**6. Therapy**

Cancer during pregnancy has for a long time been mistreated because of the lack of evidence about the efficacy and safety of the various available treatments in this peculiar population. By now, it is known that it should be treated as BC in non-pregnant women according to the stage and molecular asset, following some precautions to minimize the risks for the fetus (**Table 2**).

#### **6.1 Surgery**

Surgery is feasible at any time during pregnancy, considering that the majority of anesthetics has been demonstrated to be safe during pregnancy [27]. However, there is a slight risk of miscarriage, especially in the first trimester [26]. The preferred approach should be decided following the same guidelines for non-pregnant women, preferably after discussion by a multidisciplinary team due to the complexity of the decisions. Seen as though adjuvant radiotherapy must always be postponed after delivery, mastectomy might be discussed with the patient, especially for diagnosis done in the first trimester. Despite the limited data available on the matter, some studies suggest the feasibility and safety of conservative surgery during pregnancy [28]. Patients with PrBC who desire conservative surgery must be informed of the possible higher risk of local recurrence caused by a delay in the adjuvant radiotherapy treatment [29, 30].


#### **Table 2.**

*Allowed and forbidden treatments in the three pregnancy trimesters.*

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

Concomitant breast reconstruction after mastectomy does not seem to increase the mother-fetus morbidity and can be taken into consideration; the physiological breast tissue modifications during and after pregnancy, although, could lead to a delay in the procedure [28]. There is still no univocal approach regarding sentinel lymph node biopsy during pregnancy: On the one hand, American Society of Clinical Oncology (ASCO) does not suggest this procedure [31]; on the other hand, National Comprehensive Cancer Network (NCCN) guidelines and European Society of Medical Oncology (ESMO) support the procedure when considered necessary. Although further studies are needed, the procedure is considered safe for both mother and fetus if Technetium-99 m (99mTc) colloid solution injection is administered [32], preferably using the one-day protocol, injecting the drug in the morning of the surgery day [33]. Due to the high risk of anaphylactic, a potentially life-threatening reaction, blue dye and isosulfan blue should be avoided [34], while methylene blue should be avoided especially in the first trimester because of its teratogenic effect [35].

#### **6.2 Radiotherapy**

As stated above, radiotherapy should always be postponed to after delivery because of the several toxicities that can be caused to the fetus during pregnancy, such as intrauterine growth restriction, mental retardation, risk of childhood cancer, and fetal death [26].

#### **6.3 Chemotherapy**

Chemotherapy represents a fundamental weapon in treating BC. Its possible risks for the fetus strictly depend on the gestational age. During the first trimester, chemotherapy is always contraindicated, due to its high risk of miscarriage and congenital malformations (about 14% of cases) [36–38]. If chemotherapy is strictly necessary at this time of pregnancy, its interruption may be discussed with the patient [39]. After the first trimester, the risk of congenital malformations for the fetus drops to 3%, almost equal to the general population. For this reason, chemotherapy can be considered during the second and third trimester [26].

An fetal examination with US should be performed before and periodically during the treatment.

Chemotherapy regimens must be decided according to the tumor stage and biology, as in non-pregnant women. Anthracycline regimens have been known for years to be safe in pregnant women [40–43] and should be preferred. Regimens based on anthracyclines and taxanes appear to be safe during the two last trimesters of pregnancy [44, 45]. When taxanes are indicated, weekly paclitaxel should be preferred to docetaxel every 3 weeks because of its better tolerated toxicity profile and of the no need for steroid premedication or granulocyte colony stimulating factor (GCSF) [26].

The administration of dose dense regimens is still controversial: Although some data show the safety of this approach [46], further studies are needed before it becomes clinical practice.

Chemotherapy dose should be based on body surface area as in non-pregnant women, although some possible pharmacokinetics alterations must be taken into consideration [47].

The interruption of chemotherapy should not be over 35th week of pregnancy, to permit a 3-week washout before delivery [26], reducing possible surgical complications caused by hematological toxicity.

#### **6.4 Endocrine therapy**

Endocrine therapy is contraindicated at every trimester of pregnancy. Many studies demonstrated a clear teratogenic effect of tamoxifen in animal models [48, 49] and its relationship with major and minor congenital malformations in humans [50]. Notwithstanding a possible teratogenic effect in animal models, there are still no sufficient data available for aromatase inhibitors during pregnancy [51].

#### **6.5 Target therapy**

Trastuzumab, an anti-HER2 monoclonal antibody, has become, during the last few years, the standard of care in Her 2 positive adjuvant, neoadjuvant, and metastatic settings, representing a practice-changing drug. Being a type G Immunoglobulin, it is capable to trespass the blood placenta barrier from the second trimester to the due date. It interferes with the organogenesis process and causes oligo- and/or anhydramnios, as well as unknown long-term consequences on the fetus [33]. For this reason, it is contraindicated during every gestational age. Seen as though these complications have been shown only in the case of trastuzumab administration after the second trimester, incidental trastuzumab administration during the early stage of pregnancy (first trimester) does not necessarily require pregnancy interruption [52].

In the last few years, new anti-HER2 agents have become a part of our clinical practice, as Pertuzumab, trastuzumab-emtasine (T-DM1), or trastuzumab-deruxtecan (TDX). There are no data available on their safety during pregnancy.

#### **6.6 Immunotherapy**

Immunotherapy with anti-PD1/PD-L1 monoclonal antibodies has its peculiar role in the treatment of BC, especially in the triple negative forms. Some preclinical studies demonstrated a higher risk of late miscarriage and birth mortality if administered during pregnancy in animal models, probably caused by the non-acquisition of immune tolerance against the fetus [53, 54]. Hence, it is contraindicated till further studies about its security are conducted.

#### **6.7 Supportive care**

Most of the supportive care drugs used in non-pregnant women can safely be administrated even during pregnancy. Steroids should be avoided during the first trimester due to the risk of congenital malformations. They can be administered in the second and third trimester, preferably using methylprednisolone and hydrocortisone that are metabolized in the placenta and do not seem to reach the fetus [33]. Ondansetron can be safely administered, as well as H2 antagonists; there are no sufficient data about anti-NK1 agents [16]. Granulocyte-colony stimulating factors (G-CSFs) have shown no significant fetal toxicities in the only retrospective analysis that has analyzed their safety during pregnancy, but further studies may be needed [55].

#### **7. Fetal outcome**

As stated above, during the second and third trimester, chemotherapy can be safely administered. Nevertheless, it may be connected to an increased risk of

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

complications for the fetus, such as intrauterine growth restriction (7–9 up to 22%) or premature rupture of membranes (17–27%) [41, 56].

Mother and fetus should be strictly monitored before, during, and after the oncologic treatment, and after delivery, the placenta should be sent for histological exam, to assess if any BC cells are detected [57]. Moreover, a multidisciplinary approach is fundamental in this population of patients: Only the cooperation between all the figures involved (Oncologist, Surgeon, OBG-YN, Radiologist, Psychologist) can lead to the best approach for each patient.

Babies born from mothers treated for cancer during pregnancy have been followed during a long-term follow-up and have shown cognitive and physical functions not different from the general population, but more studies are needed [17].

#### **8. Conclusions**

PrBC incidence is slowly rising; thus, the awareness of its correct management is fundamental for every physician. It should be treated following non-pregnant BC guidelines, applying the abovementioned precautions to limit the possible risks for the fetus. There is no evidence of increased OS after pregnancy interruption; hence, this possibility must be discussed with the patient only in select cases, for instance, when the immediate start of chemotherapy is mandatory. Taking into consideration the complexity of the disease, a multidisciplinary approach is crucial to define the best therapeutical path.
