Safe use of ribociclib in a patient with HR+/HER2− metastatic breast cancer receiving chronic hemodialysis

Abstract

İntroduction

The standard treatment for hormone receptor-positive and HER2-negative metastatic breast cancer is a combination of CDK4/6 inhibitors and endocrine therapy.

Case report

In this case, our aim was to demonstrate the safety and effectiveness of ribociclib in a patient with metastatic breast cancer undergoing hemodialysis three days a week.

Management & Outcome

A 59-year-old female patient with end-stage kidney disease who undergoes hemodialysis was diagnosed with metastatic breast cancer. The tumour is hormone receptor positive and HER2 negative. She received ribociclib with a reduced dose due to haematological toxicity, as well as letrozole and denosumab due to bone metastasis. PET/CT scans revealed that the primary tumour had regressed by 50%, with partial regression of the metabolic activity of the bone metastases. Ribociclib was administered safely and effectively for nine months.

Discussion

We presented our experience of using ribociclib in a patient with metastatic breast cancer who was receiving hemodialysis. Ribociclib was administered safely, and a response to the treatment was achieved.

Introduction

Cyclin-dependent kinase (CDK) 4/6 inhibitors are drugs that are used alongside endocrine therapy (ET), such as fulvestrant and aromatase inhibitors, to treat hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer.^1–3 They suppress DNA synthesis by preventing the cell cycle from progressing from the G1 phase to the S phase. ⁴ Despite their effectiveness in treating tumours, some patients treated with CDK4/6 inhibitors have experienced nephrotoxic events.^5,6 Four oral CDK 4/6 inhibitors are currently approved for use in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer: palbociclib, ribociclib, abemaciclib and dalpiciclib.^1,7–10 In recent years, the incidence of renal impairment has increased globally, with renal insufficiency being prevalent among cancer patients. Only 39% of patients with breast cancer have a glomerular filtration rate (GFR) in the normal range (GFR ≥90 ml/min/1.73 m²).^11–13 Ribociclib is primarily excreted via hepatic elimination, with around 7% and 8% excreted via the kidneys and intestines, respectively and it is extensively metabolised. The major contributors to this are cytochrome P450 (CYP) 3A4 (63%) and flavin-containing monooxygenase 3 (16%).^14,15 For patients with chronic kidney disease and an eGFR of less than 30 ml/min/1.73 m², it is suggested that the initial dose of ribociclib is reduced to 200 mg once daily. No dosage adjustment of ribociclib is necessary if the eGFR is 30–89 ml/min/1.73 m². ¹⁶ This case report presents a metastatic breast cancer patient with chronic kidney disease who undergoes hemodialysis three days a week. The patient is being treated with CDK 4/6 inhibitors (ribociclib) and endocrine therapy, which is being administered safely and effectively.

Case report

On 7 March 2024, a 59-year-old woman with chronic kidney disease, arrhythmia and hypertension, who was undergoing hemodialysis, presented to our outpatient clinic with a complaint of a mass in her right breast. Mammography revealed a 4 × 4 cm spicular border mass in the retroareolar region, which was causing pectoral muscle retraction. Ultrasonography revealed pathological right axillary lymphadenopathy in addition to these findings. A Tru-Cut biopsy was performed. The pathological results were invasive carcinoma, grade 2, estrogen receptor 91–100% positive, progesterone receptor 11–20% positive, human epidermal growth factor receptor 2 negative, Ki-67 15%. Alkaline phosphatase was 354 U/L. Widespread bone metastases were detected using fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT). Treatment was initiated in April 2024 with the following: −600 mg of ribociclib daily for 21 days, followed by a 7-day break, −2.5 mg of letrozole daily, −120 mg of subcutaneous denosumab monthly. The patient received ribociclib before hemodialysis. She has end-stage kidney disease and undergoes hemodialysis, so we did not reduce the dose initially. Treatment was suspended after follow-up tests conducted two weeks later revealed a QTc interval of 442 milliseconds, grade 3 neutropenia, grade 3 anaemia, and grade 2 thrombocytopenia according to Common Terminology Criteria for Adverse Events (CTCAE) Version 6.0. The patient was monitored for hepatic toxicity. The patient's liver transaminase enzymes never increased. Two weeks later, when the haematological side effects had regressed to grades 1–2, ribociclib was restarted at a reduced dose of 400 mg daily. Three months later, a PET/CT scan revealed a 50% reduction in the size of the primary malignant tumour in the right breast retroareolar area according to RECIST, as well as a partial reduction in the metabolic activity of the bone metastases. The patient has been receiving ribociclib and letrozole for nine months, continues to respond to treatment, and remains on therapy.

Discussion

Chronic kidney disease (CKD) is a long-term condition arising from a structural or functional abnormality in the kidneys that lasts for more than three months. It has a detrimental effect on general health and impacts many organ systems, particularly the cardiovascular system and mineral-bone metabolism.^17,18 CKD is characterised by tubulointerstitial fibrosis (TIF), tubular atrophy, and the accumulation of extracellular matrix proteins. While increased cell cycle processes play a role in promoting repair after acute injury, irregularity of renal tubular epithelial cells during this process may contribute to fibrosis.^19–21 A trial showed that there was no significant difference in the pharmacokinetics of ribociclib between cancer patients with mild or moderate renal impairment and those with normal kidney function. ¹⁶ As patients with end-stage renal disease were excluded from the ribociclib study, there is limited data on its efficacy and safety in this patient group. ²

In a real-life trial, an increase in creatinine was observed in 17.9% (n = 19) of the 106 patients in the study population. Of these patients, 8.5% (n = 9) had grade 1 elevation, 8.5% (n = 8) had grade 2 elevation, and 0.9% (n = 1) had grade 3 elevation. Creatinine elevation occurred in 25% (n = 12) of ribociclib users and 12.1% (n = 7) of palbociclib users. No patient required a dose reduction or discontinuation of treatment due to elevated creatinine levels. Of those with high creatinine levels, 36.8% (n = 7) were aged over 65. ²² A trial has demonstrated six cases of acute kidney injury related to CDK 4/6 inhibitor therapy, all of which were confirmed by biopsy. In this publication, renal replacement therapy was administered to one of the six patients due to acute kidney injury. Stage 3 acute kidney injury (AKI) developed in three patients. The median time from the initiation of CDK4/6 therapy to AKI was 278 days (interquartile range 183–430 days). Renal ultrasound results revealed cortical echogenicity in three patients. Additionally, the results of the serological workup (e.g., antinuclear antibodies, double-stranded DNA, antinuclear cytoplasmic antibodies, C3 and C4, rheumatoid factor, and serum protein electrophoresis) were normal in all patients. The most common histopathological finding on biopsy was acute tubular necrosis. Treatment was discontinued or the dose reduced in four of the six patients. ²³

Although ribociclib carries a higher risk of acute kidney injury than palbociclib, the National Comprehensive Cancer Network (NCCN) recommends ribociclib and an aromatase inhibitor as a Category 1 first-line treatment. As abemaciclib is not reimbursed in our country, the patient was started on aromatase inhibitor and ribociclib therapy as a first-line treatment. As ribociclib is largely eliminated via the hepatic route, a reduction in dosage was not initially considered. Due to its protein binding, it is not dialysable; therefore, the patient took the treatment every morning, either on an empty stomach or after breakfast, before dialysis. A reduced dose of ribociclib was administered to our patient undergoing regular hemodialysis treatment due to haematological toxicity. The treatment was well tolerated, resulting in a partial response to the disease.

Conclusion

In the treatment of our patient, the primary dose-limiting factor was haematological toxicity. Hepatic toxicity was never observed. Ribociclib is known to cause hepatic, haematological and cardiac toxicity, especially in patients with renal impairment, so close monitoring of the patient is essential. Coordination between the nephrology and oncology departments is important. It is also important to emphasise that ribociclib can be administered safely and effectively with dose modifications.