Study on the Safety and Tolerability of Postoperative Radiotherapy Concurrent With CDK4/6 Inhibitors in HR+/HER2- High-Risk Breast Cancer
Phase: EARLY_PHASE1
Conditions: Breast Cancer
Sponsor: Guizhou Provincial People's Hospital

 
 
Item Number: Version Number: V1.0 Date: 202505.30 
 
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Project source: Oral longitudinal project Oral horizontal project    ☑ 
Spontaneous research 
 
Safety and tolerability of concurrent CDK4/6 inhibitors with 
radiotherapy after surgery for HR+/HER2- high-risk breast 
cancer 
 
 
 
Study Project Title: Safety and Tolerability Study of Concurrent CDK4/6 
Inhibitors with Postoperative Radiotherapy for HR+/HER2- High-risk Breast 
Cancer 
Project leader/undertaking department: Li Yong/Department of Oncology, 
Guizhou Provincial People's Hospital 
Project entrusting unit: Department of Oncology, Guizhou Provincial 
People's Hospital 
Project undertaking unit: Department of Oncology, Guizhou Provincial 
People's Hospital 
Project sponsor: Department of Oncology, Guizhou Provincial People's 
Hospital 
Research Duration: November 2025 - November 2026 
Version number: V1.0 
Version date: October 30, 2025 

 
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1. Research background 
     According to data released by the World Health Organization (WHO) 
International Agency for Research on Cancer, the number of new breast cancer 
cases worldwide reached about 2.3 million in 2022, ranking first among female 
cancer incidences. In recent years, the incidence of breast cancer in our 
country has increased year by year, with 416,000 new cases of breast cancer 
and 117,000 deaths in our country in 2020 [2]. The current treatment methods 
of breast cancer are mainly closely related to the molecular typing of breast 
cancer. The concept of molecular typing of breast cancer was first proposed 
in 2000 by Professors Perou and Sorlie of Stanford University in the United 
States [3], and has been widely used in clinical practice. There are currently 
four main molecular types of breast cancer, namely: Luminal A, Luminal B, HER2 
overexpression, and basal cell-like/triple negative. Among them, Luminal Type 
A mainly refers to high expression of ER (estrogen receptor) and PR 
(progesterone receptor), negative HER2 (human epidermal growth factor 
receptor 2), and low expression of Ki67. This type of breast cancer is sensitive 
to 
endocrine 
therapy 
and 
has 
the 
best 
prognosis, 
while 
HR-positive/HER2-negative breast cancer is also the most common subtype of 
breast cancer, accounting for 65%-75% of all breast cancers [4]. The main 
treatments for this subtype are surgery, endocrine therapy (ETs), targeted 
therapy, chemotherapy, antibody-drug conjugates (ADCs), and immunotherapy. 
Although HR+/HER2- early-stage breast cancer patients generally have a good 
prognosis after standard endocrine therapy, 30% of high-risk patients still 
have recurrence and metastasis within 5 years after standard treatment [5], 
and the risk of recurrence peaks within 2-3 years after surgery. Therefore, 

 
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endocrine intensive therapy for high-risk patients is currently a hot topic 
of clinical attention. The current evaluation criteria for high-risk patients 
after breast cancer surgery in our country are: 1. When the number of lymph 
nodes is positive 1~3, ER/PR is positive and HER2 is negative, any of the 
following conditions can be judged as high-risk: grade III. Tumor size (pT) 
greater than 5cm; Polygenic testing is at high risk. 2) If the number of lymph 
nodes is positive 1~3, ER is negative and PR is negative; or HER2 positive. 
2. The number of positive lymph nodes is greater than or equal to 4. With the 
advancement of science and technology, the continuous development of targeted 
drugs has led to the birth of targeted drugs that can accurately act on the 
inside of cancer cells. The mechanism by which CDK4/6 inhibitors work is mainly 
due to cyclin-dependent kinase (CDK)4/6, a key regulator of the cell cycle, 
which can trigger the cell cycle from pre-DNA synthesis (G1 phase) to DNA 
replication (S1) by forming a complex with cyclin D, phosphorylating Rb, and 
releasing E2F [6]. In HR+ breast cancer, the CDK4/6-cyclinD-Rb pathway is very 
important and is a key downstream target for HR signaling. Therefore, it blocks 
the activity of CDK4/6 kinase, restores cell cycle control, blocks tumor cell 
proliferation, and inhibits the growth of breast cancer cells. Johnston et 
al. [7] published in The Lancet is an open-label, randomized phase III trial 
that included patients with early-stage HR+/HER2- breast cancer at high risk 
of recurrence. Early findings from this trial confirm that endocrine therapy 
in combination with CDK4/6 inhibitors can be used as intensive therapy for 
patients with early-stage HR+/HER2- breast cancer. The updated results of the 
study further confirmed that CDK4/6 inhibitors + endocrine adjuvant therapy 
can bring significant iDFS benefit (2 years: 92.7% vs 89.9% (2.8% benefit); 

 
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3 years: 89.2% vs 84.4% (gain 4.8%); 4 years: 85.8% vs 79.4% (benefit 6.4%)) 
and a 33.6% reduction in the risk of invasive disease or death (HR: 0.664, 
P<0.001). The DRFS-free survival rate of distant recurrence (DRFS) in the 
intention-to-treat (ITT) population increased with the extension of follow-up, 
and the DRFS rate of CDK4/6 inhibitor + endocrine adjuvant therapy increased 
by 5.9% (88.4% vs. 82.5%) at 4 years. A randomized, open-label, global 
multicenter phase III clinical trial initiated by Slamon et al. [8, 9] included 
a total of 5101 patients with stage II-III. early-stage HR+/HER2- breast cancer 
at risk of recurrence from 20 countries, randomly divided into two groups in 
a 1:1 ratio, respectively receiving CDK4/6 inhibitors (400 mg/day, 3 weeks 
of administration + 1 week of discontinuation for 3 years) + endocrine therapy 
(AI for ≥ 5 years, men and premenopausal women receiving OFS treatment at 
the same time) or endocrine therapy alone. The results of the trial, presented 
at the 2023 ASCO Congress, showed that patients treated with CDK4/6 inhibitors 
+ endocrine therapy (AI+OFS) had longer iDFS than ET alone (90.4% vs 87.1%), 
with an absolute difference of 3.3%. The recurrence wind direction was reduced 
by 25.2% (HR: 0.748; 95% CI: 0.618-0.906; P=0.0014), and the safety was good. 
The recent SABCS congress presented the final iDFS data for the study with 
a median follow-up of 33.3 months [10]. At a median follow-up of 33.3 months, 
the 3-year iDFS rates in the CDK4/6 inhibitor + NSAI group and the NSAI group 
were 90.7% (95%CI: 89.3%-91.8%) and 87.6% (95%CI: 86.1%-88.9%), respectively. 
Compared with NSAI alone, the CDK4/6 inhibitor + NSAI group showed a 
significant benefit in 3-year iDFS (HR: 0.749; 95% CI: 0.628-0.892; P=0.0006), 
and the safety was consistent with the results of previous studies. These 
studies suggest that CDK4/6i combined with endocrine therapy has good safety 

 
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and efficacy. 
At the same time, radiotherapy is not only an important means of 
comprehensive treatment of breast cancer, which can reduce the recurrence rate 
and prolong survival of patients after breast-conserving surgery and high-risk 
mastectomy surgery. Adjuvant radiotherapy is mainly aimed at killing potential 
residual tumor cells in the ipsilateral breast after breast cancer surgery, 
chest wall after mastectomy, and regional lymph nodes, thereby reducing the 
risk of recurrence, prolonging patient survival, and improving the cure rate. 
Preclinical studies [11] have shown potential synergistic effects of 
radiotherapy combined with CDK4/6 inhibitors. Some preclinical studies [12-15] 
have also shown that CDK4/6 inhibitors can sensitize radiotherapy by 
anti-angiogenesis, inhibition of DNA damage repair, and inhibition of 
mammalian rapamycin target protein signaling, which provides a theoretical 
basis for radiotherapy combined with CDK4/6 inhibitors for the treatment of 
ER+Her2- metastatic breast cancer. Guerini et al. [16] reported 18 cases of 
metastatic breast cancer treated with CDK4/6 inhibitors combined with 
radiotherapy, with pain control in all patients within 3 months after the end 
of radiotherapy, with a median follow-up time of 13.7 months (range 2~29 
months), and by the end of follow-up, a total of 6 patients had tumor recurrence 
(including 3 deaths), and another 12 patients had no tumor progression and 
were still receiving CDK4/6 inhibitor therapy. Compared with historical data, 
radiotherapy combined with CDK4/6 inhibitors controlled distant metastases 
of breast cancer similar to radiotherapy alone, but overall survival was 
prolonged and there was no increase in adverse effects. A study published by 
Beddok et al. [17] in 2020 evaluated the safety and efficacy of radiotherapy 

 
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(local breast and lymph node irradiation) in combination with piperciclib in 
nine patients with de novo metastatic breast cancer. Two patients discontinued 
pipercilib during radiotherapy due to grade 2 radiation dermatitis, pain, and 
grade 2 radiation esophagitis. Because of the lack of studies on radiotherapy 
in combination with CDK4/6 inhibitors, most radiation oncologists preferred 
to suspend CDK4/6 inhibitors during radiotherapy because the safety of this 
combination was still unclear at the time. In a study by Meattini et al. [18], 
5 patients who received palliative radiotherapy combined with rebocillin and 
letrozole for metastatic breast cancer had 2 grade III.~IV. adverse reactions, 
including 1 case of neutropenia and 1 case of gastrointestinal adverse 
reactions. In the preclinical trial of 5 patients with metastatic breast cancer 
who received palliative radiotherapy combined with pipesciclib and 
fulvestrant reported by Hans et al. [19], all patients had good local tumor 
control and pain relief, and the adverse reactions of this treatment regimen 
were mainly reflected in the blood system, with a total of 2 cases of grade 
III. neutropenia, 2 cases of grade III. thrombocytopenia, and 1 case of grade 
III. anemia, as well as 2 cases of grade I.~II. gastrointestinal adverse 
reactions, and no skin adverse reactions were observed. Among the 18 patients 
treated with radiotherapy combined with CDK4/6 inhibitors, 11 patients 
developed grade III.~IV. neutropenia within 3 months after radiotherapy, and 
4 patients who had been treated with CDK4/6 inhibitors for more than 3 months 
before the start of radiotherapy had previously experienced grade III.~IV. 
hematologic adverse reactions, and 1 case had grade III. gastrointestinal 
adverse reactions. Although the incidence of hematologic adverse reactions 
was high in the above clinical trials, the addition of radiotherapy did not 

 
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additionally increase the incidence and severity of adverse reactions compared 
with CDK4/6 inhibitors combined with endocrine therapy for metastatic breast 
cancer [20-23], and hematologic adverse reactions were easily controlled and 
did not lead to permanent discontinuation of CDK4/6 inhibitors. A 
meta-analysis [24] evaluated the safety and feasibility of CDK4/6i in 
combination with radiotherapy, and the results showed that the addition of 
radiotherapy to CDK4/6i in patients with HR+/HER2- advanced breast cancer is 
safe and well-tolerated as a viable treatment option, and its overall incidence 
of adverse reactions is comparable to that of CDK4/6i alone. From the above 
studies, it can be seen that the addition of RT on the basis of CDK4/6 inhibitors 
has a synergistic effect, but may this combination increase the risk of adverse 
reactions, and how much does the adverse risk increase? The conclusion is still 
uncertain. There is currently a lack of prospective data evaluating the safety 
of CDK4/6 inhibitors in combination with RT. 
Therefore, based on the above studies, we propose the following design: 
to explore the tolerability and safety of postoperative radiotherapy combined 
with CDK4/6 inhibitors and endocrine adjuvant therapy in patients with 
high-risk breast cancer after HR+/HER2- surgery. At the same time, because 
breast cancer has gradually become a chronic disease, it affects the patient's 
life for a long time. Patient-reported outcome [25], or patient-reported 
outcome, is a report that directly reflects the patient's assessment of their 
own health status. It emphasizes the outcome of the assessment of one's own 
illness and corresponding treatment feelings that are directly reported by 
the patient and are not modified or interpreted by others. While conducting 
research, we will also use PRO scales (FACT-B, FACT-ES, FACT-F) to evaluate 

 
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patients' multi-dimensional feelings such as physical function, emotional 
state, and treatment-related symptoms during treatment, so as to obtain more 
realistic and reliable data on the patient's symptom assessment and gain. 
2. Research purpose 
1. Primary objective: This study aims to observe the tolerability and 
safety of postoperative adjuvant radiotherapy combined with CDK4/6 inhibitors 
in patients with hormone receptor-positive, HER2-negative high-risk breast 
cancer.  
2. Secondary Objectives: 
（1） To explore the combined gain of radiotherapy combined with CDK4/6i 
in 1+1>2 clinical practice. 
（2） To evaluate the progression-free survival (PFS) and overall 
survival (OS) of patients receiving this combination therapy regimen 
3. Study design type, principles and study steps 
1. Study design 
This study is a prospective, exploratory, observational, single-center 
study. 
2. Sample size and grouping method 
Sample content estimate: Thirty patients with HR+/HER2- high-risk early 
breast cancer will be collected. As TITE-CRM trial designs typically include 
24 to 36 participants (Daniel Normolle JCO 2006). And the simulation study 
showed that 30 patients had good operability in the correct selection of MTD. 
Therefore, 30 patients will receive this combination regimen. 
Group method: There was no control group in this study. 
3. Research period 

 
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May 2025 to May 2026 
4. Subject selection 
Selection Criteria: 
1. Age 18-60 years old, gender is female  
2. Postoperative pathological examination confirmed the diagnosis of HR+, 
HER2- invasive breast cancer:  
1) ER positive and/or PR positive is defined as: all tumor cells stained 
positively 
The proportion of tumor cells ≥ 10%;  
2) HER2 negativity is defined as: standard immunohistochemistry (IHC) test 
is 0/1+; 
ISH test is negative.  
3. Radical surgery or breast-conserving surgery to randomization no more 
than 6 months;  
4. Radical surgery Postoperative pathological examination showed the 
presence of lymph nodes in the ipsilateral axilla of the breast lesion 
Metastasis (Lymph node micrometastasis, ipsilateral internal mammary 
lymph nodes, and supraclavicular lymph nodes are allowed.) 
but the number of metastases in ipsilateral medial mammary lymph nodes 
and supraclavicular lymph nodes is not included in the positive one 
calculation of sexual lymph nodes), the specific requirements are as 
follows:  
1) Number of lymph node metastases≥ 4;  
2) When the number of lymph node metastases is 1 to 3, at least one of 
the following high-risk factors must be met:  

 
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i. Postoperative pathological detection of primary tumor diameter ≥5cm;  
ii. Primary lesion histology grade III (excluding grade II-III);  
iii. Invasive cancer residue in breast lesions after neoadjuvant therapy;  
iv. Ki-67≥30%。  
6. Eastern Cooperative Oncology Group (ECOG) physical status score of 0-2 
points.  
7. Willing and able to comply with the planned visits with the consent 
of the person and signed the informed consent form 
visual examination, study treatment plan, laboratory tests, and other 
research procedures. 
Exclusion Criteria: 
1. Diagnosis of HER2-positive breast cancer by pathological examination 
(HER2-positive definition: standard immunization 
Histochemistry (IHC) test is 3+ or ISH test is positive). 
2. Recurrent disease locally or regionally in which breast malignancy has 
occurred.  
3. The clinical stage of the tumor is stage IV (metastatic) breast cancer.  
4. Bilateral breast cancer (including contralateral carcinoma in situ).  
5. History of severe lung diseases such as interstitial pneumonia.  
6. Previous treatment with CDK4/6 inhibitors and other anti-tumor 
biologics 
therapy, targeted therapy, or tumor immunotherapy.  
7. Major surgical procedures, any investigational drugs, and others within 
4 weeks prior to randomization 
Anti-cancer therapy or use of immunomodulators (excluding surgery for 

 
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breast cancer, chemotherapy, radiotherapy and 
endocrine therapy).  
8. Presence of other serious physical or psychiatric illness or laboratory 
abnormalities that may increase participation 
risks of the study, or interfering with the results of the study, and the 
investigator deems it unsuitable to participate in this study 
Research patients. 
Midway exit criteria: 
1. Subjects withdraw informed consent to participate in the study and 
refuse further follow-up;  
2. Other circumstances in which the investigator deems it necessary to 
withdraw from the study, such as subjects due to incarceration 
the ability to express one's will freely due to prohibition or isolation, 
etc.; 
3. Loss to follow-up;  
4. Subject death;  
5. Research steps and related examinations 
5.1. Screening period  
Screening assessment of patients was performed during the patient's 
pre-hospitalization, and the investigator screened pre-hospitalized 
patients eligible for enrollment from the electronic inpatient medical 
record system. Informed consent signed by the subject must be obtained 
prior to any study-specific procedures or assessments. The personal 
information, disease history, family history, marital and childbearing 
history, postoperative pathology and other related laboratory tests of 

 
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pre-hospitalized patients were queried and collected from the electronic 
inpatient medical record system, and whether the subjects were eligible 
for inclusion in this study were clarified. 
5.2.Observation and data collection period  
After the patient is enrolled, the next patient's CDK4/6i dose is 
determined based on the DLTs observed in all previously evaluated patients 
by dose allocation model (empirical logic model, obtained using the R dfcrm 
software package). CDK4/6i (abeciclib, oral) is 50 mg bid starting at the 
other dose levels: 100 mg bid, 150 mg bid. At the same time, since the 
routine hospitalization time of radiotherapy patients is about 36 days, 
the patient's vital signs, test items, adverse reactions and related 
treatment measures will be recorded on D10, D20, D30, and D40 respectively 
during the hospitalization of patients using radiotherapy combined with 
CDK4/6 inhibitor combination treatment regimen. If the patient's radiation 
therapy is delayed for any reason, the recording time should be postponed 
according to the actual situation. (The day before radiotherapy (T0), the 
4th week during radiotherapy, (T1), after radiotherapy (T2), 1 month after 
radiotherapy (T3), and 3 months after radiotherapy (T4)) The patients were 
evaluated by FACT-B, FACT-ES, and FACIT-F scales.   
5.3.Data analysis period  
The tolerability and safety of the combination treatment regimen were 
evaluated by statistical methods, and the changes in the quality of life 
of the patients during the quality of life period were evaluated to form 
the study conclusions. Data cleaning and preprocessing, safety analysis 
(incidence and severity of AEs; Serious adverse events and treatment 

 
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correlation analysis), results summary and report. 
4. Evaluation indicators/research endpoints  
1. Observe indicators 
(1) Primary endpoints: To determine the incidence of early DLTs (early 
adverse reactions related to radiotherapy combined with CDK4/6i), and to 
determine the MTD of radiotherapy combined with CDK4/6i and the tolerability 
and safety of the combination treatment regimen.  
(2) Secondary endpoints: 
• Subjects' quality of life measurement scales FACT-B, FACT-ES, FACT-F 
questionnaire scores; 
5. Arrangement of visits and data collection during the study 
This study mainly collected the patient's laboratory examinations in the 
electronic medical record system during hospitalization, such as blood routine, 
liver and kidney function, electrolytes, tumor markers, etc., as well as the 
adverse event record form (including occurrence time, grading, treatment and 
outcome). 
1 month and 3 months after the end of the combination treatment program, 
the patient was followed up in the outpatient clinic due to routine clinical 
diagnosis and treatment, and the follow-up evaluation and PRO scale 
questionnaire score were performed during the outpatient review. 
6. Clinical evaluation 
Safety evaluation: Safety will be monitored by assessing adverse events 
and laboratory data, and the severity of adverse events and early and late 
toxicities will be graded using NCI CTC-AE version 4.03.  
7. Project risk and benefit assessment 

 
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1. Risks: Patients may be at risk of privacy leakage.  
2. Benefit: Patients have no direct benefit. 
8. Subject protection measures 
1. Participation in this study is completely voluntary, and the study 
subjects have the right to refuse to participate in the study, which will not 
affect the doctor's treatment of the study subjects. Even if the study subject 
agrees to participate in the study, he or she can withdraw from the study at 
any time during the study process, which again does not affect due rights.  
2. This study is an observational study, which will not affect the effect 
of treatment, the risk is small, and if there are corresponding adverse 
reactions, our department will provide symptomatic supportive treatment for 
the patient to minimize the damage. 
3. To protect your privacy, we will mark your personal information with 
a research number in a non-personally identifiable way. The results of this 
project study may be published in medical journals, but we will keep your 
research records confidential as required by law. Your personal information 
will be kept strictly confidential and will not be disclosed unless required 
by relevant laws.  
9. Quality control and quality assurance of research 
1. The subjects have good compliance. 
2. Study participants are professionally trained. 
10. Data preservation 
Saved in written form in a locked file cabinet and saved in a computer 
in an encrypted folder. 
11. Statistical processing 

 
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The results of this study were mainly statistically descriptive. The 
measurement data lists the mean, standard deviation, median, maximum value, 
and minimum value, and the numerical data and grade data list the frequency 
(composition ratio), rate, and trusted interval. All statistical analyses will 
be programmed and calculated using SAS 9.0 or above statistical analysis 
software. All statistical tests were two-tailed tests, and a P value of less 
than or equal to 0.05 would be considered statistically significant for the 
difference tested, with confidence intervals of 95% confidence.  
1) Basic characteristics of the patient 
Quantitative data such as age, height, and weight were calculated, 
including mean, standard deviation, median, maximum, and minimum values, and 
qualitative data such as gender and ECOG score were calculated for frequency 
and percentage.  
2) Efficacy analysis 
i. 
DLTs: Defined as any grade ≥3 adverse events (AEs) including NCI-CTCAE v.4.03 scores, 
which are related to CDK4/6i and/or radiation therapy; 
ii. 
MTD: Defined as the dose closest to the probability of DLT occurrence but less than or equal 
to 25%. 
3) Dose escalation model 
CDK4/6 inhibitor dose allocation will be centrally defined by modeling 
the probability of DLTs based on DLTs observed in all previously evaluated 
patients. The dose-toxicity relationship will be empirical model. 
Intra-patient dose escalation is not allowed, and dose skipping during 
escalation is not allowed. 
4) Safety analysis 

 
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The safety analysis will be based on the safety set, and the safety analysis 
will be limited to descriptive statistical summary, mainly including the 
following aspects: basic characteristics of the patient (including 
socio-demographic information, past medical history and previous medication 
history); The incidence of adverse events, the incidence of grade 3 and above 
adverse events, as well as their clinical characteristics, severity, time of 
occurrence, duration, treatment and prognosis, and the correlation between 
them and combination treatment regimens; Changes in vital signs, physical 
examination, laboratory tests before and after medication, and relationship 
with the trial drug when abnormal changes occur. The severity of AEs is graded 
according to NCI CTCAE V5.0 (grade 1 to 5). The incidence of adverse events 
occurring after treatment will be summarized by systemic organ classification 
(SOC) and preferred term (PT).  
15. Ethical considerations 
The study will follow the relevant regulations of the World Medical 
Assembly "Declaration of Helsinki" and other relevant regulations, and the 
clinical study will be carried out before the study begins and the study 
protocol is approved by the ethics committee. Before each subject is selected 
for this study, the investigator is responsible for fully and comprehensively 
introducing the purpose, procedures and possible risks of this study to the 
subject or his legal representative, as well as the corresponding information 
of alternative treatment, and signing a written informed consent form to let 
the subjects know that they have the right to withdraw from this study at any 
time, and the informed consent form is kept as a clinical study document for 
future reference. The personal privacy and data confidentiality of the 

 
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subjects will be protected during the research process. 
16. Data confidentiality 
The results of this research may be published in medical journals, but we will keep 
patients' information confidential as required by law, unless required by relevant laws, 
patients' personal information will not be disclosed. When necessary, government 
management departments, hospital ethics committees, and their relevant personnel may 
consult the patient's information in accordance with regulations. 
 
 
 
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