Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
[Downloaded free from http://www.oncotargets.com on Friday, October 28, 2016, IP: 51.39.73.212] Editorial Access this article online Quick Response Code: Website: www.oncotargets.com DOI: 10.4103/2395-4469.192739 Pregnancy‑associated breast cancer: Controversies and consensus! T he term pregnancy‑associated breast cancer (PABC) refers to all breast cancers diagnosed during pregnancy up to 1 year following delivery. PABC accounts for approximately 2% of primary breast cancer patients.[1‑4] The incidence of breast cancer is rising in India and all over the world. This is anticipated to lead to an increased proportion of breast cancer in pregnant women. One of the primary reasons for this is that women tend to postpone childbearing to their thirties.[2‑4] The median age of women diagnosed with PABC is below 35 years.[3] However, the biology of breast cancer in very young women has a more aggressive phenotype.[5,6] The physiological changes associated with normal pregnancy include increase in plasma and red cell volume, physiological anemia, increase in cardiac output, stroke volume, and heart rate and tidal volume.[7,8] There is increased blood flow to kidneys, liver, and most organs. Changes in hematological system are hypercoagulability and alteration in absolute blood cell counts. Gastrointestinal symptoms are nausea, vomiting in early pregnancy and delayed gastric emptying, and constipation in later parts of gestation. Overall pregnancy is a hyperdynamic state and alters the dynamics of drugs administered. This will have an effect on treatment, side effects, monitoring of disease, and oncological outcomes.[9,10] complicate the whole scenario even further. The treating physician should aim at understanding the underlying issues, minimize harm, follow best possible scientific evidence, and also be aware of gaps in available evidence. It is very important to include the pregnant lady and her family at every stage of management and adequate information and support given to them. The key to understanding teratogenic effects is to know the dynamics of substances that cross placental barrier such as molecular weight, protein binding, and bioavailability to the fetus. Chemotherapeutic agents as well as drugs used for treating side effects of chemotherapy and perioperative medication should be screened for potential teratogenic effects.[12] Radiation exposure of the fetus either during investigations or treatment definitely contributes to teratogenic effects. Teratogenic effects are highest if the fetus is exposed to any teratogen in the first trimester. Other concerns during pregnancy are intrauterine growth restriction, intrauterine death, and preterm birth and are caused by interaction of multiple factors related to host, disease, and treatment.[13] Future risk of cancer, genetic mutations, and effect on IQ and learning is not well understood and should not be underestimated. The bioavailability of chemotherapeutic substances in breast milk and functionality of the breast for breastfeeding following surgery along with psychological issues should be addressed. General Principles of Management of Pregnancy‑associated Breast Cancer Principles of Management Specific to Pregnancy‑associated Breast Cancer There are standard international consensus guidelines for management of breast cancer. However, management of newly diagnosed or recurrent breast cancer associated with pregnancy is a sensitive issue and needs multidisciplinary approach. There are many factors which interact in this situation such as highly increased endogenous hormone levels, teratogenic effects of investigations and treatment on the fetus, and safety of breastfeeding making it a unique situation.[11] Emotional and body image issues associated with diagnosis and treatment Any suspicious breast lump should be biopsied under local anesthesia during pregnancy. Ultrasound is safe. Mammography and chest X‑ray with adequate shielding of the abdomen can be offered if necessary. Magnetic resonance imaging is reserved for cases with metastatic potential and should be used with caution as gadolinium crosses the placenta. Bone scan is reserved for suspected skeletal metastasis.[14] © 2016 Oncobiology and Targets | Published by Wolters Kluwer - Medknow Continuation or termination of pregnancy should be discussed with care. Information on treatment 1 [Downloaded free from http://www.oncotargets.com on Friday, October 28, 2016, IP: 51.39.73.212] Bajpai and Shylasree: Pregnancy and breast cancer options based on stage of disease, teratogenicity of drugs, and future fertility should be given before obtaining informed consent. Management of pregnancy is similar to any high‑risk pregnancy emphasizing on the multidisciplinary approach and frequent monitoring of both mother and fetus/baby. Stage versus stage, the management of breast cancer during pregnancy is similar to nonpregnancy and should be managed as closely as possible to standards for young, nonpregnant women with breast cancer.[15,16] Breast surgery is safe during pregnancy as long as blood loss, maternal hypotension, and subsequent fetal hypoxia are minimized. Standard guidelines for anesthesia and positioning of the lady during surgery should be followed.[8] Precautions for preventing deep vein thrombosis and antibiotic prophylaxis should be taken. The physical and psychological effects of surgical stress on pregnancy are not well understood, so an effort to minimize stress wherever possible is desirable. Maternal administration of tocolytic agents and antenatal steroids for improving fetal lung maturity should be considered in threatened preterm labor. Due to detrimental effects of radiation on the fetus, radiation therapy should be withheld until after delivery. Deferring radiotherapy during pregnancy has not shown to worsen the prognosis of the disease significantly. Systemic Therapy in Pregnancy‑associated Breast Cancer Chemotherapy is contraindicated during the first trimester due to potential teratogenicity with possible threefold rise in congenital malformations. In subsequent trimesters, drugs such as anthracyclines and taxanes are relatively safe and should be offered as per standard protocols. However, regular cardiac monitoring of mother and fetus is necessary to avoid complications and fetal loss. There are studies in small number of patients (84, 40, and 10), wherein postchemotherapy exposure in utero, children were found to have normal physical and mental development. In a systematic review after taxane exposure in PABC patients, healthy neonates were born, and 90% of those remain completely healthy at a median follow‑up of 16 months. The antimetabolite methotrexate (in the cyclophosphamide, methotrexate, and 5‑fluorouracil regimen) is contraindicated during pregnancy. Hence, safer regimens which can be used are anthracycline based such as AC, EC, CAF, and CEF (A‑adriamycin, E‑epirubicin, C‑cyclophosphamide, and F‑5 Fluorouracil).[4,15,16] International guidelines (ESMO and NCCN) suggest to completely avoid the use of trastuzumab and lapatinib during pregnancy due to the risk of oligo‑ and/or anhydramnios. Inhibition of vascular endothelial growth factor which regulates amniotic fluid circulation and Her2/neu on fetal renal epithelium is the mechanism behind this side effect. The rate of spontaneous miscarriage is also unacceptably increased to around 25%. Drugs such as nab‑paclitaxel and antiangiogenic drug bevacizumab and other anti‑her2 therapies are also not 2 recommended in PABC due to limited data and high risk of complications.[15,16] Hormonal agents such as tamoxifen affect the growing embryonic tissues and can lead to abortions and congenital abnormalities such as ambiguous genitalia and Goldenhar’s syndrome. Therefore, adjuvant tamoxifen should be stated only after delivery.[15,16] Breastfeeding is generally not recommended when the patient is on chemotherapeutic agents. Supportive Care Granulocyte‑stimulating factors should be used only if absolutely indicated (pregnancy category C); There are limited data for the use of bisphosphonates in this situation.[15,16] The consensus statement in most studies and international panels reads as despite lack of long‑term follow‑up of children exposed in utero to chemotherapy, in light of current existing evidence, when indicated, physicians should not withhold chemotherapy in the second and third trimester to improve survival. However, one should optimize management so as to save both precious lives together.[15,16] Conclusion PABC is a unique situation. As the incidence of PABC is increasing, clinicians should be equipped with knowledge to manage such women. Due to the lack of best‑quality randomized evidence, clinical practice decisions are largely guided by the evidence generated from retrospective analyses, case reports, and a small number of prospective studies. The management should be tailored according to the stage of the pregnancy as well as the malignancy with critical evaluation of the needs of the mother and risks to the fetus. Anthracycline‑based chemotherapy appears safe during the second and third trimesters; limited data demonstrate taxane safety as well, weekly dosing is advantageous to allow closer monitoring with prompt termination of therapy if need arises. Surgery can be done in all trimesters; radiation and targeted therapy (including hormone therapy) should be started after delivery. Long‑term safety data of systemic therapy are sparse. Standard consensus guidelines should be followed and the best dealt with a multidisciplinary approach. Jyoti Bajpai, T. S. Shylasree1 Departments of Medical Oncology and 1Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India Address for correspondence: Dr. Jyoti Bajpai, Department of Medical Oncology, Tata Memorial Hospital, Mumbai ‑ 400 012, Maharashtra, India. E‑mail: [email protected] References 1. Stensheim H, Møller B, van Dijk T, Fosså SD. Cause‑specific survival for women diagnosed with cancer during pregnancy or lactation: A registry‑based cohort study. J Clin Oncol 2009;27:45‑51. Oncobiology and Targets - Vol 3 | 2016 [Downloaded free from http://www.oncotargets.com on Friday, October 28, 2016, IP: 51.39.73.212] Bajpai and Shylasree: Pregnancy and breast cancer 2. Andersson TM, Johansson AL, Hsieh CC, Cnattingius S, Lambe M. Increasing incidence of pregnancy‑associated breast cancer in Sweden. Obstet Gynecol 2009;114:568‑72. 3. Matthews TJ, Hamilton BE. Delayed childbearing: More women are having their first child later in life. NCHS Data Brief 2009;(21):1-8. 4. Bajpai J, Shylasree TS, Joshi S, Shetty N, Swain M, Sarin J, et al. Pregnancy and breast cancer. Converge breast cancer update 2014. Oncology Gold Standard Book Series. ISBN No: 978-81-923972-21;327-344. 5. Collins LC, Marotti JD, Gelber S, Cole K, Ruddy K, Kereakoglow S, et al. Pathologic features and molecular phenotype by patient age in a large cohort of young women with breast cancer. Breast Cancer Res Treat 2012;131:1061‑6. 6. Azim HA Jr., Michiels S, Bedard PL, Singhal SK, Criscitiello C, Ignatiadis M, et al. Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res 2012;18:1341‑51. 7. Lee W. Cardiorespiratory alterations during normal pregnancy. Crit Care Clin 1991;7:763‑75. 8. Yeomans ER, Gilstrap LC 3 rd . Physiologic changes in pregnancy and their impact on critical care. Crit Care Med 2005;33 10 Suppl: S256‑8. 9. Raphael J, Trudeau ME, Chan K. Outcome of patients with pregnancy during or after breast cancer: A review of the recent literature. Curr Oncol 2015;22 Suppl 1:S8‑18. 10. Hahn KM, Johnson PH, Gordon N, Kuerer H, Middleton L, Ramirez M, et al. Treatment of pregnant breast cancer patients Oncobiology and Targets - Vol 3 | 2016 11. 12. 13. 14. 15. 16. and outcomes of children exposed to chemotherapy in utero. Cancer 2006;107:1219‑26. Litton JK, Theriault RL, Gonzalez‑Angulo AM. Breast cancer diagnosis during pregnancy. Womens Health (Lond) 2009;5:243‑9. Leslie KK, Koil C, Rayburn WF. Chemotherapeutic drugs in pregnancy. Obstet Gynecol Clin North Am 2005;32:627‑40. Zemlickis D, Lishner M, Degendorfer P, Panzarella T, Sutcliffe SB, Koren G. Fetal outcome after in utero exposure to cancer chemotherapy. Arch Intern Med 1992;152:573‑6. Kal HB, Struikmans H. Radiotherapy during pregnancy: Fact and fiction. Lancet Oncol 2005;6:328‑33. Loibl S, von Minckwitz G, Gwyn K, Ellis P, Blohmer JU, Schlegelberger B, et al. Breast carcinoma during pregnancy. International recommendations from an expert meeting. Cancer 2006;106:237‑46. Amant F, Deckers S, Van Calsteren K, Loibl S, Halaska M, Brepoels L, et al. Breast cancer in pregnancy: Recommendations of an international consensus meeting. Eur J Cancer 2010;46:3158‑68. This is an open access article distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as the author is credited and the new creations are licensed under the identical terms. How to cite this article: Bajpai J, Shylasree TS. Pregnancyassociated breast cancer: Controversies and consensus!. Oncobiol Targets 2016;3:6. 3