Although PABC is still relatively rare, with an incidence of only 0.2%–3.8% [9], the number of cases is likely to increase because it is common to delay childbearing in today’s society [10]. The older age at pregnancy usually indicates a higher risk of developing cancer [11]. Once a PABC diagnosis is made, challenges lie not only in deciding on the choice of the mother’s treatment and the survival of the fetus but also in addressing a series of complex problems, such as distant metastasis and preterm birth complications [5].
In this present study, we reviewed 25 studies in the past 20 years to gain a deeper understanding of PABC (Table 2). Almost all existing studies regarded PABC as the experimental group and non-PABC as the control group. PABC was defined as breast cancer occurring during pregnancy or within 1 year after pregnancy in 16 studies, while it was defined as breast cancer diagnosed during pregnancy or within 2 years postpartum in 8 studies. The survival rates for PABC compared to those for non-PABC were conflicting. Eight studies [12–17,7,18] showed no difference in survival between PABC and non-PABC after correcting for prognostic factors including age, tumor size, and lymph node status, while 12 studies [19–30] demonstrated a worse prognosis for PABC after excluding these factors. Five studies [31–35] classified PABC into antepartum and postpartum breast cancer, three studies showed that the prognosis of PABC occurring postpartum was worse than that of PABC during gestation, one study concluded that the prognosis of PABC occurring in the antepartum period was worse, and one study indicated that PABC occurring postpartum had a worse survival rate than non-PABC. The reasons for the poor prognosis of PABC may include several factors. First, the physical changes in the mammary gland, including increased cell turnover and glandular tissue during pregnancy, make the diagnosis of PABC difficult [36]. In addition, fluctuations in hormone levels during pregnancy may promote tumor progression and breast involution; moreover, tissue remodeling of the breasts after breastfeeding may promote tumorigenesis [37,38].
The first part of the classification in our study was based on first-pregnancy and non-first-pregnancy status to explore the effect of parity on PABC. The frequency of PABC in women with more than one pregnancy has increased as more women have chosen to have a second child since China abolished the restriction in which one couple could only have one child. Our study proves that the proportion of PABC that developed during the second or third pregnancies of women was extremely high relative to the proportion of newborns. Our study also showed that compared with the non-first-pregnancy group, the first-pregnancy group presented with less aggressive tumors, which were more likely to be smaller in size, show HR positivity, exhibit lower Ki–67 expression and have a lower histological grade, which were related to a better prognosis. However, our survival analysis showed the opposite result: the PABC patients in the first-pregnancy group were more likely to have a worse outcome. There are several possible reasons for this result. First, our data showed that a woman in her first pregnancy was more likely to delay treatment until the fetus was born. Delayed treatment may be a vital factor for a poor prognosis. Second, there may be a protective effect from the previous pregnancy on women with PABC who have had more than one child [39]. In addition, the women in the first-pregnancy group were younger than those in the non-first-pregnancy group. Studies have indicated that breast cancer in young women is an invasive disease with a poor prognosis, and age may be a factor that is independent of pregnancy, resulting in a poorer survival rate for the younger first-pregnancy group [40–42]. In addition, previous studies have shown that a family history of breast cancer can increase the risk of PABC, so the family history of breast cancer should be assessed when studying PABC [43,44]. In our sample, more patients in the first-pregnancy group had a family history of breast cancer (10.1% in the first-pregnancy group vs. 8.9% in the nonpregnancy group); however, whether this is related to the poor prognosis observed in this group requires further research.
The other part of our study classification divided the research population into three subgroups: the pregnancy (abortion) group, pregnancy (non-abortion) group and lactation group. Some scholars have proposed that there are two subtypes of PABC: breast cancer diagnosed during pregnancy and breast cancer diagnosed postpartum. The importance of this classification is emphasized because some epidemiological data indicate that postpartum cases may have specific deteriorating outcomes and that postpartum breast degeneration may increase the metastatic potential of PABC [45]; however, other studies present the opposite view that pregnancy was more detrimental [46]. In our study, the pregnancy group was subdivided into the pregnancy (abortion) group and pregnancy (non-abortion) group based on the different hormonal status and treatment methods of the groups to explore how pregnancy impacted DFS. The survival analysis results indicated that the pregnancy (abortion) group and the lactation group tended to have better survival rates than the pregnancy (non-abortion) group. In our study, we found that patients in early pregnancy were more likely to terminate their pregnancies, while those in late pregnancy usually preferred to delay treatment until delivery of the fetus. Notably, the pregnancy (abortion) group tended to have smaller tumor sizes, less Ki–67 positivity, and a smaller proportion of TNBC, indicative of a good prognosis. Ki–67 is an independent prognostic factor for breast cancer [47], and TNBC has a higher rate of recurrence and worse prognosis than other breast cancer subtypes [48,49]. There are three possible reasons for the worse prognosis in the pregnancy (non-abortion) group. First, the poor prognosis was often because the mother in middle-late pregnancy chose not to receive treatment until the fetus was born to ensure normal fetal growth. Delayed treatment led to an increased risk of recurrence and distant metastasis. Second, the poor prognosis may be caused by fluctuating hormone levels and microenvironmental changes. Reproductive events can affect breast tissue differentiation through hormonal mechanisms. Estrogen levels increase steadily during pregnancy and peak in mid-late pregnancy. In addition, estrogen plays a variety of roles in tumor transformation in breast tissue, both as a carcinogen and as a tumor growth-inducing factor [50,2]. Furthermore, under the long-term influence of microenvironmental factors, such as growth factors, most patients in the pregnancy (non-abortion) group had high HER–2 positivity rates and high Ki–67 expression during late pregnancy, which may have resulted in their poor prognosis [47].
Starting chemotherapy in mid-late pregnancy without delaying chemotherapy until after delivery is generally preferred, as unnecessary delays may result in a worse prognosis. FAC (fluorouracil, adriamycin and cyclophosphamide) is a commonly used chemotherapy regimen, and studies have shown that it is safe in mid-late pregnancy [51]. Doxorubicin and cyclophosphamide can be excreted through milk and are therefore prohibited during lactation [51]. However, in China, people generally do not undergo chemotherapy during mid-late pregnancy. Mid-pregnancy women with PABC choose to either terminate the pregnancy or delay chemotherapy until delivery, while late-pregnancy women usually start chemotherapy treatment after delivery. In our study population, 20 (30.3%) PABC patients with HER–2 positivity did not receive Herceptin treatment, 18 (85.7%) of whom were diagnosed with PABC before 2017. This may be because it was not until 2017 that Herceptin was included in the scope of medical insurance reimbursement in China. Before 2017, the high price of Herceptin restricted its use. Previous studies have also indicated that pregnant mothers cannot benefit from termination of pregnancy; therefore, it is not recommended for the purpose of improving prognosis [52,41]. However, in our study population, 23 (25.8%) patients diagnosed during pregnancy still had spontaneous or elective abortions. Nineteen (82.6%) of them were non-first pregnancies, which may have been because women who had already given birth to one baby were more likely to choose abortion.
It should be acknowledged that there were some limitations in our present study. First, the analysis was not adjusted for potential confounding factors, including age, tumor size and lymph node status, for the analysis of PABC survival. In addition, this study was a single-center study with a limited population, and the sample size enrolled in the study was not large enough to obtain a more reliable conclusion. However, the lack of statistically significant differences in the prognosis between the subgroups does not mean that we need to ignore the true relevance of these findings. Moreover, some information about the clinicopathological features of PABC is absent. HR status was lacking for 4 patients because their pathological biopsies from an external hospital were not promptly entered into the electronic case system of our hospital 14 years ago. The HER–2 status of 9 people was unknown because the overexpression status of HER–2 in their tumors was unclear when detected by immunohistochemistry, and patients refused to undergo another biopsy for further FISH analyses due to the high cost at that time—up to approximately $350. Ki–67 information was lacking for 42 people because the clinical significance of Ki–67 was not realized more than a decade ago. Information about histological grades was lacking for 70 (34.5%) patients, which may be due to the reduction or even disappearance of tumor residuals after neoadjuvant chemotherapy.
In conclusion, PABC is an invasive disease with poor prognosis in young women, and because of fetal factors, women in mid-late pregnancy often choose to delay treatment until delivery. With the abolishment of China’s one-child policy, an increasing number of women are having more than one child, which underlies the upward trend in the occurrence of PABC. Our single-center study provides some information on the characteristics and survival rates of PABC patients. However, further research on PABC in a large population and investigations into the physiological mechanisms are needed in the future.