Advances in the Treatment of Breast Cancer at Different Stages of Pregnancy

Abstract

Pregnancy-associated breast cancer (PABC) refers to newly occurring breast cancer from the beginning of pregnancy to within one year after delivery. In recent years, with changes in societal attitudes toward fertility, the number of women marrying and giving birth at older ages has steadily increased. The delay in the age of childbearing has gradually increased the risk of women being exposed to breast cancer during pregnancy, and thus the incidence of PABC has been on the rise. The treatment of PABC is challenging. The treatment plan should not only control the tumor progression of the patient but also ensure the healthy development of the fetus. Therefore, it is very important to formulate an individualized diagnosis and treatment plan. Thus, this article explores the diagnosis and treatment methods of PABC to respectively expound the feasibility and safety of the relevant diagnosis and treatment means in the first, second and third trimesters of pregnancy.

Introduction

Pregnancy-associated breast cancer (PABC) is the second most common malignant tumor during pregnancy, with an overall incidence rate of 1/10,000 to 1/3,000, accounting for 0.2% to 3.8% of breast cancer.^1,2 PABC refers to breast cancer diagnosed during pregnancy and within one year after delivery.¹ With the increase of women who marry and have children at an older age, the incidence of PABC is on the rise. Previous research have shown that PABC patients are mainly concentrated in the 32–38 age group, and the incidence rate increases with age.³ During pregnancy, due to the influence of hormones, the density and thickness of breast glands increase, making it difficult to detect breast tumor lesions at an early stage. For this reason, most patients are discovered at the middle or advanced stage.^1,4 Compared with non-gestational breast cancer, the treatment of PABC is challenging in terms of selection. On the one hand, the potential impact of the treatment method on fetal development must be considered; on the other hand, it is necessary to ensure the control of the tumor and its progression. Thus, individualized treatment plans are an important factor in ensuring a good outcome for both the mother and the baby. The treatment chosen for the patient should not only guarantee their own safety but also ensure the health of the fetus. This article reviews treatment methods—including surgery, targeted therapy, chemotherapy, endocrine therapy, and radiotherapy—according to the first, second, and third trimesters of pregnancy.

Material and Method

This article is a narrative review, and literature search was conducted using the PubMed database (https://pubmed.ncbi.nlm.nih.gov). Keywords: “breast cancer during pregnancy”, “early pregnancy”, “second trimester”, “third trimester”, and “treatment”.

Inclusion criteria: The language of publication is English; The types of research include meta-analysis, systematic review, prospective or retrospective clinical studies, international clinical guidelines, and explicitly mention the diagnosis and treatment methods and approaches for PABC patients at different stages of pregnancy.

Exclusion criteria: Literature, case reports (n < 5), basic research experiments and animal experiments unrelated to the diagnosis and treatment of PABC patients. The time range for literature retrieval is from 2016 to 2026. Although some studies were not included in this search scope, their research designs, clinical thinking or basic theories have certain reference value for this article. Thus, they are cited in the text to ensure the completeness of the content.

Results

The screening methods for breast cancer during pregnancy mainly include breast ultrasound, mammography, and Magnetic Resonance Imaging (MRI). The main diagnostic methods are hollow needle puncture and mass resection.⁵ Ultrasound examination has the advantages of simple operation, high sensitivity and no radiation. It is the most commonly used examination method and is non-invasive to the human body.^5,6 The above screening and diagnostic methods for breast cancer during pregnancy and their core application criteria are detailed in Table 1.

Table 1.

Comparison of Core Recommendations of Diagnostic Strategies in the Three Major Guidelines of NCCN, ESMO and ASCO^6,7

Diagnosis and Treatment Dimension	NCCN (version1.2026)	ESMO	ASCO	Core Consensus
Local imaging	Ultrasound is the core diagnostic tool; Molybdenum target is a selective supplementary examination (used when ultrasound is suspicious). MRI is an optional examination but not universally recommended	Ultrasound is the first choice. Mammography is supplemented only when ultrasound suggests malignancy. Contrast-free DWI-MRI can be routinely used for tumor range assessment	Ultrasound is the first choice for the assessment of primary tumors and regional lymph nodes. Molybdenum target microcalcification screening DWI-MRI is preferred for tumor range assessment	Ultrasound is the first choice throughout the pregnancy, and gadolinium contrast agents are absolutely contraindicated throughout the pregnancy. Molybdenum targets require strict abdominal protection
Pathological diagnosis	Hollow CNB is the gold standard for diagnosis. The pathological report should follow the norms of the CAP, clearly stating details such as tumor grade and vascular invasion	CNB is the gold standard. Immunohistochemistry emphasizes subtype-guided treatment	CNB is the preferred method for diagnosis, while FNAC only assists in lymph node assessment. The immunohistochemical results serve as the core basis for treatment stratification, and it is necessary to precisely clarify the biological characteristics of the tumor	CNB is the gold standard for the diagnosis of primary tumors, while FNAC only assists in the assessment of lymph nodes. Immunohistochemical tests must include ER, PR, HER2 and Ki-67
Whole-body staging	Early-stage asymptomatic patients do not require routine whole-body imaging examinations. FDG-PET/CT is only used when the standard staging results are suspicious and can be performed simultaneously with diagnostic CT	The initial screening consists of chest X-ray and abdominal ultrasound. For advanced assessment, whole-body diffusion combined with MRI is preferred. Use with caution in nuclear medicine examinations	Give priority to non-radiation/low-radiation methods; MRI is the first choice for one-stop staging. Nuclear medicine examinations are for second-line emergency use and should not be routinely conducted	Give priority to non-radiation/low-radiation methods; Nuclear medicine examination is for second-line emergency use

Abbreviations: MRI, Magnetic Resonance Imaging; DWI-MRI, Diffusion-Weighted Imaging Magnetic Resonance Imaging; CNB, core needle biopsy; CAP, College of American Pathologists; FNAC, fine needle aspiration cytology; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; FDG-PET/CT, fluorodeoxyglucose-positron emission tomography/computed tomography; CT, computed tomography.

Early Pregnancy

The early stage of pregnancy refers to the period from the beginning of pregnancy to the third month of pregnancy,⁴ represents a critical window for fetal organogenesis. Accordingly, therapeutic strategies must be selected with extreme caution. If the fetus is exposed to cytotoxic substances in the first three months of pregnancy, it may interfere with the development of the fetus’s organs, and in the most severe cases, lead to congenital malformations or even miscarriage.⁸ Thus, the treatment methods chosen during the PABC stage of early pregnancy are of great significance. Timely communication with the patient is necessary not only to ensure the safety of both the mother and the baby but also to guarantee the normal development of the fetus.

Surgical Treatment

For patients with PABC in the early stage of pregnancy, surgical treatment remains a very important therapeutic approach. Surgery can be performed at any stage of pregnancy for PABC patients. The possibility of miscarriage caused by surgery in the first three months of pregnancy is only 1.0–2.0%, while the risk of miscarriage in the middle and late stages of pregnancy is 1.5–2.0%.⁹ Therefore, previous data strongly recommend surgical treatment in the early stage of pregnancy. During the operation, the fetal heartbeat should be closely monitored to detect any problems in a timely manner. The scope of breast cancer surgery includes the breast and axillary lymph nodes. Total mastectomy can be used at every stage of pregnancy, especially in the early stage of pregnancy. For patients with aesthetic concerns, tissue expanders can be implanted after total mastectomy, which does not significantly affect the incidence of adverse outcomes for the patient or fetus.⁸ Alternatively, breast-conserving surgery (BCS) can be performed, which can preserve the patient’s secondary sexual characteristics and alleviate the psychological distress. Patients who choose to undergo BCS should postpone radiotherapy and chemotherapy, although there may be a risk of local recurrence. No perioperative complications occurred in 30 patients in the early stage of pregnancy who received BCS. When adjuvant radiotherapy was postponed until after delivery, the 5-year survival rate was 97%. No isolated local recurrence was observed during short-term follow-up, and there was no fetal death or neonatal malformation.⁹ This indicates that it is safe for patients in the early stage of pregnancy to choose BCS. This provides a basis for clinical decision-making.

Axillary Lymph Node Surgery

Axillary lymph node surgery is equally important. Lymph node biopsy can avoid unnecessary complete axillary lymph node dissection. Previous studies have shown that the risk of axillary lymph node metastasis in patients with PABC is higher than that in non-PABC patients,¹⁰ and axillary lymph node examination should be conducted as early as possible. For PABC patients with negative axillary lymph nodes, sentinel lymph node biopsy is recommended. This method is the first choice for reducing the risk of lymphedema. Injection of 99mTc colloid solution should be the first choice for patients undergoing sentinel lymph node biopsy. It has a low teratogenic rate,^5,8 so it is safe to use in the early stage of pregnancy. However, no dyes are allowed to be used, as blue dyes and isosulfan blue carry the risk of causing allergic reactions in the mother, and methylene blue has teratogenic effects.^5,8 A retrospective study found that among 145 patients with PABC, those who underwent sentinel lymph node biopsy (SLNB) had a lower recurrence rate than non-PABC patients,¹¹ and the 5-year survival rate of patients with negative axillary lymph nodes was 61%.¹² For patients with positive axillary lymph nodes, axillary lymph node dissection (ALND) should be performed immediately to prevent the spread to other tissues or organs and ensure the safety of both the mother and the baby.

Targeted Therapy

In recent years, targeted therapy has made progress in breast cancer during pregnancy. Trastuzumab is the standard treatment regimen for human epidermal growth factor receptor-2 (HER2)-positive breast cancer. Previous studies have shown that trastuzumab can be used in the early stage of pregnancy for PABC patients under 30 years old, and with no adverse amniotic outcomes, but this is based on small-sample studies.¹³ Based on a study involving 18 patients and 19 newborns, 16.7% of whom received trastuzumab in the early stage of pregnancy,⁸ no adverse events occurred. Moreover, after a median follow-up of nine months,⁸ only the children exposed to trastuzumab in the early stage of pregnancy were healthy and showed no congenital malformations. Previous studies have found that PABC patients who only received trastuzumab treatment in the first trimester of pregnancy had a significantly lower possibility of developing gestational and neonatal complications than those exposed during the second and third trimesters (P=0.043). Compared with patients under 30 years old, the possibility of complications in newborns of PABC patients over 30 years old is significantly increased (P=0.04).¹³ The above data show that patients with PABC in the early stage of pregnancy can be treated with trastuzumab, and the fetus is healthy at birth with almost no adverse outcomes. This might also be related to the low metastatic monoclonal antibody in the placenta during the early stage of pregnancy.^8,13 It is important to note that trastuzumab use in the first trimester contradicts most international guidelines. The available evidence is observational and insufficient to recommend routine use. Further studies are needed to verify the feasibility of the drug. Trastuzumab should be discontinued in a timely manner, as the shorter the exposure time, the faster the amniotic fluid returns to normal volume.¹³ If the patient must receive trastuzumab treatment during pregnancy, it is necessary to prevent the fetus from being exposed for too long and having adverse outcomes. Pertuzumab, Trastuzumab-emtansine (T-DM1), and neratinib have been used for early use. However, there are no data available on their use in pregnant women so far, and thus they are all contraindicated. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6 inhibitors) are core targeted drugs for patients with hormone receptor-positive breast cancer, but there is a lack of relevant clinical data to support their safety when used during pregnancy.⁸

Chemotherapy, Radiotherapy, Endocrine Therapy, and Immunotherapy

Radiotherapy and chemotherapy are currently not recommended for PABC patients in the early stage of pregnancy. A retrospective analysis indicated that if PABC patients underwent chemotherapy in the early stage of pregnancy, the rate of fetal malformations was as high as 14%.¹⁴ The ESMO guidelines suggest that chemotherapy after 15 weeks of pregnancy is associated with a teratogenic risk comparable to that of the general population. Therefore, chemotherapy is not recommended in the early stage of pregnancy. According to international guidelines, radiotherapy is not recommended during pregnancy as it poses a risk of causing birth defects or even death to the fetus. Previous studies have confirmed that for patients who undergo BCS in the early stage of pregnancy and delay radiotherapy until after delivery, both maternal and neonatal outcomes are favorable. However, the research was based on patients with tumors smaller than or equal to 2.5 cm, no multicentric lesions, and non-hereditary breast cancer.⁹ If radiotherapy is to be performed, it is recommended to postpone it until after the end of pregnancy.¹⁵ Endocrine therapy and immunotherapy should not be carried out during pregnancy either; they are contraindicated.

For patients diagnosed with early-stage TNBC who are eligible for neoadjuvant therapy, adding anti-PD-1 treatment to carboplatin and paclitaxel, along with the standard anthracycline drug treatment regimen, can significantly improve pCR and event-free survival.⁷

Mid Pregnancy

The second trimester refers to the period from the 4th to the 7th month of pregnancy.⁴ This period is a crucial stage for the rapid development of the fetus. Accordingly, a personalized treatment plan, tailored to multiple factors, is vital to ensure the safety of both the patient and the fetus.

Surgical Treatment

Surgical treatment during the second trimester of pregnancy is safe,¹⁰ and individualized assessment should be conducted based on specific circumstances. Multidisciplinary collaboration is also required during the surgical process.

Chemotherapy

By the second trimester of pregnancy, the major organ development of the fetus has been completed, and chemotherapy can be carried out during this period. Chemotherapy can be administered after the first three months of pregnancy,^2,16 and the incidence of fetal malformations is reduced to 3%, which is comparable to that of non-PABC patients.⁸ However, it is necessary to pay attention to the dosage of the drug and closely monitor the conditions of the mother and the fetus. First-line chemotherapy drugs for breast cancer, such as anthracyclines, taxanes, platinum agents, and cyclophosphamide can be used in the second trimester of pregnancy. These drugs are relatively safe to use in the second trimester.⁸ One study demonstrated that 75 patients with pregnancy‑associated breast cancer in the second trimester received combination chemotherapy with 5‑fluorouracil, doxorubicin, and cyclophosphamide. Based on a multivariable Cox model adjusted for age, disease stage, and year of diagnosis, the predicted 5‑year disease‑free survival and overall survival were 65% and 78% among these patients, whereas the corresponding rates would be 71% and 81% if they were not pregnant.¹⁷ Previous studies have confirmed that chemotherapy is safe to use in the second trimester of pregnancy.

Among the 11 PABC patients in the previous study, 2 began neoadjuvant chemotherapy (NACT) in the second trimester of pregnancy and adopted the AC regimen. All patients successfully delivered their babies, and the neonatal weights were all within the normal range. No obvious defects were observed.²

Targeted Therapy

Targeted therapy is not recommended for PABC patients in the second trimester of pregnancy.^8,16 The second trimester of pregnancy is a crucial period for the growth and development of various organs of the fetus, such as the kidneys and lungs. Monoclonal antibodies can block the epidermal growth factor receptors in the kidneys of the fetus, leading to a decrease in the proliferation of renal cells. Some researchers have shown that the use of monoclonal antibodies in the second trimester of pregnancy can block the epidermal growth factor receptors in the fetal kidneys, thereby reducing the proliferation of fetal kidney cells.¹³ Previous studies have shown that when exposure to trastuzumab occurred from the first trimester to the second trimester, the incidence of fetal kidney damage was 13.04% (3/23).¹³ Among them, 8.70% (2/23) of the newborns died after birth, and 4.35% (1/23) of the newborns survived after experiencing transient renal failure.¹³ In one report, there were 18 patients and 19 newborns. Among them, 80% of the patients were administered trastuzumab in the second and third trimesters of pregnancy, and the probability of adverse events was 73.3%.⁸ The most common adverse event is oligohydramnios or anhydramnios. It can be seen that the incidence rate is closely related to the exposure time. The rate of amniotic fluid loss in the middle and late stages of pregnancy is 85%.¹³ On the one hand, the mechanism by which trastuzumab causes amniotic fluid reduction may be related to the production of vascular endothelial growth factor or aquaporin in the basement membrane of renal tubules. On the other hand, the IgG concentration in the fetus begins to increase from 18 weeks and rises rapidly from 24 to 26 weeks.¹³ It is speculated that as the fetus develops into the second trimester of pregnancy, its permeability to monoclonal antibody drugs increases. Therefore, it is found that there is a high possibility of adverse events when trastuzumab is administered during the second trimester of pregnancy. Trastuzumab is not recommended for PABC patients in the second trimester of pregnancy.

Endocrine Therapy, Radiotherapy, and Immunotherapy

Endocrine therapy, radiotherapy, and immunotherapy are contraindicated during pregnancy.^5,8,16 Endocrine therapy can affect the hormone levels of patients. Previous studies have shown that if tamoxifen or raloxifen is used during pregnancy in PABC patients, it may lead to fetal spinal deformities, ear defects, craniofacial anomalies, and cardiac malformations.¹⁸ Therefore, it is recommended to use endocrine therapy after pregnancy. Radiotherapy is contraindicated during pregnancy due to the potential teratogenic risk of its radiation.

Late Pregnancy

The third trimester of pregnancy refers to the period from 7 to 10 months of gestation.⁴ At this stage, the fetus’s various organs are relatively mature and the survival rate is high. For this reason, there are more treatment options available for PABC. However, it is necessary to discuss individualized treatment plans in collaboration with multiple disciplines and aspects to prevent premature birth of the fetus.

Surgical Treatment

Choosing a surgical treatment plan is safe for PABC patients in the third trimester of pregnancy. One study reported that one patient with PABC underwent radical mastectomy in the third trimester of pregnancy. The newborn was healthy and free of deformities after delivery.² This demonstrates the feasibility of performing surgery for PABC patients in the third trimester of pregnancy.

Chemotherapy

Chemotherapy in the third trimester of pregnancy can be safely carried out.^2,8,16 Previous studies have shown that there is no statistically significant difference in the teratogenic rate of PABC patients in the third trimester who undergo chemotherapy compared with those who give birth prematurely.¹⁹ Moreover, for PABC patients in the third trimester of pregnancy, the drugs used for chemotherapy are mainly anthracyclines or taxanes, and no significant increase in neonatal complications has been found.¹¹ A retrospective study treated 75 patients in the third trimester with 5-fluorouracil, doxorubicin and cyclophosphamide, and found that the patients’ DFS, OS and progression-free survival were significantly improved.⁸ Previous studies have shown that chemotherapy should be stopped at 33 weeks⁴ and no later than 35 weeks¹⁶ under close monitoring of fetal development. It is important to ensure that the patient’s bone marrow has recovered before delivery to avoid any accidents during the delivery process. If severe vomiting occurs during chemotherapy, ondansetron can be used to control it. It was found that the risk of major deformities did not increase,⁸ but dexamethasone is not recommended. The fetus may have the risk of cleft palate, impaired kidney function, low birth weight, and impaired brain development.⁸ In a study on neoadjuvant chemotherapy (n=5), 60% of PABC patients initiated neoadjuvant chemotherapy (NACT) in the third trimester of pregnancy. The AC regimen was used for NACT, and no adverse impact on fetal and maternal outcomes was observed.² However, this is a study based on a small sample size. In the future, a larger sample size will be needed for exploration.

Targeted Therapy, Radiotherapy, and Immunotherapy

Radiotherapy has a potential teratogenic effect on the fetus, so it is not recommended to use radiotherapy in the third trimester of pregnancy. Moreover, if trastuzumab treatment is considered in the third trimester of pregnancy, the amniotic fluid loss rate is 85%.¹³ A meta-analysis showed that when the fetus was exposed to trastuzumab only in the middle and late stages of pregnancy, the risk of complications, oligohydramnios or amniotic fluid loss was significantly higher than that in the early stage of pregnancy (70.8% vs. 16.7%, P = 0.026). The health rate of the fetus at birth was also lower than that in the early stage of pregnancy (41.7% vs. 75.0%).²⁰ Accordingly, trastuzumab is not recommended for use in the third trimester of pregnancy. After the patient has given birth and recovered, radiotherapy, endocrine therapy and targeted therapy can be considered. The use of immunotherapy targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1) in pregnant animal models suggests an increase in miscarriage, preterm birth, and fetal mortality in the third trimester of pregnancy.⁸ Thus, immunotherapy is not recommended for use during pregnancy.

The contraindications and recommended protocols for various therapeutic approaches in the above-mentioned different pregnancy trimesters are systematically summarized in Table 2.

Table 2.

Contraindications, Evidence Level, and Recommended Clinical Approaches for Pregnancy‑associated Breast Cancer (PABC) Treatment in Different Trimesters

Pregnancy Stage	Treatment Method	Contraindications	Potential Adverse Fetal Outcomes	Evidence Level	Recommended Clinical Approach
Early pregnancy	Surgery	None	The risk of miscarriage through surgery in the early stage of pregnancy is only 1.0% to 2.0%, which is comparable to that in the middle and late stages	IIb	Total mastectomy /BCS+ sentinel lymph node biopsy
	Chemotherapy	Exposure to cytotoxic substances during the fetal formation period	The fetal malformation rate is as high as 14%, which can cause abnormal organ development and even miscarriage	I	Not recommended
	Targeted therapy	The permeability of the placenta to monoclonal antibodies	The transport rate of monoclonal antibodies to the placenta in the early stage of pregnancy is extremely low	IIa	It is not recommended without the support of a large sample
	Endocrine therapy	Drugs can disrupt fetal hormonal homeostasis through the placenta and affect organ development	Fetal spinal deformities, facial deformities, abnormal heart development, etc.	I	Not recommended
	Radiotherapy	Teratogenic risk, no safe exposure threshold	Exposure may result in fetal malformations or fetal death.	I	Not recommended
	Immunotherapy	Drugs can affect the immune development of the fetus through the placenta, increasing the intrauterine mortality rate of the fetus	Animal experiments have confirmed a significant increase in the risk of miscarriage and premature birth during pregnancy, but there is no data from human pregnancy safety experiments	I	Not recommended
Mid pregnancy	Surgery	None	The fetal development is basically complete and the surgical safety is high	IIb	Mastectomy/BCS+sentinel lymph node biopsy
	Chemotherapy	None	The rate of fetal malformations is approximately 3%, which is comparable to that of the general population	IIa	Anthracyclines, taxanes, platinums, cyclophosphamide
	Targeted therapy	The permeability of the placenta to monoclonal drugs increases, inhibiting the proliferation of renal tissue	The risk of amniotic fluid reduction is up to 85%, and the risk of fetal complications is 70.8%. Renal insufficiency	IIa	Not recommended
	Endocrine therapy	Drugs can disrupt fetal hormonal homeostasis through the placenta and affect organ development	Fetal spinal deformities, facial deformities, abnormal heart development, etc.	I	Not recommended
	Radiotherapy	Teratogenic risk, no safe exposure threshold	The fetus is born with malformations or even dies	I	Not recommended
	Immunotherapy	Drugs can affect the immune development of the fetus through the placenta, increasing the intrauterine mortality rate of the fetus	There is no experimental data on human pregnancy safety.	I	Not recommended
Late pregnancy	Surgery	None (to avoid inducing premature birth)	At this stage, the fetus is relatively fully developed and there is no obvious risk of deformity	IIb	Radical cure
	Chemotherapy	None (stop at least at 35 weeks))	There was no statistically significant difference in the teratogenic rate between the population and the premature birth group	IIa	Mainly anthracyclines and taxanes; AC regimen neoadjuvant chemotherapy
	Targeted therapy	The permeability of the placenta to monoclonal drugs increases, inhibiting the proliferation of renal tissue	The risk of amniotic fluid reduction is up to 85%, and the risk of fetal complications is 70.8%. Renal insufficiency	IIa	Not recommended
	Endocrine therapy	Drugs can disrupt fetal hormonal homeostasis through the placenta and affect organ development	Fetal spinal deformities, facial deformities, abnormal heart development, etc.	I	Not recommended
	Radiotherapy	Teratogenic risk, no safe exposure threshold	The fetus is born with malformations or even death	I	Not recommended
	Immunotherapy	Drugs can affect the immune development of the fetus through the placenta, increasing the intrauterine mortality rate of the fetus	There is no data from human pregnancy safety experiments.	I	Not recommended

Abbreviations: BCS, breast-conserving surgery; AC regimen, anthracycline-cyclophosphamide regimen.

Discussion

Breast cancer during pregnancy (PABC) presents significant challenges in clinical practice. Achieving a precise balance between effective maternal tumor control and ensuring fetal safety is essential during the diagnosis and treatment process. This narrative review systematically examines the feasibility and safety of diagnostic and treatment strategies for PABC across the first, second, and third trimesters of pregnancy. The findings underscore that individualized diagnosis and treatment plans tailored to the stages of pregnancy are fundamental to clinical practice. Surgical intervention has been demonstrated to be safe and feasible throughout the entire gestational period. Sentinel lymph node biopsy (SLNB) can be performed using radioactive tracers, while the use of blue dye is strictly prohibited. Chemotherapy may be administered with caution during the second and third trimesters, with anthracyclines or taxanes recommended as preferred regimens. Notably, targeted therapy, immunotherapy, radiotherapy, and endocrine therapy are contraindicated throughout pregnancy. This conclusion aligns closely with the physiological characteristics of fetal development and the potential risks associated with various intervention methods.

The clinical recommendations regarding PABC in this article align closely with the core guidelines established by NCCN, ESMO, and ASCO. A comparative analysis of these diagnostic and treatment strategies across the three guidelines is provided in Table 1 and Table 3. All three guidelines consistently recommend ultrasound as the first-line imaging modality for PABC patients during pregnancy, while core needle biopsy (CNB) is recognized as the gold standard for pathological diagnosis. For axillary staging, the use of radioactive tracers for sentinel lymph node biopsy (SLNB) is advised. The use of dye reagents is universally prohibited due to the associated risks of maternal allergy and fetal teratogenicity. A central consensus among the guidelines is that chemotherapy during the early stages of pregnancy is deemed an absolute contraindication because of its significant teratogenic risk. Additionally, HER2-targeted therapies, immune checkpoint inhibitors, and endocrine agents are all prohibited throughout pregnancy. Some minor discrepancies exist among the guidelines. Notably, the ESMO guidelines allow for restrictive palliative radiotherapy (with a fetal radiation dose ≤100 mGy) for the supraclavicular region during the first and second trimesters in extreme cases where the mother’s life is critically endangered. In contrast, the NCCN guidelines offer more detailed recommendations regarding adjuvant chemotherapy agents. These differences arise from the interpretation of evidence levels and variations in clinical practice scenarios. Nevertheless, all guidelines uphold the fundamental principle of prioritizing fetal safety. The recommendations are primarily grounded in high-level evidence or clinical consensus to prevent the overreliance on low-level evidence in clinical practice.

Table 3.

Comparison of Core Recommendations of Treatment Strategies in the Three Major Guidelines

Diagnosis and Treatment Dimension	NCCN	ESMO	ASCO	Core Consensus
Surgery	BCS can be considered in the early stage of pregnancy, but adjuvant radiotherapy needs to be postponed. Avoid non-emergency surgeries during the early stage of pregnancy. Twenty weeks later, the left uterine displacement position was adopted for the operation. SLNB prohibits the use of blue dye and recommends low-dose 99mTc albumin nanocolloid	Avoid non-emergency surgeries during the early stage of pregnancy. Twenty weeks later, the left uterine displacement position was adopted for the operation. SLNB prohibits the use of blue dyes and can use 99mTc sulfur colloid	Avoid the embryo implantation period in the early stage of pregnancy; SLNB prohibits the use of blue dye and only allows radioactive tracers	SLNB prohibits the use of blue dyes and gives priority to the use of radioactive tracers. Vaginal delivery is the preferred choice. Cesarean section is only applicable to obstetric indications. Avoid non-emergency surgeries in the early stage of pregnancy
Chemotherapy	Absolute contraindications in the early stage of pregnancy; It can be used in the middle and late stages of pregnancy. After 35 weeks, the 3-week cycle protocol should be discontinued, and 2 to 3 weeks should be reserved for bone marrow recovery. Preferred options: doxorubicin/cyclophosphamide, weekly paclitaxel; The dose-intensive AC regimen combined with G-CSF is safe to use; Adjuvant medications: For antiemetic use, ondansetron/metoclopramide should be selected. G-CSF should be used with caution, and NK1 antagonists should be avoided	Absolute contraindications in the early stage of pregnancy; It can be used in the middle and late stages of pregnancy. Preferred regimen: anthracyclines + cyclophosphamide; Adjuvant medications: For antiemetic use, ondansetron/metoclopramide is selected. For glucocorticoids, methylprednisolone/prednisolone is chosen. NK1 antagonists should be used with caution	The risk of teratogenicity in the early stage of pregnancy is 21.7%. It is absolutely contraindicated. The risk of malformations in the second and third trimesters of pregnancy is 3%, so it can be used with caution. Preferred regimen: anthracyclines + cyclophosphamide as the basic solution; Adjuvant medication: The antiemetic regimen is the same as ESMO. Betamethasone/dexamethasone is contraindicated	Absolutely contraindicated in the early stage of pregnancy, but can be used in the middle and late stages of pregnancy. Contraindicated drugs: methotrexate, idarubicin, HER2-targeted drugs, PARP inhibitors, etc. Carboplatin takes precedence over cisplatin. Betamethasone/dexamethasone is contraindicated as an adjuvant medication
Targeted therapy and immunotherapy	Absolutely contraindicated drugs throughout the course: anti-HER2 drugs, CDK4/6 inhibitors, immune checkpoint inhibitors (ICIs), antibody-drug conjugates (ADCs), PARP inhibitors, anti-angiogenic drugs, etc. Unplanned pregnancy requires immediate discontinuation of medication	Contraindicated agents: HER2 targeted drugs, ICIs, PARP inhibitors, anti-angiogenic drugs, etc. In the event of unplanned pregnancy, the drug should be discontinued immediately; termination of pregnancy is not automatically indicated.	Absolute contraindicated drugs throughout the entire course: all targeted drugs, ICIs; Emphasize that drugs can lead to risks such as fetal immune rejection and organ damage; Unplanned pregnancy requires immediate discontinuation of medication	Absolute contraindications throughout pregnancy; Unplanned pregnancy requires immediate discontinuation of medication
Radiotherapy	Conventional radiotherapy should not be performed at any stage of pregnancy. All radical radiotherapy was postponed until postpartum. Palliative radiotherapy can only be considered in extreme cases where the mother’s life is threatened	Relative contraindications throughout pregnancy; Absolute contraindications in the third trimester of pregnancy; In the early and middle stages, restrictive radiotherapy can be performed on the supraclavicular area, using an ultra-low fractionated regimen (26Gy/5 times) to shorten the treatment cycle. The radiation dose to the fetus is ≤100mGy	Radiotherapy for the breast or chest wall is strictly prohibited in the second and third trimesters of pregnancy. For early to mid-term use in the supraclavicular region. Conventional fractionated radiotherapy is prohibited, and ultra-low fractionated regimens are preferred	Contraindications throughout pregnancy with conventional radiotherapy; Palliative radiotherapy can only be performed when the mother’s life is threatened in the early and middle stages. The radiation dose to the fetus is ≤100mGy
Endocrine therapy	Absolutely contraindicated drugs throughout the course: tamoxifen, aromatase inhibitors (AI), gonadotropin-releasing hormone (GnRH) agonists/antagonists, etc. All endocrine treatments were postponed until postpartum initiation	Absolutely contraindicated throughout pregnancy; The teratogenic risk of tamoxifen is over 20%, and AI inhibits the synthesis of fetal estrogen. Restart endocrine therapy after giving birth	Absolute contraindications throughout the process, no indications for use during pregnancy. After childbirth, corresponding endocrine therapy is initiated based on the subtype of the tumor	It is absolutely contraindicated throughout pregnancy and has no indications for use during pregnancy. Endocrine therapy should be postponed until after childbirth

Abbreviations: BCS, breast-conserving surgery; SLNB, sentinel lymph node biopsy; 99mTc, technetium-99m; G-CSF, granulocyte colony-stimulating factor; AC regimen, anthracycline-cyclophosphamide regimen; NK1 antagonists, neurokinin 1 antagonists; HER2, human epidermal growth factor receptor 2; PARP, poly(ADP-ribose) polymerase; ESMO, European Society for Medical Oncology; ICIs, immune checkpoint inhibitors; Gy, Gray (absorbed dose unit); CDK4/6, cyclin-dependent kinase 4/6; ADCs, antibody-drug conjugates; AI, aromatase inhibitors; GnRH, gonadotropin-releasing hormone.

The current clinical evidence for PABC primarily stems from small-sample retrospective studies and observational data, lacking large-sample prospective multicenter trials to offer evidence-based support. This limitation is notably evident in the debate surrounding trastuzumab use in early pregnancy. Small-sample studies suggest that low-dose trastuzumab in early pregnancy does not show significant short-term adverse neonatal effects, attributed to the relatively low placental permeability of monoclonal antibodies during this period, potentially lowering fetal exposure risk. However, this finding contradicts NCCN, ESMO, and ASCO guidelines recommending against trastuzumab use throughout pregnancy, precluding its routine clinical recommendation. The guideline’s contraindication is rooted in insufficient long-term safety data on trastuzumab, unclear placental transport mechanisms, and unknown potential fetal risks. Existing short-term study outcomes inadequately support its clinical use. Clinical practice should prioritize guideline adherence, avoid overinterpreting low-grade evidence, and minimize potential clinical hazards.

Molecular subtypes of breast cancer significantly influence the prognosis of PABC and the selection of treatment strategies, serving as critical factors for stratified analysis in clinical practice. For HER2-positive PABC, trastuzumab is the standard postpartum treatment regimen. However, only small exploratory studies have been conducted during the early stages of pregnancy, and due to unresolved safety concerns, its use is contraindicated throughout the entirety of pregnancy. In patients with hormone receptor-positive PABC, endocrine therapy is strictly prohibited during pregnancy due to a teratogenic risk exceeding 20%. Following childbirth, individualized endocrine regimens should be developed based on the receptor expression status. TNBC presents the most significant challenges in the diagnosis and treatment of PABC, as no targeted or immunotherapy regimens are available during pregnancy. Chemotherapy combining anthracyclines and taxanes may only be administered during the second and third trimesters. Furthermore, the overall prognosis for TNBC patients remains relatively poor compared to other subtypes, largely due to the absence of effective targeted intervention methods. Currently, there is a dearth of evidence-based data regarding subtype-specific diagnosis and treatment, which constitutes a core focus for future research.

The unique characteristics of breast cancer during pregnancy have led existing studies to primarily focus on maternal survival during pregnancy and the short-term period following childbirth. Consequently, there is a limited understanding of tumor recurrence and metastasis patterns, as well as long-term survival rates extending beyond five years. Additionally, long-term follow-up data regarding the risk of breast cancer recurrence in subsequent pregnancies is lacking. Regarding offspring outcomes, the potential long-term adverse effects of intrauterine fetal exposure to PABC diagnosis, treatment, and intervention methods require urgent and thorough investigation. Current research typically concludes at the birth stage of newborns, leaving a gap in relevant data concerning long-term health issues, such as neurodevelopmental abnormalities, cardiotoxicity, and growth retardation in children during their developmental years. For this reason, establishing a long-term follow-up system for mother-infant pairs affected by PABC holds significant clinical importance. This system should not only monitor the recurrence and metastasis of maternal tumors but also track the physical and neurodevelopmental progress of the offspring, thereby providing a comprehensive assessment of the long-term safety associated with PABC diagnosis, treatment, and intervention.

Conclusions

Pregnancy-associated breast cancer (PABC) presents heterogeneous physiological features and fetal development trajectories across gestational stages, so a “one-size-fits-all” strategy is inappropriate. Diagnostic and therapeutic plans should be individualized to each patient, with the aim of selecting approaches that optimize outcomes for both mother and fetus. Complex clinical decisions for PABC rarely fall within the remit of a single specialty; therefore, care should be delivered by a multidisciplinary team that includes breast surgery, obstetrics, oncology, and neonatology. Treatment decisions must be made jointly by clinician and patient after thorough discussion of risks, and plans should be adapted to reflect the patient’s informed preferences. Individualized management and coordinated multidisciplinary collaboration are essential to achieve dual protection of mother and infant.

Although a phased treatment framework has been formed for PABC at present, there are still areas that need to be broken through. Emerging experimental research suggests that bioactive marine peptides exhibit anti-proliferative, pro-apoptotic, and anti-angiogenic effects in breast cancer models, indicating potential as future therapeutic agents. However, their safety, placental transfer, and fetal effects remain unexplored, precluding clinical application during pregnancy.²¹ First, expand evidence-based medical evidence to fill the treatment gap. Most of the existing studies are based on small-sample retrospective analyses. From a mechanistic perspective, targeting DNA damage response pathways such as ATR–CHK1 has emerged as a promising anticancer strategy. Natural compounds modulating this pathway have shown antitumor activity in preclinical cancer models, but their role in pregnancy-associated breast cancer remains unexplored and requires rigorous safety evaluation.²² In the future, multi-center, prospective cohort studies need to be conducted to include a larger sample size of PABC patients, clarify the optimal dosage and timing of administration, and provide higher-level evidence for individualized treatment. Future international multicenter registration studies should also be promoted to further improve the reliability and generalizability of research conclusions through real-world data. Meanwhile, the safety and applicability of novel strategies such as targeted therapy and immunotherapy during pregnancy can be actively explored to provide more treatment options for PABC. Recent studies have highlighted the potential of mitochondrial metabolic regulation centered on OXPHOS inhibition combined with nanomedicine delivery systems in breast cancer treatment, providing new strategies for the safe and effective management of PABC.^23,24 Second, strengthen long-term follow-up and pay attention to the health of the offspring and the prognosis of the patients. At present, most studies focus on short-term outcomes during pregnancy and after childbirth, while there is insufficient follow-up data on the long-term survival rate of PABC patients and the growth and development of their offspring. Going forward, a long-term follow-up system needs to be established, which should not only track the recurrence and metastasis of tumors but also monitor the physiological development indicators of the offspring.

Funding Statement

This research was funded by Hebei Natural Science Foundation (No. H2024405018).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors have no relevant financial or non-financial interests to disclose.