Chemotherapy for Breast Cancer During Pregnancy, With Neonatal Lupus in the Newborn

Oncology (Williston Park). 30(6):584–587.

Figure. Skin rash (white arrows) in a baby girl born to a mother with Sjögren syndrome and stage II triple-negative breast cancer who received chemotherapy with doxorubicin and cyclophosphamide during the last trimester of her pregnancy. Punch biopsy of the rash demonstrat- ed increased connective tissue mucin and suggested neonatal lupus.

Table. Laboratory Findings (Clinical Immunology)

The Case

A 34-year-old, gravida 2, para 1, previously healthy African-American woman presented with a right breast mass on self-examination in the second trimester of pregnancy. Her medical history was not significant for any comorbidities, including lupus and Sjögren syndrome. She had no history of smoking or illicit drug use, and she rarely drank alcohol. Prior to the initial evaluation by her obstetrician, she did not have a primary care physician, was taking vitamins only, and had no reported allergies. Her Eastern Cooperative Oncology Group Performance Status was 0.

Ultrasound of the right breast showed a 17 × 19 × 11-mm hypoechoic mass. Core biopsy of the mass revealed a poorly differentiated breast carcinoma; grade 3; estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-negative-ie, a triple-negative breast cancer (TNBC). The preoperative axillary ultrasound was negative. She underwent a right lumpectomy and sentinel node dissection. The pathology report from the lumpectomy and sentinel node dissection confirmed a T1 tumor that was triple negative; three sentinel nodes were all negative for metastatic disease (pT1N0).

The patient was referred to the nearest academic cancer center for further management. Physical examination revealed enlarged right axillary lymph nodes. She subsequently had a restaging computed tomography (CT) scan of the thorax and ultrasound of the breasts and axillae (a limited staging workup because of her pregnancy). The CT scan and ultrasound demonstrated multiple pathologically enlarged right axillary lymph nodes. Given her TNBC and multiple enlarged axillary lymph nodes, an ultrasound-guided biopsy of one of the palpable right lymph nodes was performed; this confirmed the presence of metastatic poorly differentiated carcinoma, ER-, PR-, and HER2-negative (TNBC), consistent with the primary breast cancer. Her final stage was changed to stage II (pT1c pN1 cM0).

After restaging, the case was discussed at a multidisciplinary breast tumor board. The patient was offered adjuvant chemotherapy with 4 cycles of doxorubicin and cyclophosphamide (AC) chemotherapy until the 35th week of pregnancy, which would allow her to have a 3-week window between the last dose of chemotherapy and her delivery. She continued weekly fetal growth monitoring in the obstetrics department during chemotherapy, with normal prenatal test results. After 4 cycles of AC chemotherapy, she successfully delivered a healthy baby girl by Cesarean section. She then completed a 12-week course of weekly paclitaxel; she was advised not to breastfeed during postpartum chemotherapy. Postpartum CT scans of the chest, abdomen, and pelvis, and a bone scan, demonstrated no evidence of distant metastasis.

Newborn’s postnatal presentation. The baby was born without any skin rashes; however, she developed a skin rash all over her body 72 days later (Figure). Physical examination revealed red skin patches. She had no fever, shortness of breath, wheezing, nausea/vomiting, or diarrhea. A punch biopsy of the left occipital scalp revealed an increased presence of connective tissue mucin, suggestive of neonatal lupus erythematosus. An electrocardiogram (ECG) showed no evidence of heart block. The baby was given fluconazole and miconazole/zinc oxide creams for the skin rash, with improvement of symptoms.

Mother’s postpartum presentation. After the baby was diagnosed with neonatal lupus, the mother was referred to rheumatology to investigate for lupus and other autoimmune diseases. Notable serology findings included positive results on an antinuclear antibodies (ANA) screen, a rheumatoid factor level of 77.0 IU/mL, a complement 3 level of 164.0 mg/dL, a complement 4 level of 38.0 mg/dL, anti-Smith antibody level < 0.2 U, anti-Ro/(SSA) antibody level > 8.0 U, anti-La/(SSB) antibody level > 8.0 U, and anti–U1 ribonucleoprotein (RNP) antibody level < 0.2 U (Table).

Further recall by the patient revealed a history of dry eyes (diagnosed by an ophthalmologist); severe dry skin throughout her life; and multiple dental cavities, indicative of dry mouth. A clinical diagnosis of Sjögren syndrome was made.

What is the most likely cause of the baby’s neonatal lupus?

A. It was directly caused by chemotherapeutic agents during late pregnancy.

B. Maternal autoantibodies alone caused the neonatal lupus.

C. Late-pregnancy chemotherapy increased transplacental transfer of autoimmune antibodies and sensitized the newborn to the autoantibodies.

Discussion

Breast cancer in pregnancy is a rare occurrence, with an overall incidence of 27.9 per 100,000 deliveries.[1] The average patient is between 32 and 38 years of age. Because more women are choosing to delay childbearing, it is likely that the incidence of breast cancer during pregnancy will increase. The diagnosis of breast cancer during pregnancy is often delayed because breast tissue is more dense during pregnancy, making it more difficult to distinguish between cancer and normal breast tissue. In addition, routine breast cancer screenings and routine visits to a breast physician are often deferred until after delivery. Pregnancy-associated breast cancer may have biologic and pathologic features different from those of its nongestational counterpart. These tumors are often hormone receptor–negative, large, and high grade, and lymph nodes are often positive.[2] In addition, full staging, which would normally include CT scans of the abdomen and pelvis, as well as a bone scan or positron emission tomography scan, cannot be performed in order to prevent radiation exposure to the fetus. Overall survival and disease-free survival of pregnant women with breast cancer may be worse than in stage-matched nonpregnant women.[3] The management of pregnant breast cancer patients is a challenge because the risks and benefits of laboratory investigations and clinical management strategies must always be considered from the perspective of optimizing the wellbeing of both mother and fetus.

Hormone therapy, targeted therapy, and radiation therapy are contraindicated during pregnancy because they carry higher risks of fetal malformation. Surgery can be performed during pregnancy without causing harm to the mother or fetus. In addition, therapeutic abortion is a patient option, although it has not been shown to afford a survival benefit.[4] Chemotherapy can be administered at certain times during pregnancy; the times during which it is contraindicated are the first trimester (because of the high risk of fetal malformation) and after 35 weeks of gestation or within 3 weeks of planned delivery (in order to avoid potential hematologic complications during delivery).[5] Doxorubicin, cyclophosphamide, fluorouracil, and their various combinations can be used to treat breast cancer during pregnancy; however, there are insufficient safety data to recommend the use of taxanes.[6] With the preceding agents, the risk of fetal malformation in the second and third trimester is around 1.3%, not different than that of fetuses not exposed to chemotherapy during gestation.[5,6] Considerations for postpartum chemotherapy are the same as for non–pregnancy-associated breast cancer. The patient in this case developed breast cancer in the second trimester and underwent lumpectomy and sentinel lymph node dissection. Careful planning was done to make it possible to offer her 4 cycles of adjuvant AC chemotherapy during the third trimester so as to allow a 3-week window between her last chemotherapy dose and her delivery.

Until now, there has been no published report demonstrating that neonatal lupus resulted from use of any antineoplastic agents during pregnancy. While chemotherapy regimens such as AC are considered safe when administered during the second and third trimesters,[6] nonetheless, when this baby girl was diagnosed with neonatal lupus, we wondered whether the AC chemotherapy was somehow implicated. However, cyclophosphamide has in fact been used to treat systemic lupus,[7] making Answer A unlikely. Neonatal lupus as a result of maternal transplacental autoimmune antibody transfer is rare, with an incidence rate of 1% to 2% in pregnant women with documented anti-Ro/SSA or anti-La/SSB antibodies[8,9]-but it does occur, and it seemed possible that the neonatal lupus in this newborn resulted from such a mechanism. However, we noted that this same patient also delivered a healthy son 2 years earlier who did not suffer from neonatal lupus. Thus, Answer B is also unlikely, since transplacental autoantibody transfer alone did not cause her son to develop neonatal lupus. The only difference, then, between the two pregnancies was the maternal chemotherapy administered to the mother during the latter part of the second pregnancy. Therefore, we speculate that late-pregnancy chemotherapy may increase transplacental autoantibody transfer in women with Sjögren syndrome and possibly in those with other autoimmune diseases. Furthermore, in utero exposure to AC chemotherapy during the last trimester of pregnancy somehow appeared to sensitize the newborn to develop lupus as a result of exposure to transplacental autoantibodies (Answer C is thus correct).

Outcome of This Case

Because the mother’s axillary lymph nodes were positive for metastatic disease, she underwent a full right axillary lymph node dissection after completion of all adjuvant postpartum chemotherapy, showing no evidence of residual disease in any of the 24 lymph nodes. The patient is currently undergoing adjuvant radiotherapy to her right breast and axilla, and is doing well. Her daughter’s condition is stable and the skin rashes are slowly resolving; a follow-up ECG was normal.

Conclusion

This is the first report of an association between gestational AC chemotherapy in a woman who carries anti-Ro/SSA and anti-La/SSB antibodies and the development of neonatal lupus in her baby. The case highlights a new and unusual potential adverse effect of AC chemotherapy administered during pregnancy-namely, that such chemotherapy may increase the risk of neonatal lupus in the newborn if the mother has Sjögren syndrome or possibly other autoimmune diseases. It is impractical to recommend routine screening for anti-Ro/SSA and anti-La/SSB antibodies prior to administration of gestational chemotherapy due to the rarity of these findings. However, it would seem prudent to carefully monitor for potential fetal or neonatal lupus (eg, check for heart block and/or skin lesions) in the fetuses and neonates of pregnant women with known autoimmune diseases such as Sjögren syndrome or systemic lupus erythematosus who receive chemotherapy. Rapid intervention, including the use of corticosteroids, is needed to avoid severe complications, such as complete heart block, in a fetus or neonate with lupus. Future research is needed to confirm our observations and to explore possible mechanisms of chemotherapy-associated neonatal lupus in pregnant women carrying autoimmune antibodies.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

E. David Crawford, MD, serves as Series Editor for Clinical Quandaries. Dr. Crawford is Professor of Surgery, Urology, and Radiation Oncology, and Head of the Section of Urologic Oncology at the University of Colorado School of Medicine; Chairman of the Prostate Conditions Education Council; and a member of ONCOLOGY's Editorial Board.

If you have a case that you feel has particular educational value, illustrating important points in diagnosis or treatment, you may send the concept to Dr. Crawford at david.crawford@ucdenver.edu for consideration for a future installment of Clinical Quandaries.

References:

1. Andersson TM, Johansson AL, Hsieh CC, et al. Increasing incidence of pregnancy-associated breast cancer in Sweden. Obstet Gynecol. 2009;114:568-72.

2. Gogia A, Deo SV, Shukla NK, et al. Pregnancy associated breast cancer: an institutional experience. Indian J Cancer. 2014;51:167-9.

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4. Cardonick E. Pregnancy-associated breast cancer: optimal treatment options. Int J Womens Health. 2014;6:935-43.

5. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. Breast cancer. Version 1.2016. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 5, 2016.

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7. McCune WJ, Golbus J, Zeldes W, et al. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. N Engl J Med. 1988;318:1423-31.

8. Buyon JP, Clancy RM. Neonatal lupus: review of proposed pathogenesis and clinical data from the US-based Research Registry for Neonatal Lupus. Autoimmunity. 2003;36:41-50.

9. Hon KL, Leung AK. Neonatal lupus erythematosus. Autoimmune Dis. 2012;2012:301274.