospitals. J Clin Oncol 2005; 23:4192-4197. 6. Sood AK, Shahin MS, Sorosky JI. Paclitaxel and platinum chemotherapy for ovarian carcinoma during pregnancy. Gynecol Oncol 2002; 83:599-600. 7. Mendez LE, Mueller A, Salom E, et al. Paclitaxel and carboplatin chemotherapy administered during pregnancy for advanced epithelial ovarian cancer. Obstet Gynecol 2003; 5:1200-1202. 8. Ferrandina G, Distefano M, Testa A, et al. Management of an advanced ovarian cancer at 15 weeks of gestation: case report and literature review. Gynecol Oncol 2005; 97:693-696. 9. Gadducci A, Cosio S, Fanucchi A, et al. Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and review of the literature. Anticancer Res 2003; 23:5225-5230. 10. Gonzalez-Angulo AM, Walters RS, Carpenter RF Jr, et al. Paclitaxel chemotherapy in a pregnant patient with bilateral breast cancer. Clin Breast Cancer 2004; 5:317-319. 11. De Santis M, Lucchese A, De Carolis S, et al. Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel. Eur J Cancer Care (Engl) 2000; 9:235. 12. Petrek J. Breast cancer and pregnancy. In: Harris JR, Lippman ME, Morrow M, eds. Diseases of the Breast. Philadelphia: Lippincott-Raven; 1996:883. 13. Middleton LP, Amin M, Gwyn K, et al. Breast carcinoma in pregnant women: assessment of clinicopathologic and immunohistochemical features. Cancer 2003; 98:1055-1060. 14. Aziz S, Pervez S, Khan S, et al. Case control study of novel prognostic markers and disease outcome in pregnancy/lactation-associated breast carcinoma. Pathol Res Pract 2003; 199:15-21. 15. Elledge RM, Ciocca DR, Langone G, et al. Estrogen receptor, progesterone receptor, and HER-2/neu protein in breast cancers from pregnant patients. Cancer 1993; 71:2499-2506. 16. Nicklas AH, Baker ME. Imaging strategies in the pregnant cancer patient. Semin Oncol 2000; 27:623-632. 17. Ahn BY, Kim HH, Moon WK, et al. Pregnancy- and lactation-associated breast cancer: mammographic and sonographic findings. J Ultrasound Med 2003; 22:491-497. 18. Schackmuth EM, Harlow CL, Norton LW. Milk fistula: a complication after core breast biopsy. Am J Roentgenol 1993; 161:961. 19. White TT. Carcinoma of the breast and pregnancy; analysis of 920 cases collected from the literature and 22 new cases. Ann Surg 1954; 139:9-18. 20. Zemlickis D, Lishner M, Degendorfer P, et al. Maternal and fetal outcome after breast cancer in pregnancy. Am J Obstet Gynecol 1992; 166:781-787. 21. Merkel DH. Pregnancy and breast cancer. Semin Surg Oncol 1996; 12:370-375. 22. Mayr NA, Wen BC, Saw CB. Radiation therapy during pregnancy. Obstet Gynecol Clin North Am 1998; 25:301-321. 23. Tewari K, Bonebrake RG, Asrat T, et al. Ambiguous genitalia in infant exposed to tamoxifen in utero. Lancet 1997; 350:183.
Clinical Breast Cancer June 2006 • 169
Taxanes for Breast Abbreviated Title Cancer During Pregnancy 24. Cullins SL, Pridjian G, Sutherland CM. Goldenhar’s syndrome associated with tamoxifen given to the mother during gestation. JAMA 1994; 271:1905-1906. 25. King RM, Welch JS, Martin JK Jr, et al. Carcinoma of the breast associated with pregnancy. Surg Gynecol Obstet 1985; 160:228-232. 26. Maghfoor I, Doll DC. Chemotherapy in pregnancy. In: Perry MC, ed. The Chemotherapy Source Book. 3rd ed. Philadelphia: Lippincott Williams &Wilkins; 2001:537. 27. Gwyn K, Theriault R, Sahin A, et al. Treatment of breast cancer (Br Ca) during pregnancy (Pg) using a standard protocol: update of the M.D. Anderson experience. Proc Am Soc Clin Oncol 2001; 20:18b (Abstract #1821). 28. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for nodepositive breast cancer. N Engl J Med 2005; 352:2302-2313. 29. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003; 21:976-983.
170 • Clinical Breast Cancer June 2006
30. Mamounas EP, Bryant J, Lembersky C, et al. Paclitaxel (T) following (AC) as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B 28. Proc Am Soc Clin Oncol 2003; 22:4 (Abstract #12). 31. Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dosedense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup trial C9741/Cancer and Leukemia Group B trial 9741 [published erratum in J Clin Oncol 2003; 21:2226]. J Clin Oncol 2003; 21:1431-1439. 32. USP DI®. Drug Information for the Health Care Professional. 26th ed; 2006. 33. Kai S, Kohmura H, Hiraiwa, et al. Reproductive and developmental toxicity studies of paclitaxel. (II)--Intravenous administration to rats during the fetal organogenesis. J Toxicol Sci 1994; 19(suppl 1):69-91. 34. Leslie KK. Chemotherapy and pregnancy. Clin Obstet Gynecol 2002; 45:153-164. 35. Watson WJ. Herceptin (trastuzumab) therapy during pregnancy. Obstet Gynecol 2005; 105:642-643.