A historic development that transformed breast cancer treatment: CDK4/6 inhibitors

Hormone-positive, metastatic (stage 4) breast cancer has seen one of the most important developments in its treatment over the past 50 years through the discovery and treatment success of CDK4/6 inhibitors, which are cyclin-dependent kinase inhibitors.

The treatment success achieved by adding CDK4/6 inhibitors to conventional hormonal treatment has virtually removed chemotherapy from consideration as the first treatment choice for almost all patients. Although this development does not mean that chemotherapy is completely unusable in patients with advanced hormone receptor-positive breast cancer, its preference worldwide has decreased considerably. In patients with very widespread disease at initial diagnosis and a tendency for organ function to deteriorate, a condition we call visceral crisis, chemotherapy may be the first option to obtain a rapid response, but it should be remembered that this group of patients is quite rare.

What is a CDK4/6 inhibitor? How does it work?

CDK4/6 inhibitors are mitosis (cell division) cycle-blocking, next-generation anticancer agents. There are 3 internationally approved drugs in this group with similar mechanisms of action: palbociclib (Reampla), ribociclib (Valamor) and abemaciclib.

Although CDK4/6 inhibitors (suppressors) do not act directly on the female hormone, they are drugs that exert anticancer activity in hormone-positive breast cancers through the cell cycle . CDK inhibitors have brought a breath of fresh air to the treatment of hormone-positive breast cancer.

The changing face of metastatic breast cancer treatment

Today, a complete cure for metastatic breast cancer is not possible. Treatment aims to control the disease that has metastasized, prolong the patient's life as much as possible, and improve quality of life. 

• Some patients treated for a diagnosis of early-stage breast cancer will experience recurrence (relapse) over time. In this group of patients with metastatic recurrence, before deciding on treatment, a breast biopsy should be performed to obtain information about the biology of the newly detected metastatic cancer.
• Studies show that, in about 15% of patients whose breast cancer reappears with metastasis (recurs), there are differences from the initial type of cancer. These changes may also lead to important changes in treatment strategies. For example, a patient initially diagnosed with hormone-sensitive breast cancer may recur several years after treatment, and biopsies taken at recurrence may reveal a hormone-insensitive type of cancer.
• A patient diagnosed with hormone-sensitive (hormone-positive) metastatic breast cancer is generally started on CDK4/6 inhibitors and an appropriate endocrine drug according to menopausal status, as this is usually less toxic than chemotherapy. If patients are diagnosed before menopause, a menopausal state is induced with medication (drugs that stop estrogen release from the eggs), and hormonal treatment and CDK4/6 inhibitors are given.
• If first-line treatment was started with chemotherapy in patients with aggressive, rapidly progressing disease who may develop organ failure, chemotherapy can often be stopped and endocrine treatment started after 4-6 months of treatment in patients with a good response.
• Patients whose disease is not progressing rapidly or in whom widespread visceral metastases (to organs such as the liver and lungs) are absent are suitable candidates for combined endocrine treatment. Our approach to first-line treatment in these patients is as follows:
• For such patients diagnosed after menopause, we recommend a cyclin-dependent kinase (CDK) 4/6 inhibitor in combination with an aromatase inhibitor. However, other acceptable options include a CDK 4/6 inhibitor in combination with fulvestrant.
• An aromatase inhibitor alone is an option if patients do not prefer or cannot tolerate the above approaches, or if they have a low disease burden.
• For premenopausal patients (patients who are menstruating and have not yet entered menopause), ovarian suppression or ablation induces a medicated menopausal state and stops the ovaries (eggs) from producing estrogen and progesterone. We recommend adding a CDK 4/6 inhibitor drug alongside an aromatase inhibitor in these patients.
• Some patients started on endocrine treatment together with CDK4/6 will develop resistance to treatment early or late, and disease progression will be observed. In this group, depending on the tumor's genetic characteristics (for those with PIK3CA-mutant cancers), a new targeted drug called alpelisib (Piqray) can be used in second-line treatment together with a different endocrine treatment.
• Together with a different targeted drug called everolimus, it may be preferred in second-line treatment alongside an aromatase inhibitor or tamoxifen in patients without a specific genetic change (mutation)
• Switching to chemotherapy may be appropriate for patients who have received two or more lines of endocrine treatment and whose disease is progressing.

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