Oral Tamoxifen and Abemaciclib in Postoperative Therapy for Male Breast Cancer: A Case Report

Introduction

Systemic therapies for breast cancer have evolved substantially in the past decade. In particular, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are effective agents for improving the prognosis of patients with hormone receptor-positive (HR+) breast cancer [1]. CDK4/6 kinases associate with cyclin D proteins during the G1 to S phase transition of the cell cycle. The cyclin D-CDK4/6 complex phosphorylates retinoblastoma proteins, leading to their dissociation from E2F transcription factors, which are ultimately responsible for cell cycle progression [2]. Various factors, including the overexpression of cyclin D, mutation or amplification of CDK4/6, and loss of cyclin D-CDK4/6 negative regulators, elicit the activity of cyclin D-CDK4/6, which hyperphosphorylates retinoblastoma proteins, ultimately leading to uncontrolled cell proliferation [3]. Thus, specific targeting of CDK4/6 has garnered special interest as an anti-cancer therapy. Palbociclib, ribociclib, and abemaciclib, developed as CDK4/6 inhibitors, have been approved in combination with an aromatase inhibitor as first-line therapy for HR+/human epithelial growth factor receptor-2 negative (HER2−) advanced or metastatic breast cancer [4]. Patients with advanced breast cancer and HR+/HER2− status could dramatically improve their short-term prognosis by combining CDK4/6 inhibitors and endocrine therapy [5]. Further examination of overall survival in the PALOMA-3 [6], MONALEESA-3 [7], MONALEESA-7 [8], and MONARCH-2 [9] studies further demonstrated that, compared with patients with HR+/HER2− advanced breast cancer receiving endocrine monotherapy, those receiving CDK4/6 inhibitors in combination with endocrine therapy also experienced considerably longer overall survival [10]. Moreover, abemaciclib, when combined with endocrine therapy, was the first CDK4/6 inhibitor to demonstrate a significant improvement in invasive disease-free survival in patients with HR+/HER2− node-positive early breast cancer at a high risk of early recurrence [11,12]. This progress has been accelerated by the fact that the large number of women affected by breast cancer makes it easier to conduct large-scale clinical trials.

Male breast cancer is an uncommon malignancy, accounting for approximately 1% of all breast cancer cases, with a male-to-female incidence ratio of approximately 1: 100 [13]. Although rare, its incidence has shown a gradual increase, which is likely attributable to heightened clinical vigilance and advancements in diagnostic tools. The most frequent presenting symptom is a painless unilateral breast mass, although some patients can exhibit nipple inversion, discharge, ulceration, or localized discomfort [14].

The diagnostic strategy for male breast cancer is similar to that used for female patients and typically involves clinical evaluation, imaging, and histopathological confirmation [15]. Mammography remains a useful modality, with a reported sensitivity of 92% and specificity of 90%, although its diagnostic utility can be compromised by the limited volume of male breast tissue. Thus, ultrasound-guided core needle biopsy is frequently used for definitive diagnosis [15]. Invasive ductal carcinoma is the predominant histological subtype, while hormone receptor positivity is highly prevalent and has been reported in up to 90% of cases [15]. Given that diagnostic delays remain common, early recognition and intervention are key to optimizing patient outcomes [15]. Invasive ductal carcinoma accounts for most (approximately 90%) of breast cancer cases in men [15]. Less common histologic variants include medullary, papillary, and lobular types. Ductal carcinoma in situ is relatively rare among men, potentially due to late detection and social stigma, which can contribute to delayed diagnosis. Notably, a high proportion of male breast cancers express hormone receptors, with estrogen receptor positivity reported in up to 90% of cases. [15]. Hormone receptor expression, including estrogen and progesterone receptors, tends to be more frequent in male patients than in female patients with breast cancer [16]. Although treatment principles mirror those established for women and typically involve surgical resection followed by appropriate adjuvant therapies, such as endocrine therapy, chemotherapy, and/or radiotherapy [17], outcomes in men can be less favorable due to diagnostic delays. Reported 5-year survival rates range from 40% to 65% overall but vary significantly by stage: from 75% to 100% in stage I and 20% to 30% in stage IV [15]. Interestingly, when adjusted for tumor grade, stage, and age, male patients did not appear to have a significantly worse prognosis than their female counterparts [15].

Moreover, only few male patients (approximately 0.4%) were included in the monarchE trial [18]. Therefore, the use of CDK4/6 inhibitors in male breast cancer patients is difficult to evaluate in clinical trials. Only scattered papers exist, consisting of small series, in which dozens of cases were collected and examined, and case reports as real-world data. In particular, there are very few case reports on the use of abemaciclib as adjuvant therapy for male breast cancer.

In this case report, we used abemaciclib as a postoperative adjuvant therapy for locally advanced male breast cancer, without recurrence. This report describes a rare case of advanced male breast cancer that achieved favorable outcomes with postoperative treatment including abemaciclib, suggesting the potential usefulness of abemaciclib in postoperative adjuvant therapy for advanced male breast cancer, similar to its use in women.

Case Report

A 43-year-old Japanese man presented with left areolar skin erosion accompanied by pruritus. He was initially referred from a local clinic to our Dermatology Department, where he received a diagnosis of dermatitis and was treated with topical medications. Despite 3 months of therapy, his symptoms showed no improvement. Consequently, a skin biopsy was performed for further investigation.

Histopathological examination revealed invasive ductal carcinoma of no special type, graded as histological grade 2 based on a Nottingham score of 3/2/1 – 3 for tubule formation, 2 for nuclear pleomorphism, and 1 for mitotic count. Immunohistochemical analysis demonstrated strong positivity for estrogen receptors (90%) and moderate positivity for progesterone receptors (60%). HER2 testing was negative, with a score 0 as determined by VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The Ki-67 proliferation index was 15%. These findings confirmed the diagnosis of invasive breast cancer, and the patient was referred to our department for further evaluation and management.

The patient’s medical history included type 2 diabetes mellitus, hypertension, and panic disorder with comorbid mood disorders, all of which were well controlled with medications. The patient’s medications are listed in Table 1. He had no family history of allergies, did not smoke or consume alcohol, and had a hemoglobin A1c level of 7.2% (reference range: 4.6–6.2%). Tumor marker levels were within the normal limits: carcinoembryonic antigen of 2.4 ng/mL (reference range: ≤5.0 ng/mL) and CA15-3 at 13.6 U/mL (reference range: ≤25.0 U/mL). Genetic analysis using BRACAnalysis (Myriad Genetics, Inc, Salt Lake City, UT, USA) revealed no pathogenic variants in BRCA1 or BRCA2.

Further staging investigations, including contrast-enhanced magnetic resonance imaging (Figure 1) and computed tomography (CT) (Figure 2), revealed locally advanced breast cancer with axillary lymph node metastases up to level II. No distant metastases or other clinically significant findings were detected, apart from laboratory abnormalities related to diabetes.

Surgical management consisted of a left mastectomy and axillary lymph node dissection. Intraoperatively, 1 lymph node was found adherent to the dorsal thoracic artery, and there was swelling in a level III lymph node, which complicated the complete resection. Postoperative pathological evaluation confirmed invasive ductal carcinoma of no special type and histological grade 1 (2/2/1). The tumor measured 50 mm with skin ulceration, and extensive lymph node involvement was observed. Pathologic lymph node staging was pN3a, with 16 of 17 positive axillary nodes (Figure 3). Surgical margins were negative. The disease was staged as pathological stage IIIC, based on skin involvement (pT4b) and extensive axillary lymph node metastases (pN3a).

Adjuvant treatment included chemotherapy with dose-dense doxorubicin and cyclophosphamide, followed by weekly paclitaxel and postmastectomy radiation therapy at a dose of 50 Gy. The patient was started on tamoxifen and abemaciclib for postoperative endocrine therapy. Abemaciclib was initially prescribed at 150 mg orally, twice daily. However, within 2 weeks, the patient developed severe diarrhea (over 8 episodes daily), which significantly affected his quality of life. The dose was then reduced to 100 mg/day.

Ten weeks after initiating abemaciclib administration, laboratory blood test results revealed elevated serum creatinine levels (Table 2). Nevertheless, assessment using cystatin C indicated preserved renal function. As the patient continued to experience diarrhea several times per day, the abemaciclib dose was further reduced to 50 mg/day (Figure 4). The patient remained on tamoxifen and abemaciclib, despite these dose adjustments, without recurrence. Annual follow-up imaging, including non-contrast-enhanced CT, showed no evidence of local or distant relapse, including lymph node enlargement (Figure 5). The patient continued the treatment without recurrence.

Discussion

This case suggests that abemaciclib can be as effective in treating advanced HR+/HER2− breast cancer in male patients as it is in female patients. Abemaciclib is the first CDK4/6 inhibitor approved for use in combination with standard adjuvant endocrine therapy. It has been shown to reduce the risk of recurrence in patients with HR+/HER2− early breast cancer who have residual disease after preoperative chemotherapy. Its efficacy is maintained regardless of residual tumor or nodal burden [19]. The results of the monarchE trial showed a significant effect. However, because breast cancer is less common in men than in women, limited data are available regarding the availability of CDK4/6 inhibitors in male patients. An article by a Turkish oncology group on the efficacy of palbociclib and ribociclib in the first-line treatment of metastatic HR+/HER2− male breast cancer showed that the efficacy and safety in male patients were similar to those in female patients [20]. A case report described a male patient with stage IV breast cancer who was treated with second-line abemaciclib, leuprolide, and fulvestrant, resulting in complete remission [21]. The anti-cancer activity of abemaciclib (used in combination with fulvestrant in 4 cases) was reported in 6 male patients with metastatic breast cancer [22]. Although the use of abemaciclib differs in the present case compared with these previous reports, similar efficacy appears to have been demonstrated. However, we were unable to find any case reports on the use of abemaciclib as a postoperative adjuvant therapy for locally advanced male breast cancer. This makes the present report a valuable contribution to the literature.

In the present case, we observed markedly elevated creatinine levels after the use of abemaciclib. Laboratory-based elevations in creatinine were observed in 98.3% of abemaciclib-treated patients in the MONARCH 2 and 3 trials. Creatinine elevation is known to occur with abemaciclib due to in vitro inhibition of the renal tubular transporters organic cation transporter 2, multidrug and toxin extrusion 1 (MATE1), and MATE2-K, and is not associated with reduced renal function [23]. If a clinician suspects the deterioration of renal function, alternative measurements, including cystatin C, should be evaluated to accurately assess renal function, and dose alterations should follow the protocol or local label guidelines for non-hematological toxicities [24]. Based on this insight, we measured the cystatin C levels and confirmed that the patient’s renal function was not impaired.

The patient received a diagnosis of locally advanced breast cancer with a large tumor burden. Therefore, there is a high risk for early recurrence. However, we believe that abemaciclib has positive effects on the prevention of recurrence. Furthermore, by accumulating additional case reports, we may be able to clarify the usefulness of abemaciclib as postoperative adjuvant therapy for locally advanced male breast cancer.

Conclusions

We report a rare case of advanced male breast cancer with a successful outcome following postoperative treatment that included abemaciclib. Given the rarity of male breast cancer and the challenges in conducting large-scale clinical trials, accumulating additional case reports is essential to better evaluate the efficacy and safety of adjuvant abemaciclib in this population.