Editor's Note: On May 16, 2024, the European Society for Medical Oncology Breast Cancer Annual Meeting (ESMO BC) reported updated results from the CAPItello-291 study (183MO). The data showed that the AKT inhibitor capivasertib combined with fulvestrant provided benefits in second-line treatment without affecting the benefits of subsequent treatments. This further solidified capivasertib's role in the post-CDK4/6 inhibitor (CDK4/6i) era, leading the way in precision therapy for HR+ breast cancer. Oncology Frontier interviewed Professor Yiding Chen from The Second Affiliated Hospital of Zhejiang University School of Medicine to analyze the progress of the CAPItello-291 study and discuss superior treatment options in the post-CDK4/6i era from mechanisms to clinical applications.Oncology Frontier: What is the status of AKT inhibitor capivasertib in the booming development of precision therapy targets in the post-CDK4/6i era?
Professor Yiding Chen: In terms of CDK4/6i resistance mechanisms, up to 50% of HR+ advanced breast cancer patients have PIK3CA/AKT1/PTEN pathway abnormalities, leading to endocrine therapy and CDK4/6i resistance. For Chinese patients, the proportion of PAM pathway abnormalities is higher than in Western populations, about 63%, indicating that Chinese breast cancer doctors should pay more attention to this pathway in clinical practice. Although PI3K, AKT, and mTOR are the three main nodes in the PAM signaling pathway, their importance is not the same. PI3K-AKT is closely linked, with AKT strictly regulated by PI3K and acting on over 100 downstream substrates, making it a core mediator of the PAM pathway. In contrast, mTOR is regulated not only by AKT but also by various other signals, making it difficult to completely block mTOR action by only targeting the PAM pathway, which complicates clinical treatment. Therefore, targeting AKT is central to the development of drugs in the PAM pathway.
Clinically, capivasertib targets AKT and is effective for patients with PIK3CA, AKT1, and PTEN abnormalities, i.e., AKT pathway (PI3K-AKT-PTEN) abnormalities. Among the approved PI3K, AKT, and mTOR inhibitors, only capivasertib has been proven beneficial for patients with PIK3CA/AKT1/PTEN pathway abnormalities and effective in CDK4/6i-treated patients through phase III clinical research. Capivasertib has gained widespread recognition for its efficacy and controllable safety, with major ≥ grade 3 adverse events being rash (15.5%), diarrhea (7.0%), and hypokalemia (5.6%), which are manageable in clinical practice. Based on its reliable mechanism, strong efficacy, and controllable safety, capivasertib has been recommended in domestic and international guidelines: The NCCN Guidelines 2024 v2 recommend capivasertib combined with fulvestrant as a standard treatment for patients with PIK3CA or AKT1 activating mutations or PTEN alterations in the second-line and beyond. The updated “Breast Cancer Diagnosis and Treatment Guidelines and Norms 2024” of the Chinese Anti-Cancer Association and the “Breast Cancer Diagnosis and Treatment Guidelines 2024” of the Chinese Society of Clinical Oncology also include AKT inhibitors combined with endocrine therapy as an option for CDK4/6i-treated patients in the second-line and beyond. In the post-CDK4/6i era, the standard treatment status of AKT inhibitor capivasertib in HR+ breast cancer in the second-line and beyond is evident.
Oncology Frontier: For precision therapy in the post-CDK4/6i era, do you support further screening of advantageous populations through genetic testing? When should testing be performed?
Professor Yiding Chen: With the development of precision medicine, the concept of individualized treatment centered on patients has gained traction, making it a trend to screen advantageous populations through genetic testing. For example, the CAPItello-291 study, both in previous and the latest data presented at ESMO BC, showed that capivasertib provided significant benefits to the entire population and even greater efficacy for patients with PIK3CA/AKT1/PTEN pathway abnormalities, improving PFS1 and PFS2. Thus, selecting PIK3CA/AKT1/PTEN pathway abnormal patients as advantageous treatment populations is bound to bring more benefits to patients.
According to the PI3K-AKT-mTOR pathway spectrum of the Chinese population mapped by Fudan Cancer Hospital, the mutation rate of the PAM pathway in Chinese breast cancer patients is 60%, with PIK3CA mutations at 44%, PTEN loss at 12%, and AKT1/2/3 mutations at 10%, 10%, and 15%, respectively, indicating a significantly higher frequency of AKT1 mutations in Chinese patients than in Western populations, particularly in Luminal A-type breast cancer. The hotspot mutation E17K of AKT1 is a driver mutation, suggesting potential benefits of targeted AKT therapy for Chinese patients with Luminal A-type breast cancer. Ideally, genetic and molecular marker testing should be performed as early as possible after diagnosis so that this information can be considered when formulating initial treatment plans. For patients already in later stages of treatment, retesting to assess treatment response and resistance is equally important.
With advances in technology and the emergence of high-throughput testing methods, genetic testing is becoming more accurate and comprehensive. The accessibility of these methods may be limited by regional, economic factors, and the distribution of medical resources, so improving the accessibility and affordability of testing methods is crucial for optimizing clinical practice. However, we cannot idealize the situation without considering real-world constraints. When faced with lower accessibility, clinicians should consider using simpler methods such as the PI3KCA test kit as an economical alternative, providing patients with more affordable diagnostic options. Therefore, in current clinical practice, we should actively conduct testing for patients who can afford it, select advantageous populations, and provide precise treatment plans. Standardized testing processes, including sample collection, processing, storage, and analysis, should be established to ensure standardized diagnosis and treatment. Communication between doctors and patients is also vital, as doctors need to explain the significance of testing, possible results, and their impact on treatment decisions to patients.
In summary, as targeted therapy and personalized medicine develop, genetic and molecular marker testing plays an increasingly prominent role in breast cancer treatment. By optimizing testing processes, improving the accuracy and availability of testing methods, and continuously exploring new research directions, we can better guide clinical treatment decisions, bringing better treatment outcomes and quality of life to patients.
