Gestational breast cancer: current challenges in staging and treatment of breast cancer

Abstract

Gestational breast cancer (GBC) is the most common form of invasive cancer in pregnancy and has unique challenges in both staging and treatment given the dual goal of appropriate cancer management and minimising the risk of fetal toxicity. A 38-year-old woman with no significant medical history and 21 weeks pregnant presented with a palpable right breast mass. She was diagnosed with human epidermal growth factor receptor 2-positive infiltrating ductal carcinoma with advanced disease. The patient underwent treatment; however, unfortunately, she passed away after developing devastating distant disease recurrence.

We highlight both the challenges and current guidelines for management of GBC. Our goal is to discuss the current limitations of GBC management and the necessity of further investigation for safe novel imaging and treatment modalities for pregnant women. It is crucial to increase awareness across multiple subspecialities, as a multidisciplinary team is necessary for proper treatment of GBC.

Background

Gestational breast cancer (GBC) is the most common invasive cancer of pregnant women and is especially prevalent in women aged more than 35 years.¹ The incidence of GBC is increasing as more women delay childbearing, representing 1 in 3000 breast cancer patients.^{1 2} The definition of GBC is broad, including breast cancer diagnosed during pregnancy and up to 1 year postpartum.² Pathophysiology of GBC is not fully understood, but some postulate that high levels of hormones during pregnancy may lead to growth and survival advantages for tumours.³ Cancer diagnosed following delivery may be affected by a tumour-promoting environment created by the natural involution of breast tissue associated with growth, remodelling and inflammatory upregulation.²

GBC prognosis compared with non-pregnant breast cancer patients is controversial with mixed survival outcome data. A study by Azim et al⁴ showed pregnancy-associated breast cancer to be associated with higher risk of death compared with non-pregnant controls, especially in the subset diagnosed following delivery. Another study by Hartmann and Eslick⁵ showed increased risk of death for pregnancy-associated breast cancer, but there were significant variations in the time of diagnosis and treatment.^{4 5} A newer study by Litton et al⁶ showed comparable survival rates in a small cohort of 75 GBC patients compared with non-pregnant breast cancer patients, proposing that older studies may have less optimal treatment options, therefore impacting survival. Data isolated for GBC diagnosed following delivery notes worsened prognosis.^{2 3} Johansson et al³ noted that at 2 years post diagnosis in GBC patients, the highest peak of mortality occurred in women diagnosed 4–6 months after delivery. Studies such as these demonstrate the complexity of GBC pathophysiology and highlight the need for further academic exploration.

While the standard of care for management of non-pregnant breast cancer patients is well known, there is less certainty for GBC as clinical trials often exclude pregnant patients. All breast cancer patients typically undergo mammogram and breast ultrasound with biopsy, but more advanced imaging (eg, bone scans, MRIs and CT scans) are limited by concern for fetal safety. This concern extends to treatment options and shared decision-making is a key tenet of management as physicians attempt to balance appropriate cancer treatment and fetal safety. A multidisciplinary team of primary care, medical oncology, surgery, radiation oncology, anaesthesiology, obstetrics and neonatology physicians, as well as psychologists, social workers and others is crucial for appropriate oncology management.

Through an illustrative and unfortunately ultimately tragic patient encounter, we demonstrate the important need for increased awareness of GBC management guidelines across multiple specialities, as well as a need to further advance knowledge in staging and treatment.

Case presentation

A 38-year-old woman at 21 weeks gestation with no significant medical history presented with a palpable right breast mass. Family history was significant for breast and ovarian cancer in two paternal aunts (unknown age at diagnosis). Physical examination revealed a 9×11 cm mass in the outer right breast with overlying skin dimpling and palpable mobile right axillary lymphadenopathy. Mammogram with abdominal shielding and ultrasound showed diffuse right breast abnormalities in the lower outer right breast (figure 1). Pathology from the ultrasound-guided core needle biopsy showed infiltrating ductal carcinoma grade 2, oestrogen receptor (OR) 0%, progesterone receptor (PR) <1%, human epidermal growth factor receptor 2 (HER2)/neu positive (3+) by immunohistochemistry (IHC) and Ki-67 proliferation rate of 10%–20% (figure 1). Axillary lymph node biopsy was consistent with metastatic adenocarcinoma. Given her axillary lymphadenopathy biopsy, there was concern for advanced disease. Staging scans were pursued with chest radiograph, liver ultrasound and blood work, including complete blood count and comprehensive metabolic panel. These tests did not show evidence of metastatic disease.

Figure 1.

Diagnostic imaging workup. (A) Right-sided diagnostic breast ultrasound showing diffuse abnormal tissue and two focal hypoechoic areas (noted by the yellow limit marks). (B) Right-sided mammogram in the mediolateral view demonstrating diffuse abnormalities.

Treatment

Neoadjuvant chemotherapy was recommended due to advanced disease, followed by a combination of adjuvant chemotherapy with HER2-directed therapy, surgery and radiation. Special consideration was given to the timing of treatment, requiring significant coordination between a multidisciplinary team. She was given adriamycin and cyclophosphamide every 3 weeks for four cycles starting in week 22 of gestation (second trimester) and ending in week 31. Delivery was planned for 3 weeks following the last dose of chemotherapy to allow for cell count recovery. Pegfilgrastim was avoided due to her pregnancy. At week 34 of gestation, concern for decreased fetal movements prompted a caesarean section. She delivered a healthy baby boy with no complications. The patient had no issues following delivery and shortly after underwent complete staging. This included CT imaging of the chest, abdomen and pelvis along with a bone scan. CT scan revealed a 3 mm left upper lobe lung lesion. The bone scan revealed an L3 lesion concerning for metastasis, confirmed on MRI of the lumbar spine (figure 2). At this time, she was started on weekly paclitaxel with trastuzumab and pertuzumab for anti-HER2/neu therapy. Positron emission tomography (PET) scan demonstrated the same L3 lesion and a possible new sclerotic lesion in the left sacral ala. Due to prior treatment and the sclerotic appearance of the bone, biopsy was not pursued. BRCA (breast cancer gene) testing revealed a BRCA2 genetic variant of uncertain significance, and it is not known at this time whether this variant has a role in genetic predisposition to cancer. Prophylactic surgery is not typically offered to patients with BRCA variants of uncertain significance; however, after a discussion of risks and benefits, the patient elected to proceed with prophylactic left mastectomy given this finding.

Figure 2.

Bone scan. Left-sided anterior bone scan with black arrow demonstrating a focal lesion of moderate intensity at the L3 body concerning for metastasis. Obtained following fetal delivery.

The patient subsequently underwent a bilateral mastectomy. Pathology showed residual grade 2 invasive ductal carcinoma, OR 90%, PR <1% and HER2/neu positive (3+) by IHC. Sentinel lymph node biopsy was negative for malignancy. The patient completed postmastectomy radiation. Given both residual disease and metastasis, anti-HER2/neu therapy was continued with plans to start hormone therapy if the disease recurred. Her GBC treatment regimen was well tolerated with only mild neuropathy. Surveillance PET scans showed no further lesions concerning for new metastases.

Outcome and follow-up

Approximately 14 months after completing paclitaxel and radiation, the patient complained of new pressure-like headaches for 3 weeks. Prior to completion of an ordered MRI brain, she presented to an outside hospital with worsening headaches and nausea. CT brain showed a right superior occipital lesion concerning for metastasis with associated oedema, herniation and midline shift. Despite initiation of steroids, the patient quickly became unresponsive, requiring intubation. She was transferred to the neurology intensive care unit with concern for brain death, and unfortunately expired.

Discussion

GBC is a rare form of breast cancer that requires a multifaceted approach to management in order to balance the goals of proper cancer treatment and fetal protection. From initial diagnosis to post-treatment surveillance, all members of the multidisciplinary team must be aware of the limitations inherent to GBC management as well as potential consequences. Here, we discuss the limitations of breast cancer management during pregnancy.

Challenges in diagnosis

Given the young age of many patients with GBC and current screening guidelines, diagnosis is often made by self-palpable breast mass.⁷ Pregnant patients have breast proliferation and differentiation that can lead to tenderness and increase in the density of tissue, complicating breast examination performed by primary care physicians and obstetricians.⁷ It is vital that primary care physicians and obstetricians be aware of the possibility of GBC, and all breast or axillary masses should be imaged and possibly biopsied when present for greater than 2 weeks.⁷

Challenges in staging

The use of imaging studies in pregnancy causes significant anxiety in both patients and physicians due to concerns for fetal safety. Radiation exposure is measured as radiation dose of 1 mSv per exposure to 1 mGy of radiation. All pregnant women are exposed to background radiation of typically about 2.3 mSv during the entire period of pregnancy depending on geographical location.⁸ Consensus from radiological societies on fetal harm state that less than 50 mGy of exposure is negligible, 50–100 mGy is indeterminate but unlikely to be clinically significant, and greater than 100–150 mGy has higher possibility of fetal harm.^{8 9} Table 1 shows several average radiation dose exposures for common imaging modalities. Fetal risks include spontaneous abortion (exposure at less than 2 weeks), teratogenicity (exposure at 8–15 weeks) and carcinogenesis (exposure throughout pregnancy).^{8 10} Teratogenicity is dose-dependent and can lead to malformation and developmental delay.^{8 10} Carcinogenesis is not dose-dependent, although more likely at higher doses and can lead to increased risk of childhood cancers.^{8 10} It is important to keep cumulative radiation in mind in pregnant patients given these risks.

Table 1.

^{8 9} Average radiation doses of common imaging modalities

Imaging modality	Dose to mother (mSv)	Dose to fetus (mGy)
Chest X-ray	0.06–0.29	0.0005–0.001
Abdominal X-ray	0.1–0.3	0.01–1.1
Mammogram, two views	0.1–0.7	0.001–0.01
CT abdomen	3.5–25.0	1.3–35.0
CT pelvis	3.3–10.0	10.0–50.0
CT abdomen/pelvis	3.0–45.0	13.0–25.0
Technitium 99 bone scan	6.7	10.0–50.0

*Radiation dose is measured as 1 mSv per exposure of 1 mGy.⁹

Following diagnosis with ultrasound, biopsy and mammogram, further staging depends on suspicion of advanced disease. The National Comprehensive Cancer Network (NCCN) currently recommends that pregnant patients with node-negative tumours (T1–T2) have chest X-ray with shielding and lab tests to assess blood cell count, and liver and kidney function.¹¹ Patients with node positivity or stage T3 or higher should, in addition, obtain a liver ultrasound and consider MRI spine without contrast.¹¹ CT and bone scans are typically avoided, given their elevated radiation doses (table 1). MRIs are the advanced imaging of choice by the American College of Obstetricians and Gynecologists; however, gadolinium is contraindicated as fetal malformations and demise have been noted in animal studies.^{8 12}

Our patient had node positivity on her outside hospital axillary biopsy and underwent additional staging scans per NCCN guidelines, which were all negative for metastatic disease. She did not have an MRI of the spine until after delivery, which did show concern for bony metastatic lesions. This knowledge would likely not have changed management, given limitations from delivery timing; however, the knowledge may have helped the patient in informed decision-making.

Challenges in treatment

GBC treatment should adhere as closely as possible to the standard of care for breast cancer; however, the trimester of diagnosis often determines the timing and course of treatment, given the need for fetal safety (figure 3). Surgery is often a mainstay of treatment depending on clinical context. Surgery can technically be performed all throughout pregnancy; however, it is often delayed in the first trimester due to perceived increased risk of spontaneous abortion.^{1 7} Use and safety of sentinel lymph node biopsies during pregnancy is controversial as there may be fetal risk with dye administration.¹³ NCCN guidelines currently lists blue dye as a contraindication, but allows for radiolabelled sulfur colloid dyes such as technetium-linked.^{1 11 13} Surgery also must be coordinated closely with anaesthesiology and obstetrics for close monitoring to minimise the risk of fetal hypoxia during surgery.^{7 11}

Figure 3.

Gestational breast cancer treatment modality timing. AC chemo, Anthracyclines and alkylating agents. HER2, human epidermal growth factor receptor 2; Recommended: can be considered depending on patient’s clinical situation and time of diagnosis.

Systemic chemotherapy is an important part of GBC management in certain subtypes and locally advanced breast cancer. When concerning for advanced disease, triple-negative or HER2-positive breast cancer, neoadjuvant chemotherapy is often used prior to surgery. Most chemotherapy agents are teratogenic with risks of fetal malformation during the first trimester.¹⁴ Anthracyclines and alkylating agents during the second and third trimesters are thought to have limited toxicity to the fetus, but complications include intrauterine growth restriction and preterm delivery.^{11 14} Use of taxanes in pregnancy is controversial with a current Food and Drug Administration category D label. However, new cohort studies such as by Cardonick et al¹⁵ (n=15) and Zagouri et al¹⁶ (n=50), suggest no increased risks of harm to the fetus.^{11 15 16}

Receptor-driven therapies, including both hormonal and anti-HER2-directed therapies, are delayed until after delivery. Anti-HER2 treatments, such as trastuzumab and pertuzumab, have been linked to oligohydramnios of the fetus and are contraindicated until after delivery.^{5 7 17} Hormone therapies, such as tamoxifen, are also deferred due to disruption of the normal hormone environment and association with craniofacial malformations and ambiguous genitalia birth defects.¹ Initial biopsy on our patient was HER2/neu positive with OR and PR negative; however, the pathology from the mastectomy was OR positive. This discordance in receptor expression is interesting and could be attributed to tumour heterogeneity.

The complexities of GBC management are highlighted by our patient’s case presentation. She unfortunately developed metastatic disease to the brain, resulting in her death. Complications from progression of metastatic disease can present quickly and be devastating. Therefore clinicians must have a high suspicion for disease recurrence. This is especially the case in patients with history of GBC, given the limitations on therapies.

Conclusion

The management of GBC is complex, requiring a multifaceted approach with the expertise of multiple subspecialities to ensure appropriate treatment while also minimising harm to the fetus. The challenges begin as early as the initial diagnosis and continue to the years following treatment. A high index of suspicion for both diagnosis and recurrence is important, as GBC can be difficult to diagnose in the context of pregnancy or lactation and recurrence can lead to devastating results. New symptoms should trigger prompt evaluation for recurrence or distant metastasis. Due to limitations in the management of GBC, an increased awareness of these challenges among physicians is necessary.

GBC is a rare, but unfortunately increasingly encountered breast cancer diagnosis. Several staging and treatment modalities are still controversial in pregnancy due to limited data and evidence-based medicine as clinical trials often exclude pregnant patients. Further investigations into the safety and efficacy of new and innovative diagnostic and treatment modalities for breast cancer during pregnancy are critical.

Learning points.

• Management of gestational breast cancer (GBC) is challenging due to the dual goal of appropriate cancer treatment and limiting toxicities to the fetus.

• Limitations on imaging and treatment modalities exist in GBC management due to unknown and not well-studied risks of fetal harm; however, management should reflect the standard of care for breast cancer treatment as closely as possible.

• There is a need for increased awareness of the current guidelines and associated limitations in the management of GBC across multiple subspecialities.

• Coordination between the multidisciplinary team is important for appropriate and comprehensive treatment.

• Further investigations into innovative diagnostic and treatment modalities for GBC are crucial for advancement in care.