​Professor Yang Jin: A new strategy for breast cancer endocrine combined targeted therapy | 2021 CSCO BC

*It is only for medical professionals to read for reference.
How to make a reasonable deployment of breast cancer endocrine combined targeted therapy? On April 9-10, 2021, the 2021 National Breast Cancer Conference and the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Annual Meeting were officially held in Beijing, which is waning in spring.

CSCO Breast Cancer Annual Conference is one of the most influential academic events in the field of breast cancer in China.

The conference invited well-known experts and scholars at home and abroad to give speeches and discussions, and build a broad academic exchange platform for doctors and scholars.

Professor Yang Jin from the First Affiliated Hospital of Xi'an Jiaotong University shared a new strategy for breast cancer endocrine combined targeted therapy, bringing new options for clinical practice of breast cancer patients.

Professor Yang Jin’s latest data in 2020 reported that breast cancer has surpassed lung cancer to become the world's largest tumor, and more than half of patients are HR+/HER2- breast cancer.

Although these patients can benefit from endocrine therapy, approximately 30% of patients develop primary drug resistance, and approximately 30% of patients who are initially effective develop secondary drug resistance within 10 years.

How to solve this problem? We need to target the resistance mechanism of endocrine therapy and identify subgroups suitable for new drugs.
Let us follow Professor Yang Jin to learn how to effectively line up troops.

In addition to the traditional estrogen receptor modulators tamoxifen (TAM), toremifene, aromatase inhibitors (AI) that inhibit estrogen production, letrozole, anastrozole, exemestane, etc.
, With the understanding of estrogen pathway receptors, a series of new targeted drugs have been continuously developed, such as the CDK4/6 inhibitors Palbociclib, Abemaciclib, Ribociclib, etc.
, to target secondary endocrine resistance.
CDK2/7 inhibitors, Src inhibitors, HDAC inhibitors, BET inhibitors, IGF-1 inhibitors and immunotherapy with ESR1 mutations.CDK4/6 inhibitors-the mainstay, the first choice.
With the development of clinical research at home and abroad, we are pleased to find that the targeted drugs represented by CDK4/6 inhibitors combined with traditional endocrine therapy are significantly longer than internal monotherapy After the overall survival (OS), endocrine combined targeted therapy has become the mainstream, and the recommendation level of endocrine monotherapy has gradually declined.

CDK4/6 inhibitors can effectively block the progression of tumor cells from the G1 phase to the S phase, block cell cycle progression, and inhibit tumor cell proliferation.

A number of large-scale clinical studies at home and abroad have shown that the combination of CDK4/6 inhibitors and endocrine first-line/second-line treatment improves the progression-free survival (PFS) and OS of breast cancer patients, indicating the significant efficacy advantage of this treatment program.

The clinic is very concerned, is there any difference between the Chinese population and the European and American population? The MONARCH plus study (NCT02763566) is an international multi-center, randomized, double-blind, placebo-controlled phase III study led by Professor Jiang Zefei and Professor Hu Xichun.
80% of the patients enrolled in the study were from the Chinese population.

Cohort A of the study included 306 postmenopausal HR+/HER2-advanced breast cancer patients without systemic treatment.
The results showed that the median PFS of the patients in the abesiride combined with non-steroidal aromatase inhibitor (NSAI) group was It was significantly longer than the placebo combined with NSAI group (28.
18 vs 14.
76 months, HR=0.
540, P=0.
000002).

Cohort B included 157 patients with advanced HR+/HER2-advanced breast cancer who had previously undergone endocrine therapy.
The results showed that the median PFS of patients in the abecili combined fulvestr group group was significantly longer than that of the fulvestrant single-agent group (16.
4 vs 9.
3 months, HR=0.
553, P<0.
001) and adverse reactions are controllable.

This study suggests that both Chinese people who are sensitive to endocrine therapy or those who are resistant to endocrine therapy can benefit from the combination of abesiride combined with NSAI or fulvestrant.
The benefit trend is the same as that of the global Monarch3 and Monarch2 of Abesiride, and it is in China.
It is well tolerated and safe in the population. A number of studies have shown that the combination of CDK4/6 inhibitors with NSAI or fulvestrant can bring further survival benefits.
So who is the best partner of CDK4/6 inhibitors? The PAPSIFAL study aims to explore the best endocrine drugs combined with CDK4/6 in patients with ER+/HER2- advanced breast cancer who are sensitive to endocrine therapy.
However, the CDK4/6 inhibitor combined with letrozole group and the CDK4/6 inhibitor combined with fulvex There is no difference in PFS between groups, but for patients who have previously received AI treatment, the combination of CDK4/6 inhibitors and fulvestrant seems to have a certain degree of benefit.

At the same time, ESMO OPEN’s latest meta-analysis of data from 12 clinical trials for endocrine sensitivity and 20 clinical trials for endocrine resistance showed that among endocrine sensitive populations, PFS and OS are the dual endpoints, and CDK4/6 inhibitors combined with fulvix Sitran is better than CDK4/6 inhibitor combined with AI; among endocrine-resistant people, with PFS as the endpoint, CDK4/6 inhibitor combined with fulvestrant is better than AKT inhibitor capivasertib combined with fulvestrant, and OS As the end point, CDK4/6 inhibitor combined with fulvestrant and capivasertib combined with fulvestrant are both better.

In clinical practice, the German AGO guidelines give patients the choice of past endocrine therapy drugs.
For example, patients with postoperative TAM adjuvant endocrine therapy are preferred to CDK4/6i combined with AI, and patients with advanced postoperative adjuvant AI therapy are preferred to CDK4/6i combined with fluvix Si Qun, and my country’s CSCO guidelines also emphasize the background of patients’ previous endocrine therapy to select CDK4/6i combined endocrine partners.
It can be seen that domestic and foreign guidelines have similar guidelines and recommendations in clinical operations.

▎ 2021 CSCO guidelines recommend: CDK4/6 inhibitor + AI, CDK4/6 inhibitor + Fulvestrant as a Class I recommendation for patients who have failed TAM treatment, and Fulvestrant + CDK4/6 inhibitor as AI treatment failure Class I recommendation for patients.

Based on the Monarch plus study, abexiride combined with fulvestrant IA is recommended, and piperacillil combined with fulvestrant 2A is recommended.

For patients without endocrine therapy, the guidelines recommend CDK4/6 inhibitor + AI, CDK4/6 inhibitor + fulvestrant, but the level of evidence varies.

How to choose after CDK4/6 inhibitor resistance? Should I switch to a new CDK4/6 inhibitor, or switch to an inhibitor of the PI3K/AKT/mTOR pathway, or another targeted therapy strategy? At present, there is no evidence-based medical evidence for the replacement of new CDK4/6 inhibitors.
Based on reports of small-sample clinical studies in the United States, it is recommended that Asibeli be tried again, and it is also recommended that more precise and individualized treatment be carried out based on genetic testing.

PI3K/AKT/mTOR pathway inhibitors-bypass sentinels to overcome drug resistance.
PI3K pathway participates in tumor growth, proliferation and survival.
Activating mutation and/or amplification of PIK3CA gene can lead to activation of PI3K pathway and promote endocrine resistance.
Drugs are associated with poor prognosis.

In ER+/HER2- breast cancer, the incidence of PIK3CA gene mutation is about 40%.

In the past, pan-PI3K inhibitors targeted multiple isomers of PI3K, which were more toxic and had unsatisfactory efficacy.

In the SOLAR-1 study, for patients with PI3KCA mutations with endocrine resistance, the PI3Kα subtype new inhibitor Alpelisib + Fulvestrant, compared with placebo + Fulvestrant, significantly prolonged PFS and prolonged median OS by 7.
9 months (No statistical difference), but the results of subgroup analysis of patients with liver and/or lung metastasis and PIK3CA mutations in circulating tumor DNA suggest that Alpelisib combined with fulvestrant can improve the OS of patients.

However, studies have also shown that about 38% of patients are negative for ctDNA PI3KCA, while next-generation sequencing (NGS) or polymerase chain reaction (PCR) tissues are positive for PI3KCA, and this type of patients has a significant benefit from the application of Alpelisib+fulvestrant.
It reminds us that plasma circulating tumor DNA (ctDNA) and tissue PI3KCA testing can complement each other and help screen the dominant population. The BYLieve study is the first prospective trial to evaluate the efficacy of Alpelisib combined with endocrine therapy in patients with ER+/HER2- and PIK3CA mutations in the progress of CDK4/6 inhibitor combined with endocrine therapy.
Study A cohort found that Alpelisib combined with fulvestrant treats CDK4 Patients who progressed after treatment with /6 inhibitor combined with AI drugs, survived for 6 months with a progression-free survival rate of 50.
4%.
Cohort B found that Alpelisib combined with letrozole was treated with CDK4/6 inhibitor combined with fulvestrant and progressed after treatment The patient obtained a median PFS of 5.
7 months and observed that the side effects of Alpelisib's hyperglycemia, rash, and diarrhea were predictable and manageable.

The follow-up of the BYLieve study is still ongoing, and Alpelisib is expected to become the preferred option for patients with PIK3CA mutations after CDK4/6 inhibitor resistance or recurrence and metastasis.

The FAKTION study shows that in patients with AI recurrence or progression, the AKT inhibitor Capivasertib combined with fulvestrant can significantly improve PFS, and is independent of the PAM pathway activation state, and its OS data is worth looking forward to.

The BOLERO-2 study found that in postmenopausal women with breast cancer who failed NSAI treatment, everolimus combined with exemestane can significantly prolong PFS, but OS has no benefit, and the superior population cannot be screened based on the PIK3 gene mutation status.

After the treatment of drug resistance, new inhibitors have emerged.
Previous studies have suggested that epigenetic changes are related to the disease progression and endocrine resistance of breast cancer, and HDAC is an important form of epigenetic regulation.

HDAC inhibitors can inhibit the growth of tumor cells by inducing the transcriptional activation of tumor suppressor genes and pro-apoptotic genes, and can also widely regulate the activities of a variety of signal pathways related to tumor resistance and metastasis, as well as immunity in the tumor microenvironment.

The HDAC inhibitor entinotide combined with exemestane did not improve PFS and OS in patients who had progressed after previous NSAI treatment.

The ACE study led by Professor Jiang Zefei and conducted by 22 centers across the country is the first large-scale clinical study of epigenetic modulators in the treatment of solid tumors.
This study pioneered the application of the original domestic innovative drug Cedarbenamide and Cedar This amine combined with exemestane in the treatment of HR+ postmenopausal advanced breast cancer significantly prolonged PFS compared with placebo combined with exemestane.

On January 29, 2019, following peripheral T-cell lymphoma, the National Medical Products Administration (NMPA) approved chidamide as an indication for breast cancer.

Chidamide became the first HDAC inhibitor approved globally in the field of breast cancer, providing a new treatment option for some endocrine-resistant patients.

Therefore, the new guidelines in 2021 recommend that for patients with TAM treatment failure, AI + Chidamide is a Class I recommendation, and for patients with NSAI treatment failure, steroid AI + Chidamide is a Class I recommendation.

In addition, new oral SERD alastrant, PROTACS-protein degradation targeting chimera, new FGFR inhibitor dovitinib combined with fulvestrant, and RET inhibitor vandetanib combined with fulvestrant have shown their advantages and are emerging.

IGF1 monoclonal antibody ganitumab has no positive results, but it is still worthy of attention.

Summary: In recent years, with the development of targeted therapy, HR+/HER2-advanced breast cancer has entered the era of endocrine therapy+, and various new combinations of drugs have emerged in an endless stream, bringing more treatment options to patients, but also It poses a challenge for how to accurately screen superior populations based on organizational NGS and ctDNA testing, and how to rationally line up drug combinations and treatment sequences.

Breast cancer endocrine combined targeted therapy, we are still on the way! Expert Profile Professor Yang Jin Chief Physician/Professor Doctoral Supervisor, Department of Medical Oncology, Xi’an Jiaotong University First Hospital, Deputy Director, Department of Oncology, Member of the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Specialty Committee Member, Chinese Anti-Cancer Association Member of the Standing Committee of the Breast Cancer Professional Committee of the Chinese Women's Physicians Association Member of the Standing Committee of the Clinical Oncology Committee of the Chinese Medical Doctor Association Member of the Breast Professional Committee of the Oncology Branch of the Chinese Medical Doctor Association Member of the Breast Cancer Professional Committee of the National Cancer Quality Control Center Deputy Director, Chinese Research Hospital Association Precision Medicine and Oncology MDT Specialized Committee, Breast Science Group Deputy Director, Chinese Anti-Cancer Association Tumor Integrated Heart Specialty Committee Member, Shaanxi Anti-Cancer Association Anti-Cancer Drug Professional Committee Chairman, Shaanxi Anti-Cancer Association Chairman-elect of the Biotherapy Professional Committee