The most remarkable finding from this study is the difference in prognosis between the groups: 33.3% died in the pregnant group vs 9.1% in the control group, with a statistically significant shorter OS in the pregnant group. However, after adjustment for tumor characteristics (grade and pathologic stage), these associations were attenuated. These findings support previous studies [2, 5, 11, 13, 14, 16] that suggest pregnancy-related breast cancer is more likely to present with a larger tumor, a higher stage, more poorly differentiated, and with a higher frequency of lymph node metastases. In agreement with the literature, in this study we found different tumor characteristics when comparing the groups, with PABC showing a more aggressive profile. In the pregnant group there was a higher prevalence of triple-negative tumor, poorer differentiation, and diagnosis in more advanced stages compared with the non-pregnant group.

Several explanations have been proposed for the poorer prognosis of pregnancy-related breast cancer. One is delayed diagnosis, which can occur in pregnant women because palpable masses or lumps can be ascribed to normal breast changes during pregnancy. To prevent this, any mass or lump during pregnancy or postpartum should warrant further work up.

The mechanisms driving PABC remain unclear, and many hypotheses have been postulated. During pregnancy, elevated levels of estrogen, progesterone, and insulin growth factor induce breast cell proliferation and could initiate tumorigenesis or stimulate growth of cells that have already undergone malignant transformation. However, the majority of PABC does not express hormonal receptors. In xenograft models of PABC it has been shown that, although lacking hormonal expression, systemic estrogens are needed for their formation and the progression of ER-negative cancers [11]. Another factor that influences the development of PABC is the combination of immunosuppression associated with pregnancy, immune tolerance, and inflammatory changes related to mammary gland involution [9,10,11].

Due to the poorer PABC prognosis, an increased awareness among clinicians and patients could help achieve earlier diagnoses. We suggest including clinical breast exam as part of the pregnancy visit protocol and request imaging test if there is any suspicion of breast pathology. Previous studies have suggested that ultrasound and mammography with fetal shielding are both appropriate diagnostic tools with no fetal risk [9, 16].

PABC prognosis has previously been addressed in several studies, with considerable controversy around this issue. A meta-analysis including 3628 cases and 37,100 controls showed a significantly higher risk of death in PABC compared with those not pregnant (pHR: 1.44; 95% CI [1.27–1.63]). However, this difference was only statistically significant in the group diagnosed postpartum (pHR: 1.84; 95% CI [1.28–2.65]) and not in the group diagnosed during pregnancy (pHR: 1.29; 95% CI [0.74–2.24]) [15]. The study by Viuff et al. [13] found higher overall mortality among women with PABC in the first 2 years after diagnosis compared with non-pregnant women with breast cancer, including 156 and 11,110 patients, respectively (HR 2.28 [1.48–3.52)]. In contrast, survival was comparable between the groups from 2 years after diagnosis.

A later study by Amant et al. [14], which included 311 women with PABC compared with 865 women with breast cancer who were not pregnant, found similar OS in both groups. Nevertheless, regarding the DFS analysis, although the HR 1.34 result (95% CI; 0.93–1.91) suggests better outcomes for the nonpregnant group, it is not statistically significant. An extension of this study focused on a subgroup of patients who received chemotherapy during pregnancy, comparing the prognosis between PABC treated with standard chemotherapy regimens and a non-pregnant control group [9]. Although comparable results were reported in terms of DFS and OS, a poorer OS was suggested for pregnant women receiving chemotherapy for luminal A breast cancer.

PABC treatment is challenging for clinicians, patients, and their families, because it requires careful balancing between the treatment of the mother and the safety of the fetus. Guidelines recommend following the same treatment that is standard for non-pregnant patients. Following this recommendation, no differences were observed in our study between the study and control groups in the treatment received, the only exception being that taxane-based chemotherapy and radiotherapy were delayed until birth, following the standard recommendations at the time of these patients’ diagnosis. Breast cancer surgery can be performed safely during any stage of pregnancy [1]. Chemotherapy, in a neoadjuvant or adjuvant setting, including anthracyclines, fluoropyrimidines, taxanes, and platinum derivates, is feasible after 12 weeks of pregnancy [1, 5, 21]. However, hormonal therapy is not recommended during pregnancy and should be delayed until birth [22], and trastuzumab is also contraindicated during pregnancy [23]. Radiotherapy is possible during the first half of pregnancy [1].

Despite prenatal exposure to maternal cancer, the associated maternal distress, diagnostic procedures, and oncological treatment including chemotherapy, the outcome for children in our study did not differ from that of the general population, in line with previous literature. Normal behavioral competence and cognitive and cardiac outcomes have been reported in children up to 18 years of age for fetuses exposed to chemotherapy in utero [24,25,26,27].

There are some limitations to this study that must be taken into account. This was a single-center study which, added to the rarity of this entity, resulted in a small sample size; therefore, it achieved insufficient power in the statistical analysis. Also, due to small size of the groups, it was not possible to analyze the results by the subgroup of patients diagnosed during pregnancy and during the postpartum period.