Professor Wang Shusen: Looking at the comprehensive benefits of CDK4/6 inhibitors, exploring the way to break the drug resistance| review of the annual progress of breast cancer treatment in 2022

On January 7, 2023, the "2022 Annual Progress Review of Breast Cancer Treatment", a grand event in the field of breast cancer, opened
in Beijing.
The conference reviewed the important academic progress of breast cancer in 2022, and launched the update of the 2023 version of the Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) Diagnosis and Treatment Guidelines
.
Yimaitong specially invited Professor Wang Shusen of Sun Yat-sen University Cancer Hospital to share the new progress
of CDK4/6 inhibitor research.

- Professor Wang Shusen -

Chief expert of breast cancer, Sun Yat-sen University Cancer Hospital

Professor, chief physician, doctoral supervisor

Vice Chairman of the Breast Cancer Professional Committee of the Chinese Clinical Oncology Association

Vice Chairman of the Tumor Endocrinology Professional Committee of the Chinese Anti-Cancer Association

Vice Chairman of the Breast Cancer Professional Committee of China Research Hospital Association

Chairman of the Breast Cancer Quality Control Expert Committee of Guangdong Cancer Center

Chairman of the Chemotherapy Professional Committee of Guangdong Anti-Cancer Association

Chairman of the Breast Cancer Professional Committee of Guangdong Thoracic Cancer Prevention and Treatment Research Association

CDK4/6 inhibitors benefit patients with HR+ advanced breast cancer, and CDK4/6 inhibitors combined with endocrine therapy have become the standard of care
.
Could you please talk about the research progress and results in this field in 2022? What are the benefits for breast cancer patients?

Professor Wang Shusen

Since the first CDK4/6 inhibitor was approved in 2015 for hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer, research on CDK4/6 inhibitors has been exciting, and a series of studies have consistently confirmed that CDK4/6 inhibitors are either in the first or back line, premenopausal or postmenopausal, in combination with aromatase inhibitors (AI) or in combination with fulvestrant , can improve progression-free survival (PFS) and even achieve overall survival (OS) improvement
.
Therefore, there is no doubt that CDK4/6 inhibitors have become the first-line standard of care for HR+/HER2- advanced breast cancer
.
There are many studies in this area in 2022 that deserve to be shared
further.

The DAWNA-2 study led by Academician Xu Binghe of the Cancer Hospital of the Chinese Academy of Medical Sciences evaluated the efficacy and safety
of the CDK4/6 inhibitor dalcilib combined with letrozole or anastrozole as a first-line treatment for patients with HR+/HER2- advanced breast cancer in China.
The results showed that the combination therapy with Dalsili could significantly improve PFS by 30.
6 months compared with AI alone, which once again verified the value
of CDK4/6 inhibitors in the first-line treatment of HR+/HER2- advanced breast cancer.

Whether the PFS benefit of CDK4/6 inhibitors translates into OS benefit is our focus
.
A series of clinical studies such as MONALEESA-2, MONALEESA-7, MONALEESA-3, MONARCH-2 and other clinical studies have also confirmed that CDK4/6 inhibitors
can significantly improve OS in patients with HR+/HER2- advanced breast cancer.
Although the median OS in the MONARCH-3 study has not yet reached a statistical difference, its absolute value is also very impressive, reaching 67.
1 months
.
Of course, for HR+/HER2- advanced breast cancer patients, while we pay attention to whether new drugs can make patients live longer, we also pay special attention to whether they can make patients live better.
In 2022, some studies also disclosed that CDK4/6 inhibitors improved patients' quality of life
.

The Phase II RIGHT Choice study presented at SABCS 2022 gives us another perspective on the status of
CDK4/6 inhibitors.
The study focused on patients
with HR+/HER2- advanced breast cancer with high aggressiveness (e.
g.
, symptomatic visceral metastases, rapid disease progression or visceral crisis, significant symptomatic non-visceral disease).
In some guidelines or consensus, chemotherapy or combination chemotherapy is recommended for these patients, and this study evaluated the efficacy of CDK4/6 inhibitors combined with endocrine therapy compared with investigator-selected chemotherapy regimens in HR+/HER2- advanced breast cancer, and showed a significant improvement
in CDK4/6 inhibitor combination therapy compared with chemotherapy PFS.
Therefore, the study once again tells us that CDK4/6 inhibitors combined with endocrine therapy are a reliable option
even for those patients with more aggressive HR+/HER2- advanced breast cancer.

Yimaitong: The treatment options after the progression of CDK4/6 inhibitors have always been a "boom", can you please talk about what treatment options are available based on clinical experience? What points do you think should be paid attention to when "lining up troops"?

Professor Wang Shusen

CDK4/6 inhibitors have excellent efficacy, but they still face the problem
of primary or secondary resistance.
Some basic studies have shown that the resistance mechanism of CDK4/6 inhibitors may be related to abnormal cell pathways, such as overactivation of CDK4/6, loss of RB protein or overexpression of Cyclin E, which is one of the mechanisms leading to CDK4/6 inhibitor resistance, in addition, bypass activation such as PI3K-AKT-mTOR can also trigger drug resistance
.

For different resistance mechanisms of CDK4/6 inhibitors, we need to adopt different resistance response strategies, and many explorations
have been carried out in this field.
There is limited evidence to support resistance due to CDK4/6 overactivation, and cross-line therapy with CDK4/6 inhibitors is an option
.
For patients with HR+/HER2- advanced breast cancer with PIK3CA mutation with progression of CDK4/6 inhibitor therapy, the BYLieve study suggests the value
of Alpelisib in combination with endocrine therapy.
In response to the abnormal activation of AKT signaling pathway, CAPItello-291 showed that AKT inhibitor capivasertib combined with endocrine therapy significantly improved PFS
in patients with HR+/HER2- advanced breast cancer.
Some retrospective studies and real-world studies suggest that mTOR inhibitors are also a treatment option
to consider in patients with progression of CDK4/6 inhibitors.

Of course, traditional chemotherapy drugs are still indispensable treatment for patients resistant to CDK4/6 inhibitors in clinical practice
.
In addition, antibody-drug conjugates (ADCs) have also been explored in patients with progression of CDK4/6 inhibitors, and the TROPiCS-02 study suggests that gosatuzumab also has some application value
in such patients.
The DESTINY-Breast-04 study also enrolled a subset of CDK4/6 inhibitor-resistant patients to explore the efficacy
of T-DXd in patients with advanced breast cancer with low HR+/HER2 expression.
Novel oral estrogen receptor degraders have also shown good efficacy
in patients with ESR1 mutations following progression of CDK4/6 inhibitors.

In general, the treatment of CDK4/6 inhibitor resistance is a research hotspot and a difficult point in clinical treatment, and the exploration direction tends to be diversified, and individualized treatment
is required according to different resistance mechanisms.

In the post-CDK4/6 inhibitor era, what do you think are the future research directions in terms of precision therapy? What are the opportunities and challenges?

Professor Wang Shusen

In the post-CDK4/6 inhibitor era, it is necessary to further promote the progress of basic medicine and translational research, explore the resistance mechanism of CDK4/6 inhibitors, and find corresponding treatment strategies
.
Accurate biomarker detection is the foundation of individualized therapy, and it is especially expected that translational research can make breakthroughs
in this field.
Treatment strategies for patients with advanced breast cancer with progression of CDK4/6 inhibitors are being explored in different directions, and we expect the results of the study to guide individualized treatment
for these patients.

Edited by Faline

Reviewer: Professor Wang Shusen

Typesetting: Faline

Execution: Uni‍‍‍