Effects of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study

  1. Guanglei Chen
  2. Xi Gu
  3. Jinqi Xue
  4. Xu Zhang
  5. Xiaopeng Yu
  6. Yu Zhang
  7. Ailin Li
  8. Yi Zhao
  9. Guijin He
  10. Meiyue Tang
  11. Fei Xing
  12. Jianqiao Yin
  13. Xiaobo Bian
  14. Ye Han
  15. Shuo Cao
  16. Chao Liu
  17. Xiaofan Jiang
  18. Keliang Zhang
  19. Yan Xia
  20. Huajun Li
  21. Nan Niu
  22. Caigang Liu  Is a corresponding author
  23. On behalf of the Northeastern Clinical Research Alliance of Oncology (NCRAO)
  1. Department of Oncology, Shengjing Hospital of China Medical University, China
  2. Cancer Stem Cell and Translational Medicine Laboratory, Shengjing Hospital of China Medical University, China
  3. Innovative Cancer Drug Research and Development Engineering Center of Liaoning Province, China
  4. Department of Gastrointestinal Surgery, Yantai Affiliated Hospital of Binzhou Medical University, China
  5. Liaoning Center for Drug Evaluation and Inspection, China
  6. Jiangsu Hengrui Pharmaceuticals, China

Abstract

Background:

Emerging data have supported the immunostimulatory role of radiotherapy, which could exert a synergistic effect with immune checkpoint inhibitors (ICIs). With proven effective but suboptimal effect of ICI and chemotherapy in triple-negative breast cancer (TNBC), we designed a pilot study to explore the efficacy and safety of neoadjuvant stereotactic body radiotherapy (SBRT) plus adebrelimab and chemotherapy in TNBC patients.

Methods:

Treatment-naïve TNBC patients received two cycles of intravenous adebrelimab (20 mg/kg, every 3 weeks), and SBRT (24 Gy/3 f, every other day) started at the second cycle, then followed by six cycles of adebrelimab plus nab-paclitaxel (125 mg/m² on days 1 and 8) and carboplatin (area under the curve 6 mg/mL per min on day 1) every 3 weeks. The surgery was performed within 3–5 weeks after the end of neoadjuvant therapy. Primary endpoint was pathological complete response (pCR, ypT0/is ypN0). Secondary endpoints included objective response rate (ORR), residual cancer burden (RCB) 0-I, and safety.

Results:

13 patients were enrolled and received at least one dose of therapy. 10 (76.9%) patients completed SBRT and were included in efficacy analysis. 90% (9/10) of patients achieved pCR, both RCB 0-I and ORR reached 100% with three patients achieved complete remission. Adverse events (AEs) of all-grade and grade 3–4 occurred in 92.3% and 53.8%, respectively. One (7.7%) patient had treatment-related serious AEs. No radiation-related dermatitis or death occurred.

Conclusions:

Adding SBRT to adebrelimab and neoadjuvant chemotherapy led to a substantial proportion of pCR with acceptable toxicities, supporting further exploration of this combination in TNBC patients.

Funding:

None.

Clinical trial number:

NCT05132790.

Editor's evaluation

This study presents a valuable finding of a novel combinatory regimen that integrates immunotherapy, radiotherapy, and chemotherapy in the current refractory triple-negative breast cancer. The evidence supporting the claims of the authors is solid, although inclusion of a larger number of patient samples and an animal model would have strengthened the study. The work will be of interest to Clinicians working on breast cancer.

https://doi.org/10.7554/eLife.91737.sa0

Introduction

Triple-negative breast cancer (TNBC), defined as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) negative, accounts for approximately 10–20% of all breast cancers (Costa et al., 2017). Characterized by higher tumor mutation burden and more intensive tumor-infiltrating lymphocytes infiltration in tumor microenvironment (TME) (Loi et al., 2019), TNBC is more sensitive to immune checkpoint inhibitors (ICIs) than any other subtypes (Keenan and Tolaney, 2020). Nowadays, the combination with pembrolizumab (a PD-1 blockade) and standard chemotherapy is recommended for TNBC patients with stages II–III according to National Comprehensive Cancer Network (NCCN) guidelines (Gradishar et al., 2022). However, there is still around 40% of TNBC patients cannot achieve a pathological complete response (pCR) according to KEYNOTE-522 (Schmid et al., 2020) and IMpassion031 (Mittendorf et al., 2020) trials, which call for more promising strategies.

Radiotherapy (RT) is the most critical locoregional treatment in solid malignancies and approximately half of patients may receive radiotherapy during the entire treatment period (Atun et al., 2015; Citrin, 2017). Stereotactic body radiotherapy (SBRT), a novel technique with higher doses of radiation delivery to the tumor lesion in a smaller number of fractions, can shorten treatment time and reduce exposure to the surrounding tissues (Chen et al., 2020). SBRT has already been widely applied to advanced breast cancer as salvage treatment targeting to osseous and brain metastasis or other oligometastatic sites (Nicosia et al., 2022; Viani et al., 2021). Preoperative SBRT may be advantageous for downstaging the tumor to enable breast conservation and improving pCR rate (Piras et al., 2023) and multiple trials investigating neoadjuvant SBRT in various malignancies (Holyoake et al., 2021; Kishi et al., 2020; Liu et al., 2022; Novikov et al., 2021) are currently ongoing. In addition, preclinical evidence suggested that SBRT has immunomodulatory properties by inducing cancer cells death to boost neoantigen-specific memory immune response and upregulate the expression of PD-L1 on tumor cells (Deng et al., 2014; Han et al., 2022; Park et al., 2015). Given these, it would be promising to combine SBRT with ICIs and chemotherapy under the neoadjuvant setting.

Therefore, we conducted a prospective pilot study to determine the efficacy and safety of neoadjuvant SBRT in combination with adebrelimab (SHR-1316), a potent selective PD-L1 inhibitor, plus nab-paclitaxel and carboplatin in patients with newly diagnosed early or locally advanced TNBC, to validate the feasibility of this novel regimen in neoadjuvant treatment of TNBC.

Methods

Patients

Previously untreated patients aged between 18 and 75 years, with histologically confirmed invasive TNBC (defined as negative estrogen receptor, progesterone receptor, and HER2 status by American Society of Clinical Oncology/College of American Pathologists guidelines) and pathological tumor size ≥2.0 cm in MRI assessment, were eligible for enrollment. Other inclusion criteria included Eastern Cooperative Oncology Group performance score of 0–1, adequate marrow, hepatic, renal, and cardiac function.

Key exclusion criteria included bilateral, inflammatory, or occult breast cancer; active or a history of autoimmune disease; use of glucocorticoids or other immunosuppressive therapy within 2 weeks before the first study dose; a history of interstitial pneumonia; active tuberculosis; pregnancy, lactation, and refusal to use contraception.

Study design and treatment

This study was performed in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines. The trial protocol and all amendments of this single-arm, prospective study was approved by the Institutional Review Board and Ethics Committee of Shengjing Hospital of China Medical University. Written informed consent was obtained from each patient before enrollment, and publish consents were obtained from all participated patients before submission.

All patients intravenously received 8 cycles of adebrelimab (20 mg/kg every 3 weeks). SBRT (24 Gy/3 f) targeted to breast lesion was started at the second cycle every other day, and 6 cycles of nab-paclitaxel (125 mg/m² on days 1 and 8) and carboplatin (area under the curve 6 mg/mL per min on day 1) was given every 3 weeks since the third cycle.

Patients who completed or discontinued the neoadjuvant treatment could undergo surgery. If disease progresses during the neoadjuvant phase, the patient either proceeds to surgery or receives alternative neoadjuvant therapy. Surgery was performed 3–5 weeks after the last dose of neoadjuvant therapy. Recommended surgery and adjuvant therapy were administered as per local guidelines or institutional standards.

Outcomes

The primary endpoint was pCR rate in the breast and axillary lymph nodes (ypT0/is ypN0). Secondary endpoints included ORR before surgery (defined as the proportion of patients with complete or partial response according to the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), the proportion of residual cancer burden (RCB) 0-I, and safety according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Statistical analysis

Efficacy was assessed in the modified intention-to-treat population, which included patients who had undergone radiotherapy. Safety was evaluated in all recruited patients who received at least one dose of study drug. All statistical analyses were conducted using SAS 9.4 (North Carolina, USA). Continuous data are presented as mean and standard deviation, or mean and 95% confidence interval (CI). Categorical data are expressed as frequency and percentage. The 95% CIs of pCR rate, proportion of patients with RCB 0-I, and ORR were estimated using the Clopper-Pearson method.

Results

Patient characteristics

Between December 2021 and January 2023, 13 patients were recruited in the trial (Figure 1). The baseline characteristics are shown in Table 1. The median age was 51 years (range 31–68) and the median tumor size was 33 mm (range, 22–72). Lymph node involvement was seen in 53.8% (7/13) patients and 46.2% (6/13) patients had stage III breast cancer at baseline.

Flowchart of the trial.

SBRT, stereotactic body radiotherapy.

Table 1
Baseline characteristics.
CharacteristicPatients (n=13)
Age (median, range)51 (31–68)
Age group, years
 ≤506 (46.2%)
 >507 (53.8%)
Menopausal status
 Premenopausal6 (46.2%)
 Postmenopausal7 (53.8%)
Tumor size
 T210 (76.9%)
 T33 (23.1%)
Lymph node status
 N06 (46.2%)
 N12 (15.4%)
 N25 (38.5%)
Clinical stage
 IIA6 (46.2%)
 IIB1 (7.7%)
 IIIA6 (46.2%)
Tumor grade
 II6 (46.2%)
 III5 (38.5%)
 Unknown2 (15.4%)
HER2 expression
 Negative8 (61.5%)
 1+3 (23.1%)
 2+, FISH-2 (15.4%)

Outcomes

Among the 13 treated patients, 2 (15.4%) were excluded after the first dose of adebrelimab due to protocol deviation and 1 (7.7%) discontinued after the second dose of adebrelimab due to adverse event (AE), thus only 10 (76.9%) who underwent neoadjuvant SBRT and surgery (the modified intention-to-treat population) were available for efficacy evaluation (Figure 1). Nine of the 10 efficacy-evaluable patients (90%, 95% CI 55.5–99.8%) achieved pCR in the breast and axillary lymph nodes, and the rates of RCB 0-I was 100% (95% CI 67.9–100.0%). The radiological ORR was 100% (95% CI 67.9–100.0%, Table 2 and Figure 2) with three patients achieved complete radiographic response. Four patients with positive lymph node at baseline had nodal downstaging to N0 after neoadjuvant treatment.

Table 2
Pathological and clinical response.
VariablePatients (n=10)
Total pathological complete response9 (90%)
Residual cancer burden score
 09 (90%)
 I1 (10%)
 II0
 III0
Radiological response
 Complete response3 (30%)
 Partial response7 (70%)
 Stable disease0
 Objective response rate10 (100%)
Swimming plot which demonstrates the pCR, RCB, and radiological response profile of 10 modified intention-to-treat population who received radiotherapy and undergone surgery.

Each round dot or column indicates a patient. Colors indicate different clinical stage. ID, identity; pCR, pathological complete response; RCB, residual cancer burden.

Figure 2—source code 1

R Code for Figure 2.

https://cdn.elifesciences.org/articles/91737/elife-91737-fig2-code1-v1.zip
Figure 2—source data 1

Raw information for the pCR, RCB, and radiological response profile of 10 modified intention-to-treat population who received radiotherapy and underwent surgery.

https://cdn.elifesciences.org/articles/91737/elife-91737-fig2-data1-v1.xlsx

Safety

AEs were reported in all 13 patients (Table 3). The incidence of any grade AEs was 92.3%. The grade 3 or higher treatment-related AEs occurred in 53.8% of the patients, including neutropenia (30.8%), anemia (7.7%), leukopenia (7.7%), thrombocytopenia (7.7%), creatine phosphokinase elevation (7.7%), and diarrhea (7.7%). Immune-related AEs of any grade occurred in 23.1% of the patients, including two (15.4%) patients had hyperthyroidism, one (7.7%) patient had hypothyroidism, and one (7.7%) patient experienced serious AEs due to immune-mediated myositis. Two patients required a dose reduction of carboplatin due to AEs but ultimately complete the prescribed treatment. There were no therapy-related death and no radiation-related dermatitis and skin hyperpigmentation.

Table 3
Treatment-related adverse events.
Patients (n=13)
Grade 1 or 2Grade 3Grade 4
Total5 (38.5%)6 (46.2%)1 (7.7%)
Anemia8 (61.5%)1 (7.7%)0
Alopecia9 (69.2%)00
Neutropenia4 (30.8%)3 (23.1%)1 (7.7%)
Hyponatremia8 (61.5%)00
Nausea8 (61.5%)00
Leukopenia6 (46.2%)1 (7.7%)0
Lymphopenia7 (53.8%)00
Thrombocytopenia5 (38.5%)1 (7.7%)0
Elevated alanine aminotransferase level5 (38.5%)00
Elevated aspartate aminotransferase level5 (38.5%)00
Thyroid stimulating hormone decreased5 (38.5%)00
Hyperuricemia5 (38.5%)00
Vomiting5 (38.5%)00
Fatigue4 (30.8%)00
γ-Glutamyl transferase increased3 (23.1%)00
Creatinine increased3 (23.1%)00
Thyroid stimulating hormone increased3 (23.1%)00
Creatine phosphokinase elevation1 (7.7%)1 (7.7%)0
Hyperthyroidism2 (15.4%)00
Free thyroid hormone decreased2 (15.4%)00
Hyperglycemia2 (15.4%)00
Hypokalemia2 (15.4%)00
Rash2 (15.4%)00
Peripheral neuropathy2 (15.4%)00
Diarrhea01 (7.7%)0
Immune mediated myositis1 (7.7%)00
Ventricular extrasystole1 (7.7%)00
Free thyroid hormone increased1 (7.7%)00
Hypothyroidism1 (7.7%)00
Troponin I elevated1 (7.7%)00
Proteinuria1 (7.7%)00
Constipation1 (7.7%)00

Discussion

This pioneering study reported the efficacy and safety of neoadjuvant SBRT in combination with adebrelimab, nab-paclitaxel, and carboplatin in TNBC patients. This new therapeutic regimen achieved promising anti-tumor activity with pCR rate of 90%, and the RCB 0-I and ORR rate of 100%, respectively. More importantly, this combinatory therapeutic strategy was well tolerated in this population.

For TNBC patients who are candidates for preoperative therapy, neoadjuvant chemotherapy combined with ICIs has already achieved pCR rate of 58–64.8% in KEYNOTE-522 (Schmid et al., 2020) and IMpassion031 study (Mittendorf et al., 2020). In our study, the addition of SBRT to adebrelimab and standard neoadjuvant chemotherapy achieved a significantly higher percentage of pCR (90%). Since the dose of SBRT at 24 Gy in 3 fractions (bioequivalent dose=43.2 Gy) was lower than conventional preoperative radiotherapy dose (45–50 Gy/23–25 fractions) (Ahmed et al., 2021), we thought that SBRT (24 Gy/3 f) alone could rarely achieve pCR. We speculated that the SBRT (24 Gy/3 f) may exert synergy with immunochemotherapy, and not just local tumor eradication effects.

Recently, SBRT has been preclinically identified as exerting immunomodulatory effects and synergizing anticancer immune responses combined with ICIs (Deng et al., 2014; Park et al., 2015). Pilones et al., 2020, discovered that SBRT (two doses of 12 Gy) improved the therapeutic effects of PD-1 in a TNBC murine model, and this effect was enhanced by the addition of chemotherapy. TONIC trial demonstrated that SBRT (24 Gy/3 f) combined with nivolumab can increase the proportion of patients free of progression at 24 weeks than nivolumab alone (17% vs 8%) (Voorwerk et al., 2019). Another small sample research has indicated that preoperative SBRT (19.5–31.5 Gy/3 f) with neoadjuvant chemotherapy may result in fair pCR rates of 36%, with the maximum response (pCR 67%) was obtained at a dose of 25.5 Gy/3 f (Bondiau et al., 2013), as well as no increase in the incidences of early or late-term AEs (Piras et al., 2023; Takanen et al., 2022). Together, these studies suggested that SBRT may have strong immunomodulatory effects, rendering a synergistic anti-tumor effect with immunotherapy and chemotherapy.

Another study exploring SBRT (24 Gy/3 f) in combination with pembrolizumab plus chemotherapy in a neoadjuvant setting for TNBC patients also achieved a promising pCR rate of 74% (PEARL) (McArthur et al., 2022). Noteworthy, PEARL study chose taxane-based chemotherapy in which 52% of patients received platinum, while our study used nab-paclitaxel and carboplatin-based regimens. It is well established that neoadjuvant chemotherapy containing platinum has shown an increase in pCR rates of approximately 15.1% in TNBC patients (Poggio et al., 2018). Additionally, the IMpassion 130 (Emens et al., 2021) and IMpassion 131 (Miles et al., 2021) studies have suggested that nab-paclitaxel combined with ICIs may exhibit greater efficacy than paclitaxel. Thus, it is hypothesized that the selection of a chemotherapy regimen may contribute to the difference of pCR rates between the PEARL and our study (74% vs 90%). Consequently, it is imperative to determine the optimal neoadjuvant chemotherapy partners for ICIs in TNBC population.

AEs observed in our study were generally consistent with the known safety profiles of neoadjuvant therapy for TNBC patients in KEYNOTE-522 (Schmid et al., 2020) and IMpassion031 (Mittendorf et al., 2020) trials. The addition of SBRT did not increase any grades or grade 3 or above AEs, which were 92.3% vs 99% and 53.8% vs 57–76.8%, respectively. Furthermore, consistent with the customary toxic effects observed in lung cancers with adebrelimab plus carboplatin-based chemotherapy regimen (Wang et al., 2022; Yan et al., 2023), the addition of SBRT neither brought new AEs nor increased the incidences of grade 3 or higher or serious AEs in our population. Immune-related AEs occurred in three (23.1%) patients. The addition of SBRT did not increase immune-related AEs and severity compared to KEYNOTE-522.

Our study had several limitations including a non-comparative preliminary trial with relatively small sample size, thereby impeding the comparison of our data with historical data due to insufficient statistical power. Thus, further prospective randomized clinical trial required to validate these outcomes is currently in the planning stage.

In conclusion, the addition of SBRT to adebrelimab and neoadjuvant platinum-containing therapy showed the possibility of a convenient and feasible regimen for TNBC with promising efficacy and acceptable toxicities. Neoadjuvant radiotherapy may enhance the response to immunochemotherapy through activating TME. Further confirmation of these findings in large-scale study is currently underway.

Data availability

The data are not publicly available due to privacy or ethical restrictions or laws and regulations, which are available from the principal investigator (liucg@sj-hospital.org) on reasonable request. Qualified researchers should submit a proposal to the principal investigator outlining the reasons for requiring the data. The PI and IRB affiliated to Shenging Hospital will check whether the request is subject to any intellectual property or confidentiality obligations. De-identified data will then be transferred to the inquiring investigator over secure file transfer. Commercial use of this data must comply with the requirements of Human Genetics Resources Administration of China and other country, a signed data access agreement with the principal investigator is required before commercial research be performed. Source data files have been provided for Figure 2. The code that was used to analyze the data has already been provided, shown in word document (Figure 2 - source data 1).

References

Decision letter

  1. Yaoting Ji
    Reviewing Editor; Wuhan University, Wuhan, China
  2. Diane M Harper
    Senior Editor; University of Michigan–Ann Arbor, Ann Arbor, United States
  3. Yaoting Ji
    Reviewer; Wuhan University, Wuhan, China
  4. Jieqiong Liu
    Reviewer; Sun Yat-sen University, China
  5. Xin Wang
    Reviewer; Chinese Academy of Medical Sciences & Peking Union Medical College, China

Our editorial process produces two outputs: (i) public reviews designed to be posted alongside the preprint for the benefit of readers; (ii) feedback on the manuscript for the authors, including requests for revisions, shown below. We also include an acceptance summary that explains what the editors found interesting or important about the work.

Decision letter after peer review:

Thank you for submitting your article "Efficacy and Safety of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study" for consideration by eLife. Your article has been reviewed by 3 peer reviewers, one of whom is a member of our Board of Reviewing Editors, and the evaluation has been overseen by Mone Zaidi as the Senior Editor.

The reviewers have discussed their reviews with one another, and the Reviewing Editor has drafted this to help you prepare a revised submission.

Essential revisions

Reviewer #1 (Recommendations for the authors):

1. This study investigated a novel neoadjuvant regimen in early triple negative breast cancer, and the primary endpoint was selected as the pCR rate. While overall survival is the golden parameter for evaluating cancer-related survival, and whether the improvement of pCR rate in this study could predict the long-term survival benefit should be addressed.

2. This clinical trial explored the efficacy and safety of neoadjuvant radiotherapy combined with immunotherapy and chemotherapy in early stage triple negative breast cancer. Please add the adverse effects of radiotherapy.

3. It will be better to modify the language by the English native speaker.

Reviewer #2 (Recommendations for the authors):

1. This work has innovatively and comprehensively demonstrated the efficacy and safety of immunotherapy which blocks PD-L1, combined with SBRT and chemotherapy in previous refractory triple-negative breast cancers. As side effects arise from SBRT and chemotherapy are commonly reported, whether the adverse events in this research are associated with specific immunotherapy should be explained, and strategies to deal with these AEs should be mentioned in the Discussion section.

2. The proper administration sequence of PD-L1 immunotherapy and radiotherapy should be supplemented, whether concurrent administration or sequential application of immunotherapy and radiotherapy could achieve better efficacy should be described.

Reviewer #3 (Recommendations for the authors):

1. Immunotherapy + chemotherapy is the standard treatment recommended by current guidelines for high-risk triple-negative breast cancer. In this study, radiation therapy was administered to the primary breast lesion, and radiation therapy can cause an abscopal effect, so it is recommended to supplement the regression of lymph nodes in the node positive patients after radiation therapy and at the time of surgery.

2. The relatively small sample size of this study is the major defect of this study, and further confirmatory studies are still needed.

https://doi.org/10.7554/eLife.91737.sa1

Author response

Essential revisions

Reviewer #1 (Recommendations for the authors):

1. This study investigated a novel neoadjuvant regimen in early triple negative breast cancer, and the primary endpoint was selected as the pCR rate. While overall survival is the golden parameter for evaluating cancer-related survival, and whether the improvement of pCR rate in this study could predict the long-term survival benefit should be addressed.

It is really true as Reviewer#1 suggested that overall survival is the golden parameter. However, a pooled analysis of 12 neoadjuvant chemotherapy breast cancer clinical trials found that patients with breast cancer who achieved a pCR had significantly improved survival outcomes, and the association between pCR rates and long-term outcomes was strongest in patients with triple-negative breast cancer (OS: 0·16, 0·11–0·25). Considering that pCR rate is a surrogate endpoint for OS, we will continue to follow-up the patients and report the updated survival data.

References:

Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014

2. This clinical trial explored the efficacy and safety of neoadjuvant radiotherapy combined with immunotherapy and chemotherapy in early stage triple negative breast cancer. Please add the adverse effects of radiotherapy.

Thank you for your good suggestion. The adverse effects of radiotherapy were added both on Abstract (page 2, line 42) and Results section (page 8, line 154-155).

a) Abstract (page 2, line 42): No radiation-related dermatitis or death occurred.

b) Results section (page 8, line 154-155): There were no therapy-related death and no radiation-related dermatitis and skin hyperpigmentation.

3. It will be better to modify the language by the English native speaker.

We have polished the manuscript according to the Reviewer’s comments.

Reviewer #2 (Recommendations for the authors):

1. This work has innovatively and comprehensively demonstrated the efficacy and safety of immunotherapy which blocks PD-L1, combined with SBRT and chemotherapy in previous refractory triple-negative breast cancers. As side effects arise from SBRT and chemotherapy are commonly reported, whether the adverse events in this research are associated with specific immunotherapy should be explained, and strategies to deal with these AEs should be mentioned in the Discussion section.

We have made amendments according to the Reviewer#2’s comments. The adverse effects of immunotherapy were added in Results section (page 8, line 151-152) and Discussion section (page 11, line 204-205).

a) Results section (page 8, line 151-152): Immune-related adverse events of any grade occurred in 23.1% of the patients, including 2 (15.4%) patients had hyperthyroidism, 1 (7.7%) patient had hypothyroidism, and 1 (7.7%) patient experienced serious adverse events due to immune-mediated myositis.

b) Discussion section (page 11, line 204-205): Immune-related adverse events occurred in 3 (23.1%) patients. The addition of SBRT did not increase immune-related adverse events and severity compared to KEYNOTE-522.

2. The proper administration sequence of PD-L1 immunotherapy and radiotherapy should be supplemented, whether concurrent administration or sequential application of immunotherapy and radiotherapy could achieve better efficacy should be described.

It is really true as Reviewer #2 suggested that whether concurrent administration or sequential application of immunotherapy and radiotherapy could achieve better efficacy. Data from mouse models have been obtained in support of various treatment schedules, encompassing radiotherapy immediately followed by ICIs, concomitant radiotherapy plus ICIs, as well as ICIs immediately followed by radiotherapy. The reason why we adopted immunotherapy induction administration was for preclinical research had reported that immunotherapy initiated before radiation has been shown to mediate superior therapeutic effects in mouse model.

References:

Emerging evidence for adapting radiotherapy to immunotherapy. Nat Rev Clin Oncol. 2023

Reviewer #3 (Recommendations for the authors):

1. Immunotherapy + chemotherapy is the standard treatment recommended by current guidelines for high-risk triple-negative breast cancer. In this study, radiation therapy was administered to the primary breast lesion, and radiation therapy can cause an abscopal effect, so it is recommended to supplement the regression of lymph nodes in the node positive patients after radiation therapy and at the time of surgery.

As Reviewer #3 suggested, we have compared the regression of lymph nodes between baseline and after radiation therapy/at the time of surgery, respectively. There was no obvious regression in lymph nodes after radiation therapy, but all lymph nodes shrank to normal size at the time of surgery and confirmed pCR.

2. The relatively small sample size of this study is the major defect of this study, and further confirmatory studies are still needed.

Thank you for your good suggestion. It is really true as Reviewer #3 suggested that our study is a relatively small-scale trial. Further confirmation of these findings in a large-scale study is currently underway.

https://doi.org/10.7554/eLife.91737.sa2

Article and author information

Author details

  1. 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
    Resources, Data curation, Software, Methodology
    Competing interests
    No competing interests declared
  2. Xi Gu

    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
    Validation, Methodology
    Contributed equally with
    Jinqi Xue, Xu Zhang and Xiaopeng Yu
    Competing interests
    No competing interests declared
  3. 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
    Visualization, Methodology
    Contributed equally with
    Xi Gu, Xu Zhang and Xiaopeng Yu
    Competing interests
    No competing interests declared
  4. Xu Zhang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Data curation, Validation
    Contributed equally with
    Xi Gu, Jinqi Xue and Xiaopeng Yu
    Competing interests
    No competing interests declared
  5. Xiaopeng Yu

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources, Methodology
    Contributed equally with
    Xi Gu, Jinqi Xue and Xu Zhang
    Competing interests
    No competing interests declared
  6. Yu Zhang

    1. Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    2. Department of Gastrointestinal Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
    Contribution
    Software, Methodology
    Competing interests
    No competing interests declared
  7. Ailin Li

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources, Methodology
    Competing interests
    No competing interests declared
  8. Yi Zhao

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources
    Competing interests
    No competing interests declared
  9. Guijin He

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources
    Competing interests
    No competing interests declared
  10. Meiyue Tang

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources
    Competing interests
    No competing interests declared
  11. Fei Xing

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources
    Competing interests
    No competing interests declared
  12. Jianqiao Yin

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources
    Competing interests
    No competing interests declared
  13. Xiaobo Bian

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources
    Competing interests
    No competing interests declared
  14. Ye Han

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Resources
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2929-8122
  15. Shuo Cao

    Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
    Contribution
    Methodology
    Competing interests
    No competing interests declared
  16. 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
    Software, Methodology
    Competing interests
    No competing interests declared
  17. 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
  18. Keliang Zhang

    Liaoning Center for Drug Evaluation and Inspection, Shenyang, China
    Contribution
    Investigation
    Competing interests
    No competing interests declared
  19. Yan Xia

    Jiangsu Hengrui Pharmaceuticals, Shanghai, China
    Contribution
    Methodology
    Competing interests
    Yan Xia is the employee of Jiangsu Hengrui Pharmaceuticals Co., Ltd. No other potential conflicts of interest were reported
  20. Huajun Li

    Jiangsu Hengrui Pharmaceuticals, Shanghai, China
    Contribution
    Methodology
    Competing interests
    Huajun Li is the employee of Jiangsu Hengrui Pharmaceuticals Co., Ltd. No other potential conflicts of interest were reported
  21. 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
    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Validation, Investigation, Methodology, Writing - original draft, Writing – review and editing
    Competing interests
    No competing interests declared
  22. 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, Resources, Supervision, Validation, Investigation, Visualization, Methodology, Project administration, Writing – review and editing
    For correspondence
    angel-s205@163.com
    Competing interests
    Senior editor, eLife
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2083-235X

Funding

No external funding was received for this work.

Acknowledgements

Jiangsu Hengrui Pharmaceuticals Co, Ltd provided the study drug adebrelimab free of charge for patients enrolled in the study. We thank the patients and their families involved in this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Ethics

Clinical trial registration NCT05132790.

Human subjects: The study was approved by Institutional Review Board of Shengjing Hospital, China Medical University and performed, according to the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from each patient.

Senior Editor

  1. Diane M Harper, University of Michigan–Ann Arbor, Ann Arbor, United States

Reviewing Editor

  1. Yaoting Ji, Wuhan University, Wuhan, China

Reviewers

  1. Yaoting Ji, Wuhan University, Wuhan, China
  2. Jieqiong Liu, Sun Yat-sen University, China
  3. Xin Wang, Chinese Academy of Medical Sciences & Peking Union Medical College, China

Version history

  1. Received: August 8, 2023
  2. Preprint posted: August 17, 2023 (view preprint)
  3. Accepted: November 15, 2023
  4. Version of Record published: December 22, 2023 (version 1)

Copyright

© 2023, Chen et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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  1. Guanglei Chen
  2. Xi Gu
  3. Jinqi Xue
  4. Xu Zhang
  5. Xiaopeng Yu
  6. Yu Zhang
  7. Ailin Li
  8. Yi Zhao
  9. Guijin He
  10. Meiyue Tang
  11. Fei Xing
  12. Jianqiao Yin
  13. Xiaobo Bian
  14. Ye Han
  15. Shuo Cao
  16. Chao Liu
  17. Xiaofan Jiang
  18. Keliang Zhang
  19. Yan Xia
  20. Huajun Li
  21. Nan Niu
  22. Caigang Liu
  23. On behalf of the Northeastern Clinical Research Alliance of Oncology (NCRAO)
(2023)
Effects of neoadjuvant stereotactic body radiotherapy plus adebrelimab and chemotherapy for triple-negative breast cancer: A pilot study
eLife 12:e91737.
https://doi.org/10.7554/eLife.91737

Share this article

https://doi.org/10.7554/eLife.91737

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