Overall survival rates are similar in pregnant women with breast cancer and in nonpregnant women with the disease when both groups receive the same treatment, results from an international study have shown (JCO 2013;31:2532-2539).
“It had been believed that the prognosis of breast cancer in pregnant women was worse than in nonpregnant women,” said the study's corresponding author, Frédéric Amant, MD, PhD, of the Multidisciplinary Breast Cancer Center at University Hospitals Leuven and the Department of Oncology at the Katholieke Universiteit Leuven in Belgium. “This was used as motivation to interrupt pregnancy, but abortion doesn't improve prognosis.”
This new data—the largest cohort study to date—however, show that pregnant women with breast cancer should be treated according to standard practice, he said. “We want to stress that their prognosis per stage of disease is similar to nonpregnant women,” he said, adding that pregnant women with breast cancer should not experience delays in their diagnosis or treatment.
“This paper reiterated what some of the previous research has already shown, which is that pregnancy itself does not have a negative impact on prognosis,” commented Tina Rizack, MD, MPH, a medical oncologist and hematologist at Women & Infants in Providence, RI. Outcomes are the same in pregnant and nonpregnant women of the same age and with the same stage of cancer.
The researchers conducted a cohort study using both prospective and retrospective registry data from the German Breast Group initiated in 2003 to evaluate breast cancer and from the international Cancer in Pregnancy (CIP) study begun in 2005 for all cancer types. Patients diagnosed with primary breast cancer during pregnancy between January 1, 2000, and September 30, 2011 were eligible for inclusion.
Women with in situ or primary metastatic disease or those experiencing a relapse were excluded, as were patients who became pregnant during cancer treatment or were diagnosed postpartum.
For comparison, researchers used nonpregnant women with stages I to III breast cancer from the institutional database of the Multidisciplinary Breast Cancer at the University Hospitals Leuven between January 1, 2000 and August 1, 2010. All women were 45 years old or younger.
A total of 311 pregnant patients with breast cancer were included prospectively and compared with 865 nonpregnant patients. The median ages of the pregnant and nonpregnant groups were 33 and 41 years, respectively.
In the pregnant group, taxanes were given to 47.0 percent as part of adjuvant chemotherapy and to 71.1 percent as neoadjuvant therapy. About 64 percent of the pregnant patients with breast cancer received chemotherapy during their second trimester.
In nonpregnant patients, taxanes were present in 30.9 percent of adjuvant chemotherapy regimens and in 77.5 percent of neoadjuvant regimens.
Median follow-up was 61 months, during which time 14 percent of pregnant and 12 percent of nonpregnant women died. The five-year disease-free survival (DFS) rate was 78 percent, and median DFS time was 131 months. The overall survival (OS) rate was 87 percent but median OS had not been reached during the study period.
Using multivariate regression analysis of DFS and OS adjusted for age at diagnosis, stage, grading, histology, estrogen and progesterone receptor status, HER2, trastuzumab, and chemotherapy, the researchers found that women with breast cancer during pregnancy did not have a worse prognosis. The hazard ratios for disease recurrence and OS were 1.34 and 1.19, respectively, and were not statistically significant.
Additionally, the team determined that the probable average five-year DFS rate was 65 percent for pregnant patients and would have increased to 71 percent if these women had not been pregnant. The probable average five-year OS rate was 78 percent for pregnant women and would have increased to 81 percent.
Babies Born Early
Chemotherapy exposure during the second and third trimesters of pregnancy did not increase congenital malformations, but almost half (49.6%) of the babies were born before the 37th week of gestation, compared with only 10 to 15 percent in the general population.
Putting that difference in perspective, Elyce Cardonick, MD, who specializes in Fetal & Maternal Medicine and is Associate Professor of Obstetrics & Gynecology at Cooper University Health Care in New Jersey, explained that babies are often born earlier in women with breast cancer because physicians “ask them to be born earlier so we can go on with the next form of therapy, whether this is surgery or radiation; it is not due to a higher risk for spontaneous preterm birth.
“If a woman needs radiation or lumpectomy, and she finishes her chemotherapy by week 32 of pregnancy, doctors may not want to wait until 40 weeks to deliver. Instead, they'll deliver her at 36 weeks and get a four-week earlier start on treatment.”
Overall, “the study was well powered and the largest in the field,” Amant noted.
Additionally, Cardonick said, the study did not include women diagnosed with breast cancer postpartum. Older articles often included postpartum patients, who can have worse outcomes than pregnant women and should be studied separately, she explained.
The researchers also conducted pharmacokinetic studies in the pregnant patients and treated women based on their pregnancy weight and not on an ideal weight or their prepregnancy weight, she added.
Also asked for her opinion, Jennifer Mersereau, MD, Director of the Fertility Preservation Program at the University of North Carolina at Chapel Hill School of Medicine, said, “The study is interesting because in pregnancy, you're swimming in hormones like estrogen and progesterone which are traditionally associated with breast cancer, and some might hypothesize that you would have a worse outcome.”
Estrogen, progesterone, and other hormone levels during pregnancy do not appear to have an adverse outcome on breast cancer, Rizack agreed.
Another interesting finding, Mersereau continued, is that starting chemotherapy during pregnancy, at least in the second trimester, seemed to be safe and maybe even better than waiting until patients were done with pregnancy.
Chemotherapy during the first trimester does increase the risk of fetal malformations, Amant said. Consequently, oncologists wait to administer drugs until the second or third trimester when fetal organ formation is complete. Additionally, many agents do not completely pass the placental barrier, protecting the fetus.
Added Mersereau: “We used to be concerned that chemotherapy may be harmful to the baby in utero and for this reason, sometimes women were induced to deliver early so that the mother could begin chemotherapy.”
Obstetricians Need to Take Cancer Symptoms Seriously
The take-home message for clinicians is that, “women may be experiencing cancer symptoms that are mistaken for symptoms related to pregnancy, so there is no further investigation,” Amant said. “Obstetricians should not ignore complaints. In most cases, cancer diagnosis occurs later in pregnant women compared with nonpregnant women because symptoms are underestimated.”
Typically, women younger than 40 aren't screened for breast cancer, and pregnancy is associated with many physiologic changes to the breast making diagnosis difficult, Rizack said. For example, breast volume increases, so a patient or practitioner might not feel a mass. Additionally, many breast masses that are benign are unique to pregnancy. “Unfortunately, pregnant women tend to present at a later stage.”
She pointed to a recent article in the Journal of the American Medical Association (2013;309:800-805) that showed a small but statistically significant increase in the incidence of breast cancer in women under age 40—“a delay in child bearing may be one explanation,” she said.
Multidisciplinary Care Necessary
Pregnant women with breast cancer are usually assigned a multidisciplinary group of practitioners from maternal and fetal medicine, obstetrics, surgery, and oncology to create a treatment plan, she noted; and while cases are exceedingly rare at Women and Infants Hospital where she works, they are presented before a collaborative tumor board.
In an editorial that accompanied the Amant et al article (JCO 2013;31:2521-2522) titled “Pregnancy During or After Breast Cancer Diagnosis: What Do We Know and What Do We Need to Know?,” Richard L. Theriault, DO, Professor in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, and Jennifer K. Litton, MD, Assistant Professor in the same department, wrote that “given that there will never be level 1 evidence addressing pregnancy and breast cancer risks, the recommendation to proceed with cancer treatment in a carefully coordinated, multidisciplinary care approach for the pregnant patient is sound clinical advice.”
The editorial also notes that breast cancer and a concomitant diagnosis of pregnancy is an unusual clinical situation and that many oncologists and obstetricians may have either no or only limited exposure to cancers diagnosed during pregnancy, and even fewer may have the background and experience to provide guidance.
Theriault and Litton conclude that “the proscription of pregnancy after treatment of breast cancer because of concerns of cancer recurrence and death from breast cancer is not supported by [the data in the study], even for those who have had estrogen receptor-positive disease.
Amant said that further research needs to follow up on children born to women treated for breast cancer during pregnancy to study exposure to chemotherapy and radiation. Additional data on sentinel lymph node biopsy and breast-conservation surgery performed during pregnancy would also be useful. “We also need to collect more information on certain drugs and what fraction crosses the placenta,” he said.
This was an observational study, so the women were not giving an intervention, Mersereau noted. A randomized, controlled trial that evaluates the safety of chemotherapy when started at different times during pregnancy would be valuable.
An international prospective database of treatment and outcomes in pregnant women with breast cancer would also be incredibly informative, Rizack added. In the meantime, she said, the National Toxicology Program is publishing a manuscript on the effects of chemotherapy on pregnancy, and a prepublication pdf is available online at http://1.usa.gov/17phPKH.