PAM pathway inhibitors: a "new star" in the post-CDK4/6i era, precision diagnosis and treatment is imperative!

*For medical professionals only

The 2024 edition of the "Expert Consensus on the Clinical Application of PI3K/AKT/mTOR Signaling Pathway Inhibitors in the Treatment of Breast Cancer" was updated, and the first AKT inhibitor (targeting PI3K/AKT/PTEN mutations) Capivasertib became the highlight of the update, providing a basis for guiding the precision diagnosis and treatment of HR+/HER2- advanced breast cancer.

HR+/HER2- breast cancer accounts for about 70% of all breast cancers, and the PAM signaling pathway plays an important role in the occurrence and development of breast cancer, which is closely related to endocrine therapy resistance in advanced breast cancer. It is of great significance to include the detection of key molecules in the PAM pathway in the quality control index of standardized diagnosis and treatment of breast cancer in China. At present, the 2024 version of the "Expert Consensus on the Clinical Application of PI3K/AKT/mTOR Signaling Pathway Inhibitors in the Treatment of Breast Cancer" is under active preparation, and this update will also provide important guidance for the application of PAM pathway inhibitors in the diagnosis and treatment of HR+/HER2- advanced breast cancer. Based on this, the Medical Oncology Channel invited Professor Ma Fei from the Cancer Hospital of the Chinese Academy of Medical Sciences, Professor Yang Jin from the First Affiliated Hospital of Xi'an Jiaotong University, Professor Liu Jian from Fujian Provincial Cancer Hospital, and Professor Ouyang from Hunan Provincial Cancer Hospital to express their profound views on related issues.

Q1

The 2024 edition of the Expert Consensus on the Clinical Application of PI3K/AKT/mTOR Signaling Pathway Inhibitors in the Treatment of Breast Cancer is under active preparation.

Professor Ma Fei

Aberrant activation of the PAM signaling pathway is common in breast cancer, especially in HR+/HER2- breast cancer, which is one of the most important pathways. In 2022, we formulated the first version of the "Expert Consensus on the Clinical Application of PI3K/AKT/mTOR Signaling Pathway Inhibitors in the Treatment of Breast Cancer", and after two years, based on the changes in clinical diagnosis and treatment and drug development, we ushered in the updated version of the consensus in 2024 on the basis of the 2022 version. The main background of the update is the following:

First of all, the availability of drugs continues to improve, and new innovative drugs continue to emerge, from the first mTOR inhibitor everolimus, to the PI3K inhibitor Alpelisib, and then to the world's first AKT inhibitor (for PI3K/AKT/PTEN mutation) Capivasertib, which further enriches the drug selection of PAM pathway inhibitors.

Secondly, the accumulation of more evidence-based evidence, taking Capivasertib as an example, multi-center clinical studies are emerging around the world, providing more important references for clinical diagnosis and treatment. In particular, with the increasing application of new drugs, the current clinical practice has undergone great changes, among which the proportion of first-line use of CDK4/6 inhibitors in HR+/HER2- advanced breast cancer is increasing year by year, and it is necessary to update the clinical studies that include the new population profile to the guidelines.

Thirdly, the demand for precision diagnosis and treatment of breast cancer is also changing, for example, the application of PI3K inhibitors needs to detect PIK3CA mutations, AKT inhibitors also need to pay attention to PIK3CA/AKT1/PTEN mutations, and the current clinical evidence also involves the exploration of different targets, different products and different combination treatment strategies, which together promote the update of consensus.

Professor Ouyang Zhichang

One of the highlights of this consensus update is the introduction of Capivasertib, which is based on the results of its pivotal Phase III CAPItello-291 study, which is currently the only Phase III clinical trial that has explored a targeted combination endocrine therapy strategy in patients with HR+/HER2- advanced breast cancer that includes a large number of CDK4/6 inhibitor-experienced (nearly 70% of enrolled patients have received CDK4/6 inhibitor therapy in advanced stages) and achieved positive results. In the overall population, median progression-free survival (PFS) was 7.2 months for the Capivasertib+ fulvester group, 7.3 months for patients with PIK3CA/AKT1/PTEN mutations, and 7.2 months for patients without PIK3CA/AKT1/PTEN mutations. The results fully validated the efficacy of Capivasertib+ fulvestrant in treatment-experienced HR+/HER2- advanced breast cancer, with a manageable and manageable safety profile[2]. At the same time, the efficacy and safety data of the Chinese cohort are generally consistent with those of the global population [3], and capivasertib is expected to become a new standard for new targeted endocrine therapy for HR+/HER2- advanced breast cancer in China.

Based on the results of the Phase III CAPItello-291 study, ASCO published online on March 14, 2024 the endocrine and targeted therapy recommendations for HR+/HER2- advanced breast cancer. This update recommends capivasertib + fulvestrant as a treatment strategy for patients with advanced ≥ second-line breast cancer harboring PIK3CA/AKT1/PTEN mutations[4]. This is the second major international guideline in which Capivasertib has been incorporated, following the NCCN. In addition, the 2024 CBCS guidelines in China also use it as the ≥ second-line standard of care for patients treated with CDK4/6 inhibitors.

Figure 1. Both domestic and foreign guidelines recommend Capivasertib + fulvestrant as the ≥ second-line standard of care for HR+/HER2- advanced breast cancer

Q2

In the post-CDK4/6 inhibitor treatment era, how to arrange the use of drugs, and what are the considerations for the use of PAM pathway inhibitors?

Professor Liu Jian

Throughout the world and abroad, there is no standard treatment recommendation after the failure of CDK4/6 inhibitor therapy, but some clues can be found from the progress of related research.

• PAM pathway inhibitors: The mTOR inhibitor everolimus has been approved for HR+/HER2- advanced breast cancer indications at home and abroad, but the evidence level is low in the CDK4/6 inhibitor-experienced population, and the overall benefit is not ideal. The efficacy of the PI3K inhibitor Alpelisib was validated in the Phase III SOLAR-1 and Phase II BYLieve studies, but the SOLAR-1 study enrolled only 5.9 percent of the CDK4/6 inhibitor-experienced population [5]. CAPITELLO-291 studies have shown significant efficacy in patients treated with CDK4/6 inhibitors, and have shown a wide range of applications. In terms of drug selection, the adverse reactions of PAM pathway inhibitors are worthy of attention, and the hyperglycemia of alpelisib is difficult to control in clinical practice, and the stomatitis of everolimus often needs to be reduced or discontinued, which will affect the continuous treatment benefit of patients.

• CDK4/6 Inhibitor Crossing: Despite the positive results of the MAINTAIN study, only some Phase I/II studies have explored CDK4/6 inhibitor cross-line therapy so far, and the overall median PFS is less than half a year, and the clinical practice of CDK4/6 inhibitor cross-line therapy is still cautious.

• Novel ADCs: The DESTINY Breast04 study demonstrated that trastuzumab significantly improved median PFS and median OS in patients with HR+/HER2-low advanced breast cancer, and is now approved as the standard of care for these patients. The TROPiCS-02 study also confirmed the therapeutic benefit of gosatuzumab in HR+/HER2- advanced breast cancer, which has been approved by the FDA for related indications, but has not yet been approved in China.

• Novel endocrine drugs: Based on the EMERALD study, a new generation of oral selective estrogen receptor degraders (SERDs) represented by Elacestrant has been approved by the FDA.

• HDAC inhibitors: Chidamide has been approved in China for the indication of HR+/HER2- advanced breast cancer, but there is no evidence of large-scale phase III clinical studies in CDK4/6 inhibitor-experienced populations, and only real-world research data.

• Traditional chemotherapy: Chemotherapy remains an important treatment after progression of CDK4/6 inhibitors.

At present, the drug options after the progression of CDK4/6 inhibitor therapy are becoming more and more abundant. In the context of multiple choices, we need to implement individualized precision treatment strategies according to the characteristics of different patients, which is also an important direction for future exploration.

Professor Yang Jin

PAM signaling pathway activation is closely related to tumor initiation, progression, and metastasis. In recent years, a series of novel drugs have been developed around key molecules in the PAM signaling pathway. Among them, the pivotal clinical study of the mTOR inhibitor everolimus did not include the CDK4/6 inhibitor-experienced population, and the PI3K inhibitor Alpelisib was approved for marketing in the SOLAR-1 study, but only 5.9 percent of the patients in this study had received prior CDK4/6 inhibitor therapy [5]. While the subsequent BYLieve study included 100 percent of the CDK4/6 inhibitor-experienced population, it was only a Phase II clinical trial [6], while nearly 70 percent of patients enrolled in the Phase III CAPItello-291 study of Capivasertib had received a CDK4/6 inhibitor in the advanced stage with impressive positive results. Based on this, authoritative guidelines at home and abroad recommend Capivasertib + fulvestrant as the ≥ second-line standard treatment option for HR+/HER2- advanced breast cancer.

For breast cancer patients, in addition to drug efficacy, safety will also affect the drug experience of patients, and the long-term safety, compliance and tolerability of endocrine combined targeted therapy are the prerequisites for ensuring the clinical benefit of HR+/HER2- advanced breast cancer.

• The most common adverse reactions associated with PIK3CA mutation, HR+/HER2- advanced or metastatic breast cancer (incidence of adverse reactions of all grades ≥20%) include increased blood glucose, increased creatinine, diarrhea, rash, decreased lymphocyte count, etc., and the most common grade 3/4 adverse reactions (incidence ≥2%) include hyperglycemia, rash, diarrhea, etc. In particular, the incidence of adverse reactions to hyperglycemia is high, which is also an important factor restricting its clinical application [1].
• The most common adverse reactions (incidence of all grades≥30 percent) of everolimus in patients with HR+/HER2- advanced breast cancer include stomatitis, infection, rash, fatigue, diarrhea, and decreased appetite, and the most common grade 3/4 adverse reactions (incidence ≥2 percent) include stomatitis, infection, hyperglycemia, fatigue, dyspnea, pneumonia, and diarrhea[1].
• According to the CAPItello-291 study[2], the common adverse reactions of Capivasertib were diarrhea and rash, with a grade ≥ 3 incidence of 9.3% and 12.1%, respectively, and for PAM pathway inhibitors, the adverse events of hyperglycemia and stomatitis were 2.3% and 2.0%, respectively, and the adverse reaction≥s were generally controllable.

The efficacy and safety of Capivasertib in breast cancer have been well demonstrated in other clinical trials, including a phase II FAKTION study [7] in which Capivasertib + fulvestrant significantly improved median PFS (10.3 versus 4.8 months, HR=0.56, p=0.0023) and median OS (29.3 versus 23.4 months, HR=0.66, p=) compared with fulvestrant alone0.035）。 And the overall safety is good. The phase III CAPITELLO-290 study was designed to evaluate the efficacy and safety of capivasertib + taxane versus placebo + taxane in the first-line treatment of patients with locally advanced (inoperable) or metastatic TNBC [8]. Our center was involved in this clinical trial, and the early toxicity of patients in the Capivasertib plus chemotherapy group was mainly diarrhea and rash, but with effective intervention, patients were generally well tolerated, and some patients had median PFS of more than 12 months. In conclusion, while effectively inhibiting the corresponding activation pathway, the safety and tolerability of PAM pathway inhibitors are important prerequisites to ensure the continuous treatment and ultimate benefit of patients.

Q3

What is the significance of including the detection of key molecules in the PAM pathway into the quality control indicators of breast cancer diagnosis and treatment, what are the challenges faced and what are the future directions?

Professor Liu Jian

Genes such as PIK3CA, AKT1 and PTEN in the PAM pathway are common mutations in HR+/HER2- breast cancer, and the overactivation of this pathway is highly correlated with endocrine therapy resistance. Mutations in the PIK3CA gene occur in approximately 40 percent of HR+/HER2- metastatic breast cancers, AKT1 mutations occur in approximately 5 percent, and PTEN gene alterations occur in approximately 5 percent of patients [9,10]. As more and more targeted drugs enter the clinical trial in China, it is particularly important to detect the changes of key molecules in the PAM signaling pathway to guide the selection of clinical drugs, which is also a hot and difficult problem that needs to be solved to achieve accurate diagnosis and treatment of breast cancer.

Professor Ouyang Zhichang

It is of great significance to include the detection of key molecules in the PAM pathway in the quality control index of breast cancer diagnosis and treatment in China, but it also faces challenges in terms of technology and cost. Through the popularization of technology and the formulation of norms, the wide application and standardized implementation of key molecule detection of PAM pathway in the diagnosis and treatment of breast cancer can be promoted, and more accurate and efficient diagnosis and treatment services can be provided for patients.

Professor Yang Jin

Breast cancer is the earliest model of solid tumors to implement precision diagnosis and treatment, and in this process, it is particularly important to accurately detect molecular biomarkers related to breast cancer treatment. About 50% of HR+/HER2- breast cancer patients will have changes in the PI3K/AKT/mTOR pathway [2], and it is of multiple significance to include the detection of key molecules in the PAM pathway in the quality control index of breast cancer diagnosis and treatment in China.

• First, it helps us better understand and predict the biological behavior of breast cancer. The detection of key molecules in the PAM pathway can provide information on gene expression and signal transduction of breast cancer cells, thereby revealing the pathogenesis of breast cancer and providing more accurate disease staging and prognosis assessment for clinical practice. For example, early identification of patients with PIK3CA, AKT1, or PTEN mutations can provide a basis for the research and exploration of advanced first-line CDK4/6 inhibitors + endocrine therapy + PI3K inhibitors/AKT inhibitors, and these patients may initially be initially resistant to CDK4/6 inhibitors + endocrine therapy.

• Second, it helps to guide the individualized treatment of breast cancer, so as to develop a more precise treatment plan for patients. For example, clinicians need to understand whether patients have specific gene variants or abnormal protein expression after CDK4/6 inhibitor progression, so as to select targeted drugs for them.

• In addition, it helps to improve the standardization and standardization of breast cancer diagnosis and treatment. China is a vast country with great differences in medical levels in different regions, so by formulating and implementing unified testing standards, we can ensure the consistency and effectiveness of breast cancer quality control index detection represented by the key molecules in the PAM pathway, so as to ensure the quality and effectiveness of breast cancer diagnosis and treatment, and provide patients with more reliable and safe medical services.

Looking forward to the future, I believe that the following work needs to be done in the precise diagnosis and treatment of breast cancer:

• The first is to strengthen basic research, gain an in-depth understanding of the pathogenesis of breast cancer and the role of molecular biomarkers, and provide more valuable diagnosis and treatment information for clinical practice. Professor Shao Zhimin's team took the lead in proposing four SNF molecular types for HR+/HER2- breast cancer in the world, and these four subtypes have certain differences in biological behavior and clinical characteristics, and the corresponding treatment strategies are also different. This suggests that in the future, whether it is advanced first-line therapy or CDK4/6 inhibitor-experienced patients, more diversified and layered treatment needs to be explored.

• The second is to promote technological innovation and develop more accurate, rapid and economical detection methods for key molecules in the PAM pathway, which are mainly based on the detection of tissue specimens and clinical blood specimens in the world, and still look forward to the development of more non-invasive detection technologies in the future to meet the growing clinical needs.

• The third is to strengthen multidisciplinary cooperation, integrate clinical, pathological, imaging, bioinformatics and other resources and technologies, standardize the collection, detection, interpretation and other operations, and provide comprehensive support for the accurate diagnosis and treatment of breast cancer.

• Fourth, strengthen science popularization, improve the public's awareness of breast cancer and self-protection, and promote the early detection and treatment of breast cancer.

In conclusion, the detection of key molecules in the PAM pathway is an important step in the precision diagnosis and treatment of breast cancer in China. Through continuous efforts and innovation, we are confident that we can provide more accurate, effective and humanized medical services for breast cancer patients.

Professor Ma Fei

In the field of HR+/HER2- breast cancer, there are currently more tests based on ER status, and in the future, the detection of key molecules such as the PAM pathway will also be included in the quality control indicators of breast cancer diagnosis and treatment in China to further guide treatment. This also puts forward higher requirements for accurate molecular diagnosis and molecular pathology of breast cancer. However, there are still some problems in China, such as many companion diagnostics have not yet been approved in China, relevant testing methods or instruments have not been clinically validated, and the accessibility of accurate testing is even lower than that of innovative drugs. In the future, it is hoped that by strengthening the management of the national health administrative department and continuously improving the professionalism of clinical diagnosis and treatment, we can ensure the normalization of accurate detection and promote the sustainable development and progress of breast cancer quality control.

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Bibliography:

[1] 2022 edition of "Expert Consensus on the Clinical Application of PI3K/AKT/mTOR Signaling Pathway Inhibitors in the Treatment of Breast Cancer"

[2] Turner NC, Oliveira M, Howell SJ, et al. CAPItello-291 Study Group. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1; 388(22):2058-2070.

[3] Hu X, Zhang Q, Sun T, etal. Capivasertib (C) + fulvestrant (F) for patients (pts) with aromatase inhibitor (AI)-resistant HR+/HER2– advanced breast cancer (ABC): Phase 3 CAPItello-291 trial Chinese cohort. 2023 ESMO Asia. LBA5.

[4] Burstein HJ, DeMichele A, Fallowfield L, et al. Endocrine and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer-Capivasertib-Fulvestrant: ASCO Rapid Recommendation Update. J Clin Oncol. 2024 Mar 13:JCO2400248.

[5] André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021 Feb; 32(2):208-217.

[6] Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021 Apr; 22(4):489-498.

[7] Howell SJ, Casbard A, Carucci M, et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol. 2022 Jul; 23(7):851-864.

[8] Capivasertib+Paclitaxel as First Line Treatment for Patients With Locally Advanced or Metastatic TNBC-Full Text View-ClinicalTrials.gov

[9] Miricescu D, Totan A, Stanescu-Spinu II, et al. PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. Int J Mol Sci. 2020 Dec 26; 22(1):173. doi: 10.3390/ijms22010173.

[10] Smyth LM, Zhou Q, Nguyen B, et al. Characteristics and Outcome of AKT1E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry. Cancer Discov. 2020 Apr; 10(4):526-535.

* This article is only for the purpose of providing scientific information to medical professionals and does not represent the views of this platform