Efficacy and safety of neoadjuvant stereotactic body radiation therapy plus dalpiciclib and exemestane for hormone receptor-positive, HER2-negative breast cancer: A prospective pilot study

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most prevalent subtype of breast cancer, which accounts for approximately 70% of all breast cancer (Parker et al., 2009). Neoadjuvant chemotherapy (NCT) is recommended as the first choice for patients with HR-positive, HER2-negative breast cancer, who are candidates for preoperative therapy, according to National Comprehensive Cancer Network (NCCN) guidelines (Gradishar et al., 2022). Neoadjuvant endocrine therapy (NET) is an acceptable, less toxic alternative to NCT. However, less than 10% of patients with HR-positive, HER2-negative breast cancer can achieve pathological complete response (pCR), and only 60% of patients respond to NCT or NET (Sella et al., 2021). Hence, more promising alternatives are urgently needed.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are breakthroughs in the treatment of HR-positive, HER2-negative breast cancer and have a remarkable efficacy in the advanced setting when combined with endocrine therapy (ET) (Finn et al., 2015; Goetz et al., 2017; Hortobagyi et al., 2016). Presently, abemaciclib has been approved for high-risk, early HR-positive breast cancer plus ET as adjuvant treatment, and its application is being explored in the neoadjuvant setting (neoMONARCH and NCT04293393). However, therapies with a combination of CDK4/6 inhibitors and NET only achieve a pCR rate of less than 5% (Hurvitz et al., 2020; Johnston et al., 2019). In the PALLET study, objective response rate (ORR) was not statistically significantly different between the combinational therapy and monotherapy (54.3% vs 49.5%, p=0.20; Johnston et al., 2019). Likewise, in the FELINE study, there was no statistical difference in clinical, mammographic, ultrasound, or MRI response between letrozole alone and combination of letrozole with a CDK4/6 inhibitor (Khan et al., 2020). Thus, it is reasonable to explore a novel neoadjuvant therapy for HR-positive, HER2-negative breast cancer.

Radiotherapy is one of the most important local methods to control malignancy by breaking DNA in tumor cells (Cox and Swanson, 2013). Stereotactic body radiation therapy (SBRT) is a novel and relatively safe radiotherapy technique and delivers high doses of radiation in a small number of fractions to the tumor lesion while minimizing radiation exposure to the surrounding tissues (Chmura et al., 2021). Currently, neoadjuvant radiotherapy can be applicable for inoperable breast cancer to allow an effective and sometimes more conservative surgery (Cardoso et al., 2018). Preclinical studies have indicated that CDK4/6 inhibitors can sensitize breast cancer cells to radiotherapy, possibly by inhibition of DNA damage repair response, enhancement of apoptosis and blockage of cell cycle progression, and inhibition of intra-tumor cellular metabolism and angiogenesis (Han et al., 2013; Pesch et al., 2020; Petroni et al., 2021). A preclinical study has explored different schedules of combination of radiotherapy and CDK4/6 inhibitors in human and mouse models and demonstrated that radiotherapy followed by CDK4/6 inhibitors can enhance antineoplastic effects, compared with their monotherapy alone or CDK4/6 inhibitors concurrent with or followed by radiotherapy (Petroni et al., 2021). Moreover, the combination of CDK4/6 inhibitors and radiotherapy can lead to a satisfying overall disease control and safety based on several retrospective studies in metastatic breast cancer (Bosacki et al., 2021). Nevertheless, the efficacy and safety of this regimen in neoadjuvant treatment of early or locally advanced HR-positive, HER2-negative breast cancer are unknown.

We have conducted a prospective pilot study to determine the efficacy and safety of neoadjuvant radiotherapy followed by dalpiciclib and exemestane in patients with newly diagnosed early or locally advanced HR-positive, HER2-negative breast cancer. Dalpiciclib (SHR6390) is a potent selective inhibitor of CDK4/6 and exerts synergistic antitumor effect when combined with endocrine therapy for advanced luminal breast cancer in the DAWNA-1 trials (Xu et al., 2021).

This pioneering study reported the efficacy and safety of sequential neoadjuvant radiotherapy and combination of dalpiciclib and exemestane in patients with HR-positive, HER2-negative breast cancer. This new therapeutic regimen achieved considerable anti-tumor activity with the RCB 0-I rate of 16.7% and ORR rate of 91.7%, respectively. More importantly, this combinatory therapeutic strategy was well tolerated in this population.

CDK4/6 inhibitors have recently been preclinically identified as radiosensitizers, acting mainly through hindering DNA damage repair response after radiation exposure, and enhancing cell apoptosis and blocking cell cycle, which provide a conceptual basis of combining radiotherapy with a CDK4/6 inhibitor (Whittaker et al., 2017; Xie et al., 2019). Moreover, both radiotherapy and CDK4/6 inhibitors exert immunomodulatory effects and may synergize anticancer immune responses (Pesch et al., 2020). SBRT with hypofractionation and higher radiation doses is more effective than conventional fractionation in triggering immune responses (Gandhi et al., 2015). Consistent with the basic research (Petroni et al., 2021), we used the sequential treatment with SBRT and combination of dalpiciclib and exemestane.

Unlike HER2-positive and triple-negative breast cancer, NCT or NET for HR-positive, HER2-negative breast cancer only achieves a pCR rate of ≤10% (Cortazar et al., 2014). Our study indicated that this novel therapeutic regimen achieved a pCR and RCB 0-I rate of 16.7%, while neoadjuvant therapies with combination of a CDK4/6 inhibitor and letrozole led to a pCR rate of 0–3.8% and RCB 0-I rate of 6.1–7.7% and treatment with NCT resulted in a pCR rate of 5.8–5.9% and RCB 0-I rate of 11.8–15.7% in HR-positive, HER2-negative breast cancer patients (Ma et al., 2017; Prat et al., 2020). It is notable that pCR rate (commonly defined as ypT0/isN0) is not significantly associated with the prognosis of HR-positive, HER2-negative breast cancer (Ma et al., 2017). In addition, clinical trials to test different therapies for patients with HR-positive, HER2-negative breast cancer have focused on clinical response rates as important clinical endpoints (Hurvitz et al., 2020; Johnston et al., 2019; Khan et al., 2020; Whittaker et al., 2017; Ma et al., 2017). In our study, treatment with the new therapeutic regimen led to 11 (91.7%) patients achieving objective responses by MRI, while previous studies have revealed that NET achieves an objective response rate of approximately 60% in HR-positive, HER2-negative breast cancer patients (Sella et al., 2021). One of the principal objectives of neoadjuvant therapy is to facilitate downstaging and enhance the rate of breast conservation. With the addition of SBRT, a slightly higher rate of patients changed from mastectomy to breast conservation compared with the PALLET study (25.0% vs 14.1%; Johnston et al., 2019). Consequently, our new neoadjuvant therapeutic regimen appeared to improve the likelihood of pathological downstaging and achieve a margin-free resection, particularly for those with locally advanced and high-risk breast cancer.

Considering that treatment with radiotherapy or a CDK4/6 inhibitor can enhance anti-tumor immunity in vitro, we analyzed the impact of new neoadjuvant therapeutic regimen on alternation in biomarker expression in the numbers of TILs before and after the treatment. Our study showed a modest but statistically significant increase in the tumor tissues with the addition of SBRT. Apparently, sequential neoadjuvant therapies with radiotherapy, a CDK 4/6 inhibitor, and exemestane turned non-responsive ‘cold’ tumors into responsive ‘hot’ ones. Therefore, our findings may provide significant insights into designing effective therapeutic strategies against HR-positive, HER2-negative breast cancer.

Patients with HR-positive, HER2-negative breast cancer were well-tolerated to the combinational regimen. During the observation period, those patients only developed grade 1–3 AEs, including grade 3 neutropenia (66.7%), similar to that of the combination of dalpiciclib and fulvestrant in the DAWNA-1 trial (84.2%) (Xu et al., 2021). There were no new AEs following therapies with radiotherapy and dalpiciclib in this population.

We recognized that our study had limitations, including a one-arm preliminary exploratory trial with small sample size. The small sample size limited the comparison of our data with historical data in the literature due to the potential bias. Consequently, cross-trial comparisons like this hold limited significance. Thus, further prospective randomized clinical trials with a larger population for longer treatment duration are warranted to validate the findings.

In conclusion, our study provides novel insights into the neoadjuvant treatment of HR+/HER2- breast cancer. The sequential radiotherapy and a CDK4/6 inhibitor plus ET were effective and well-tolerated, which could serve as a feasible option for neoadjuvant therapy for HR-positive, HER2-negative breast cancers. Further validation of these findings is warranted in a large-scale study.

The raw clinical and imaging data are protected under patient privacy laws. The datasets generated and/or analyzed during the current study are available from the corresponding author, Caigang Liu (liucg@sj-hospital.org), upon request for up to 10 years. De-identified clinical and experimental data may be shared upon request, subject to approval by the Institutional Ethical Committee(s). De-identified data will be transferred to the requesting investigator via secure file transfer. These data are permitted for academic use only and must comply with the regulations of the Human Genetics Resources Administration of China and other applicable jurisdictions. A signed data access agreement with the principal investigator is required prior to conducting academic research. Source data files for Figures 1, 2, 3c, 3d, and 3e have been provided.

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Author details

1. Yu Zhang

   1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
   2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
   3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang, China
   4. Department of Gastrointestinal Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China

   Contribution

   Data curation, Formal analysis, Methodology, Writing – original draft

   Contributed equally with

   Shuo Cao, Nan Niu, Huilian Shan and Jinqi Xue

   Competing interests

   No competing interests declared

2. Shuo Cao

   Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

   Contribution

   Data curation, Formal analysis, Methodology, Writing – original draft

   Contributed equally with

   Yu Zhang, Nan Niu, Huilian Shan and Jinqi Xue

   Competing interests

   No competing interests declared

3. Nan Niu

   1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
   2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
   3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang, China

   Contribution

   Resources, Data curation, Formal analysis, Validation, Methodology, Writing – original draft, Writing – review and editing

   Contributed equally with

   Yu Zhang, Shuo Cao, Huilian Shan and Jinqi Xue

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8206-941X

4. Huilian Shan

   Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

   Contribution

   Data curation, Methodology

   Contributed equally with

   Yu Zhang, Shuo Cao, Nan Niu and Jinqi Xue

   Competing interests

   No competing interests declared

5. Jinqi Xue

   1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
   2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
   3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang, China

   Contribution

   Resources, Data curation, Methodology

   Contributed equally with

   Yu Zhang, Shuo Cao, Nan Niu and Huilian Shan

   Competing interests

   No competing interests declared

6. Guanglei Chen

   1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
   2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
   3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang, China

   Contribution

   Data curation, Methodology

   Competing interests

   No competing interests declared

7. Yongqing Xu

   Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

8. Jianqiao Yin

   Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

9. Chao Liu

   1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
   2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
   3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang, China

   Contribution

   Formal analysis, Methodology

   Competing interests

   No competing interests declared

10. Lisha Sun

    1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
    3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang, China

    Contribution

    Methodology

    Competing interests

    No competing interests declared

11. Xiaofan Jiang

    1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
    3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang, China

    Contribution

    Writing – original draft

    Competing interests

    No competing interests declared

12. Meiyue Tang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

    Contribution

    Resources, Data curation

    Competing interests

    No competing interests declared

13. Qianshi Xu

    1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China

    Contribution

    Formal analysis, Methodology

    Competing interests

    No competing interests declared

14. Mingxuan Jia

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

    Contribution

    Methodology

    Competing interests

    No competing interests declared

15. Xu Zhang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

    Contribution

    Methodology

    Competing interests

    No competing interests declared

16. Zhenyong Zhang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

    Contribution

    Methodology

    Competing interests

    No competing interests declared

17. Qingfu Zhang

    Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China

    Contribution

    Formal analysis, Methodology

    Competing interests

    No competing interests declared

18. Jianfei Wang

    Jiangsu Hengrui Pharmaceuticals, Shanghai, China

    Contribution

    Methodology

    Competing interests

    is an employee of Jiangsu Hengrui Pharmaceuticals Co., Ltd

19. Ailin Li

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China

    Contribution

    Conceptualization, Methodology

    Competing interests

    No competing interests declared

20. Yongliang Yang

    School of Bioengineering, Dalian University of Technology, Dalian, China

    Contribution

    Conceptualization, Methodology, Writing – review and editing

    For correspondence

    everbright99@163.com

    Competing interests

    Reviewing editor, eLife

    "This ORCID iD identifies the author of this article:" 0000-0003-0449-0599

21. Caigang Liu

    1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, Shenyang, China
    3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, Shenyang, China

    Contribution

    Conceptualization, Supervision, Funding acquisition, Validation, Investigation, Project administration, Writing – review and editing

    For correspondence

    angel-s205@163.com

    Competing interests

    Senior editor, eLife

    "This ORCID iD identifies the author of this article:" 0000-0003-2083-235X

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