Breast cancer during pregnancy: a review

Introduction

The uniqueness of breast cancer during pregnancy presents certain limitations in the overall understanding of this condition. This article aims to review the diagnosis and available treatments while highlighting key conclusions regarding breast cancer diagnosed in pregnant women, informed by the most recent literature and current international guidelines. The physiological changes associated with pregnancy may complicate diagnosis and potentially delay timely intervention, which are critical for early detection⁽¹⁾. Imaging techniques such as ultrasound and MRI have become essential for an accurate diagnosis. Surgical options, including mastectomy and lumpectomy, are generally deemed safe regardless of the pregnancy stage⁽²⁾. Chemotherapy can be administered during the second and third trimesters; however, radia­tion therapy is typically avoided due to associated risks to the fetus. Research indicates that most infants are born healthy, and the prognosis for women diagnosed with breast cancer during pregnancy is comparable to that of women diagnosed early outside of pregnancy. The review seeks to compile the most recent insights on the causes, symptoms and diagnosis of breast cancer during pregnancy. It will present a comprehensive range of treatment and counseling options, ultimately identifying the most effective course of action for breast cancer diagnosed during pregnancy (BCDP). This review also highlights the immediate psychological impacts of cancer-related illnesses, often leading to heightened levels of stress and anxiety. To optimize outcomes for both mother and child, it is essential for obstetricians, oncologists and mental health professionals to collaborate in providing comprehensive interdisciplinary care^(3,4). Emphasizing the significance of organized treatment programs and support networks, the study underscores the necessity for ongoing research aimed at enhancing patient care and clinical recommendations in this complex situation. It is anticipated that this article will contribute to a broader understanding of this sensitive condition for patients, their families and healthcare providers. Although breast cancer during pregnancy is relatively rare, it remains one of the more prevalent pregnancy-related conditions, especially in developing countries. The morphological and functional changes that occur in breast tissue during pregnancy can make diagnosis and treatment challenging for healthcare professionals^(5,6). Both gynecologists and radiologists may find these cases particularly demanding. Furthermore, in such intricate and sensitive situations, it is imperative to consider psychological factors alongside the safety of both mother and child⁽⁷⁾. This review, grounded in recent medical literature, current international clinical standards and systematic practices, presents a detailed discussion of the clinical diagnostic and therapeutic aspects of BCDP, including surgery, chemotherapy, systemic therapies and radiotherapy.

Materials and method

The information presented herein was compiled through a systematic review of the existing literature, using the keywords “breast cancer”, “pregnancy” and “neoplasm”. Our research incorporated articles from reputable sources, including PubMed, ScienceDirect and The Cancer Journal, among others. A comprehensive list of all referenced materials is included in the references section.

Clinical presentation

Breast cancer diagnosed during pregnancy is primarily diagnosed through the identification of persistent breast tumors, with self-examination serving as the initial indication in 100% of the 142 participants studied⁽⁸⁾. Additional symptoms may include purulent or bloody nipple discharge, as well as skin thickening. Lymphadenopathy and inflammatory changes are frequently observed at the time of diagnosis^(8,9). It is important to note that pregnancy can obscure the detection of palpable masses and other breast cancer symptoms, complicating physical examinations due to the engorged and edematous nature of breast tissue⁽¹⁰⁾. Furthermore, young, premenopausal women often do not receive breast imaging screenings, which can hinder the identification of nonpalpable tumors. Pregnant individuals presenting with palpable tumors, skin abnormalities or unusual nipple secretions should not be automatically diagnosed with BCDP. Instead, a comprehensive imaging workup and clinical evaluation are recommended to ensure accurate diagnosis and appropriate management^(10,11).

Epidemiology

The most frequently encountered cancers during pregnancy include breast cancer, cervical cancer, hematological diseases and melanoma. Collectively, these four malignancies account for 50% of all cases of gestational cancer, with hematological cancers representing an additional 25%. Less common tumors that may occur during pregnancy include thyroid, colon and ovarian cancers. A variety of factors contribute to the distinctive aggressiveness associated with breast cancer diagnosed during pregnancy. Notable elements include an advanced T stage at diagnosis, early onset of the disease, and a high prevalence of HER2-positive and/or estrogen/progesterone receptor-negative tumors^(8-10). Moreover, there is an increased incidence of lymphovascular invasion and lymph node involvement in these cases. Consequently, women diagnosed with BCDP may face poorer prognoses. Subsequently, treatment options that aim to safeguard the fetus may often be restricted or deferred. Although individuals carrying the BRCA mutation face a significantly elevated risk of developing breast cancer during pregnancy, it is important to note that the majority of afflicted patients lack a family history of the disease⁽¹²⁾.

Imaging

Ultrasound (US) is established as the first-line imaging modality for the diagnosis of breast cancer in pregnant patients, owing to its high sensitivity and negative predictive values⁽¹³⁾. This technique not only aids in guiding biopsy procedures but also serves to diagnose breast cancer and provides critical information regarding nodal involvement and response to neoadjuvant therapy^(13,14). Conversely, the utility of mammography is diminished during pregnancy because of concerns about radiation exposure and increased mammographic density^(15,16). Furthermore, apprehensions regarding fetal exposure to gadolinium-based contrast agents, along with the requirement for patients to assume a prone position during the examination, contribute to the perception that contrast-enhanced breast magnetic resonance imaging (CE-MRI) is not a safe option in this context^(17-19). Diffu­sion-weighted imaging (DWI), which has undergone extensive investigation, is proving to enhance the accuracy of breast MRIs, being increasingly recognized as a valuable diagnostic approach during pregnancy^(20,21). Notably, tumor conspicuity on DWI was found to be 138% greater than that observed on CE-MRI. However, a subsequent study indicated that tumor visibility on CE-MRI is 60% lower when compared with nonlactating controls⁽²²⁾. It is important to note that DWI exhibits reduced sensitivity in cases involving non-mass enhancements and sub-centimeter lesions^(22,23). In conclusion, while mammography can be performed safely with appropriate precautions, ultrasound is recommended as the primary diagnostic technique for evaluating suspected breast cancer in pregnant individuals^(24,25). The debate regarding the application of MRI for the detection of prenatal breast cancer persists, largely due to concerns about the prone position and potential fetal exposure to gadolinium-based contrast agents^(26,27). Nonetheless, it is anticipated that the adoption of unenhanced functional MRI techniques may increase the utilization of breast MRI during both pregnancy and lactation in the foreseeable future^(28-30).

Local versus systemic treatments

• Surgery

At any stage of pregnancy, surgical intervention is generally considered to be the safest option. Numerous studies indicate that most anesthetics are safe for the fetus. Additionally, intraoperative fetal heart rate monitoring can be initiated from the 24^th to the 26^th week of gestation^(31,32). It is important to note that analgesia can alter the detection of subtle early contractions and may delay tocolysis; therefore, cardiotocography is vital in the postoperative period^(33,34). The implementation of heparin prophylaxis is also critical, as surgical venous stasis combined with the hypercoagulable state often associated with pregnancy increases the risk of pulmonary embolism and deep vein thrombosis^(31,33). Mastectomy is frequently deemed more appropriate given that breast conservation is often less feasible due to the delayed diagnosis of breast cancer during pregnancy (BCDP) and the resultant increase in tumor size at presentation⁽³⁵⁾. While breast reconstruction remains a possibility, there exists considerable discourse within the literature regarding the timing of such procedures due to physiological changes occurring during pregnancy. One ongoing debate concerns whether to place a tissue expander during pregnancy or to defer this intervention until postpartum^(32,35).

The advantages of postponing such procedures include improved psychological and cosmetic outcomes, a reduced recovery period, and minimized risks to both the patient and the fetus. Research conducted by Lohsiriwat et al. has demonstrated that this approach is noninferior in terms of obstetrical outcomes or surgical complications^(35,36). Pregnant women can undergo safe and accurate sentinel node identification through radioactive injection; how­ever, the teratogenic potential of methylene blue renders it inap­propriate for use, and limited data exist regarding the safety profile of isosulfan blue in pregnant patients^(36,37).

• Chemotherapy

Both patients and oncologists must carefully consider the ethical and therapeutic implications of a breast cancer diagnosis occurring during pregnancy^(38,39). It is inherent for women to prioritize the protection of the fetus; however, healthcare providers must balance the prognosis for the mother against the health and wel­fare of the embryo and fetus^(38-40). It is important to note that the majority of treatments can be administered safely to both pregnant and non-pregnant women^(40,41). Unfortunately, there remains a significant gap in understanding regarding this subject, with numerous aspects still uncertain, including treatment timing, medication selection, daily dosages and treatment fractions⁽⁴²⁾.

• Radiotherapy

Radiation therapy is typically regarded as safe during the first and second trimesters of pregnancy, based on findings from a 2010 international consensus meeting involving experts from eight European nations. However, it is important to note that the radiation dose associated with radiotherapy is significantly higher than that encountered during diagnostic imaging. This elevated exposure poses serious risks for fetal health⁽⁴³⁾.

The risk of fetal harm is mainly influenced by two factors: the radiation dose and gestational age at the time of exposure. Research indicates that abnormalities may arise if the in utero radiation exposure exceeds 0.2 Gy; thus, a threshold of 0.1 to 0.2 Gy is considered to be the acceptable safety limit^(43,44). Furthermore, according to the all-or-nothing principle, excessive exposure in the first two weeks following conception may lead to either implantation failure or embryonic demise. During the period from the second to the eighth week post-conception, structural malformations may occur, primarily within the organogenesis phase. Notably, the developing central nervous system is especially susceptible to radiation between weeks 8 and 25, with excessive exposure during this timeframe potentially resulting in cognitive deficits. The long-term implications of radiation exposure remain inadequately understood, leading to a general recommendation against this treatment during pregnancy in standard medical practice. It has also been established that there is no direct correlation between the severity of radiation-induced injuries and the likelihood of developing cancer, which is recognized as stochastic and proportional to radiation exposure, commencing from 0.01 Gy. Additionally, while supradiaphragmatic irradiation may reduce the radiation dose to the uterus, the risk of exposure tends to increase with advancing gestational age^(44-46).

In conclusion, it is advisable to defer this treatment until after delivery whenever feasible. Some studies have explored the potential for administering adjuvant radiotherapy during pregnancy in carefully selected patients, as initiating treatment between 8 and 12 weeks post-surgery has been associated with improved dis­ease-free survival rates (DFS) and a reduced risk of local recurrence in patients diagnosed with breast cancer⁽⁴⁵⁾.

The decision to delay radiotherapy can be challenging, particularly during the first trimester of pregnancy, when chemotherapy is often not a viable option. It is therefore essential for a multidisciplinary team of obstetricians and gynecologists to conduct a thorough assessment of each case, considering both the patient’s prognosis and gestational age. Ultimately, it is crucial for the patient to make an informed choice following comprehensive counseling, with healthcare professionals honoring the patient’s right to self-determination⁽⁴⁶⁾.

• Hormone therapy

For premenopausal women with positive hormone receptors, tamoxifen is habitually utilized as an adjuvant therapy. Current recommendations advise using nonhormonal barrier contraceptives both during and up to three months after ceasing tamoxifen medication⁽⁴⁷⁾. However, it is still unclear how an unplanned pregnancy will affect the developing fetus. The Lareb and INCIP databases, AstraZeneca’s registries, and a prospective examination of pregnancies that took place during and after breast cancer patient’s treatment with trastuzumab and/or lapatinib have all detailed the effects of tamoxifen during human pregnancy⁽⁴⁸⁾.

Buonomo and colleagues conducted a systematic study and identified 249 fetuses exposed to tamoxifen during the first trimester or later, with 68 live births. Of these, one incidence of Goldenhar syndrome and one case of genital tract malformations were discovered^(48,49).

Pregnancy remains contraindicated during therapy and for up to three months following caesarean section, since, as previously stated, there is not enough long-term data on the pediatric outcomes linked to the use of tamoxifen during pregnancy to make firm judgments about its usage⁽⁴⁹⁾.

The effects of delaying hormone therapy may be clarified by an international multicenter study that is presently underway and aims to assess the disease’s outcome and the safety of stopping hormone therapy to enable pregnancy in women with ER-positive breast cancer. The San Antonio Breast Cancer Symposium 2022 recently featured the study’s preliminary findings: a brief pause in hormone therapy has little effect on short-term oncologic results. To validate these findings, the study will continue to monitor this population until 2029⁽⁵⁰⁾.

• Immunotherapy

Triple-negative and HER2-positive breast cancers types, which are the most prevalent forms of breast cancer during pregnancy, are characterized by high immunogenicity and strong reactivity to immune checkpoint inhibitors (ICIs)⁽⁵¹⁾. But, because ICIs target the PD-1/PD-L1 pathway, they can cause an immune reaction and intrude with the fetus’s maternal immunological tolerance, increasing the chance of miscarriage, and they may be leading to considerable maternal morbidity⁽⁵²⁾. Current medications are represented by IgG4 antibodies, which can damage the fetus directly by crossing the placenta. Anti-PD-1/PD-L1 and anti-CTLA-4 inhibitors during pregnancy have been linked in animal models to higher rates of abortion, stillbirths, preterm births, and mortality, particularly when taken in the third trimester⁽⁵³⁾.

Discussion

Being a relatively uncommon condition, breast cancer diagnosed during pregnancy poses particular difficulties for diagnosis and treatment. According to earlier statistics, about 10% of breast tumors found in patients under 40 years old were discovered during pregnancy⁽¹⁾. Breast cancer cases that are detected during pregnancy and within two years of birth have increased since the 1960s⁽⁷⁾. The majority of incidences of pregnancy-related breast cancer were observed in women aged 25 to 29. In this age bracket, when having children is most common, about one-third of all breast cancers happened during pregnancy or within two years of giving birth⁽²⁾. The effects of the medications on the growing fetus and the long-term effects on children born after in utero exposure are the primary concerns regarding the best course of treatment for pregnant women with breast cancer⁽⁹⁾. According to a multicenter case-control research, early childhood cognitive, cardiac or general development was unaffected by prenatal exposure to maternal cancer, with or without treatment. Only 129 kids were included in the study, though. Systemic chemotherapy and surgery are the primary therapeutic choices for pregnant women with breast cancer⁽⁷⁾.

 A more thorough understanding of potential risk factors, clinical presentation, diagnosis mode and timing, tumor features, and prognosis are among the outstanding research concerns of interest⁽²⁾. By preventing unnecessary delays in identification and treatment, for instance, a greater understanding of pregnancy-associated breast cancer can enhance the therapeutic management of these young individuals with this disease⁽³⁾.

Conclusions

For both the mother and the doctors involved, facing breast cancer diagnosed during pregnancy is a profound and challenging journey, both physically and psychologically. Ultrasound stands as the gold standard in imaging, offering low-cost, safe solutions for the baby, while often providing a definitive diagnosis. Today, mammograms are considered safe during pregnancy, and should be utilized when necessary. For local staging, unenhanced MRI serves as a valuable tool. Surgery, systemic therapy and radiation therapy can be effective and safe for pregnant women with breast cancer, with careful adjustments made according to gestational age and cancer stage. Embracing a multidisciplinary approach is vital in harmonizing the health of the fetus with the mother’s prognosis, ensuring that both are given their best chance.   

CORRESPONDING AUTHOR: Ioana-Emanuela Atanasescu E-mail: ioana-emanuela.atanasescu@rez.umfcd.ro

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.