Harnessing the Potential of Abemaciclib in Recurrent Endometrial Cancer Treatment

Abemaciclib, a unique cyclin-dependent kinase 4/6 (CDK4/6) inhibitor primarily used in breast cancer treatment, shows promise in targeting novel mechanisms in endometrial cancer (EC) for potential therapeutic benefits in cases of recurrence, particularly in estrogen receptor (ER)-positive patients according to research published in Current Oncology. 

Recent genomic analysis by The Cancer Genome Atlas (TCGA) identified 4 molecular subtypes of EC with different prognostic outcomes. Surgical staging of EC is followed by adjuvant therapy based on recurrence risk factors, including age, tumor histology, and disease stage, with options such as radiation, chemotherapy, or a combination of both. Advanced-stage EC may benefit from platinum-based chemotherapy and immunotherapy, especially in microsatellite instability-high (MSI-high) tumors.

Treatment options for recurrent EC depend on factors like prior treatments, patient health, and recurrence location, with surgery, radiation, chemotherapy, and targeted therapies available. Hormonal therapies, like progestins and aromatase inhibitors, are options for hormone receptor-positive cancers. Abemaciclib blocks cell cycle progression in tumors with dysregulated CDK4/6 activity. Subsequent-line therapies for EC are mainly palliative and may include single-agent chemotherapy, endocrine therapy, or consideration of pathway-specific therapies in clinical trials.

Estrogen binds to the estrogen receptor in the cytoplasm and translocates to the nucleus, promoting DNA transcription into protein. In endometrial carcinoma, estrogen receptors cross-regulates with the CDK-RB-E2F pathway, leading to cell cycle progression through interactions with E2, insulin, and mitogen-activated protein kinase (MAPK) pathways.

Aberrant expression of D-cyclin activating features (DCAFs) in endometrial cancer is associated with genomic aberrations and high sensitivity to CDK4/6 inhibitors. In addition, mutation of the tumor suppressor gene PTEN is commonly observed in EC cases, leading to dysregulation of cell division and potential targeting by CDK4/6 inhibitors.

Endocrine therapy in endometrial cancer offers a favorable toxicity profile and mode of administration, but currently available hormonal treatments show modest results. CDK4/6 inhibitors have demonstrated potent antitumor activity by targeting pathways linked to endocrine therapy resistance in endometrioid ECs, suggesting potential for combination therapy with other signaling molecule inhibitors.

Abemaciclib has shown promise in treating refractory hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, with studies demonstrating significant improvements in progression-free survival and overall response rates compared to standard therapies. Approved by the US Food and Drug Administration (FDA) for use in advanced or metastatic breast cancer, abemaciclib has shown potential in combination with various therapies and at relatively low dosages for long-term administration in other cancer types as well.

The molecular characteristics of endometrial cancer help predict prognosis and response to therapy, with increased mRNA expression and transcriptional activity of E2Fs compared to normal endometrium. CDK4 is highly expressed in EC tissues and may offer an effective treatment option for advanced-stage patients. Trials with abemaciclib and endocrine therapy have shown promising results in patients with recurrent ER-positive EC, with manageable adverse events reported.

“The efficacy of abemaciclib, a CDK4/6 inhibitor, has been proven, and abemaciclib was well tolerated in breast cancer and endometroid endometrial cancer when combined with aromatase inhibitors in a phase II trial,” said researchers. “These results are hypothesis-generating and should be further studied in a phase III trial. Abemaciclib is already FDA-approved for HR+/HER2− breast cancer patients; hence, the future direction should involve testing the combination of abemaciclib with ICIs in patients with endometrial cancer as it has been proven that CDK4/6 inhibitors may promote antitumor immunity and may enhance the action of immune checkpoint inhibitors.” 

Reference
Awada A, Ahmad S. Therapeutic prospects of abemaciclib for patients with endometrial cancer. Curr Oncol. 2024;31(9):5374-5383. doi:10.3390/curroncol31090397