As one of the most common malignancies threatening women’s health, breast cancer is becoming more and more prevalent and the population affected is getting younger. Approximately 2% of patients are between the ages of 20 and 34, and 11% are between the ages of 35 and 44. Thanks to advances in treatment, despite the high incidence of breast cancer, the survival time frame of breast cancer patients is increasing, and the fertility of breast cancer patients is gaining more and more attention from health care providers and patients.
The safety of pregnancy in breast cancer patients has been controversial because adjuvant therapy can have a negative impact on the reproductive function of the patient. Whether these negative effects will adversely affect the survival and health status of the fetus, whether estrogen receptor-positive patients need to stop the use of estrogen resistance antagonists during pregnancy will have a negative effect on the survival of breast cancer patients, and whether pregnancy will increase the probability of breast cancer recurrence; these issues are not yet uniformly determined.
1.The effect of adjuvant therapy on reproductive function
(1) The effect of chemotherapy on reproductive function
Tissue cells with active division and regeneration are more sensitive to cytotoxic drugs, and the ovaries are always in a cyclic regeneration state, so they are vulnerable to damage by chemotherapy drugs. The effect of chemotherapy on ovarian function is related to the patient’s age, chemotherapy drug type, regimen, and dose. Cyclophosphamide has the most damaging effect on ovarian function, and some studies have shown that the number of follicles will decrease by 90% after 48 hours of application of cyclophosphamide, and ovarian function will diminish to the state of 10 years after 12-16 weeks of application of standard chemotherapy regimen.
Anthracyclines and paclitaxel also have significant damage to ovarian function, and the probability of premature ovarian failure after chemotherapy has been reported abroad to be 29-93% for anthracycline-based drugs and 17-93% for paclitaxel plus anthracyclines. A research study involving 368 Asians showed that premature ovarian failure occurred in 83.6% of patients receiving chemotherapy; those older than 40 years of age accounted for the majority, and 28 of 61 patients who experienced premature ovarian failure subsequently resumed menstruation.
The extent of ovarian damage from chemotherapy is influenced by the patient’s own follicular stores. Younger patients with large follicular stores are generally less prone to permanent amenorrhea, and Fomier et al. found that the probability of long-term amenorrhea was about 15% in 166 patients younger than 40 years of age who were followed up.
Therefore, for young patients who have not yet had children at the time of diagnosis of breast cancer, patients should be informed that chemotherapy may lead to infertility, follicular reserve assessment is needed, and if the probability of premature ovarian failure is high pregnancy can be considered through other measures, such as cryopreservation of oocytes, cryopreservation of embryos, cryopreservation of ovarian tissue, and use of gonadotropin-releasing hormone analog (GnRHa) during chemotherapy.
(2) Effects of endocrine therapy on fertility
The majority of breast cancer patients are estrogen receptor positive and most of them need to receive endocrine therapy in the later stages. Premenopausal patients need to take oral tamoxifen treatment for at least 5 years. Tamoxifen inhibits ovulation, causes menstrual disorders, and may even increase the incidence of endometrial cancer; however, it is also believed that tamoxifen does not necessarily cause amenorrhea, as this may be a subsequent effect of prior chemotherapy received.
Tamoxifen causing amenorrhea has been controversial [7], and most scholars believe that tamoxifen is less detrimental to ovarian function, but tamoxifen may cause fetal malformations, so patients treated with tamoxifen need to discontinue tamoxifen before pregnancy.
(3) Effects of radiotherapy on reproductive function
For patients with invasion of the pectoralis major fascia, axillary lymph node metastasis or breast-conserving surgery, postoperative radiotherapy is required. Therefore, radiotherapy is safe for fertility, but radiotherapy may be detrimental to fetal health, and pregnancy should be avoided during radiotherapy.
2.The effect of fertility on the survival of breast cancer patients
For breast cancer patients who are mostly estrogen receptor positive, the question of whether the high hormone levels in the patient’s body caused by the pregnancy process will adversely affect the patient’s prognosis has been controversial among scholars both at home and abroad. Many scholars have conducted a series of retrospective investigations on this issue, with inconsistent results. Previous studies have concluded that fertility has no effect on survival in breast cancer patients, but the sample size was small.
In 2010, verkooijen et al. followed 492 treated pregnant and 8529 treated non-pregnant breast cancer patients and found that the mean follow-up time was 14.3 years and the overall mortality rate was at 16.8%, which was significantly lower than the overall mortality rate of treated non-pregnant patients (40.7%). Another meta-analysis of 14 case-control studies on the prognosis of patients who became pregnant after breast cancer treatment showed similar results. It was suggested that the possible reason for this result was the “healthy mother effect”.
The healthy mother effect means that patients with a good early prognosis have a better chance of receiving a pregnancy, while patients with a poor late prognosis have a higher dose and course of chemotherapy, which is detrimental to reproductive function and is influenced by their disease and low expectation of post-treatment pregnancy. In order to eliminate this bias as much as possible, valachis et al. screened 20 relevant papers, excluding 11 of them with a more pronounced healthy maternal effect, and finally included an observation sample of 1097 and a control sample of 14224, concluding that pregnancy after treatment in breast cancer patients does not adversely affect patient survival.
Since this study still did not absolutely exclude the healthy mother effect and was a retrospective investigation lacking prospective studies, caution should be maintained regarding the idea that pregnancy after treatment in breast cancer patients improves survival. while following 333 breast cancer patients who became pregnant after treatment, Azim et al. divided the patients into two separate groups based on whether they were estrogen receptor positive or not and found that regardless of whether the estrogen receptor This indirectly suggests that pregnancy does not improve the prognosis of breast cancer.
In recent years, the BRCK gene has become a hot topic in the field of breast cancer treatment, and for patients carrying the BRCA gene who may have lifelong disease, there is no evidence to prove whether childbirth will adversely affect the survival of such patients. The study found that childbirth did not adversely affect their survival.
3. Effect of post-treatment fertility on the fetus in breast cancer patients
Most breast cancer patients need to undergo post-operative radiotherapy and endocrine therapy, and many young breast cancer patients are afraid to give birth because of the concern of whether these treatments will have a negative impact on the health of the fetus. However, a meta-analysis of 6 papers by deBree, E et al. found that these adjuvant treatments did not increase the probability of fetal malformations, probably because the primordial oocytes escaped the damage caused by chemotherapy drugs and were renewed to mature oocytes after treatment.
Some studies have shown that even chemotherapy received in the middle and late stages of pregnancy does not increase the probability of fetal malformation deBree, E et al. also found that four of the six papers did not mention more perinatal complications during childbirth in breast cancer patients, but two suggested that perinatal complications such as miscarriage and preterm delivery may occur in breast cancer patients, and that the fetus is born with relatively low weight.
4. Choice of timing of pregnancy
How to choose a suitable time for pregnancy for both patients and fetuses is a concern for both clinicians and patients. Mueller, BA et al. concluded that pregnancy within 3 months after diagnosis significantly increases the relative risk of death, while pregnancy after 10 months after diagnosis decreases the relative risk of death to below normal values.
Ives, A et al. found that pregnancy activity in young breast cancer patients 6 months after completion of treatment did not reduce survival time. However, in hormone receptor-positive patients, pregnancy activity should be performed after the completion of endocrine therapy because of the need to suspend tamoxifen during childbirth, which may have an impact on survival. For fetal safety reasons, pregnancy should also be carried out after 6 months after the end of treatment, when chemotherapy drugs are largely metabolized completely in the body.
5. Summary
Based on the available evidence, pregnancy activity in breast cancer patients does not reduce survival time and may be prognostically beneficial, but the timing should be appropriate. Because the current studies are retrospective analyses of patients with early and intermediate stage breast cancer, there is no data on whether fertility is beneficial or detrimental to the prognosis of patients with advanced or recurrent metastases. Therefore, a cautious attitude should be maintained regarding fertility in this group of patients.