Currently, the percentage of women giving birth after the age of 30 is increasing, this correlates with the associated increase in knowledge of breast cancer screening. 

 Consideration of pregnancy management issues and recommendations for women with cancer is a complex bioethical problem. The patient has the right to make decisions independently without the involvement of people around him and has the right to receive the necessary medical care. In this regard, the categorical demand of some doctors to terminate the pregnancy, of all the cancers detected during pregnancy, the most common are cervical cancer, breast cancer, and lymphoma. According to local statistics, over the past 10 years, the incidence of breast cancer has increased by 32.5%, while the number of women diagnosed with cancer at a younger age is increasing every year. breast cancer ranks second in terms of incidence among all malignancies diagnosed during pregnancy. Currently, the international term "pregnancy-related breast cancer" has been accepted[1].According to various sources, pregnancy-associated breast cancer occurs with a frequency of 1 clinical case in 1360 women to 1 in 3200.

Up to 7.3% of women under 45 with breast cancer are pregnant or lactating[2].

According to foreign scientists, the is 1 case of breast cancer for every 3,000 pregnancies. According to T. White, based on the observation of 45,881 women, the disease develops during pregnancy or shortly after childbirth in 2.8% of the surveyed.

Breast cancer against the background of pregnancy is characterized by a high frequency of previous hyperplastic processes in the gland tissue, chronic hypoestrogenism, late (after 30 years) first births, and aborted last pregnancies, or a large number of births, but no pregnancy at least 5 years before the last pregnancy, combined with tumor.

It is believed that pregnancy aggravates the course of breast cancer, and especially in patients with hormone-sensitive forms of the tumor.

For the choice of treatment tactics, a thorough examination of the patient and the fetus, clarification of the extent of the tumor process is necessary. The complexity of the pathology necessitates the participation of doctors of various specialties in the treatment. 

Approximately 70-80% of pregnant women with breast cancer have a nodular neoplasm. Late diagnosis of breast cancer during pregnancy is typical. The difficulty of diagnosing breast cancer during pregnancy is due to several clinical signs and physiological changes in the mammary gland. Hypertrophy, swelling of the mammary glands, changes in consistency, increased vascularization in response to hormonal stimulation, as well as several possible complications (mastitis, galactocele) complicate examination and mask the developing tumor. A sharp increase in the mass of the mammary gland during pregnancy and lactation is not always taken into account by the doctor supervising the pregnancy and can be regarded as a normal physiological phenomenon.

Especially many mistakes are made by doctors in the management of patients with diffuse forms of breast cancer, which can simulate acute and chronic mastitis.

L.Yu. Dymarsky gives the following reasons for late diagnosis:

• The erroneous opinion of doctors that breast cancer is characteristic mainly of pre-and postmenopausal women, and not of pregnant and lactating women;

•  physiological hyperplasia of the lobules and enlargement of the gland during pregnancy masks the tumor; the gland in nursing is elastic and tense, and the differential diagnosis between galactostasis, mastitis, and the tumor is not always easy. It can be specified with mammography and puncture biopsy, but these methods are rarely used in lactating women.

Approximately 50% of tumors and tumor-like formations detected in the mammary gland during pregnancy and lactation are breast cancer. Then, according to the frequency of the lesion, galactocele and chronic lactational mastitis are diagnosed. In recent years, erased forms of inflammatory lesions of the mammary gland are more common, characterized, if not by a complete absence, then at least by a weak severity of typical clinical manifestations. Of course, with an increase in such forms of inflammatory diseases, the differential diagnosis between them and malignant lesions of the breast becomes much more complicated. Accordingly, the number of cases of insufficiently substantiated and inadequate treatment measures is increasing. In addition, to is often a reluctance of patients to perform certain diagnostic procedures, in particular, a biopsy of a breast tumor. All this can lead to the fact that in a pregnant woman from the moment the first symptoms appear until the diagnosis is made, much more time passes than in a normal situation, and the treatment of such patients begins, on average, several months later than in the general group of breast cancer patients glands.

Diagnosis is based on the presence of a palpable tumor and puncture biopsy data. Physical examination should be thorough, including palpation of the lymph nodes, identification of changes in the mammary gland.

Taking into account the often obtained false-positive cytological picture in cancer of this localization during pregnancy and lactation, caused by hyperplastic processes of the mammary gland, morphological examination of a biopsy obtained as a result of trepanbiopsy of a tumor or excisional biopsy performed under local anesthesia remains a reliable diagnostic method. A biopsy allows you to obtain morphological confirmation of the diagnosis and also givesinformation on prognostic factors (receptor status, tumor ploidy, expression of -2 / neu, factors of apoptosis, angiogenesis, etc.).

Determination of levels of steroid hormone receptors in tumors during pregnancy is usually negative. This is often due to the blocking of receptors by estrogens, which are present in increased concentrations during this period.

The most informative method for assessing the condition of the mammary glands is ultrasound, especially with Doppler ultrasound. A mammogram is done if necessary. To exclude distant metastases, the patient is examined by organs and systems.

Diagnostic examinations of pregnant women with breast cancer should limit exposure to ionizing radiation as much as possible. Procedures must be followed that do not endanger the fetus.

During the first trimester of pregnancy, it is acceptable to perform only the necessary x-rays. A chest x-ray is performed with the obligatory use of a lead apron. An ultrasound scan is performed to assess the condition of the abdominal and pelvic organs. Isotope and computed tomography scans are not recommended Magnetic resonance imaging is also not safe for the fetus.

Treatment of breast cancer patients during pregnancy

vary fact of a combination of breast cancer and pregnancy cannot be a contraindication to treatment, Since the mid-50s of the last century, is has been optimistic forecasts regarding the course and long-term outcomes of the disease in patients of this group.

The statement made by several oncologists and gynecologists about the mandatory and immediate termination of pregnancy when diagnosing cancer is not absolute today. It is believed that the prognosis in the combination of breast cancer with pregnancy is generally worse, nevertheless, despite the sensitivity of tumor tissue to hormonal stimulation during pregnancy and lactation, when comparing groups of patients of the same age and stage of disease, the survival rate among pregnant and non-pregnant women is the same. Termination of pregnancy followed by chemotherapy does not improve prognosis.

In the early stages of the disease, surgical treatment is most preferred. Surgical intervention under general anesthesia is possible starting from the end of the first trimester. Surgical intervention and anesthesia do not lead to the development of miscarriage, they do not bring tangible harm to the patient and the child.

Termination of pregnancy is indicated in women in the first trimester of pregnancy. In the II and III trimesters, if desired, the patient is permissible preservation of pregnancy until natural delivery, after which chemotherapy and hormone therapy is carried out according to an individual plan, taking into account the content of estradiol and progesterone receptors in the tumor. Cesarean section in the II and III trimesters is performed with a significant local-regional spread of the process. Prophylactic oophorectomy in breast cancer patients in combination with pregnancy is inappropriate.

With a localized tumor process, termination of pregnancy is indicated if it is an early term followed by treatment of breast cancer. It is possible to use a modified radical mastectomy with the preservation of both pectoral muscles with delayed mammoplasty (after childbirth). Organ-preserving operations, in all cases requiring adjuvant irradiation, are more expedient to use at the end of the second-beginning of the third trimester when the start of radiation therapy can be delayed. Adjuvant chemotherapy with favorable prognostic factors is not indicated; with unfavorable prognosis criteria, it is possible to use adjuvant chemotherapy immediately after childbirth. Hormone therapy with a positive receptor status of the tumor is the prerogative of the postpartum period.

In locally advanced breast cancer, termination of pregnancy and treatment of breast cancer are indicated according to standard protocols, depending on the prognosis criteria. With the absolute desire of a woman to maintain a pregnancy, it is possible to prescribe chemotherapy followed by surgical intervention (radical mastectomy, radical resection), radiation, and hormone therapy in this case is postponed until the postpartum period.

Radiation therapy, due to its danger to the fetus, is not performed during pregnancy. If radiation therapy was nevertheless carried out in the first trimester, the patient should be advised to terminate the pregnancy.

Side effects of radiation are determined by the ratio of the gestational age and the value of the damaging dose:

• The embryo (1-2 weeks) is more susceptible to the effects of radiation therapy;

• At the stage of organogenesis (2-8 weeks), the teratogenic effect of radiation is most pronounced

• Threshold damaging dose - 0.1 Gray (Gy);

• A dose of 0.1-0.15 Gy leads to developmental defects, disorders of the central nervous system of the fetus;

- 0.5-2 Gy retards development;

- 0.25Gy or more leads to deformities.

Approximately 70% of breast cancer patients have positive receptors for estradiol and progesterone in tumor cells. The interaction of these receptors with steroid hormones leads to the development of proliferative processes in the pathologically altered breast tissue. More than a hundred years ago, it was shown that the removal of the ovaries, which are the main source of estrogen in premenopausal women, has an antitumor effect in patients with advanced, forms of the disease. Turning off the function of the ovaries by surgery, radiation or medication leads to a decrease in the levels of estradiol, estrone sulfate by almost 10 times compared with the norm. In this case, a certain amount of estrogen and progesterone is synthesized due to the function of the adrenal cortex through the reaction of androgen aromatization. In this case, the biosynthesis of steroid hormones occurs in adipose, muscle, bone, and tissues. This synthesis pathway is the main one during menopause. Thus, inhibition of ovarian function does not completely stop the synthesis of steroid hormones, which leads to the need for additional drug treatment to stop stimulating tumor growth. An effective strategy for the treatment of patients with hormone-sensitive breast tumors is the blockade of hormonal receptors. For this, various anti-hormonal drugs are used.

Tamoxifen, which has pronounced teratogenicity, is not used during pregnancy. It can be used for receptor-positive tumors in pregnancy-associated breast cancer patients after childbirth.

Analgesics, non-steroidal anti-inflammatory agents are safe for use during pregnancy with minimal teratogenic risk.

Medicines of the bisphosphonate group are not recommended to be prescribed to patients with breast cancer during pregnancy, as these drugs can cause various kinds of abnormalities in the development of the skeletal system in the fetus due to penetration through the placenta. Cases of reversible neonatal hypocalcemia with pamidronate have been reported.

Antiemetic drugs - ondal, metoclopramide, used during pregnancy, do not hurt the fetus, which was confirmed by two international randomized trials.

Controversial issues are safety and possible adverse reactions arising from the chemotherapy carried out during pregnancy.

The standard palpation examination when examining patients with breast cancer associated with pregnancy is ineffective and, in most cases, especially at later stages of pregnancy(II-III trimesters), does not allow differentiation of the tumor. The preferred diagnostic method during pregnancy and lactation is ultrasound, which allows a differential diagnosis between cystic and solid formations in 97% of cases. Mammography, although it is permissible during pregnancy using a lead apron to protect the abdomen, does not have a significant diagnostic value, since in 25% of cases the study gives a false negative result. 

Detection of distant metastases in the liver and small pelvis without much risk can be performed using sonography. The method of magnetic resonance imaging, used to diagnose metastases to the abdominal cavity organs, to the brain, does not imply ionizing radiation or the use of any radioactive substances, however, the drug used for contrasting (gadolinium) is classified as category C drugs (use is permissible if expected the benefit is higher than the potential risk to the fetus.

The most reliable method for diagnosing tumors is morphological examination. Excisional biopsy performed under local anesthesia is the gold standard for any obscure breast pathology. Percutaneous biopsy with a subsequent morphological examination of the "column" of tissue allows you to obtain a sufficient amount of material to verify the diagnosis[3].

Due to the late diagnosis of breast cancer during pregnancy, the average tumor size ranges from 5 to 15 cm, and common forms are observed in 72–85% of cases. At the time of diagnosis, the disease is often in an inoperable stage and distant metastases are detected in 20% of cases. The most common form in the histological examination is invasive intraductal cancer.

Most breast tumors during pregnancy are of a high grade with frequent lymph vascular invasion. Moreover, all studies have shown that most tumors are hormone-independent. In a prospective study by LP Middleton et al.,. [4]in the immunohistochemical study, 28% of tumors with estrogen receptors and 24% with progesterone receptors were hormone-positive compared to 45% and 36%, respectively, in non-pregnant young women[1].

Thus, during pregnancy, more malignant hormone-independent forms of tumors are more common; however, the histopathological and immunohistochemical characteristics of pregnancy-associated breast cancer and breast cancer in young non-pregnant women are the same.

It is more likely that it is the age that affects the malignancy of the process, and not the pregnancy itself. feature of pregnancy-associated breast cancer is an increase in the frequency of functionally significant mutations of the BRCA1 gene (17.5%) and polymorphic variants of the BRCA2 gene (40.5%), which is significantly high than the population frequency of these mutations in patients with sporadic cancer. under 35 years of age.

(Vincristine, Vinblastine), anthracyclines (doxorubicin), and cyclophosphamide have the least damaging effect. Chemotherapy with a combination of drugs according to the AC regimen (adriamycin, cyclophosphamide) does not lead to fetal malformations if treatment is carried out in the II or III trimesters of pregnancy.

The side effects of taxanes are currently being studied. Antimetabolites have a high teratogenic potential. Epirubicin is not recommended due to its ability to cross the placental barrier. Platinum preparations should also be prescribed with great caution, since cases of hearing loss, the development of the heart, and cerebral congenital malformations in the fetus have been described when these drugs are administered.

After childbirth, breastfeeding of the baby is undesirable due to the possible penetration of chemotherapy drugs into breast milk and the risk of toxic effects on the baby.

Due to early diagnosis in some young patients, treatment can be limited only to surgical intervention, which will not affect the woman's fertility, and Patients with early-stage breast cancer with poor prognostic factors and receiving adjuvant chemotherapy with or without radiation may develop temporary or permanent amenorrhea (premature menopause). The development of amenorrhea depends on the age of the woman receiving adjuvant chemotherapy. In women over 40 years of age, amenorrhea develops within 2-4 months. from the start of chemotherapy, women aged 30 to 39 years need a large cumulative dose of drugs to induce ovarian dysfunction, and women younger than 30 years old, despite the gonadotoxic effect of cytostatics, the menstrual cycle persists.

The duration of chemical castration depends on the chemotherapy regimen and the patient's age. The standard for the adjuvant cytostatic effect is 6 courses of chemotherapy according to the CMF scheme (cyclophosphamide, 5-fluorouracil, methotrexate). This treatment regimen leads to the development of amenorrhea in 20-75% of premenopausal breast cancer patients. The use of only cyclophosphamide alone and its alkylating agents block ovarian function in 9% of patients.

Cytostatic effects, based on anthracycline-containing derivatives, are also prescribed for adjuvant chemotherapy. So, the CAF scheme (cyclophosphamide, doxorubicin, 5-fluorouracil) leads to the development of artificial menopause in 60% of patients. A scheme involving the use of 6 courses of epirubicin in combination with cyclophosphamide and 5-fluorouracil causes amenorrhea in 51% of cases. Fewer courses (4) and lower doses of chemotherapy suppress ovarian function in about 34% of patients [5,6].

Taxane-containing regimens (docetaxel, doxorubicin, cyclophosphamide) suppress ovarian function significantly more (in 62% of cases) compared to anthracycline-containing regimens.

The frequency of induced chemical castration depends on the age of the patient. It has been established that in patients under 40 years of age it develops in 22-61% of cases, in women over 40 - in 61-97% of cases [7,8].

Two-phase III clinical trials were conducted [9-11], which involved studying the likelihood of developing chemical castration in patients with breast cancer. The study involved 423 premenopausal patients.

The treatment was carried out according to the scheme - 6 courses of polychemotherapy according to the scheme: epirubicin, cyclophosphamide, 5-fluorouracil. The level of amenorrhea was: 24%, 38%, and 67% in patients under the age of 35 years, 35-40 years, and over 40 years, respectively (Fig. 1). Although a pronounced trend towards an increase in the incidence of amenorrhea with increasing age, a small number of patients develop chemical castration due to cytostatic treatment, despite a very young age. This suggests that many different factors can lead to chemical castration in breast cancer patients. 

Figure Image is Available in PDF Format

Fig. 1. Development of chemical castration in patients with breast cancer, depending on age (Patel, S. J.)

Adjuvant hormone therapy with tamoxifen increases the incidence of artificial menopause in a small number of patients, mainly in women over 40 years of age. The risk of menopause after taking tamoxifen increases by 10% compared to using chemotherapy alone. Gonadotropic releasing factors lead to reversible inhibition of ovarian function. The reversibility of this effect also depends on the age of the patients. It was found that in 90% of patients under 40 years of age after 2 years of pharmacological castration, ovarian function is restored 1 year after the end of treatment. In patients over 40 years of age, ovarian function is restored only in 70% of cases[12].

As a result of the conducted studies, it was found that the absence of monthly ovarian function does not necessarily indicate its failure. Premenopausal estradiol levels have been found in patients with amenorrhea during chemotherapy. Various tests: determination of the concentration of the follicle-stimulating hormone, ultrasound examination of the pelvic organs, etc., can help in the diagnosis of ovarian failure and, accordingly, predict a reduced likelihood of pregnancy.

Breast cancer is very common, accounting for 1 in 9 people, and this is a common cause of death for women aged 33 to 55 years. Breast cancer is considered a serious issue as it affects more than 5000 women especially of reproductive age. Between 1991 and 1997 there were 1.3–2.4 cases of breast cancer in women per 10 000 live births, 1.2 although when breast cancer is diagnosed in women aged 30 years or less, 10–20% of cases may be associated with pregnancy or occur within 1 year postpartum.

Where the development of the special diagnosis and reached more than 80 percent to the ages ranging between 40 and 50 However, the survival rate may be lower in very young women. Treatment of pregnancy-associated cancer should be in a multidisciplinary team according to standard UK guidelines4 with the inclusion of the obstetric team as core members. Fewer than 10% of women diagnosed with breast cancer become pregnant, but increasing numbers of women are seeking following pregnancy treatment. Young women presenting with breast cancer often have fertility-related concerns7–9 and need well-informed discussions on fertility, pregnancy, and lactation after breast cancer and the availability of fertility preservation procedures[13]. Since cytostatic have the greatest damaging effect on rapidly dividing cells, it has been suggested that the state of induced gonadal inhibition during the administration of chemotherapy drugs can protect the ovaries[14].

Table 1- Pregnancy duration and breast cancer risk

Figure Image is Available in PDF Format

Fig 2-Pregnancy and breast cancer risk

Possibility of pregnancy in women undergoing treatment for breast cancer

Young women who have been treated for early breast cancer who are still fertile may want to have a baby.

Pregnancy is highly undesirable during the first 6 months. after the end of chemotherapy due to the teratogenic effect of cytostatics, in addition, during the first 3-5 years after treatment, because of the unclear prognosis for the expectant mot. Pregnancy can contribute to the recurrence of the disease and the manifestation of latent metastases[2]. At the same time, after surgical treatment, a significant number of patients undergo adjuvant chemoradiation treatment, which can adversely affect the development of the fetus. When deciding on pregnancy in a young patient, it is advisable to examine the presence of mutations in the BRCA-1 and BRCA-2 genes due to

 the high risk of transmitting the hereditary form of breast and ovarian cancer to the offspring.

The question of the possibility of pregnancy after treatment for breast cancer has not yet been resolved. Along with the opinion about the need to categorically prohibit subsequent pregnancies, in the literature one can find data on the possible minimum safe interval between the end of treatment and the development of pregnancy from 6 months. up to 5 years. At the same time, one cannot but reckon with the frequent possibility of late breast cancer metastases. Therefore, weighing the medical and ethical aspects, the doctor has no reason to prohibit, but he should not recommend a new pregnancy after treatment for breast cancer.

Due to the undesirability of pregnancy in the coming years after the treatment of malignant tumors, contraception should be included in the complex of measures for the rehabilitation of these patients. Steroid preparations containing estrogens and progesterones are not recommended for cancer patients (except chorionic carcinoma of the uterus). In women of reproductive age, the use of intrauterine contraception is justified.

The ideal interval between the end of breast cancer treatment and the development of pregnancy is unknown. Patients are advised to plan a pregnancy no earlier than two years after completing therapy for breast cancer since disease progression occurs most often during this period. Such advice can be given to women with a favorable prognosis. For younger patients, it is desirable to postpone pregnancy for at least 3 years, and for patients with stage III of the disease, a delay in pregnancy should be planned for at least 5 years.

Thus, the treatment of breast cancer patients during pregnancy is currently a serious problem for clinical oncologists.

The treatment plan for pregnant women diagnosed with breast cancer is determined individually, taking into account the stage of the disease, the timing of pregnancy, prognosis factors, and the patient's desire to maintain this pregnancy.

Maintaining pregnancy in breast cancer patients is always a difficult decision based on assessing the extent of the process, the duration of the pregnancy, and the biological characteristics of the tumor in each case.

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the Fallujah Maternity and Children's Hospital, Al-Anbar, Iraq

1. Zemlickis, D., Lishner, M., Degendorfer, P., Panzarella, T., Burke, B., Sutcliffe, S. B., & Koren, G. (1992). Maternal and fetal outcome after breast cancer in pregnancy. American journal of obstetrics and gynecology, 166(3), 781-787. Berry, D. L., Theriault, R. L., Holmes, F. A., Parisi, V. M., Booser, D. J., Singletary, S. E., ... & Hortobagyi, G. N. (1999). Management of breast cancer during pregnancy using a standardized protocol. Obstetrical & gynecological survey, 54(10), 620-621. 

2. Bonnier, P., Romain, S., Giacalone, P. L., Laffargue, F., Martin, P. M., & Piana, L. (1995). Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy. Obstetrics & Gynecology, 85(1), 11-17. 

3. Opdahl, S., Alsaker, M. D. K., Janszky, I., Romundstad, P. R., & Vatten, L. J. (2011). Joint effects of nulliparity and other breast cancer risk factors. British journal of cancer, 105(5), 731-736. 

4. Nicklas, A. H., & Baker, M. E. (2000, December). Imaging strategies in the pregnant cancer patient. In Seminars in oncology (Vol. 27, No. 6, pp. 623-632).

5. Hogge, J. P., De Paredes, E. S., Magnant, C. M., & Lage, J. (1999). Imaging and management of breast masses during pregnancy and lactation. The breast journal, 5(4), 272-283. 

6. Lyman, G. H., Giuliano, A. E., Somerfield, M. R., Benson, A. B., Bodurka, D. C., Burstein, H. J., ... & Winer, E. P. (2005). American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. Journal of clinical oncology, 23(30), 7703-7720. 

7. Liberman, L., Giess, C. S., Dershaw, D. D., Deutch, B. M., & Petrek, J. A. (1994). Imaging of pregnancy-associated breast cancer. Radiology, 191(1), 245-248.

8. De Santis, M., Straface, G., Cavaliere, A. F., Carducci, B., & Caruso, A. (2007). Gadolinium periconceptional exposure: pregnancy and neonatal outcome. Acta obstetricia et gynecologica Scandinavica, 86(1), 99-101. 

9. Yang, W. T., Dryden, M. J., Gwyn, K., Whitman, G. J., & Theriault, R. (2006). Imaging of breast cancer diagnosed and treated with chemotherapy during pregnancy. Radiology, 239(1), 52-60. 

10. Kal, H. B., & Struikmans, H. (2005). Radiotherapy during pregnancy: fact and fiction. The lancet oncology, 6(5), 328-333. 

11. Hamaoka, T., Madewell, J. E., Podoloff, D. A., Hortobagyi, G. N., & Ueno, N. T. (2004). Bone imaging in metastatic breast cancer. Journal of Clinical Oncology, 22(14), 2942-2953. 

12. Travis, R. C., & Key, T. J. (2003). Oestrogen exposure and breast cancer risk. Breast Cancer Research, 5(5), 1-9. 

13. Scott-Conner, C. E., & Schorr, S. J. (1995). The diagnosis and management of breast problems during pregnancy and lactation. The American journal of surgery, 170(4), 401-405.