Trial Title:
Multigene Risk Score Combined With Ki-67 Dynamic Assessment in Stratified Neoadjuvant Endocrine Therapy Treatment With or Without CDK4/6 Inhibitors in HR+/HER2- Breast Cancer
NCT ID:
NCT06650748
Condition:
Breast Cancer
Early-stage Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Letrozole
Conditions: Keywords:
Early-stage Breast Cancer
neoadjuvant endocrine therapy
CDK4/6
HR+/HER2-
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Dalpiciclib
Description:
Dalpiciclib, oral administration, 125g each time, once daily, days 1-21, with a 28-day
cycle (3 weeks on/1 week off). Continuous medication for 6 cycles, or disease
progression, intolerable toxicity, withdrawal from the study for any reason or death,
whichever occurs first; or after researcher's judgement, patient would no longer benefit
from the treatment.
Arm group label:
Arm 1
Arm group label:
Arm 3
Intervention type:
Drug
Intervention name:
Letrozole
Description:
2.5 mg, oral, once daily (continuously), with a 28-day cycle. Continuous medication for 6
cycles, or disease progression, intolerable toxicity, withdrawal from the study for any
reason or death, whichever occurs first. Refer to drug instructions for specific usage
Arm group label:
Arm 1
Arm group label:
Arm 2
Arm group label:
Arm 3
Arm group label:
Arm 4
Summary:
This is a prospective, single-center, randomize-controlled study. The purpose of this
study is to evaluate the efficacy of neoadjuvant CDK4/6 inhibitors in patients with
high-risk EPclin multigene risk analysis and non-response to Ki-67 2W, and to explore
predictive biomarkers for sensitivity to CDK4/6 inhibitor therapy.
Detailed description:
China is a country with a high incidence of breast cancer. For operable hormone
receptor-positive (HR+) / human epidermal growth factor receptor 2-negative (HER2-)
breast cancer, traditional neoadjuvant chemotherapy often fails to achieve clinical
complete response (CCR) and has poor tolerability. Endocrine therapy plays a significant
role in the treatment of advanced and early-stage HR+/HER2- breast cancer, but its
efficacy in neoadjuvant settings needs further exploration. Studies have shown that the
CCR and breast conservation rate of neoadjuvant endocrine therapy for HR+/HER2- breast
cancer are similar to those of neoadjuvant chemotherapy, with lower toxicity. Therefore,
by precisely stratifying the recurrence risk of HR+/HER2- patients and treating them
according to different risk levels, the response rate to neoadjuvant endocrine therapy
can be further improved, which would be more beneficial for the patients. With the
clinical application of CDK4/6 inhibitors, the effectiveness of neoadjuvant endocrine
therapy is expected to be enhanced.
In PALLET study, the combination of palbociclib and letrozole significantly inhibited
Ki-67 expression, leading to a higher number of patients achieving a state of cell cycle
arrest (CCCA) (defined as Ki-67≤2.7%). NeoMONARCH study suggests that a regimen
containing abemaciclib is significantly superior to anastrozole monotherapy, with
statistical significance (P < 0.001). The NeoPAL and CORALLEEN studies indicate that
neoadjuvant endocrine therapy with palbociclib or ribociclib is comparable in efficacy to
neoadjuvant chemotherapy, yet has fewer side effects.
EndoPredict (12-gene assay, EPclin) is a second-generation multigene testing scoring tool
that combines the molecular biological status of the tumor with clinical factors (tumor
size and lymph node status). For early-stage HR+/HER2- breast cancer patients, the EPclin
test result helps to distinguish between low and high recurrence risk populations,
allowing for a more precise assessment of patient prognosis. In the validation study for
premenopausal patients, a total of 385 patients with stage ≤pT3 and pN0~1, who received
only endocrine therapy for ER+/HER2- early invasive breast cancer, were enrolled. The
results showed that the 10-year distant recurrence-free survival (DRFS) rate for patients
in the EPclin low-risk group reached 97%, while the 10-year DRFS rate for the EPclin
high-risk group was 76% (P=0.004). For postmenopausal patients, the prognostic value of
EPclin was independently validated through the ABCSG6&8 study. The study included 1,702
patients with ER+/HER2- early invasive breast cancer who underwent surgery and received
only five years of endocrine therapy. The results showed that the 10-year distant
recurrence rate for patients in the EPclin low-risk group was 4%, while the 10-year
distant recurrence rates for patients in the EPclin high-risk group were 28% and 22%
(P<0.001). A retrospective analysis of ABCSG-34 demonstrated that for patients undergoing
neoadjuvant endocrine therapy, the application of EPclin for prognostic assessment
revealed a negative correlation between risk levels and residual cancer burden (RCB).
That is, among patients receiving neoadjuvant endocrine therapy (NET), a higher
proportion of low-risk patients compared to high-risk patients ultimately had an RCB of
0-I.
This study focuses on early-stage HR+/HER2- breast cancer, conducting recurrence risk
analysis through EPclin multigene testing, and integrating the dynamic changes of Ki67
after two weeks of neoadjuvant endocrine therapy. Patients are risk-stratified and
treated with or without CDK4/6 inhibitors. The study explores the improvement in PEPI
scores after surgery and analyzes the effectiveness of multigene testing combined with
Ki67 dynamic changes as a predictor for the efficacy of CDK4/6 inhibitor treatment in
HR+/HER2- breast cancer with high recurrence risk and insensitivity to endocrine therapy.
The study also seeks to explore methods for predicting sensitivity to CDK4/6 inhibitor
treatment.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Females aged 18 to 70 years;
2. Patients with histologically confirmed HR+/HER2- invasive breast cancer that is
sensitive to endocrine therapy. Tumor diameter >2 cm, clinically positive axillary
lymph nodes not more than 2 (T2N1M0), Ki67≥+20%. Endocrine therapy sensitivity is
defined as ER expression >50% by immunohistochemistry. HER-2 negativity is defined
as HER-2 results of 0 or 1+ by immunohistochemistry, or negative by FISH;
3. Within 28 days before the first dose of study medication, patients must have at
least one measurable lesion according to RECIST 1.1 standards, as assessed by
ultrasound or MRI;
4. Laboratory test values: a. Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5 ×
10^9/L); b. Platelet count (PLT) ≥ 100,000/mm3 (100 × 10^9/L); c. Hemoglobin (Hb) ≥
9 g/dL (90 g/L); d. Serum creatinine ≤ 1.5 times the upper limit of normal (ULN) or
creatinine clearance ≥ 30 ml/min (based on the Cockroft-Gault formula); e. Total
bilirubin (BIL) ≤ 1.5 times the upper limit of normal (ULN), Gilbert's syndrome; f.
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ≤ 2.5
times the upper limit of normal (ULN); g. INR or PT ≤1.5 ULN, APTT ≤1.5 ULN.
5. Subject agrees to collect tumor biopsy specimen during the screening period;
6. Subject signed the informed consent form, expressing willingness and ability to
comply with the planned visits, study treatments, laboratory tests, and other trial
procedures.
Exclusion Criteria:
1. Coexisted with other malignant tumors within 5 years prior to first medication,
except for cured squamous cell carcinoma of the skin, basal cell carcinoma,
non-muscle-invasive bladder cancer, carcinoma in situ of the cervix/breast, etc;
2. Had a serious infection within 1 month before screening or required systemic
treatment for any active infection within 2 weeks before first medication;
3. History or current presence of autoimmune diseases, including but not limited to
Crohn's disease, ulcerative colitis, systemic lupus erythematosus, sarcoidosis,
Wegener's syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis), autoimmune hepatitis, systemic sclerosis
(scleroderma, etc.), Hashimoto's thyroiditis (exceptions are noted below),
autoimmune vasculitis, autoimmune neuropathy (Guillain-Barre syndrome), etc. The
following exceptions apply: Type I diabetes, thyroid dysfunction requiring only
hormone replacement therapy (including thyroid dysfunction caused by autoimmune
thyroid disease), psoriasis or vitiligo not requiring systemic treatment;
4. History of organ transplantation or allogeneic hematopoietic stem cell
transplantation;
5. Patients who received systemic anti-cancer treatment within 2 weeks before the first
dose, including chemotherapy, immunotherapy, hormone therapy, biological therapy
(cytokines or growth factors that control the progression of cancer);
6. Metastatic breast cancer;
7. Positive for human immunodeficiency virus antibodies (HIV-Ab) or syphilis antibodies
(Anti-TP); positive for hepatitis C virus antibodies (HCV-Ab), with hepatitis C
virus RNA quantification > the upper limit of the normal value of the detection
unit; positive for hepatitis B surface antigen (HBsAg) and/or hepatitis B core
antibodies (HBcAb), with HBV DNA quantification > the lower limit of detection of
the detection unit;
8. History of alcohol abuse or drug abuse.
Gender:
Female
Gender based:
Yes
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Beijing Cancer Hospital
Address:
City:
Beijing
Country:
China
Contact:
Last name:
Zhaoqing Fan
Start date:
November 15, 2024
Completion date:
April 1, 2028
Lead sponsor:
Agency:
Peking University
Agency class:
Other
Source:
Peking University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06650748
