**1. Introduction**

Breast cancer (BC) is the most frequent female cancer worldwide, and the leading cause of cancer-related death among women [1]. It is also one of the most common types of cancer encountered during pregnancy [2,3]. Data regarding the global burden of disease between 1990–2017 among Romanian women of fertile age (15–49 years) reveal that although the number of BC-related deaths has decreased, the importance of BC as a cause of mortality has increased by 38.51%. The estimated probability of pregnancy-associated breast cancer (PABC) is 1.29/100,000 among women aged 15–49 years, mainly due to pregnancy at an older age. We expect 59 new cases of PABC per year in Romania (Appendix A).

PABC guidelines were first introduced in 1999 [4]. Since then, substantial progress has been made regarding management and follow-up care. In 2017, Romania joined the International Network on Cancer, Infertility, and Pregnancy (INCIP). Globally, PABC accounts for 0.2–7% of BC cases [5–7]. PABC is not a single disease, but rather several diseases distinguished by the biological effects of pregnancy, variations in serum hormone levels [8], extracellular matrix modifications, and distinctive gene expression patterns in mammary epithelial cells [9]. Research over recent decades has focused on identifying potential PABC biomarkers [10]. Cancer screening can be performed in pregnant women by using a non-invasive prenatal screening test (NIPT) involving plasma cell-free DNA sequencing [11]. Higher maternal serum levels of cell-free DNA (cfDNA) are detected in cases of PABC with a euploid fetus, likely due to both harbored fragments of cell-free fetal DNA and cell-free tumoral DNA [12–14]. It has been hypothesized that hypertension during pregnancy or preeclampsia may decrease the risk of breast cancer development [15–17].

Traditionally, BC is considered PABC when the disease is diagnosed during pregnancy or in the first postpartum year [18,19]. Breast cancer diagnosed between 1 and 10 years after childbirth in women under 45 years of age seems to be a different entity, carrying increased risks of distant metastases and death, which can be explained at the molecular level by the phenomenon of breast involution [20,21].

In the recent past, the diagnosis of breast cancer during pregnancy has often been followed by induced abortion, as many doctors, patients, and patients' relatives have been concerned about the poor prognosis and high risk of maternal death or fetal adverse reaction following the disease or treatments. However, therapeutic abortion is no longer routinely recommended upon PABC diagnosis. With the application of a standard treatment, experts consider the prognosis of cancer during pregnancy to be similar to that in non-pregnant patients [22]. Studies have shown that BC diagnosis during pregnancy may be delayed due to the fact that this pathology is not specific to pregnancy, and because of the physiological increase of mammary gland size [23]. Staging and treatment regimens for PABC are similar in non-pregnant patients. Surgery and sentinel lymph nodes biopsy (SNB) are allowed during pregnancy, despite controversial findings regarding the safety and accuracy of the results [24,25]. SNB in pregnant breast cancer patients appears to be safe and accurate using either methylene blue dye or technetium 99 m (99 mTc) sulfur colloid and gamma probe according to a retrospective study [25]. However, recommendations from the American Society of Clinical Oncology (ASCO) still state that pregnant patients should not undergo sentinel lymph node biopsy (SLNB), based on cohort studies and informal consensus [26]. In contrast with ASCO, The National Comprehensive Cancer Network NCCN concluded that insufficient data exist on which to base recommendations regarding the use of SLNB in pregnant women and SLNB should not be offered to pregnant women under 30 weeks of gestation [27].

During surgery, pregnant women are considered at increased risk of hypoxemia, desaturation, and thrombosis. The more advanced the term, the more difficult it is to intubate, especially obese pregnant patients. The patient should be positioned as far as possible in the left lateral position to avoid aortocaval compression and hypotension that decreases uterine vascularization. Intraoperative cardiotocography for fetal heart rate monitoring may indicate a reduced fetal heart rate variability during general anesthesia. Administration of intravenous tocolytic drugs, e.g., betamimetics or atosiban may be used for the inhibition of uterine contractility [28,29].

In the second or third trimester, adjuvant or neoadjuvant chemotherapy (CMT) regimens include anthracycline-based treatment, followed by taxanes (paclitaxel and docetaxel) [30–33], and the main known fetal risks include intrauterine growth restriction and a small-for-gestational age newborn. During the postpartum period, the recommended treatment includes anti-HER-2 targeted therapy for HER-2+ tumors, and endocrine therapy for oestrogen-receptor (ER)-positive tumors. Radiotherapy is considered relatively safe during the first and second trimesters of pregnancy, although this is based on theoretical assumptions and few experiences [34,35]. In utero radiation exposure of >10 mGy has

been associated with microcephaly, childhood cancers, and mental retardation [36–40]. Radiotherapy during pregnancy remains controversial. Some guidelines suggest that it can be safely used in the first or second trimester of pregnancy [19], while Romanian guidelines contraindicate radiotherapy for BC during pregnancy [41].

Upon diagnosis of cancer during pregnancy, selection of the optimal treatment approach requires a multidisciplinary team of healthcare professionals—including an obstetrician, a specialist in maternal–fetal medicine, a medical oncologist, an oncology surgeon, a pediatrician, a geneticist, a psycho-oncologist, and a radiotherapist. A multidisciplinary team can advise the patient and her family about the available treatment regimens, the potential risks for both the mother and the fetus, the prognosis, and the necessity of a long-term follow-up.

In the present study, we aimed to describe the characteristics, management, and follow-up care of women with PABC at a tertiary-level hospital in Romania.
