The importance of resuming hormone treatment after pregnancy. Case presentation: invasive ductal carcinoma RH+, HER2/Neu+

Introduction

Breast cancer is the most common malignancy in women, accounting for between 20% and 32% of all cancers. Currently, the incidence of breast cancer in pregnant women is increasing, and one of the reasons is the increased age at the first pregnancy. Fertility concerns impair the quality of life and can negatively affect treatment decisions and disease outcomes, as some patients may drop out of recommended treatments due to their risk of infertility.

Approximately 1/1000 cases of pregnancy are complicated with a preneoplastic/neoplastic lesion (Figure 1).

Breast cancer can be treated during pregnancy, especially in the last two trimesters, but in early pregnancy the options are limited, as chemotherapy is contraindicated.

General rules for administering chemotherapy during pregnancy⁽²⁾:

• Do not administer in the first trimester of pregnancy. Although administered in the last two trimesters, cases of premature birth and mental retardation syndrome for the child have been reported in patients who have been chemotreated.
• Use the standard protocol.
• Doses will be calculated according to body weight.
• The recommended dose will be maintained, in the absence of other restrictions.
• In weeks 35-37 of pregnancy, the doses will be discontinuous.

The surgery necessary for the treatment has no restrictions during pregnancy, and even post-mastectomy reconstructive surgeries can be performed. Radiotherapy can be applied in isolated cases in the first trimester. In the second and third trimesters, radiotherapy is contraindicated, and irradiation should be performed after birth. Endocrine therapy and targeted therapy are contraindicated (risk of fetal malformations, oligohydraminosis, spontaneous abortions etc.)⁽³⁾ – Figure 2.

However, pregnancies associated with breast cancer should be classified as potentially high risk and monitored at short intervals.

Case presentation

This article presents a case of breast cancer managed during pregnancy and describes the characteristics of the patient and the treatment received.

We report the case of a 32-year-old woman, diagnosed in 2018 with breast cancer, T1bN0Mx HR+, Her 2/Neu+, who underwent conservative surgery (the lesion were classified as pT2pN1), chemotherapy, radiotherapy, anti-HER2 therapy and endocrine therapy.

The patient stopped endocrine therapy after two years and one month of administration after the desire to become pregnant.

Case report

The patient is a 32-year-old Caucasian female, with no known family history, no pathological medical history, no pregnancies or abortions, but with the desire to have a child in the future.

She discovered a formation in the inner quadrant of the right breast on self-palpation in May 2018. She performed a mammogram that detected a small formation of 0.9 cm, being classified as BI-RADS 4.

Subsequently, she was biopsied, and the result yielded poorly differentiated infiltrating ductal adenocarcinoma, grade II/III, HR+, HER2+. The Multidisciplinary Commission indicated primary surgical treatment. Lumpectomy and selective sentinel lymphadenectomy were performed and, subsequently, the lesion was classified as pT2pN1. A new meeting of the Multidisciplinary Commission decided chemotherapy and trastuzumab, along with hormone therapy for a period of five years. The patient underwent adjuvant chemotherapy with two EC 100 and 11 Taxol® weekly along with trastuzumab and, shortly after, irradiation to the breast and the right lymph node areas.

The patient completed one year of trastuzumab treatment, and adjuvant endocrine therapy (tamoxifen) was recommended for five years.

The patient presented in clinical and radiological remission at two years and one month after the end of radiotherapy and the start of hormone therapy, and she informed us that she decided to stop taking tamoxifen for two months because she was planning to become pregnant. During the consultation, the eventuality of pregnancy after the temporary interruption of hormone therapy was discussed (POSITIVE study – Figure 3). She was informed about the risks, and a PET scan was recommended before a multidisciplinary consultation appointment for pregnancy decision. Also,  continuation of contraception was recommended, as the patient should wait three months after stopping tamoxifen (Figure 4) before pregnancy.

The last mammogram classified her BI-RADS 2 bilaterally. An 18F-FDG PET-CT from June 2021 (Figure 5) found no scintigraphic abnormalities suggestive for the presence of progressive lesions.

The patient underwent standard monitoring, modified as in the case of an early pregnancy. During the period when she stopped tamoxifen, in April 2022, the patient gave birth to her first child.

The patient did not resume tamoxifen after her first pregnancy; one year and four months passed, and she argued the decision of a second pregnancy. We emphasized the importance of continuing this treatment for a total of five years, as the benefit is undoubtedly in such cases, with lymph nodes microinvasion and, especially, HER2+++. However, the patient refused to resume the treatment, and she decided to have a second pregnancy.

The second pregnancy occurred 11 months after the first pregnancy, ending with a term birth, at 37 weeks.

In November 2023, two years and seven months after she stopped tamoxifen, the patient presented shortly after the second birth at the Emergency Department with a back pain in postpartum context. Unfortunately, the investigations revealed metastatic bone and liver recurrence. She initially presented diffuse metastatic osteosis, significant sacral lesions, and epiduritis around the sacral roots. Advanced T6 involvement involving the posterior edges of T5 and T6, with significant epidural metastases responsible for spinal cord compression, determined emergency decompression surgery at the T6 level. The histopathology of the surgical specimen confirmed the location of an adenocarcinoma of breast origin, hormone receptor negative, HER2 amplified (IHC score 3+).

The current 18F-FDG PET-CT shows numerous secondary biliary liver and bone lesions, intensely hypermetabolic, with pathological collapse of T6 and T9, with epidural metastasis from T5 to T8 (Figure 6 A, B).

The patient received timely treatment with radiation along with pain management with analgesics and corticosteroids.  We decided systemic metastatic first-line chemotherapy with weekly paclitaxel in combination with Phesgo® every three weeks. The patient also receives denosumab every month.

After six months of treatment, we will discuss her inclusion in the clinical trial HER2CLIMB 05, evalua­ting the interest of adding tucatinib to Phesgo® for maintenance.

Discussion

The POSITIVE study (Figure 3) tried to determine whether temporarily stopping hormone therapy to allow pregnancy would increase the risk of cancer recurrence. The study followed 497 patients with HR-positive breast cancer. As previously reported, 368 patients became pregnant after discontinuing therapy and had similar outcomes to those of patients who did not interrupt the treatment, suggesting that discontinued treatment for up to two years could be a viable option for patients who want to become pregnant.

The main objectives were the lack of recurrence of breast cancer and the absence of progression. Secondary goals include the ability to become pregnant, pregnancy outcomes, birth outcomes, breastfeeding, use of assisted reproductive technology, resumption of endocrine therapy, and distant relapses.

For selected women with early hormone receptor-positive breast cancer, the temporary discontinuation of endocrine therapy to attempt a pregnancy did not confer a higher short-term risk of breast cancer events, including distant recurrence, compared to that in the external control cohort. Further follow-up is essential to inform about the long-term safety⁽⁴⁾.

Pregnancy after breast cancer does not appear to negatively affect survival outcomes. However, the optimal time to discontinue hormone therapy should be discussed with each woman, taking into account the stage of the tumor, the risk of recurrence, and the completion of treatment.

The results of the POSITIVE study are encouraging for patients who want to have a pregnancy during hormone treatment for breast cancer, but the interruption should be for a period of maximum two years.

From the beginning, the reported case had a series of negative prognostic factors (HER2+, invaded locoregional nodes, degree of differentiation [G] II/III). Nevertheless, the patient wanted to give birth to a child, and she stopped endocrine therapy. After the first pregnancy, the endocrine therapy was not resumed, and the patient gave birth to her second child, 11 months after the first pregnancy.

Tamoxifen therapy was stopped for a total of two years and seven months. Shortly after the second birth, the patient presented a progression of the oncological disease (hepatic, bone and epidural metastasis).

Metastatic epidural metastases occur in 5-10% of cancer patients, and they represent a neurological emergency. The diagnosis should be suspected in any cancer patient with back pain or new neurological symptoms, and it requires prompt diagnostic evaluation to avoid serious and irreversible neurological deficits. Contrast-enhanced MRI of the entire spine should be obtained in patients in whom a diagnosis of MESCC is suspected. Timely treatment with radiation (along with surgery in selected cases) is critical for preserving the neurological function as well as for achieving local tumor control and pain control. Medical treatments also include pain management with analgesics and corticosteroids⁽⁶⁾. The prognosis of epidural metastases is poor.

From an ethical point of view, however, the choice to give life or thinking of your own life remains a dilemma.

Conclusions

Following available guidelines, most chemotherapy agents can be safely administered during the second and third trimesters of pregnancy.

Chemotherapy is generally safe beyond the first trimester of gestation. However, increased rates of premature delivery and growth retardation have been reported⁽²⁾.

The use of radiotherapy, targeted agents and endocrine therapy should be postponed after delivery.

The results of the POSITIVE study are encouraging for patients who want to have a pregnancy during hormone treatment for breast cancer, but the interruption should be for a period of maximum two years.

The optimal time to discontinue hormone therapy should be discussed with each woman, taking into account the stage of the tumor, the risk of recurrence, and the completion of treatment.  

Informed consent: The informed consent was obtained from the patient for the publication of this report.

 

CORRESPONDING AUTHOR: Ştefania-Loredana Negoianu E-mail: loredanastefania@icloud.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.