Impact of Hormone Therapy Cessation on Tumor Growth: Case Study of Ki-67 Reduction

Abstract

Long known to be effective for symptom relief of menopause, HRT is also known to be associated with an elevated risk of hormone-dependent cancers, such as breast cancer. Much less studied is the impact cessation of HRT has on the tumor biology of hormone receptor-positive breast cancers. Herein, we present a case of a 64-year-old female with 15 years of HRT who was diagnosed with an infiltrating ductal carcinoma that is poorly differentiated and hormone receptor-positive. Within one week of withdrawal of HRT, a sharp decrease in the proliferation index marker Ki-67 was observed from 70% to 50%, translating to a relative decline of 28.6%. Tumor grading also improved from poor to moderate differentiation. The treatment modality adopted was curative, and the patient has been free of recurrence for more than one year since the surgery was performed. This case discusses the potential benefits of HRT discontinuation in hormone receptor-positive breast cancer and presents the utility of Ki-67 as a marker for the evaluation of tumor response to hormonal changes. Additional research will be required to realize the broader implications of HRT in the patient population.

Introduction

Most women experience a better quality of life with hormone replacement therapy, particularly in alleviating symptoms caused by menopausal changes. However, long-term use of HRT, specifically in postmenopausal women, remains controversial, as it increases the chances of cancer triggered by hormones; this would include endometrial and breast cancers. The most significant risk, however, seems to occur in hormone receptor-positive breast cancers, in which exogenous hormonal stimulation, such as that associated with HRT, can stimulate the growth of cancer cells. There is a grave paucity of studies on the effects of cessation of HRT after a diagnosis of hormone receptor-positive breast cancer and, most importantly, its relation to modifications in tumor proliferation.

This case study reports one such unique event of an appreciable decline in the proliferation index of a tumor, as measured by Ki-67, in a patient with hormone receptor-positive breast cancer after the abrupt stoppage of long-term HRT. So far as we could trace back, this is the first report showing a relative decline in Ki-67 by 28.6% in a node-positive hormone receptor-positive breast cancer after HRT withdrawal. This patient's case illustrates some of the benefits of stopping HRT in the management of a tumor and will encourage further research into Ki-67 as an important marker in assessing the effectiveness of treatment in hormone-driven breast cancers.

Case Presentation

We present a case of a 64-year-old female who, for the last 15 years, received hormone replacement therapy initiated at the time of her menopause to treat the vasomotor symptoms and osteoporosis routinely occurring upon menopause onset. She had no family history of breast or ovarian cancer but had been on continuous combined estrogen-progesterone therapy since the initiation of her menopause.

This patient, diagnosed with invasive ductal carcinoma of the left breast in 2023, was known for a suspicious lesion found on mammography, followed by a core biopsy, which was finally confirmed to be poorly differentiated, hormone receptor-positive, HER2-negative invasive ductal carcinoma. IHC findings revealed strongly positive estrogen receptor (ER), at 90%, and progesterone receptor (PR), at 85%, along with a high Ki-67 proliferation index at 70%. It measured 3.2 cm in greatest dimension and had extended to two axillary nodes, a condition that authenticated the node-positive status of the cancer.

She was advised to discontinue her long-term HRT and an AI was added to her treatment regimen. Aromatase inhibitors reduce the circulating estrogen level in postmenopausal women, thus impairing the growth stimulus for hormone receptor-positive breast cancers.

Clinical Course and Outcomes

HRT Cessation and Tumor Grade Improvement

It was thus at the time of biopsy that the tumor could be classified as being poorly differentiated, thereby describing a high-grade malignancy with aggressive biological behavior. Six weeks post-biopsy, immediately after her HRT had stopped, she underwent surgical excision of the tumor by lumpectomy with sentinel lymph node dissection. Pathology on the tumor at the time of surgery remarkably showed a shift of grade of the tumor from poorly differentiated to moderately differentiated. This histological change meant a less malignant nature for the tumor and hence gave an area of interaction or common link between the theory of removal of exogenous hormones used through HRT and tumor biology.

Reduction in Proliferation Index (Ki-67)

One of the interesting observations noted in this case was the significant reduction of the Ki-67 proliferation index, a marker that is used to measure the proliferation rate of cancer cells. The index at the time of biopsy was 70% and is consistent with the highly proliferative nature of the tumor. After withdrawal of HRT and AI therapy, the proliferation index decreased to 50% at surgery. This decline would be a promising 28.6% relative decline in tumor growth that may be an immediate effect of the removal of exogenous hormone stimulation.

The most interesting is the decrease in Ki-67, which correlates with good prognosis for patients with breast cancer. High values of Ki-67 are seen with poor outcomes, and its decrease is often a favorable response to the therapy. Such a marked decrease in Ki-67 after HRT cessation may suggest that exogenous hormones supplied by the therapy themselves could have been driving tumor proliferation, and their withdrawal could have contributed to the slowing of cancer growth in this patient.

Postoperative Course and Follow-Up

The patient’s postoperative course was unremarkable, and she recovered well from surgery. She continued aromatase inhibitor therapy without complications. At her one-year follow-up, she remained disease-free, with no signs of recurrence on clinical examination or imaging. Her case continues to be monitored, and she will remain under regular surveillance as part of her long-term breast cancer care.

Discussion

This case report provides a unique perspective on the potential effects of hormone replacement therapy cessation in hormone receptor-positive breast cancer. While it is well established that HRT increases the risk of developing hormone-dependent cancers, there is limited evidence on how discontinuing HRT after cancer diagnosis might influence tumor biology and proliferation. This case suggests that HRT cessation, in combination with AI therapy, may contribute to tumor differentiation and a reduction in proliferation, as evidenced by the decrease in Ki-67.

Role of Ki-67 in Breast Cancer

Ki-67 is a nuclear protein that is expressed in proliferating cells and serves as a key marker for cell proliferation. In breast cancer, Ki-67 is commonly used as a prognostic marker and as an indicator of response to treatment. A high Ki-67 index is often associated with more aggressive tumors, whereas a lower Ki-67 level suggests a better prognosis. In hormone receptor-positive breast cancer, changes in the Ki-67 index are precious in assessing the effectiveness of endocrine therapies, including aromatase inhibitors.

In this case, the reduction in Ki-67 following HRT cessation suggests that the exogenous hormones provided by the therapy were contributing to the tumor’s high proliferation rate. The patient’s response to the removal of these hormones, coupled with the initiation of aromatase inhibitor therapy, highlights the interplay between hormonal influences and tumor growth in breast cancer.

Clinical Implications of HRT Discontinuation

This case raises important questions about the clinical management of hormone receptor-positive breast cancer in postmenopausal women with a history of long-term HRT use. Should immediate discontinuation of HRT be considered standard practice in these patients upon cancer diagnosis? The observed changes in tumor grade and Ki-67 in this case suggest that HRT discontinuation could potentially have a beneficial impact on tumor behavior and patient outcomes.

However, further studies are needed to explore the broader implications of HRT cessation in this context. Randomized clinical trials would be precious in determining whether HRT discontinuation leads to consistent reductions in tumor proliferation and improved survival outcomes in patients with hormone-dependent cancers.

Conclusion

This case example illustrates a significant lowering of the Ki-67 proliferation index post-HRT cessation in a postmenopausal woman who had developed hormone receptor-positive, node-positive breast cancer. The patient's tumor showed histological improvement and reduced proliferation upon the withdrawal of exogenous hormones; thus, withdrawal of HRT may offer clinical benefit in managing cancers hormone dependent. This case emphasizes further research into the role of HRT cessation within the treatment of breast cancer, and in particular, there is a significant role of Ki-67 as a marker for monitoring treatment response in this population.

References

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