On October 18, 2024, the 18th National Breast Cancer Conference and the 19th Shanghai International Breast Cancer Forum grandly opened, gathering significant global advancements in breast cancer. In the era following CDK4/6 inhibitors for hormone receptor-positive (HR+) breast cancer, targeted endocrine therapies based on the PIK3CA/AKT1/PTEN pathway have brought new hope to patients. At this conference, Dr. Virginia Kaklamani from The University of Texas MD Anderson Cancer Center shared important insights on the progress of treating HR+ metastatic breast cancer and discussed post-CDK4/6 inhibitor strategies and clinical practice experiences for HR+ advanced breast cancer in the "Viewpoint · SIBCS Special" column of Oncology Horizon.

Oncology Frontier: What is the current status of diagnosis and treatment for HR+ advanced breast cancer in the United States? what are the unmet clinical treatment needs?

Dr. Virginia Kaklamani：HR+ breast cancer is the most common molecular subtype, and the emergence of new treatment methods in recent years has brought many changes to clinical practice. In the past, HR+ advanced breast cancer was mainly treated with endocrine therapies such as aromatase inhibitors (AI) and fulvestrant. Nowadays, CDK4/6 inhibitors, oral selective estrogen receptor downregulators (SERDs), and PIK3CA/AKT1/PTEN pathway inhibitors have provided more treatment options, bringing good news to patients. Against this backdrop, the biggest challenge in the treatment of HR+ advanced breast cancer is endocrine resistance, whose resistance mechanisms include changes in various different pathways. For instance, mutations or deletions at different sites of the PIK3CA/AKT1/PTEN pathway can lead to endocrine resistance, resulting in a poorer prognosis.

Oncology Frontier: What is the therapeutic value of the PIK3CA/AKT1/PTEN pathway in HR+ advanced breast cancer? Alpelisib, capivasertib, and inavolisib have been approved for targeting this pathway. How should these three drugs be selected for the treatment of HR+ advanced breast cancer? What are their safety profiles?

Dr. Virginia Kaklamani：One of the main mechanisms of endocrine resistance is the activation and upregulation of the PIK3CA/AKT1/PTEN pathway. Cancer cells with mutations in PI3K, AKT, or PTEN respond poorly to endocrine therapy and have a worse prognosis. Therefore, the development of AKT inhibitors or PI3K inhibitors targeting this pathway is crucial. In the United States, the marketed drugs include the PI3K inhibitors Alpelisib and Inavolisib, as well as the AKT inhibitor Capivasertib. Capivasertib can be used for patients with PI3K/AKT/PTEN mutations and has a broader range of applications. The side effects of these drugs differ; common adverse reactions include diarrhea, rash, stomatitis, and hyperglycemia. Alpelisib and Everolimus are associated with more severe hyperglycemia, often leading to dose limitations. Capivasertib is more likely to cause diarrhea but has a relatively lower incidence of hyperglycemia. An advantage of Capivasertib is its effectiveness not only in patients with PI3K mutations but also in those with AKT and PTEN mutations, offering more comprehensive target inhibition compared to the other two drugs.

It is well known that hormone receptor-positive (HR+) advanced breast cancer is primarily treated with CDK4/6 inhibitors combined with endocrine therapy, and in cases with PI3K mutations, the treatment can be further combined with alpelisib. So, how should we decide on second-line treatment? If the disease progresses rapidly with first-line CDK4/6 inhibitor combined endocrine therapy, chemotherapy or antibody-drug conjugates (ADCs) will be adopted; if the first-line treatment has a remission time of more than 12 months, treatment will be guided by genetic testing. We first perform next-generation sequencing (NGS) to determine if there are specific mutations. If there are PIK3CA/AKT1/PTEN pathway mutations, we will choose alpelisib or capivasertib. Although the post-MONARCH study has made some progress in the cross-line treatment of CDK4/6 inhibitors, the benefit to patients is very limited, with a progression-free survival (PFS) increase of only 0.7 months, and a hazard ratio (HR) of 0.86 for the PIK3CA/AKT1/PTEN pathway mutation population, so I generally do not consider CDK4/6 inhibitor cross-line therapy in clinical second-line treatment. Alpelisib and capivasertib can both improve patient prognosis, but the aforementioned adverse reactions need to be considered comprehensively. If alpelisib is chosen, metformin and other drugs can be used prophylactically to avoid hyperglycemia, and diphenhydramine can be used to prevent rash; if capivasertib is chosen, no prophylactic medication is needed, only the potential risk of diarrhea should be informed to the patient before treatment, and active treatment should be taken if adverse reactions occur. If there are no mutations, everolimus will be considered first, followed by cross-line treatment with CDK4/6 inhibitors.

Oncology Frontier：What is the incidence of gene mutations related to the PIK3CA/AKT1/PTEN pathway in HR+ breast cancer? In clinical practice, how should the timing and methods for detecting PIK3CA/AKT1/PTEN pathway alterations be properly managed?

Dr. Virginia Kaklamani：Gene testing is one of the most important things in treating breast cancer. Clinically, it is necessary to make treatment decisions by testing circulating tumor DNA (ctDNA) in the blood or tumor tissue of HR+ breast cancer, including testing for ESR1 mutations, PI3K mutations, AKT mutations, and PTEN mutations. In the United States, the probability of PI3K mutations is about 30%-40%, and AKT mutations or PTEN mutations account for about 5%-10%. Research data from Professor Zhimin Shao’s team shows that this proportion is even higher in the Chinese population, so conducting gene testing is very important. Since related gene mutations can exist in both the primary lesion and the metastatic lesion, and can occur during the development from endocrine sensitivity to endocrine resistance, multi-target gene testing should be performed for advanced recurrent patients whenever possible, to identify patients who can benefit from targeted therapies such as AKT inhibitors. In clinical practice, I will implement NGS testing for all HR+ advanced breast cancer patients, and the specific timing is before the first-line treatment to determine subsequent treatment strategies; if for some special reasons the patient did not receive NGS testing during the first-line treatment, I will also arrange the relevant testing in a timely manner during the second-line treatment, in order to provide targeted, personalized, and precise treatment for the patients.

Oncology Frontier：What changes have the advent of PIK3CA/AKT1/PTEN pathway inhibitors brought to breast cancer clinical practice? What are the research directions or application prospects for these novel targeted therapies?

Dr. Virginia Kaklamani：Three targeted therapy drugs have been approved for the PIK3CA/AKT1/PTEN pathway. The first is the PI3K inhibitor Alpelisib. The SOLAR-1 study demonstrated that Alpelisib combined with fulvestrant improved progression-free survival (PFS) compared to fulvestrant alone, but only in patients with PI3K mutations . The second is Capivasertib, the only approved AKT inhibitor to date. In the CAPItello-291 trial, which enrolled about 70% of patients previously treated with CDK4/6 inhibitors, Capivasertib combined with fulvestrant approximately doubled the median PFS compared to fulvestrant alone, at 7.2 months versus 3.6 months. The PIK3CA/AKT1/PTEN mutation group and the Intent-to-Treat (ITT) population showed consistent results, reaching 7.3 months, and there was also a trend of improvement in overall survival (OS), leading to its approval in the United States . The third is Inavolisib, another PI3K inhibitor recently approved by the FDA. The INAVA120 study showed that Inavolisib combined with palbociclib and fulvestrant as a first-line treatment had good efficacy in patients with PI3K mutations who were resistant to endocrine therapy. However, the inclusion criteria strictly defined this as a population progressing during or within 12 months after completing adjuvant endocrine therapy, a group that constitutes a small proportion of the clinical population, possibly only about 10% of patients . These studies have rewritten the treatment approach for HR+ breast cancer and highlight the importance of using genetic testing results to guide precision treatment as a significant therapeutic strategy. Looking to the future, more inhibitors targeting the PIK3CA/AKT1/PTEN pathway and more combination therapy regimens are being continuously explored, which will bring more possibilities for the treatment of HR+ breast cancer.

Dr. Virginia Kaklamani

Professor of Hematology/Oncology at the University of Texas Health Science Center at San Antonio MD, Professor

Deputy Director of Clinical Research and Co-Director of the Cancer Genetics Program at the University of Texas Health Science Center at San Antonio

Director of the Breast Cancer Program at the Mays Cancer Center, University of Texas MD Anderson Cancer Center

Co-Chair of the San Antonio Breast Cancer Symposium

A.B. Alexander Distinguished Chair in Oncology