CLINICAL OBSTETRICS AND GYNECOLOGY Volume 59, Number 4, 779–788 Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Pregnancy-associated Breast Cancer ASHLEY S. CASE, MD Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mountain Area Health Education Center, Hope Women’s Cancer Center, Asheville, North Carolina Abstract: Breast cancer is one of the most common malignancies affecting pregnancy. Pregnancyassociated breast cancer refers to breast cancer that is diagnosed during pregnancy or within the first postpartum year. The incidence is increasing as more women delay childbearing. Breast cancer can be safely diagnosed, staged, and treated during pregnancy while protecting the fetus and mother with excellent outcomes for both. Avoiding diagnostic delays is vital to prognosis. This article provides an overview of the diagnosis, staging, management, and prognosis of pregnancy-associated breast cancer. Relevant current literature is reviewed. Key words: pregnancy, breast cancer, treatment
Introduction Pregnancy-associated breast cancer (PABC) refers to breast cancer that is diagnosed during pregnancy or within the first postpartum year. As many as 1 in 5 breast cancers diagnosed in women younger than 30 years is associated with a pregnancy. Although breast cancer is one of the most frequently occurring cancers in women of reproductive age, PABC is still a rare event. The incidence is approximately Correspondence: Ashley S. Case, MD, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mountain Area Health Education Center, Hope Women’s Cancer Center, 100 Ridgefield Court, Asheville, NC. E-mail: [email protected] The author declares that there is nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
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15 to 35 per 100,000 deliveries with more cases diagnosed during the first postpartum year.1,2 This constitutes approximately 7% of all breast cancers in women below 45 years of age. The incidence has been shown to be increasing likely related to higher rates of cancer in general as well as a delay in childbearing to a later maternal age for personal and professional reasons. Breast cancer incidence does increase with age, and the majority of women who are diagnosed with PABC are between 32 and 38 years of age. PABC presents a unique and often challenging scenario in that the situation necessitates careful consideration of the best interests of both the mother and fetus. Care should involve a multidisciplinary team including an obstetrician, maternalfetal medicine specialist, medical oncologist, surgical oncologist, nutritionist, geneticist, neonatologist, pharmacist, social worker, and psychosocial support services. Treatment decisions are individualized and consider disease extent, minimizing harm to the fetus, gestational age, pregnancy impact, and fertility planning. Although earliest studies recommended termination of pregnancy, most recent literature suggests that PABC can be safely managed with good outcomes. VOLUME 59
/
NUMBER 4
/
DECEMBER 2016
www.clinicalobgyn.com | 779
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
780
Case
Diagnosis A diagnosis of PABC is more complicated and often confounded by the physiological changes that accompany pregnancy. Normal physiological changes including engorgement and tenderness that occur to the breast during pregnancy may compromise the physical exam, make small masses more difficult to detect, and may limit the utility of mammography. Lack of detection, hesitation to proceed with testing due to fear of fetal harm, and limitations of imaging may lead to delays in diagnosis. An average delay of 5 to 15 months from the onset of symptoms has been reported.3,4 Avoiding a delay in diagnosis is vital as these delays will adversely affect outcomes. Even a 1 month delay in diagnosis can increase the risk of nodal involvement by 1% to 2%.5 PABC generally presents as a painless palpable mass, skin changes including thickening, or bloody nipple discharge. A complete breast exam including the axilla is recommended at first prenatal visit. Breast self-awareness should be emphasized with any new changes detected during pregnancy addressed promptly. Providers should have a high index of suspicion and any mass that has been present for more than 2 weeks should be evaluated further with imaging and/or biopsy, even though most masses will be benign. Newly found masses should not be attributed to pregnancy changes alone. Differential diagnoses of breast masses in pregnancy include a lactating adenoma, fibroadenoma, cystic disease, lobular hyperplasia, mild retention cyst (galactocele), abscess, lipoma, hamartoma, leukemia, lymphoma, phyllodes tumor, sarcoma, neuroma, or tuberculosis. Mammography and ultrasound are the recommended imaging modalities to evaluate a breast mass in pregnancy. These evaluations as well as a core needle biopsy for a suspicious finding can all be safely performed during pregnancy at any gestational age. A fine needle aspiration may not be reliable due to the normal hyperproliferative changes in the
breast during pregnancy. Ultrasound is often the first imaging modality utilized to evaluate a breast mass in pregnancy. Ultrasound is useful in evaluating a mass for cystic or solid components, characterizing margins, echo pattern, shape, vascularity, and acoustic features. In addition regional lymph nodes can be evaluated. Sensitivity and specificity are not altered by pregnancy.6 In contrast to ultrasound, changes in density as well as increased water and decreased fat content of the breasts in pregnancy may alter the mammographic appearance of a mass. Despite these limitations, mammography is recommended during pregnancy to detect microcalcifications, architectural distortion, focal asymmetry, masses, or multifocal disease. Mammography has a sensitivity of approximately 86% during pregnancy.6 With abdominal shielding mammography has minimal fetal risks; average fetal radiation is estimated at 0.004 Gy.7,8 Many patients and physicians have undue anxiety regarding the radiation exposure and this should be addressed. The threshold for negative effects of radiation on the fetus is approximately 100 mGy, with uncertainty at doses between 50 and 100 mGy.9 Magnetic resonance imaging (MRI) requires the use of gadolinium which crosses the placenta with unknown fetal effects. The sensitivity and specificity in pregnant women has not been reported and images may be difficult to interpret with normal physiological changes in the breast during pregnancy. MRI also requires women to be prone for the study. Although no harmful effects have been reported, the National Radiological Protection Board advises that MRI be avoided in the first trimester if possible during organogenesis.10 MRI can be considered after the first trimester if further imaging is warranted for treatment planning. Any suspicious breast mass during pregnancy should be biopsied for definitive diagnosis with core needle biopsy
www.clinicalobgyn.com
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Pregnancy-associated Breast Cancer being the preferred technique. Confirmed cancers should also undergo testing for hormone receptor status and human epidermal growth factor receptor 2 (HER2) overexpression. Clinically concerning lymph nodes should also undergo fine needle aspiration or core biopsy. The pathologist should be alerted of the pregnancy due to the hyperproliferative changes of the breast during pregnancy. The most common histologic type of PABC is invasive ductal carcinoma. Unfortunately, many of these cancers are poorly differentiated and compared with nonpregnant women, diagnosed in more advanced stages.11,12 In addition, estrogen receptor and progesterone receptor are less likely to be expressed in PABC.13 However, hormone receptor-positive disease is more often seen in postmenopausal women and age at diagnosis may be the driving biological feature rather than the pregnancy. Also, high levels of estrogen and progesterone found in pregnancy can bind receptor sites resulting in false-negative assays. The percentage of HER2-positive tumors appears to be similar to nonpregnant women. In general, tumor mutations do not differ between pregnant and nonpregnant women, although small series have shown differences in gene expression analyses.14 A thorough family history must be taken and genetic counseling should be offered according to national guidelines. Many women with PABC will meet the guidelines for testing due in part to their young age and a positive test will impact treatment recommendations. In young women with triple-negative breast cancer, the probability of detecting a germline BRCA mutation is approximately 20%.15 A staging evaluation follows diagnosis utilizing the TNM staging system of the American Joint Committee on Cancer. Studies which will affect treatment planning or management should be performed, and since breast cancer is often diagnosed at an advanced stage during
781
pregnancy, comprehensive staging studies are often necessary. The risk of not staging is often greater than potential harm to the fetus. Imaging modifications may be implemented to minimize radiation to the fetus. Most common metastatic sites include the lungs, liver, and bone. Chest x-rays with abdominal shielding to evaluate the lungs and abdominal ultrasounds to evaluate the liver are safe during pregnancy. A chest x-ray with abdominal shielding leads to a fetal exposure of 0.0001 Gy.16 Computed tomography scans are usually avoided due to the radiation dose with MRI being preferred to evaluate visceral organs. Bone scans can often be delayed until postpartum, but if a woman is symptomatic or metastases are suspected a noncontrast skeletal MRI is a safe way to evaluate for bony metastasis. Another option is a ‘‘low-dose’’ bone scan that has been described to expose the fetus to 0.08 rad as compared with the standard 0.19 rad for a conventional bone scan.17 Other modifications for a bone scan in pregnancy include using an indwelling catheter to drain radioactive material quickly from the bladder along with aggressive hydration. Alkaline phosphatase does increased during pregnancy due to placental production and is not indicative of bony disease. MRI of the brain can be performed on women with central nervous system symptoms to evaluate for brain metastases. Information on the safety and efficacy of positron-emission tomography during pregnancy is limited and further investigation is required. Baseline laboratory evaluation including liver and renal function should be completed. An echocardiogram should be considered before anthracycline chemotherapy. A thorough obstetric evaluation should be performed along with frequent monitoring of the pregnancy by a skilled obstetrician. Many women are followed by a specialist in maternal-fetal medicine. Fetal dates must be confirmed since the www.clinicalobgyn.com
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
782
Case
gestational age is important in treatment planning. Amniocentesis to document pulmonary maturity may be required for early delivery considerations.
Treatment Treatment of PABC is essentially according to the guidelines of nonpregnant women with some therapeutic decision modifications for consideration of the fetus. Treatment decisions are individualized with informed consent being an important component in each individual plan. Gestational age, stage of disease, preferences of patient and family are all important components in formulating treatment recommendations. Most importantly, treatment should not be delayed due to the pregnant state. These unnecessary delays may be associated with worse disease-free survival as well as increased risks of metastases and disease progression.5,18 Goals of treatment are the same as for nonpregnant women and are to control the cancer locally and prevent systemic spread. Some women will elect to terminate the pregnancy. This is an individualized complex decision that requires input from a multidisciplinary clinical team and should only be made once all options have been discussed and the patient is fully informed. Discussions involve risks of fetal toxicity or maternal health complications from treatment during pregnancy, prognosis, ability to care for her infant/child, and effects of treatment on future fertility. Early termination does not improve outcomes for women with PABC.19 Patients should be made aware that cancer can be safely managed during pregnancy with good outcomes for both the mother and fetus. With the exception of local radiation, the same options are recommended for local treatment in the pregnant and nonpregnant state. Surgical options include mastectomy or breast conserving surgery along with axillary lymph node dissection or sentinel lymph node biopsy. Breast
and axillary lymph node dissection during any trimester of pregnancy are associated with minimal fetal risk.2,20,21 A conversation regarding the pros and cons of each approach is similar to the conversation undertaken with women in the nonpregnant state. There is not a survival advantage of mastectomy over breast conservation for PABC. For those women who elect to proceed with breast conserving surgery, radiation is generally delayed until after delivery. The necessary dosage may result in too high a fetal exposure. Usual radiation treatment doses are between 46 and 60 Gy. This could result in a first trimester fetal dose of 0.04 to 0.15 Gy, or a third trimester dose as high as 2 Gy.22,23 Although it is undetermined as to the exact threshold for congenital malformations, it is suggested that the threshold for possible effects is 0.10 to 0.20 Gy in fetuses
Pregnancy-associated Breast Cancer ASHLEY S. CASE, MD Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mountain Area Health Education Center, Hope Women’s Cancer Center, Asheville, North Carolina Abstract: Breast cancer is one of the most common malignancies affecting pregnancy. Pregnancyassociated breast cancer refers to breast cancer that is diagnosed during pregnancy or within the first postpartum year. The incidence is increasing as more women delay childbearing. Breast cancer can be safely diagnosed, staged, and treated during pregnancy while protecting the fetus and mother with excellent outcomes for both. Avoiding diagnostic delays is vital to prognosis. This article provides an overview of the diagnosis, staging, management, and prognosis of pregnancy-associated breast cancer. Relevant current literature is reviewed. Key words: pregnancy, breast cancer, treatment
Introduction Pregnancy-associated breast cancer (PABC) refers to breast cancer that is diagnosed during pregnancy or within the first postpartum year. As many as 1 in 5 breast cancers diagnosed in women younger than 30 years is associated with a pregnancy. Although breast cancer is one of the most frequently occurring cancers in women of reproductive age, PABC is still a rare event. The incidence is approximately Correspondence: Ashley S. Case, MD, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mountain Area Health Education Center, Hope Women’s Cancer Center, 100 Ridgefield Court, Asheville, NC. E-mail: [email protected] The author declares that there is nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
/
15 to 35 per 100,000 deliveries with more cases diagnosed during the first postpartum year.1,2 This constitutes approximately 7% of all breast cancers in women below 45 years of age. The incidence has been shown to be increasing likely related to higher rates of cancer in general as well as a delay in childbearing to a later maternal age for personal and professional reasons. Breast cancer incidence does increase with age, and the majority of women who are diagnosed with PABC are between 32 and 38 years of age. PABC presents a unique and often challenging scenario in that the situation necessitates careful consideration of the best interests of both the mother and fetus. Care should involve a multidisciplinary team including an obstetrician, maternalfetal medicine specialist, medical oncologist, surgical oncologist, nutritionist, geneticist, neonatologist, pharmacist, social worker, and psychosocial support services. Treatment decisions are individualized and consider disease extent, minimizing harm to the fetus, gestational age, pregnancy impact, and fertility planning. Although earliest studies recommended termination of pregnancy, most recent literature suggests that PABC can be safely managed with good outcomes. VOLUME 59
/
NUMBER 4
/
DECEMBER 2016
www.clinicalobgyn.com | 779
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
780
Case
Diagnosis A diagnosis of PABC is more complicated and often confounded by the physiological changes that accompany pregnancy. Normal physiological changes including engorgement and tenderness that occur to the breast during pregnancy may compromise the physical exam, make small masses more difficult to detect, and may limit the utility of mammography. Lack of detection, hesitation to proceed with testing due to fear of fetal harm, and limitations of imaging may lead to delays in diagnosis. An average delay of 5 to 15 months from the onset of symptoms has been reported.3,4 Avoiding a delay in diagnosis is vital as these delays will adversely affect outcomes. Even a 1 month delay in diagnosis can increase the risk of nodal involvement by 1% to 2%.5 PABC generally presents as a painless palpable mass, skin changes including thickening, or bloody nipple discharge. A complete breast exam including the axilla is recommended at first prenatal visit. Breast self-awareness should be emphasized with any new changes detected during pregnancy addressed promptly. Providers should have a high index of suspicion and any mass that has been present for more than 2 weeks should be evaluated further with imaging and/or biopsy, even though most masses will be benign. Newly found masses should not be attributed to pregnancy changes alone. Differential diagnoses of breast masses in pregnancy include a lactating adenoma, fibroadenoma, cystic disease, lobular hyperplasia, mild retention cyst (galactocele), abscess, lipoma, hamartoma, leukemia, lymphoma, phyllodes tumor, sarcoma, neuroma, or tuberculosis. Mammography and ultrasound are the recommended imaging modalities to evaluate a breast mass in pregnancy. These evaluations as well as a core needle biopsy for a suspicious finding can all be safely performed during pregnancy at any gestational age. A fine needle aspiration may not be reliable due to the normal hyperproliferative changes in the
breast during pregnancy. Ultrasound is often the first imaging modality utilized to evaluate a breast mass in pregnancy. Ultrasound is useful in evaluating a mass for cystic or solid components, characterizing margins, echo pattern, shape, vascularity, and acoustic features. In addition regional lymph nodes can be evaluated. Sensitivity and specificity are not altered by pregnancy.6 In contrast to ultrasound, changes in density as well as increased water and decreased fat content of the breasts in pregnancy may alter the mammographic appearance of a mass. Despite these limitations, mammography is recommended during pregnancy to detect microcalcifications, architectural distortion, focal asymmetry, masses, or multifocal disease. Mammography has a sensitivity of approximately 86% during pregnancy.6 With abdominal shielding mammography has minimal fetal risks; average fetal radiation is estimated at 0.004 Gy.7,8 Many patients and physicians have undue anxiety regarding the radiation exposure and this should be addressed. The threshold for negative effects of radiation on the fetus is approximately 100 mGy, with uncertainty at doses between 50 and 100 mGy.9 Magnetic resonance imaging (MRI) requires the use of gadolinium which crosses the placenta with unknown fetal effects. The sensitivity and specificity in pregnant women has not been reported and images may be difficult to interpret with normal physiological changes in the breast during pregnancy. MRI also requires women to be prone for the study. Although no harmful effects have been reported, the National Radiological Protection Board advises that MRI be avoided in the first trimester if possible during organogenesis.10 MRI can be considered after the first trimester if further imaging is warranted for treatment planning. Any suspicious breast mass during pregnancy should be biopsied for definitive diagnosis with core needle biopsy
www.clinicalobgyn.com
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Pregnancy-associated Breast Cancer being the preferred technique. Confirmed cancers should also undergo testing for hormone receptor status and human epidermal growth factor receptor 2 (HER2) overexpression. Clinically concerning lymph nodes should also undergo fine needle aspiration or core biopsy. The pathologist should be alerted of the pregnancy due to the hyperproliferative changes of the breast during pregnancy. The most common histologic type of PABC is invasive ductal carcinoma. Unfortunately, many of these cancers are poorly differentiated and compared with nonpregnant women, diagnosed in more advanced stages.11,12 In addition, estrogen receptor and progesterone receptor are less likely to be expressed in PABC.13 However, hormone receptor-positive disease is more often seen in postmenopausal women and age at diagnosis may be the driving biological feature rather than the pregnancy. Also, high levels of estrogen and progesterone found in pregnancy can bind receptor sites resulting in false-negative assays. The percentage of HER2-positive tumors appears to be similar to nonpregnant women. In general, tumor mutations do not differ between pregnant and nonpregnant women, although small series have shown differences in gene expression analyses.14 A thorough family history must be taken and genetic counseling should be offered according to national guidelines. Many women with PABC will meet the guidelines for testing due in part to their young age and a positive test will impact treatment recommendations. In young women with triple-negative breast cancer, the probability of detecting a germline BRCA mutation is approximately 20%.15 A staging evaluation follows diagnosis utilizing the TNM staging system of the American Joint Committee on Cancer. Studies which will affect treatment planning or management should be performed, and since breast cancer is often diagnosed at an advanced stage during
781
pregnancy, comprehensive staging studies are often necessary. The risk of not staging is often greater than potential harm to the fetus. Imaging modifications may be implemented to minimize radiation to the fetus. Most common metastatic sites include the lungs, liver, and bone. Chest x-rays with abdominal shielding to evaluate the lungs and abdominal ultrasounds to evaluate the liver are safe during pregnancy. A chest x-ray with abdominal shielding leads to a fetal exposure of 0.0001 Gy.16 Computed tomography scans are usually avoided due to the radiation dose with MRI being preferred to evaluate visceral organs. Bone scans can often be delayed until postpartum, but if a woman is symptomatic or metastases are suspected a noncontrast skeletal MRI is a safe way to evaluate for bony metastasis. Another option is a ‘‘low-dose’’ bone scan that has been described to expose the fetus to 0.08 rad as compared with the standard 0.19 rad for a conventional bone scan.17 Other modifications for a bone scan in pregnancy include using an indwelling catheter to drain radioactive material quickly from the bladder along with aggressive hydration. Alkaline phosphatase does increased during pregnancy due to placental production and is not indicative of bony disease. MRI of the brain can be performed on women with central nervous system symptoms to evaluate for brain metastases. Information on the safety and efficacy of positron-emission tomography during pregnancy is limited and further investigation is required. Baseline laboratory evaluation including liver and renal function should be completed. An echocardiogram should be considered before anthracycline chemotherapy. A thorough obstetric evaluation should be performed along with frequent monitoring of the pregnancy by a skilled obstetrician. Many women are followed by a specialist in maternal-fetal medicine. Fetal dates must be confirmed since the www.clinicalobgyn.com
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
782
Case
gestational age is important in treatment planning. Amniocentesis to document pulmonary maturity may be required for early delivery considerations.
Treatment Treatment of PABC is essentially according to the guidelines of nonpregnant women with some therapeutic decision modifications for consideration of the fetus. Treatment decisions are individualized with informed consent being an important component in each individual plan. Gestational age, stage of disease, preferences of patient and family are all important components in formulating treatment recommendations. Most importantly, treatment should not be delayed due to the pregnant state. These unnecessary delays may be associated with worse disease-free survival as well as increased risks of metastases and disease progression.5,18 Goals of treatment are the same as for nonpregnant women and are to control the cancer locally and prevent systemic spread. Some women will elect to terminate the pregnancy. This is an individualized complex decision that requires input from a multidisciplinary clinical team and should only be made once all options have been discussed and the patient is fully informed. Discussions involve risks of fetal toxicity or maternal health complications from treatment during pregnancy, prognosis, ability to care for her infant/child, and effects of treatment on future fertility. Early termination does not improve outcomes for women with PABC.19 Patients should be made aware that cancer can be safely managed during pregnancy with good outcomes for both the mother and fetus. With the exception of local radiation, the same options are recommended for local treatment in the pregnant and nonpregnant state. Surgical options include mastectomy or breast conserving surgery along with axillary lymph node dissection or sentinel lymph node biopsy. Breast
and axillary lymph node dissection during any trimester of pregnancy are associated with minimal fetal risk.2,20,21 A conversation regarding the pros and cons of each approach is similar to the conversation undertaken with women in the nonpregnant state. There is not a survival advantage of mastectomy over breast conservation for PABC. For those women who elect to proceed with breast conserving surgery, radiation is generally delayed until after delivery. The necessary dosage may result in too high a fetal exposure. Usual radiation treatment doses are between 46 and 60 Gy. This could result in a first trimester fetal dose of 0.04 to 0.15 Gy, or a third trimester dose as high as 2 Gy.22,23 Although it is undetermined as to the exact threshold for congenital malformations, it is suggested that the threshold for possible effects is 0.10 to 0.20 Gy in fetuses
