Professor Liu Jian: Re-discussion on several hot issues of endocrine therapy for breast cancer | 2021 CSCO BC

*For medical professionals to read only, how should HR+/HER2- endocrine therapy for advanced breast cancer be laid out? Here comes the expert's explanation! 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.

In the hormone receptor positive (HR+) breast cancer session, Professor Liu Jian from Fujian Cancer Hospital commented on several hot topics in breast cancer endocrine therapy.

The "Medical Oncology Channel" summarized the themes of Professor Liu's report for readers.

The advent of Professor Liu Jian's CDK4/6 inhibitors has brought HR+/HER2- advanced breast cancer into the era of targeted endocrine therapy.

At present, HR+/HER2-advanced breast cancer targeted endocrine drugs mainly include the following four categories: CDK4/6 inhibitors: Palbociclib, Abemaciclib, RibociclibHDAC inhibitors: Chidamine mTOR inhibitors: Everolimus PI3K inhibitor: Alpelisib plays an important role in all stages of HR+/HER2-advanced breast cancer.
Targeted endocrine drugs play an important role.
For specific groups of people, which drugs are more suitable, let us listen to what Professor Liu Jian said.
of.

HR+/HER2-adjuvant targeted endocrine therapy for early breast cancer: a long way to go.
The clinical research drugs for HR+/HER2-adjuvant targeted endocrine therapy for early breast cancer include abecili, piperacill, ribociclib, and everolimus.

Table 1 Efficacy and safety differences of early adjuvant endocrine therapy The PALLAS study is a randomized, prospective, open-label international multi-center phase III clinical trial conducted in more than 400 centers in 21 countries around the world, aiming to evaluate pipercillil Combined with standard adjuvant endocrine therapy for the efficacy and safety of early invasive (stage Ⅱ-Ⅲ) breast cancer.

Pebacillil was treated for 2 years, but the primary endpoint of invasive disease-free survival (iDFS) was not reached.

The PENELOPE-B study is a randomized, double-blind, placebo-controlled phase III clinical trial.
After neoadjuvant chemotherapy and tumor resection, there are still invasive disease (non-pCR) and HR+/HER2 with high risk of recurrence.
-Carried out in patients with early breast cancer, and evaluated the efficacy and safety of 1 year of piperacillil treatment combined with standard adjuvant endocrine therapy for at least 5 years, and placebo combined with standard adjuvant endocrine therapy for at least 5 years.

The results showed that the study did not meet the primary endpoint of iDFS.

The MonarchE study is a randomized, open-label, multi-center phase III clinical study that enrolled 5637 patients with node-positive HR+/HER2- high-risk early breast cancer.

The subjects were randomly assigned to the standard adjuvant endocrine therapy group or the standard adjuvant endocrine therapy group at a ratio of 1:1 for a 2-year treatment period.

The interim analysis showed that the study reached the primary endpoint of iDFS.
Compared with standard adjuvant endocrine alone, abesiride significantly reduced the risk of recurrence by 25% (HR: 0.
747; 95% CI: 0.
598-0.
932; p=0.
0096).

UNIRAD enrolled 1278 patients with HR+/HER2- high-risk early breast cancer.
After completing the initial treatment and adjuvant hormone therapy for ≤3 years, they were randomly assigned to the placebo group (P-HT) and the everolimus group (E- HT) for a 2-year treatment period.

The results showed that everolimus combined with hormone therapy did not increase the patient's 3-year DFS rate.

HR+/HER2-advanced breast cancer first- and second-line targeted endocrine therapy: three-legged first-line and second-line targeted endocrine therapy for advanced breast cancer, abecilil, piperacillil, and ribociclib all performed well.

In the first-line treatment, abesiclib, piperaciclib, and ribociclib performed similarly in terms of HR, PFS, and ORR.
Because the structure of abesiclib is quite different from the other two drugs, there are also differences in adverse events and less blood toxicity.
However, the digestive tract is relatively more toxic.

Table 2 Efficacy and safety differences of first-line targeted endocrine therapy In the PALOMA-2 study, patients were randomly assigned to the pipercillil + letrozole group and the placebo + letrozole group at 2:1, and the study reached the primary endpoint.

The median PFS of the piperacillil + letrozole group was 24.
8 months.
Compared with the placebo group, the piperacillil group reduced the risk of disease progression or death by 42%.

In the MONALEESA-2 study, patients were randomly assigned to the letrociclib+letrozole group and the placebo+letrozole group 1:1.

Compared with the control group, the ribociclib+letrozole group had a median PFS of 25.
3 months (95%CI: 23.
0-30.
3) and 16.
0 months (95%CI: 13.
4-18.
2), and the risk of progression and death was reduced by 43.
2% ( HR: 0.
568, 95%CI: 0.
457-0.
704, log rank P=9.
63×10-8).

The MONALEESA-7 study is a global, randomized, double-blind, placebo-controlled Phase III study that compared ribociclib and placebo in combination with endocrine therapy for premenopausal or perimenopausal HR+/HER2-advanced breast cancer.

The median PFS of the two groups were 23.
8 months and 13.
0 months, respectively (HR: 0.
553; 95% CI: 0.
441-0.
694; p<0.
0001).

In the Monarch 3 study, patients were randomized 2:1 to receive Abexicil + non-steroidal aromatase inhibitor (AI) or placebo + non-steroidal AI treatment.
The study reached the primary research endpoint, and the Abexicil group was significantly extended PFS, the two groups were 28.
2 months and 14.
8 months respectively.

In the second-line target therapy, in addition to the PALOMA3, MONALEESA3, MONARCH2, and MONARCH plus studies in combination with three CDK4/6 inhibitors and fulvestrant, there is also an ACE study in the combination of chidamide and exemestane.

Table 3 Differences in efficacy and safety of targeted endocrine second-line therapy.
The MONARCH plus study led by Professor Jiang Zefei from the Fifth Medical Center of PLA General Hospital.
The enrolled population is mainly Chinese patients.
Cohort A is Abexiride combined with AI vs.
AI monotherapy , Cohort B is the initial endocrine therapy for advanced breast cancer as a combination of abesiride combined with fulvestrant versus fulvestrant as a single agent.

Due to the more applications of AI in adjuvant endocrine therapy for Chinese patients, clinical attention is paid more to the results of cohort B.

Cohort B showed that the median PFS of the abecilide+fulvex group and the placebo+fulvex group were 11.
47 months and 5.
59 months, respectively (HR: 0.
376, 95%CI: 0.
240-0.
588, P< 0.
0001).

HR+/HER2- Late-line Endocrine Therapy for Advanced Breast Cancer: Eight Immortals Cross the Sea, Each Shows Its Magical Powers With the wider clinical application of CDK4/6 inhibitors, the problem of CDK4/6 inhibitor resistance is inevitably more and more prominent.

With the continuous emergence of new targeted drugs, the back-line treatment presents a situation where a hundred flowers are blooming.

Drug-related studies that have been approved for marketing mainly include PI3K inhibitors + fulvestrant, mTOR inhibitors + fulvestrant, everolimus, alpelisib, taselisib and other drugs show their respective advantages and suitable for the population.

Table 4 Differences in efficacy and safety of targeted endocrine posterior therapy The SOLAR-1 study was carried out in patients with PIK3CA mutations in HR+/HER2-advanced breast cancer who had progressed during or after treatment with AI, and evaluated alpelisib and fluvix Efficacy and safety of Si-qun combined therapy.

The median PFS in the Alpelisib+fulvestrant treatment group was 11 months, and that of the fulvestrant group was 5.
7 months.

Alpelisib+fulvestrant combination therapy significantly reduced the risk of disease progression or death by 35% (HR: 0.
65, 95% CI: 0.
50-0.
85, p<0.
001).

In terms of ORR, the Alpelisib+fulvestrant treatment group was more than twice the fulvestrant treatment group (36% vs 16%).

In terms of safety, most adverse events are mild to moderate in severity, and can generally be managed through dose adjustment and medical measures.

The BYLieve study is a single-arm clinical study evaluating alpelisib combined with fulvestrant for late-line treatment of patients with advanced breast cancer with HR+/HER2- and PIK3CA mutations.

In cohort A, the 6-month PFS rate of patients who received CDK4/6 inhibitor combined with AI treatment was 50.
4%, and the median PFS was 7.
3 months (95%CI: 5.
6-8.
3), reaching the primary endpoint (95%CI Lower bound value> 30%).

The SANDPIPER study is the largest first phase III clinical study of taselisib.

The study included 516 patients with ER+/HER2- or metastatic breast cancer who had disease progression or recurrence after first-line AI treatment.

Compared with patients in the placebo+fulvestr group, patients with PIK3CA mutations who received taselisib+fulvestrant treatment had a 30% reduction in the probability of tumor progression.
Taselisib delayed tumor progression by a median of 2 months.
The taselisib combined treatment group and The tumor progression time in the placebo group was 7.
4 months and 5.
4 months, respectively.

The BOLERO-2 study is a global multicenter, phase III, randomized, double-blind clinical study that compares everolimus combined with exemestane and placebo combined with exemestane in the treatment of postmenopausal HR+ and non-steroidal AI Efficacy in breast cancer patients who have recurred or progressed after treatment.

Everolimus combined with exemestane treatment improved the PFS of HR+/HER2- advanced breast cancer patients who had received non-steroidal AI treatment (11.
0 months vs 4.
1 months).

Conclusion Although the combination of CDK4/6 inhibitors and endocrine therapy is the best choice for advanced HR+/HER2- breast cancer, only MonarchE (abexicil) has achieved positive results in the field of adjuvant targeted endocrine therapy for early high-risk breast cancer.

More exploration is still needed to find advantageous populations for assisted targeted endocrine therapy.

The first and second-line targeted endocrine therapy presents a situation where the three males of abecilil, piperacillil and ribociclib coexist.

In the study of back-line targeted endocrine therapy, due to different drugs and large differences in the enrolled population, the efficacy data cannot be homogeneously compared.
Everolimus, Alpelisib, Taselisib, etc.
show their respective advantages and suitable populations.

Expert profile: Professor Liu Jian, Executive Director, Chief Physician, Master Supervisor, Department of Breast Oncology, Fujian Provincial Tumor Hospital, Expert of the Provincial Health Committee Member of the Standing Committee of Fujian Provincial People’s Congress, Deputy Chairman of the Fujian Provincial Committee of the Democratic Progressive Fujian Provincial Committee of the Department of Breast Diseases Fujian Province Chairman of the Medical Oncologists Branch of the Medical Doctors Association Deputy Chairman of the Breast Disease Expert Training Committee of the Chinese Medical Doctors Association Deputy Chairman of the Breast Disease Branch of the Chinese Primary Care Wisdom and Health Foundation Deputy Chairman of the Supervision Committee of the Critical Disease Relief Fund of Fujian Red Cross China Anti-Cancer Standing member of the Breast Cancer Professional Committee of the Association Standing member of the Breast Cancer Professional Committee of the Chinese Society of Clinical Oncology (CSCO) Standing member of the Chinese Society of Clinical Oncology Expert Committee of Oncology and Cardiology Standing Member of the "Medical Reference (Breast Channel)" Committee Member and Secretary of the Breast Cancer Group, National Cancer Center for Quality Control, Breast Cancer Expert Committee, Member of the National Anti-tumor Drug Clinical Application Monitoring Expert Committee, Member of the Chinese Medical Association Oncology Branch, Mammology Group Member, Chinese Preventive Medicine Association Maternity and Child Health Branch Committee Member of the Mammology Group "JCO Chinese edition of Breast Oncology Special, "Chinese Journal of Endocrine Surgery", "Journal of Oncology", "European Cancer Yearbook Chinese Edition (Breast Cancer)", "Chinese Journal of Oncology", "Journal of Clinical Oncology", "Chinese Oncology" Editorial Board