Special Issues in the Young and Pregnant Patient with Breast Cancer

Hatem A. Azim Jr.¹ and Fedro A. Peccatori²

¹Université Libre de Bruxelles, Brussels, Belgium

²European Institute of Oncology, Milan, Italy

Case study 84.1

A 33-year-old woman was recently diagnosed with a pT_1c (1.8 cm) pN₀ left breast cancer for which she was subjected to lumpectomy and sentinel lymph node sampling. Pathology revealed invasive ductal carcinoma grade II, estrogen receptor (ER) 30%, progesterone receptor (PgR) 0%, Ki67 14%, and HER2 score +1 by immunohistochemistry.

1. Would genomic testing by Oncotype DX^TM or MammaPrint^® be helpful in managing this patient?

Oncotype DX and MammaPrintare the most widely available genomic tests that are used to determine the risk of relapse in patients with ER-positive breast cancer. They have been shown to add prognostic information to classic clinico-pathological prognostic factors; however, their value in young populations has not been widely explored. The fact that breast cancer arising in young women (below 35 or 40 years) has poorer prognosis compared to that in older women, poses a question of whether these tests could be of value in young populations. A large gene expression analysis has tried to address this question and found that genomic tests were able to add significant prognostic information to Adjuvant Online. This was observed in patients 40 years or younger as well as in other age groups with no interaction according to age.

This patient was diagnosed with an ER-positive tumor, with features suggesting incomplete endocrine sensitivity, manifested by the relatively low expression of ER (30%) and the lack of PgR expression (0%). Ki67 was 14%, which is rather borderline in defining highly proliferative ER-positive breast cancer. Hence, genomic tests could provide more accurate information on the absolute risk of relapse, which could aid the decision-making process. While these tools were not developed as predictive tools, preliminary evidence suggests that patients with high Oncotype Dx^TMscores derive high benefit from adjuvant chemotherapy, while no benefit was observed in those with low scores. Nevertheless, the exact clinical utility of these tests has yet to be determined in two large prospective phase III trials (TailorX and MINDACT), which have already completed accrual and are expected to report in the coming few years.

Case study 84.2

A nulliparous 36-year-old patient was diagnosed with a pT_1c pN_1a infiltrating ductal carcinoma that is ER- and PgR-negative and HER2-positive (+3 by immunohistochemistry). She was offered adjuvant treatment with FEC100 (5-fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m²) ×3 followed by Docetaxel (100 mg/ m²) ×3 cycles. The patient will also receive trastuzumab starting with docetaxel to complete a total duration of 1 year.

1. In your opinion, which of the following factors are the most important in determining the risk of chemotherapy-induced amenorrhea (CIA) in this patient? (Choose all that apply.)

Age
The dose of anthracycline
The sequential use of docetaxel
The dose of cyclophosphamide
Concomitant administration of trastuzumab with chemotherapy

The possible impact of chemotherapy on the ovarian function is a frequent concern, particularly for young women who have not started or completed their families.

Age remains the most important determinant of CIA irrespective of the regimen used. At the ages of 37–39, there is physiologically accelerated atresia of the oocytes. Hence, CIA rates have been largely variable according to the patient age being above or below 40, which coincides with the physiological decline in ovarian reserve. Table 84.1 summarizes the risk of CIA with different regimens according to age.

Table 84.1 Risk of chemotherapy-induced amenorrhea with different regimens according to age.

Alkylating agents are the most gonadotoxic chemotherapeutic agents. Cyclophosphamide has been shown to induce apoptosis of the primordial follicles. The incorporation of taxanes in the adjuvant setting has not been shown to increase the risk of CIA associated with classic anthracycline-based regimens. On the contrary, regimens in which 3–4 cycles of a taxane are given in sequence to 3–4 cycles of an anthracycline-based therapy appeared to be less gonadotoxic compared to 6–8 cycles of anthracycline- and cyclophosphamide-based regimens. This is believed to be largely related to the lower cyclophosphamide dose administered in the sequential regimens. Current available evidence on trastuzumab is limited; however, it does not appear to increase the risk associated with CIA.

Case study 84.3

A 39-year-old breast cancer patient, who completed 5 years of adjuvant tamoxifen 6 months ago, presented to your office pregnant at week 8 of gestation. She was worried following her visit to her obstetrician, who recommended an abortion for fear that pregnancy could stimulate breast cancer recurrence. The patient would like to keep her pregnancy, but would like to understand whether taking this decision would have a detrimental effect on breast cancer outcome.

1. What would you advise her?

Pregnancy after ER-positive breast cancer increases the risk of recurrence, but abortion is not recommended as it is not clear that it improves prognosis.
Pregnancy after ER-positive breast cancer increases the risk of recurrence, and hence abortion is preferred as it could reduce such risk.
Pregnancy following breast cancer does not appear to be detrimental irrespective of ER status.
Pregnancy following breast cancer is protective and should be encouraged.

Pregnancy following breast cancer, particularly ER-positive breast cancer, represents one of the most controversial issues in managing young breast cancer patients. Despite several studies that have been reported for more than 3 decades showing that pregnancy after breast cancer is safe, these studies suffered major flaws regarding patient selection, low statistical power, and the lack of information on outcome according to endocrine receptor status. This has resulted in more breast cancer survivors being advised against pregnancy, with induced abortion rates reaching up to 30%. This reflects a conception that pregnancy is detrimental and that abortion might reduce such risks.

Recently, a multicenter, prospectively powered study was reported that aimed to address many of the limitations highlighted here. This study included more than 1200 patients, of whom 333 patients became pregnant after breast cancer diagnosis. Importantly, all patients had known ER status. This study showed that pregnancy after ER-positive breast cancer does not increase the risk of breast cancer recurrence at least during the first 5 years following conception. In the same study, patients who underwent abortion did not appear to have a superior outcome compared to those who continued their pregnancy to term. Hence, women who completed their adjuvant therapy should not be denied the opportunity to become pregnant. Promotion of abortion in these patients for therapeutic reasons remains unjustified in the absence of supporting evidence.

Case study 84.4

A 35-year-old breast cancer patient, who is ER-negative and HER2-positive, was treated with adjuvant chemotherapy (AC) ×4 followed by four cycles of docetaxel along with one year of adjuvant trastuzumab. Three years later, she is disease-free and considering becoming pregnant for the first time.

1. Would you be concerned that the treatment she received could have adverse effects on the fetal outcome?

No, no significant increase in fetal adverse effects is foreseen.
Yes, prior exposure to chemotherapy could increase the risk of fetal anomalies.
Yes, prior exposure to trastuzumab could increase the risk of fetal anomalies.
Yes, prior exposure to both chemotherapy and trastuzumab could increase the risk of fetal anomalies.

There is no evidence that pregnancy in breast cancer survivors is associated with a significant increase in fetal or infant risk of malformations. Data from two large population-based cohort studies from Sweden and Denmark are rather reassuring in this regard. However, in the Swedish cohort, increased risks of delivery complications, caesarean section, very preterm birth (<32 weeks), and low birth weight (<1500 g) were reported compared to healthy controls. These findings have potential implications for vigilant pregnancy surveillance. Of note, these pregnancies should be regarded as high risk, considering that the average maternal age is usually higher compared to the general population. Taking into account the time of oocyte maturation, it is recommended to wait for 6–12 months from the end of chemotherapy before becoming pregnant.

A 6-month period should be allowed before becoming pregnant after cessation of trastuzumab. Based on available data, prior maternal exposure has not been shown to affect fetal outcome, at least in the short term. This is based on data from the Herceptin Adjuvant (HERA) trial, in which patients who became pregnant >3 months after stopping trastuzumab did not experience a high rate of spontaneous abortions or fetal adverse events at delivery.

2. How would you counsel a patient who became accidentally pregnant on maintenance therapy with trastuzumab or tamoxifen? (Choose all that apply.)

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