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Breast cancer has surpassed lung cancer to become the world's largest tumor, and about 60% of breast cancer patients in China are HR+/HER2-type.
These patients can benefit from endocrine therapy, but about 30% of patients will develop resistance to primary endocrine therapy, and about 30% of newly effective patients develop secondary drug resistance within 10 years.
The way to find endocrine therapy resistance is to be solved.
Must do.
The 2021 National Breast Cancer Conference and the Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) Annual Conference were held in Beijing from April 9th to April 10th in the form of "online + offline".
During the meeting, Professor Yang Jin from the First Affiliated Hospital of Xi'an Jiaotong University shared a targeted joint strategy for endocrine therapy for breast cancer.
Let us follow Professor Yang to learn how to identify subgroups suitable for new drugs and conduct effective deployment.
Professor Yang Jin, Chief Physician, Department of Oncology, First Hospital of Xi'an Jiaotong University, Doctoral Supervisor, Deputy Director, Department of Oncology, Deputy Director, Department of Oncology, Member of the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Specialty Committee Member, Chinese Anti-Cancer Association Breast Cancer Specialty Committee Member, Chinese Research Hospital Society Breast Cancer Specialty Committee Standing Committee Member of the Standing Committee of the Clinical Oncology Committee of the Chinese Women Physicians 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 Chairman of the Breast Group of the Tumor Marker Committee of the Chinese Anti-Cancer Association Traditional Endocrine Therapy Drugs include aromatase inhibitors (AI) and estrogen receptor modulators.
With the understanding of the estrogen receptor pathway, a series of targeted drugs have been developed in clinical research, such as the CDK4/6 inhibitor-Piper Palbociclib, Abemaciclib, Ribociclib, PI3K inhibitor, HDAC inhibitor, mTOR inhibitor, CDK2/7 inhibitor, etc.
CDK4/6 inhibitors-the mainstay of choice Over the past ten years, based on the positive results of progression-free survival (PFS), mTOR inhibitors, CDK4/6 inhibitors, HDAC inhibitors and PI3K inhibitors have been approved for clinical practice.
.With the further maturity of overall survival (OS) data, targeted drugs represented by CDK4/6 inhibitors have shown significant benefits for OS.
According to domestic and foreign guidelines, the recommended level of endocrine monotherapy has gradually declined, and combined endocrine targeting has become the mainstream choice.
CDK4 and CDK6 are key regulators of the cell cycle.
CDK4/6 inhibitors can block cells from G1 phase to S phase, block cell cycle progression, and thereby inhibit tumor cell proliferation.
A series of clinical trials of CDK4/6 inhibitors combined with non-steroidal AI (NSAI) or fulvestrant showed that CDK4/6 inhibitors combined with endocrine first-line/second-line treatment increased the PFS and OS of advanced breast cancer, indicating this Significant advantages of the program.
Is there any difference between Chinese population data and international data? The MONARCH plus study (NCT02763566) answered this question.
The study is an international multi-center, randomized, double-blind, placebo-controlled Phase III study led by Professor Jiang Zefei and Professor Hu Xichun.
More than 80% of the patients enrolled were from the Chinese population.
The study was divided into two cohorts, A and B, and included two different groups of people.
Cohort A enrolled patients with HR+/HER2-advanced breast cancer who had not received systemic treatment and were randomized 2:1 to receive abecili+letrozole/anastrozole or placebo+letrozole/anastrozole.
The results showed that the combination of abesiride and NSAI significantly prolonged the PFS of patients (less than 14.
7 months, HR=0.
499, 95% CI 0.
346-0.
719, P=0.
0001), which is consistent with the data of the MONARCH 3 study.
At the same time, the data released by the CSCO conference in 2020 showed that abexiride combined with endocrine therapy significantly improved the PFS of Chinese advanced breast cancer patients with visceral metastasis (22.
32 vs 13.
28 months, HR=0.
502, 95% CI 0.
307-0.
820).
The data is also consistent with the MONARCH 3 research data. Cohort B included HR+/HER2-advanced breast cancer patients who had previously undergone progress in endocrine therapy, and were randomly assigned to receive treatment with abecili + fulvestrant or placebo + fulvestrant according to 2:1.
The results showed that abexiride combined with fulvestrant can prolong the PFS of patients with endocrine resistance (11.
5 vs 5.
months, HR=0.
376, 95% CI 0.
240-0.
588, P<0.
0001).
For primary/secondary The risk of PFS in resistant patients is reduced by more than 50%.
CDK4/6 inhibitor combined with NSAI or Fulvestrant, which is better? The PAPSIFAL study compared the efficacy of piperacillil in combination with letrozole or fulvestrant.
The results showed that there was no difference in PFS between the two groups, but for patients who have previously received AI treatment, piperacillil combined with fulvestrant seems to have a certain degree of benefit.
At the same time, a meta-analysis published in ESMO OPEN in 2020 showed that among endocrine therapy-sensitive populations, with PFS and OS as the dual endpoints, the efficacy of CDK4/6 inhibitor combined with fulvestrant is better than combined AI; In the drug population, PFS is the end point, CDK4/6 inhibitor combined with fulvestrant is better than AKT inhibitor combined with fulvestrant, and OS is the end point, and both are better.
In the German AGO guidelines HR+/HER2- advanced breast cancer treatment route recommendation, the choice of CDK4/6 inhibitor combined with AI or fulvestrant is based on postoperative adjuvant endocrine therapy.
If you have previously received tamoxifen (TAM) treatment, the combination with AI is preferred; if you have previously received AI treatment, the combination with fulvestrant is preferred.
This year's CSCO guidelines also emphasized the choice of CDK4/6 inhibitor combination therapy in accordance with previous endocrine therapy programs.
The guidelines recommend that for patients with TAM treatment failure, CDK4/6 inhibitors combined with AI or fulvestrant are recommended as level I; for patients with failed AI treatment, fulvestrant + CDK4/6 inhibitors are recommended for level I.
Based on the Monarch plus research data, abexiride combined with fulvestrant is recommended as 1A, and piperazil combined with fulvestrant is recommended as 2A.
For patients without endocrine therapy, a new fulvestrant + CDK4/6 inhibitor regimen is added.
After CDK4/6 inhibitor progresses, should I switch to another CDK4/6 inhibitor, switch to PI3K/AKT/mTOR inhibitor, or switch to other strategies? At present, there is no evidence-based medical evidence to replace another CDK4/6 inhibitor.
A small sample study in the United States tried follow-up treatment with abexiride in patients with resistance to pipercillide, which showed a certain effect of OS and PFS.
PI3K/AKT/mTOR pathway inhibitors—bypass sentinels overcome drug-resistant PI3K inhibitors.
In the past, PI3K inhibitors were more toxic and had unsatisfactory efficacy.
The SOLAR-1 study compared the efficacy of a new PI3Kα subtype inhibitor Alpelisib+fulvestrant and placebo+fulvestrant in the endocrine-resistant PI3KCA mutation cohort and the wild-type cohort.
The results showed that in the PI3KCA mutation cohort, the PFS of the Alpelisib group was significantly prolonged (11.
0 vs 5.
7 months).
Although there was no statistical difference in the prolongation of OS by 7.
9 months, in patients with lung and/or liver metastases, the Alpelisib group significantly improved OS.
At the same time, the study showed that 38% of patients with PI3KCA plasma circulating tumor DNA (ctDNA) were negative.
Next-generation sequencing (NGS) or polymerase chain reaction (PCR) was used to detect tissue PI3KCA status, and the results were positive.
Longer PFS.
Therefore, it is suggested that our PI3KCA ctDNA-negative patients can appropriately supplement the tissue PI3KCA test to help screen the dominant population.
The BYLieve study evaluated the efficacy of Alpelisib combined with endocrine therapy for CDK4/6 inhibitor + AI/fulvestrant treatment progress in HR+/HER2-, PIK3CA mutant breast cancer patients.
The results showed that in the A cohort, Alpelisib combined with fulvestrant was used in patients with progression of CDK4/6 inhibitor + AI treatment.
The 6-month survival and progression-free survival rate was 50.
4%, which was consistent with the tumor regression pattern of the SOLAR-1 study.
In cohort B, Alpelisib combined with letrozole was used for patients with progression of CDK4/6 inhibitor + Fulvestrant.
The 6-month survival and progression-free survival rate was 46.
1%, and the median PFS was 5.
7 months.
In addition, hyperglycemia, skin rash, and diarrhea are all expected adverse events (AE) of Alpelisib, which are predictable and manageable.
The AKT inhibitor FAKTION study shows that the AKT inhibitor Capivasertib combined with fulvestrant can significantly improve the PFS of patients with previous AI recurrence/progress, independent of the PAM pathway activation state.
Although the OS data is still immature, its HR value is comparable to that of PFS, and the result is worth looking forward to.
The mTOR inhibitor BOLERO-2 study shows that in postmenopausal advanced breast cancer patients who have failed NSAI treatment, everolimus combined with exemestane can significantly prolong PFS, but OS has no benefit and cannot be screened based on PI3KCA gene mutation status Advantageous group.
HDAC inhibitors-Epigenetic home-made original HDAC inhibitors can overcome endocrine resistance.
The E2112 study data released in 2020 suggest that entinote combined with exemestane did not improve the PFS and OS of patients who progressed after previous NSAI treatment, which can be described as a disaster.
The difference is that in the ACE study led by Professor Jiang Zefei, the original domestic innovative drug chidamide combined with exemestane achieved encouraging positive results.
Compared with the E2112 study, this study covers a more frontline population, and the results show that chidamide combined with exemestane significantly prolongs the PFS of patients.
According to the positive data of the ACE study, in the 2021 guidelines, HDAC inhibitors are directly labeled as Chidamide.
The guidelines suggest that for patients who have failed TAM treatment, AI + Chidamide is a level I recommendation; for patients who have failed NSAI treatment, steroidal AI + Chidamide is a level I recommendation.
Finally, Professor Yang said that in the treatment of HR+/HER2- breast cancer, the combination of endocrine targeting strategies can be described as a powerful combination.
New oral selective estrogen receptor degradants (SERD), PROTACS-targeted chimera for protein degradation, FGFR inhibitors and other drugs are emerging and emerging, presenting a new blueprint for the treatment of HR+/HER2- breast cancer, which needs to be further verified.
Summary In the combined strategy of HR+/HER2-advanced breast cancer endocrine targeting, the "troika" of CDK4/6 inhibitors has become a standard treatment option; PI3K/AKT/mTOR inhibitors in the PAM pathway have their own magical powers and are worth looking forward to; Chidamide, as a domestically developed original research drug, has shown its effective results; other targeted drugs are emerging in endlessly and need to be verified.
How to effectively combine targeted therapy drugs and choose the right population? International HR+/HER2-advanced breast cancer treatment pathway recommendations have triggered thoughts, and accurate screening of superior populations based on tissue NGS and ctDNA testing will be the future direction.
We are still on the way for the exploration of breast cancer endocrine combined targeted therapy!
These patients can benefit from endocrine therapy, but about 30% of patients will develop resistance to primary endocrine therapy, and about 30% of newly effective patients develop secondary drug resistance within 10 years.
The way to find endocrine therapy resistance is to be solved.
Must do.
The 2021 National Breast Cancer Conference and the Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) Annual Conference were held in Beijing from April 9th to April 10th in the form of "online + offline".
During the meeting, Professor Yang Jin from the First Affiliated Hospital of Xi'an Jiaotong University shared a targeted joint strategy for endocrine therapy for breast cancer.
Let us follow Professor Yang to learn how to identify subgroups suitable for new drugs and conduct effective deployment.
Professor Yang Jin, Chief Physician, Department of Oncology, First Hospital of Xi'an Jiaotong University, Doctoral Supervisor, Deputy Director, Department of Oncology, Deputy Director, Department of Oncology, Member of the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Specialty Committee Member, Chinese Anti-Cancer Association Breast Cancer Specialty Committee Member, Chinese Research Hospital Society Breast Cancer Specialty Committee Standing Committee Member of the Standing Committee of the Clinical Oncology Committee of the Chinese Women Physicians 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 Chairman of the Breast Group of the Tumor Marker Committee of the Chinese Anti-Cancer Association Traditional Endocrine Therapy Drugs include aromatase inhibitors (AI) and estrogen receptor modulators.
With the understanding of the estrogen receptor pathway, a series of targeted drugs have been developed in clinical research, such as the CDK4/6 inhibitor-Piper Palbociclib, Abemaciclib, Ribociclib, PI3K inhibitor, HDAC inhibitor, mTOR inhibitor, CDK2/7 inhibitor, etc.
CDK4/6 inhibitors-the mainstay of choice Over the past ten years, based on the positive results of progression-free survival (PFS), mTOR inhibitors, CDK4/6 inhibitors, HDAC inhibitors and PI3K inhibitors have been approved for clinical practice.
.With the further maturity of overall survival (OS) data, targeted drugs represented by CDK4/6 inhibitors have shown significant benefits for OS.
According to domestic and foreign guidelines, the recommended level of endocrine monotherapy has gradually declined, and combined endocrine targeting has become the mainstream choice.
CDK4 and CDK6 are key regulators of the cell cycle.
CDK4/6 inhibitors can block cells from G1 phase to S phase, block cell cycle progression, and thereby inhibit tumor cell proliferation.
A series of clinical trials of CDK4/6 inhibitors combined with non-steroidal AI (NSAI) or fulvestrant showed that CDK4/6 inhibitors combined with endocrine first-line/second-line treatment increased the PFS and OS of advanced breast cancer, indicating this Significant advantages of the program.
Is there any difference between Chinese population data and international data? The MONARCH plus study (NCT02763566) answered this question.
The study is an international multi-center, randomized, double-blind, placebo-controlled Phase III study led by Professor Jiang Zefei and Professor Hu Xichun.
More than 80% of the patients enrolled were from the Chinese population.
The study was divided into two cohorts, A and B, and included two different groups of people.
Cohort A enrolled patients with HR+/HER2-advanced breast cancer who had not received systemic treatment and were randomized 2:1 to receive abecili+letrozole/anastrozole or placebo+letrozole/anastrozole.
The results showed that the combination of abesiride and NSAI significantly prolonged the PFS of patients (less than 14.
7 months, HR=0.
499, 95% CI 0.
346-0.
719, P=0.
0001), which is consistent with the data of the MONARCH 3 study.
At the same time, the data released by the CSCO conference in 2020 showed that abexiride combined with endocrine therapy significantly improved the PFS of Chinese advanced breast cancer patients with visceral metastasis (22.
32 vs 13.
28 months, HR=0.
502, 95% CI 0.
307-0.
820).
The data is also consistent with the MONARCH 3 research data. Cohort B included HR+/HER2-advanced breast cancer patients who had previously undergone progress in endocrine therapy, and were randomly assigned to receive treatment with abecili + fulvestrant or placebo + fulvestrant according to 2:1.
The results showed that abexiride combined with fulvestrant can prolong the PFS of patients with endocrine resistance (11.
5 vs 5.
months, HR=0.
376, 95% CI 0.
240-0.
588, P<0.
0001).
For primary/secondary The risk of PFS in resistant patients is reduced by more than 50%.
CDK4/6 inhibitor combined with NSAI or Fulvestrant, which is better? The PAPSIFAL study compared the efficacy of piperacillil in combination with letrozole or fulvestrant.
The results showed that there was no difference in PFS between the two groups, but for patients who have previously received AI treatment, piperacillil combined with fulvestrant seems to have a certain degree of benefit.
At the same time, a meta-analysis published in ESMO OPEN in 2020 showed that among endocrine therapy-sensitive populations, with PFS and OS as the dual endpoints, the efficacy of CDK4/6 inhibitor combined with fulvestrant is better than combined AI; In the drug population, PFS is the end point, CDK4/6 inhibitor combined with fulvestrant is better than AKT inhibitor combined with fulvestrant, and OS is the end point, and both are better.
In the German AGO guidelines HR+/HER2- advanced breast cancer treatment route recommendation, the choice of CDK4/6 inhibitor combined with AI or fulvestrant is based on postoperative adjuvant endocrine therapy.
If you have previously received tamoxifen (TAM) treatment, the combination with AI is preferred; if you have previously received AI treatment, the combination with fulvestrant is preferred.
This year's CSCO guidelines also emphasized the choice of CDK4/6 inhibitor combination therapy in accordance with previous endocrine therapy programs.
The guidelines recommend that for patients with TAM treatment failure, CDK4/6 inhibitors combined with AI or fulvestrant are recommended as level I; for patients with failed AI treatment, fulvestrant + CDK4/6 inhibitors are recommended for level I.
Based on the Monarch plus research data, abexiride combined with fulvestrant is recommended as 1A, and piperazil combined with fulvestrant is recommended as 2A.
For patients without endocrine therapy, a new fulvestrant + CDK4/6 inhibitor regimen is added.
After CDK4/6 inhibitor progresses, should I switch to another CDK4/6 inhibitor, switch to PI3K/AKT/mTOR inhibitor, or switch to other strategies? At present, there is no evidence-based medical evidence to replace another CDK4/6 inhibitor.
A small sample study in the United States tried follow-up treatment with abexiride in patients with resistance to pipercillide, which showed a certain effect of OS and PFS.
PI3K/AKT/mTOR pathway inhibitors—bypass sentinels overcome drug-resistant PI3K inhibitors.
In the past, PI3K inhibitors were more toxic and had unsatisfactory efficacy.
The SOLAR-1 study compared the efficacy of a new PI3Kα subtype inhibitor Alpelisib+fulvestrant and placebo+fulvestrant in the endocrine-resistant PI3KCA mutation cohort and the wild-type cohort.
The results showed that in the PI3KCA mutation cohort, the PFS of the Alpelisib group was significantly prolonged (11.
0 vs 5.
7 months).
Although there was no statistical difference in the prolongation of OS by 7.
9 months, in patients with lung and/or liver metastases, the Alpelisib group significantly improved OS.
At the same time, the study showed that 38% of patients with PI3KCA plasma circulating tumor DNA (ctDNA) were negative.
Next-generation sequencing (NGS) or polymerase chain reaction (PCR) was used to detect tissue PI3KCA status, and the results were positive.
Longer PFS.
Therefore, it is suggested that our PI3KCA ctDNA-negative patients can appropriately supplement the tissue PI3KCA test to help screen the dominant population.
The BYLieve study evaluated the efficacy of Alpelisib combined with endocrine therapy for CDK4/6 inhibitor + AI/fulvestrant treatment progress in HR+/HER2-, PIK3CA mutant breast cancer patients.
The results showed that in the A cohort, Alpelisib combined with fulvestrant was used in patients with progression of CDK4/6 inhibitor + AI treatment.
The 6-month survival and progression-free survival rate was 50.
4%, which was consistent with the tumor regression pattern of the SOLAR-1 study.
In cohort B, Alpelisib combined with letrozole was used for patients with progression of CDK4/6 inhibitor + Fulvestrant.
The 6-month survival and progression-free survival rate was 46.
1%, and the median PFS was 5.
7 months.
In addition, hyperglycemia, skin rash, and diarrhea are all expected adverse events (AE) of Alpelisib, which are predictable and manageable.
The AKT inhibitor FAKTION study shows that the AKT inhibitor Capivasertib combined with fulvestrant can significantly improve the PFS of patients with previous AI recurrence/progress, independent of the PAM pathway activation state.
Although the OS data is still immature, its HR value is comparable to that of PFS, and the result is worth looking forward to.
The mTOR inhibitor BOLERO-2 study shows that in postmenopausal advanced breast cancer patients who have failed NSAI treatment, everolimus combined with exemestane can significantly prolong PFS, but OS has no benefit and cannot be screened based on PI3KCA gene mutation status Advantageous group.
HDAC inhibitors-Epigenetic home-made original HDAC inhibitors can overcome endocrine resistance.
The E2112 study data released in 2020 suggest that entinote combined with exemestane did not improve the PFS and OS of patients who progressed after previous NSAI treatment, which can be described as a disaster.
The difference is that in the ACE study led by Professor Jiang Zefei, the original domestic innovative drug chidamide combined with exemestane achieved encouraging positive results.
Compared with the E2112 study, this study covers a more frontline population, and the results show that chidamide combined with exemestane significantly prolongs the PFS of patients.
According to the positive data of the ACE study, in the 2021 guidelines, HDAC inhibitors are directly labeled as Chidamide.
The guidelines suggest that for patients who have failed TAM treatment, AI + Chidamide is a level I recommendation; for patients who have failed NSAI treatment, steroidal AI + Chidamide is a level I recommendation.
Finally, Professor Yang said that in the treatment of HR+/HER2- breast cancer, the combination of endocrine targeting strategies can be described as a powerful combination.
New oral selective estrogen receptor degradants (SERD), PROTACS-targeted chimera for protein degradation, FGFR inhibitors and other drugs are emerging and emerging, presenting a new blueprint for the treatment of HR+/HER2- breast cancer, which needs to be further verified.
Summary In the combined strategy of HR+/HER2-advanced breast cancer endocrine targeting, the "troika" of CDK4/6 inhibitors has become a standard treatment option; PI3K/AKT/mTOR inhibitors in the PAM pathway have their own magical powers and are worth looking forward to; Chidamide, as a domestically developed original research drug, has shown its effective results; other targeted drugs are emerging in endlessly and need to be verified.
How to effectively combine targeted therapy drugs and choose the right population? International HR+/HER2-advanced breast cancer treatment pathway recommendations have triggered thoughts, and accurate screening of superior populations based on tissue NGS and ctDNA testing will be the future direction.
We are still on the way for the exploration of breast cancer endocrine combined targeted therapy!
