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Neurodevelopment of Children Exposed in-Utero to Chemotherapy for Maternal Breast Cancer (Dr. I Nulman)
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Pregnancy in Women with Multiple Sclerosis
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Cancer in Pregnancy: Breast Cancer in Pregnancy
Breast cancer is the most common tumor of reproductive age. Three percent of breast cancer occurs in pregnancy. This translates to a rate of 10 - 40 cases per 100,000 deliveries. About 15% of breast cancers are seem in women of child-bearing age and there is evidence that the incidence of breast cancer in premenopausal women is increasing. In addition, the current trend to defer pregnancy unitl later in life may increase the incidence of breast cancer in pregnancy. However, because of the relative rareness of this association, there is a paucity of information on the effects of the disease and its therapy on pregnancy outcome.
A high index of suspicion is required in the evaluation of a mass in the breast of a pregnant woman. During pregnancy, a woman's body undergoes substantial physiological changes, including enlargement of the breasts, which makes it more difficult to notice the small lumps that forewarn one of cancer. Also it is probable that women and their physicians relate findings consistent with breast cancer to pregnancy-induced engorgement. It has been reported that the average delay from first symptoms to treatment exceeds 5 months.1 Also, we reported that a pregnant woman has 2.5 fold higher risk of being diagnosed with metastatic breast cancer and a decreased chance of diagnosis of stage I 2. Similar findings have been reported also by other authors 3,4.
To detect breast cancer, pregnant and lactating women should practice self-examination and be examined by a physician as a part of the routine prenatal care. A finding of a suspicious mass should lead, without delay, to a diagnostic evaluation. Mammograms are not performed routinely due to concern about fetal irradiation. However, a bilateral mammographic examination of both breasts with modern equipment would yield less than 50 mrad (500 µGy) to the human embryo5 which is well below the 10 rad (100 mGy) toxic level. However, it is likely that the sensitivity of mammography is diminished during pregnancy due to increased glandularity and water content of the breast. 6,7 Breast ultrasonography is accurate and safe in differentiating cysts from solid tumors6. Thus the shortcomings of the non-invasive diagnostic procedures mandate a proper tissue sampling, in a timely manner, in most patients with suspicious lesion.
Fine needle aspiration (FNA) of a suspected lesion in the breast carries the risk of both falsely positive and negative results. The hyper-proliferative cellular state of the mammary tissue leads to the possibility of false positive diagnosis of malignancy. On the other hand the needle technique runs the risk of missing the mass.8 Although excisional biopsy under local anesthesia during pregnancy may be problematic because of hypervascularity and edema with risks of post-operative hematoma, infection and milk fistula, it should be performed. There is no evidence to suggest that a breast biopsy constitutes a risk to the mother or the fetus. Determination of receptor hormonal status by immunochemistry technique is indicated for treatment accuracy.
Most recent reports do not show an advantage in survival after therapeutic abortion8.
Metatastic workup can be performed during pregnancy but should be limited to those situations in which there is a high suspicion of metastasis and their establishment would alter the course of therapy. This problem is complicated by the fact that some tests utilized for staging require ionizing radiation which may be harmful to the developing fetus.
Pathology and Biology
The pathology is identical to that found in non-pregnant women, including the incidence of inflammatory carcinoma of 1.5-4 percent 9. However recent histopathological reports of 14 cases found that breast carcinomas diagnosed in pregnancy are mostly estrogen and progesterone receptor negative with a higher incidence of cancerization of lobus and of grade 3 invasive ductal carcinomas 10. The stage distribution at the time of presentation is as follows: stage 1: 28%, stage 2: 30% and stage 3 and 4: 42% 11.Very little information is available about the accuracy and the value of steroid hormone receptor status during pregnancy. Most probably, pregnant women, like most young patients, are estrogen receptor and progesterone receptor negative. No data on pregnant patients with accurate hormone receptor status exist for formulating recommendations on therapeutic abortions, hormonal manipulation or subsequent pregnancies.
Early stage cancer - Stage I and II
About 60% of pregnant women with breast cancer present with early stage cancer. Stages I and II breast cancers are best treated with surgery. A modified radical mastectomy is currently the standard treatment for early stage disease 8-12. When the mother is near term, treatment can be delayed until delivery, at which time breast conservation surgery and definitive breast irradiation can be administered. Lumpectomy with radiation therapy during pregnancy may provide high doses of radiation exposure to the fetus 13. A recent report suggested that the fetal dose is low, no biological effects or the radiation on the embryo are expected 14. If adjuvant chemotherapy is considered necessary, it should be delayed until the second trimester (see below). See also - General anesthesia during pregnancy
Late stage cancer - Stages III and IV
Advanced stage III and IV breast cancer usually requires chemotherapy after surgical resection of the tumor. Radiation treatment may be necessary for local control.
Cancer chemotherapeutic drugs are very potent teratogens. Currently, there is very little information on the effect of cancer chemotherapy on the fetus 15. The risk of malformations when chemotherapy is administered in the first trimester has been estimated to be approximately 10% for single agent chemotherapy regimens and 25% for combination chemotherapy 16,17. Thus chemotherapeutic agents should be avoided during the first trimester. There is no evidence of an increased risk of teratogenicity during second and third trimesters 15. A recent report on a small series of breast cancer patients confirmed, in a prospective manner, that chemotherapy is indeed effective and safe when administered after the first trimester18.
The long-term nonteratogenic effects of chemotherapy remain largely unknown. There have been reports on increased risk of stillbirth, lowbirth weight and intrauterine growth retardation following treatment in the second and third trimester 2,15,19. When chemotherapy is administered during pregnancy, delivery of the infant should be timed to avoid the chemotherapy nadir and its associated problems. Only few reports associate chemotherapy administered to the mother with neonate hematopoietic depression which is self-limiting but increases the risk of neonatal infection and hemorrhage 20. The very limited available information does not suggest that children, born to mothers who were treated with chemotherapy during pregnancy, may have impaired mental and physical development and infertility 20,21. The incidence of second malignancies in these children should be evaluated. To date there is only a single case report that describes the occurrence of multiple malignancies in a son of a patient with acute lymphocytic leukemia who was exposed in utero to cyclophosphamide and steroids. His twin sister was not affected22. Antineoplastic agents administered systematically may reach significant levels in breast milk, therefore breastfeeding is contraindicated.
Systemic complications of cancer or its treatment during pregnancy
Most series report that actual survival and disease free survival are the same in gestational and non-gestational women with breast cancer matched by age and stage 2,12,23. However, pregnant women have a significantly higher risk of being diagnosed with metastatic disease. The detection of breast cancer in advanced stages during pregnancy is probably related to delayed diagnosis and compromises survival 2,12,24.Young women, pregnant or not, usually have estrogen receptor negative tumors which have a biologically aggressive course and carry a poor prognosis. Thus, physiological elevation of circulating hormones in pregnancy should not affect the aggressiveness of ER negative tumors. This is supported by the similar survival of matched non-pregnant controls and by the lack of survival benefit with termination of pregnancy 2,25. Studies have also revealed that prior and subsequent pregnancy are important prognostic factors.
Chidren born to women with breast cancer are more likely to be preterm and/or have a small birth weight for gestational age. Also, there is a higher rate of stillbirth in pregnancy probably due to suboptimal intrauterine conditions 2. The adverse effects of chemotherapy and radiotherapyduring pregnancy have already been discussed. Although the results pertaining to children's neurodevelopment in the majority of reports are encouraging, mental health effects, as well as cognitive and behavioural effects merit close attention. There are no reports of breast cancer associated with fetal metastasis. A recent review described placental metastasis in eight women. All these pregnancies resulted in healthy infants 26.
Cytotoxic agents administered systematically may reach significant levels in breast milk and affect the nursing baby. Therefore breastfeeding is contraindicated during chemotherapy administration. Also, lactation should be stopped before diagnostic open breast biopsy due to the high complication rate including infection and milk fistula.
Despite limited data, it appears that in utero exposure to chemotherapy is not associated with significant gonadal dysfunction. Secondary sexual development signs in different research cohorts and direct evidence of normal fertility in a few cases indicate that there are no adverse effects of exposure to chemotherapy during fetal life on fertility during adolescence.
- Max MH, Kalmer TW: Pregnancy and breast cancer. South Med J. 76:1088-1090, 1983.
- Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Burke B, Sutcliffe SB, Koren G,: Maternal and fetal outcome after breast cancer in pregnancy. Ame. J. Obstet Gynecol 166:781-7,1992.
- Nugent P, O'Connel TX: Breast cancer and pregnancy. Arch Surg 120:1221-1224, 1985.
- Ribeiro G, Jones DA, Jones M: Carcinoma of the breast associated with pregnancy. Br J Surg 73:607-609,1986.
- Wagner LK, Lester RG, Saldana L: Exposure of the pregnant patient to diagnostic radiations: A guide to medical management. Philadelphia, Pa:Lippincot pp. 40-60, 1985.
- Liberman L, Giess CA, Dershaw DD, Deutch BM, Petreck JA: Imaging of pregnancy-associated breast cancer. Radiology 191:245-248,1994.
- Barnavon Y, Wallack MK: Management of the pregnant patient with carcinoma of the breast. Surg, Gynecol & Obstet. 171:347-352,1990.
- Petreck JA. Breast cancer during pregnancy. Cancer 74:518-527,1994.
- Clark RM, Reid J: Carcinoma of the breast in pregnancy and lactation.Int J Radiat Oncol Biol Phys. 4:693-698, 1978.
- Shousha S: Breast carcinoma presenting during or shortly after pregnancy and lactation. Arch Pathol Lab Med 124(7): 1053-60, 2000.
- Scotte K, Cocquyt V, Van den Broecke R., Dhondt M., Van Belle S.: Breast cancer during pregnancy: cases and review of treatment and prognosis. Acta Clin Belg 55(2):102-9, 2000.
- Difronzo LA, O'Connel TX: Breast cancer in pregnancy and lactation.Surg. Clin. of N. America 76:267-278, 1996.
- Florica JV: Breast cancer and pregnancy. Obstet and Gynecol Clin of N.America 2:721-732,1994.
- Antypas C, Sandilos P, Kouvavis J et al. Fetal dose evaluation during breast cancer radiotherapy. Int J Radiat Oncol Biol phys 40: 995-999, 1998.
- Zemlickis D, Lishner M, Koren G: Review of fetal effects of cancer chemotherapeutic agents. In: Koren G, Lishner M, Farine D (eds): Cancer in Pregnancy. Cambridge University Press, pp 168-180,1996.
- Doll DC, Ringenberg S, Yarbro YW: Management of cancer during pregnancy. Arch Intern Med 148:2058-2064,1988.
- Nicholson Ho: Cytotoxic drugs in pregnancy: Review of reported cases .J. Obsetet Gynecol Br Common W. 75:307-312,1968.
- Berry DL, Theriault RL, Holmes FA, Parisi VM et al: Management of breast cancer during pregnancy using a standardized protocol. J. Clin. Oncol. 17:855-861, 1999.
- Zemlickis D, Lishner M, Degendrofer P, Panzarella T, Sutcliffe SB,Koren G: Fetal outcome following in utero exposure to cancer chemotherapy:The Toronto study. Arch. Intern. Med 15:573-576, 1992.
- Blatt J, Milvihill JJ, Ziegler JL et al: Pregnancy outcome following cancer chemotherapy. Ame. J. Med 39:828-832,1980.
- Aviles A, Diaz-Maqueo JC, Talavera A, Guzman R, Garcia EL. Growth and development of children of mothers treated with chemotherapy during pregnancy. Current status of 43 children. Am. J. Hematol 36:243-248,1991.
- Zemlickis D, Lishner M, Erlich R, Koren G: Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide.Teratogenesis, Cacinogen, Mutagen 13:139-143,1993.
- Tretli S, Kyalheim G, Thoreson S et al: Survival of breast cancer patients diagnosed during pregnancy or lactation. Br J Cancer58:382-384,1988.
- Anderson BO, Petrek JA, Byrd DR Senie RT, Borgen PJ. Pregnancy influences breast cancer stage at diagnosis in women 30 years of age and younger. Annals of Surg. Oncol 3: 204-11, 1996.
- Antonelli NM, Dotters DJ, Katz VL, Kuller JA. Cancer in pregnancy: A review of the literature. Obstet & Gynecol survey 51:125-142,1996.
- Dildy-III GA, Moise Jr KJ, Carpenter JR RJ et al: Maternal malignancy metastatic to the products of conception: A review. Obstet Gynecol Srv.44:535-540, 1989.