Breast Cancer and Pregnancy: Epidemiology, Phenotypes, Presentation during Pregnancy, and Therapeutic Approaches

*Massimiliano Berretta, Oreste Claudio Buonomo, Gianluca Vanni and Bianca Arianna Facchini*

## **Abstract**

Breast cancer (BC) represents the most frequent cancer worldwide, with almost 2.26 million new diagnoses recorded in 2020, and is the most common malignant neoplasia diagnosed during pregnancy. Pregnancy-related Breast Cancer (PrBC), indeed, is diagnosed in 1 in 2000–4000 pregnant women every year in Europe. PrBC is frequently characterized by unfavorable biological marks that, along with the late diagnosis, the limited imaging applicable, and the often-suboptimal treatments necessary to protect the fetus, could possibly lead to a worse prognosis in this population of patients. Babies born from mothers treated for cancer during pregnancy have been followed during a long-term follow-up and have showed cognitive and physical functions not different from the general population, but more studies are needed. Taking into consideration the complexity of the disease, a multidisciplinary approach is crucial to define the best therapeutical path.

**Keywords:** breast, cancer, pregnancy, PrBC, BC

## **1. Introduction**

Breast cancer (BC) represents the most frequent cancer worldwide with almost 2.26 million new diagnoses recorded in 2020. Despite the progress made throughout the years to identify new anticancer drugs aiming to improve BC patients' prognosis, it still represents the first cause of cancer-related death in women [1].

BC represents one of the most frequent cancers in women in their reproductive age, with nearly 7% of all BC being diagnosed under 40 years of age [2].

It is well known that, BC being a frequently hormone-related malignancy, its onset may be induced by a higher exposure to estrogens, as may happen with physiological hormones in early menarche, older age at menopause, first pregnancy after the age of 30 and nulliparity, or with the exposure to external sources of hormones, during hormone replacement therapy or due to oral contraceptives.

Other risk factors are represented by personal and family history of BC, dense breast tissue, and lifestyle-based risk factors [3, 4].

Pregnancy represents a protective factor against BC [5], and even the age of the woman at the first pregnancy seems to play a crucial role in preventing the onset of this disease, pregnancy being considered protective if under 30 years of age [6, 7].

### **2. Pregnancy-related breast cancer epidemiology**

Cancer occurs in around one in 1000 pregnancies, with BC being the most frequent, followed by cervical cancer, lymphoma, ovarian cancer, leukemia, colorectal cancer, and melanoma [8], reflecting cancer epidemiology in women in their reproductive years. In Europe, Pregnancy-related Breast Cancer (PrBC), indeed, is diagnosed in 1 in 2000–4000 pregnant women every year [9], representing approximately 0.2–2.6% of all breast cancer cases, and its incidence is probably bound to increase due to the progressively older age of women at the first pregnancy.

The terms PrBC and Pregnancy-associated breast cancer (PABC) have been used for a long time as synonyms, but a recent, more precise definition has allowed to distinguish the two entities: While PrBC includes only BC cases that are diagnosed during pregnancy, PABC also includes cases of BC diagnosed in the post-partum phase, till 1 year after delivery [10].

Risk factors for PrBC seem to be consistent with the general population, and no specific pregnancy-related risk factors have been identified. Women with BRCA mutations have a higher risk of developing PrBC. As these cancer cases are often diagnosed in particularly young women, genetic counseling should be considered [11, 12].

## **3. Presentation**

Clinical presentation of PrBC is similar to BC in non-pregnant women, the palpation of a mammalian lump frequently being the first symptom. Nipple discharge, cutaneous lesions, or palpable lymph-nodes could also occur. The breast tissue physiological modifications that happen during pregnancy, such as engorgement and increased density, along with the young age of the patient and pregnancy itself, often lead to an underestimation of the symptoms and delayed diagnosis. Indeed, women during pregnancy have a 2.5 higher risk of being diagnosed at a higher stage, causing a worse prognosis [13].

### **4. Biology**

Some studies suggest that PrBC biology has no significant difference from nonpregnant patients' BC [14]. Notwithstanding, the hormonal modifications that occur in a pregnant woman with their growth-promoting effect suggest a possible lead to more aggressive forms of BC [15]. In fact, PrBC seems characterized by a lower expression of hormone receptors, with a higher rate of aggressive forms such as triple-negative or HER2-positive forms [16]. Moreover, several studies have shown that these types of tumors seem to be marked by unfavorable molecular characteristics, for instance, a high expression of cancer targets as PD1/PD-L1, RANK ligand, and IGF, and show a lower prevalence of tumor-infiltrating lymphocytes [17]. A recent study has aimed to

*Breast Cancer and Pregnancy: Epidemiology, Phenotypes, Presentation during Pregnancy… DOI: http://dx.doi.org/10.5772/intechopen.109344*

identify specific genomic alterations in PrBC, demonstrating through a whole genome sequencing a higher rate of mismatch repair deficiency mutational signature, besides other mutations such as in the mucin gene family [18]. The expression of several other oncogenes could be altered, such as MYC, SRC, FOS, JUN, and KLF1 [19].

These biological marks, along with the late diagnosis, could possibly lead to a worse prognosis in this population of patients, further worsened by the limited staging exams applicable and suboptimal therapies that have to be administered to protect the fetus.

Further studies are needed to clarify the biology of this particular kind of cancer.

#### **5. Diagnosis**

Clinical examination represents the first step of the diagnostical process but needs to be always followed by imaging and biopsy. It is well known that ionizing radiations are dangerous during pregnancy due to their teratogen effect on the fetus. This makes the diagnosis and staging more complex, often leading to suboptimal results. **Table 1** summarizes allowed and forbidden diagnostical examinations during pregnancy.

Every breast lump that persists for more than 2 weeks should be investigated, even though around 80% of them result in benign lesions [20].

Breast ultrasound (US) represents the first choice when a mammalian lump during pregnancy is detected, it being non-invasive and safe for the fetus, thanks to the absence of ionizing radiations. It allows, on the one hand, to identify benign lesions that have no need to be studied with further exams and that represent the most common lesions identified during pregnancy and, on the other hand, to detect suspicious lesions that may need a biopsy [21]. US can be used to explore local lymph nodes and identify suspicious nodes that might need fine needle aspiration or biopsy.

Mammography with abdominal shield can be safely administered in these patients at every gestational age [22], but possible limitations related to parenchymal modifications during pregnancy must be considered. Contrast-enhanced breast MRI,


#### **Table 1.**

*Allowed and forbidden diagnostical examinations in each pregnancy trimester.*

instead, should be avoided due to the capacity of gadolinium to cross the hematoplacentar barrier and to the lack of data assessing its safety for the fetus [23]. The combination of mammography and breast US has a high detection rate, comparable to contrast-enhanced breast MRI, which can safely be avoided during pregnancy [24].

When a suspect lesion is identified, biopsy represents the gold standard. The pathologist should always be informed of the pregnancy status to better analyze the biotic sample.

The stage, according to American Joint Committee on Cancer (AJCC), should always be assessed. Abdominal and pelvis ultrasound and chest X-ray with abdominal shield are the first-choice imaging exams during pregnancy, while computed tomography, bone scintigraphy, and PET scan should be avoided due to the higher rate of ionizing radiation [25]. If strictly necessary, diffusion-weighted whole-body MRI without gadolinium might be an option in case of advanced disease or metastases after the first trimester [26].
