In this phase 2 trial (NCT05582499), patients with stage II-III hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer were categorized into endocrine-based and targeted-based groups based on previously proposed similarity network fusion (SNF) subtyping by digital pathology classification and were then randomly assigned in a 1:1 ratio to receive precision or control treatment. The primary endpoint was pathological complete response (pCR). Among 251 randomized patients, 49 were classified into an endocrine-based group and 202 into a targeted-based group. Patients receiving precision treatment had a significantly higher pCR rate (11.1% [90% confidence interval (CI), 6.8-16.8] vs. 4.0% [90% CI, 1.6-8.2]; p = 0.033), with the benefit mainly derived from the targeted-based group (13.9% in precision vs. 4.0% in control; p = 0.026). Toxicity was manageable. Our findings highlight that guiding neoadjuvant precision treatment by SNF subtyping in patients with HR+/HER2- breast cancer showed potential clinical benefits, with improvement of pCR in the targeted-based group and better tolerance in the endocrine-based group.

Neoadjuvant therapy (NAT) has emerged as a standard treatment strategy for locally advanced breast cancer (BC), yet robust biomarkers for response prediction remain elusive. Here, we established a real-world NAT cohort of 1,161 Chinese BC patients, including 1,145 cases with matched clinicopathological data and targeted sequencing, to systematically evaluate genomic features associated with NAT outcomes. We identified both cross-subtype and subtype-specific genomic associations with treatment response. PI3K-pathway alterations emerged as a consistent feature of resistance across subtypes, whereas mutations such as ERBB2 in HER2+ disease and MAP3K1 in triple-negative breast cancer were associated with subtype-specific response patterns. Regimen-level analyses further showed that some genomic associations were treatment-context dependent across chemotherapy-, endocrine-, anti-HER2-, and immunotherapy-containing regimens. Among patients with non-pathological complete response (non-pCR), genomic profiling further refined risk stratification for distant recurrence by revealing subtype-specific prognostic alterations, including TOP3B and SETD2. Furthermore, a machine-learning model integrating genomic and clinicopathological features showed favorable performance for NAT response prediction. Overall, our study provides a comprehensive genomic framework for response prediction and recurrence risk assessment, supporting more precise stratification and biomarker-guided treatment optimization in Asian breast cancer patients.

BACKGROUND:Increasing axillary pathologic complete response (pCR) rates after neoadjuvant chemotherapy (NACT) challenge the need for routine axillary surgery. On-treatment core needle biopsy (CNB) can assess early response, but its predictive and prognostic value for axillary surgery de-escalation remains unclear. METHODS:This prospective cohort included breast cancer patients receiving on-treatment CNB (after 2-4 cycles) of the primary tumor during NACT (2013-2021). Early responders were defined as having no residual disease of on-treatment CNB. These results were compared with axillary pCR and survival outcomes. RESULTS:The overall axillary pCR rate of 1693 patients was 54.3%. Of 500 early responders, 83.4% achieved axillary pCR. In clinically node-negative (cN0) patients, 98.0% (99/101) of those early responders presented with no nodal disease. While 79.7% of cN+ early responders achieved axillary pCR, this rate increased to 89.6% when combined with post-treatment MRI complete response (92.6% in cN1 and 90.0% in cN2 patients). Survival analysis revealed early responders with superior five-year overall and event-free survival with HR-negative tumors (p < 0.001). CONCLUSIONS:On-treatment CNB reliably identifies patients likely to achieve axillary pCR, offering an approach to guide de-escalation strategies and potentially identifying patients who may benefit from tailored systemic and surgical treatments.

1020 Background: Basal-like immune-suppressed (BLIS) triple-negative breast cancer (TNBC) is associated with a poor prognosis; however, prior analyses from the FUTURE and FUTURE-SUPER clinical trials indicated clinical responsiveness to anti-angiogenic therapy. We conducted this study to evaluate the safety and efficacy of combining bevacizumab with antibody–drug conjugates (ADCs) in patients with the BLIS subtype. Methods: The FUTURE 2.0 study (NCT05749588) is an ongoing, open-label, multi-arm phase II platform trial evaluating novel molecularly targeted agents in patients with histologically confirmed TNBC who progressed after ≥1 line of systemic therapy for recurrent or metastatic disease. This report presents results from the BLIS arms: arm C (HER2-low) and arm D (HER2-zero). In arm C, patients received either SHR-A1811 (anti-HER2 ADC, 4.8 mg/kg IV q3w) alone (C1) or with bevacizumab (15 mg/kg IV q3w) (C2). In arm D, patients received either SHR-A1921 (Trop2-targeted ADC, 3.0 mg/kg IV q3w) alone (D1) or with bevacizumab (7.5 mg/kg IV q3w) (D2). The primary endpoint was confirmed objective response rate (ORR). Safety was assessed in all treated patients with available safety data. Results: From April 2022 to October 2025, 100 women were enrolled: 60 assigned to bevacizumab-combination arms (C2 and D2) and 40 to ADC monotherapy arms (C1 and D1). All 100 patients completed at least one post-baseline assessment. Confirmed ORR was 40.0% (8/20; 95% CI: 21.9–61.3%) in C1, 86.7% (26/30; 95% CI: 70.3–94.7%) in C2, 40.0% (8/20; 95% CI: 21.9–61.3%) in D1, and 83.3% (25/30; 95% CI: 66.4–92.7%) in D2. All four arms met the protocol-specified ORR success criterion with high posterior probability. Median PFS was 9.2 months in the combination group versus 4.6 months in the monotherapy group (HR = 0.47; 95% CI: 0.30–0.74), indicating a clinically meaningful improvement. Grade ≥3 treatment-related adverse events occurred in 27.5% (11/40) of monotherapy patients and 33.3% (20/60) of combination patients. No treatment-related deaths occurred. Conclusions: This study provides preliminary evidence of synergy between bevacizumab and ADCs, supporting a promising new strategy—especially for basal-like, immune-suppressed TNBC. Phase III trials are ongoing to confirm the efficacy and safety of this combination. Clinical trial information: NCT05749588 . The efficacy table. ADC monotherapy ADC combined with bevacizumab A1811 N=20 A1921 N=20 Total N=40 A1811+ Bev N=30 A1921+ Bev N=30 Total N=60 ORR, n (%, 95% CI) 8 (40.0) 21.9 – 61.3 8 (40.0) 21.9 – 61.3 16 (40.0) 26.4 – 55.4 26 (86.7) 70.3 – 94.7 25 (83.3) 66.4 – 92.7 51 (85.0) 73.9 – 91.0 mPFS (mo, 95% CI) 4.9 4.1 – 5.7 4.4 3.7 – 5.1 4.6 3.9 – 5.3 9.1 7.2 – 11.1 9.3 8.2 – 10.5 9.2 7.3 – 11.0 HR in PFS, 95% CI 0.470.30 – 0.74 ( P =0.001)

e13054 Background: The combination of CDK4/6 inhibitors and endocrine therapy (ET) has become the first-line standard treatment for HR+/HER-2- advanced breast cancer (ABC). A certain number of patients who are not sensitive to endocrine therapy and progress rapidly during CDK4/6 inhibitor treatment 20% to 30% of the patients experienced disease progression within 12 months. Screening of those insensitive individuals and further exploration of the optimal treatment strategies is currently the greatest challenge faced by HR+ ABC. Methods: This is a randomize, open-labeled, multi-center phase Ib/II trial (NCT05759572). AI-assisted digital pathology classified of SNF4 subtype patients had pathologically confirmed hormone receptor-positive, HER2-negative with untreated ABC were enrolled. In safety lead-in phase, 9 patients were enrolled (following the 3+3+3 protocol) to receive oral apatinib (250 mg per day) with dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) and endocrine therapy to determine the safety and dose for subsequent phase II part. In pahse II patients were randomly assigned (1:1) to receive dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) and endocrine therapy with or without oral apatinib (250 mg per day). Randomisation was stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting. Safety was analyzed in all randomly assigned patients who received at least one dose of study treatment. Results: Between March 1, 2023, and August 1, 2024, 157 patients were screened and 145 were eligible and enrolled. In safety lead-in phase 9 patients were enrolled and the recommended phase 2 dose was determined as oral apatinib (250 mg per day) and dalpiciclib (125 mg per day for 3 weeks, followed by 1 week off) with endocrine therapy. In phase II part 136 patients were randomly assigned to the apatinib+dalpiciclib with ET ( precision group, n = 68) or dalpiciclib with ET (control group, n = 68). Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (27.8m vs 19.4m; stratified hazard ratio 0.57 [95% CI 0.36–0.91]; two-sided log-rank p = 0.017). Adverse events of grade 3 or 4 were reported in 72(93.5%) of 77 patients in the precision group and 62 (91.1%) of 68 patients in the control group. The most common adverse events of grade 3 or 4 were neutropenia (71 [92.2%] in the precision group vs 62 [91.1%] in the control group) and leukopenia (70 [91.0%] in the precision group vs 60 [88.2%]). Conclusions: AI-assisted digital pathology classification identified SNF4 patients who were resistant to ET combined with CDK4/6 inhibitor. The first-line treatment of apatinib combined with ET and CDK4/6 inhibitor, significantly improved the prognosis of these SNF4 patients with tolerated toxicity. Further prospective phase III trial has currently been conducted. Clinical trial information: NCT05759572 .

508 Background: Weekly paclitaxel and trastuzumab represents a standard option for most stage I human epidermal growth factor receptor type 2 (HER2)-positive breast cancer (BC)s based on results of the single arm phase II APT trial. However, the protocol-induced toxicity was not absent, prompting interest in better tolerated approaches that retain high clinical efficacy. The series of “IRIS” study including cohort A(2020, capecitabine and trastuzumab), B(2020, endocrine therapy and trastuzumab), C (2021, short-period capecitabine and trastuzumab) and D (2021, vinorelbine and trastuzumab) were designed as single arm trials regarding de-escaltion of adjuvant therapy without intravenous chemotherapy in early-stage HER2+ BCs. Herein we reported the results of IRIS-A, a single-group, phase II study to determine whether treatment with capecitabine and trastuzumab was well tolerated and yielded clinically acceptable outcome among stage IA HER2-positive breast cancer. Methods: Patients with stage IA (T1N0: hormonal receptor (HR) < 10%, T≤2cm or HR≥10%, 1cm < T≤2cm) confirmed HER2+ BC were received oral capecitabine (1000 mg/m 2 twice daily for two weeks), and trastuzumab( 8 mg/kg load→6 mg/kg) every 3 weeks for 6 cycles, followed by 11 cycles of trastuzumab monotherapy (6 mg/kg once every 3 weeks). The primary end point was survival free from invasive disease (iDFS). Results: A total of 187 patients were enrolled in this study between May 20, 2020 and May 27, 2021 at Fudan University Shanghai Cancer Center in China. Among all these patients, 80.2% had tumors that measured 0.5 cm or less in the greatest dimension; a majority of tumors (87.2%) were hormone-receptor-negative. The median follow-up period was 62 months( ranges 56-68). The 5-year rate of survival free from invasive disease was 97.9% (95% confidence interval [CI], 94.4 to 99.2). Among the 4 relapses seen, 2 were due to contralateral primary invasive breast cancer (HER2-negative). Excluding these 2 patients and nonbreast cancers, 2 disease-specific events (1 with ipsilateral axilla and ipsilateral breast) were noted. There was no death in this trial. A total of 5 patients (2.7%) reported at least one episode of grade 3 adverse effect (AE)s, which did not influence the completion of treatment. The most common AE was hand-foot syndrome (46.5%), with 1.1% of patients experiencing a grade 3 event. Conclusions: Among patients with stage IA HER2+ BCs, treatment with adjuvant capecitabine plus trastuzumab was associated with an excellent 5-year iDFS of 97.9%. No adverse events that influence treatment continuity were observed. The regimen used in this trial would be an alternative in patients with small size HER2+ tumors with fewer toxic effects than the established regimens. A phase III study using the same protocol is being conducted currently. Clinical trial information: NCT04383275 .

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer without effective targeted therapies. Integrative analysis of transcriptomic and proteomic datasets of TNBC in our center revealed that bisphosphate nucleotidase 1 (BPNT1), a member of inositol monophosphatase superfamily with poorly characterized functional and mechanistic roles in human cancer, was abnormally upregulated in TNBC and its high expression was associated with poor patient prognosis. Loss- and gain-of-function assays revealed that BPNT1 acted as a novel oncogenic driver to promote TNBC cell proliferation, migration, invasion in vitro and to accelerate xenograft tumor growth and lung metastasis in mice. Mechanistically, BPNT1 recruited E3 ubiquitin ligase STUB1 (STIP1 homology and U-box containing protein 1) to induce proteasomal degradation of tumor suppressor protein LIMA1 (LIM domain and actin binding 1), thus promoting the epithelial-mesenchymal transition process and TNBC progression. Notably, re-expression of LIMA1 in BPNT1-overexpressing cells partially attenuated BPNT1-driven EMT and malignant phenotypes of TNBC cells. Furthermore, knockdown of BPNT1 enhanced the sensitivity of TNBC cells to the chemotherapeutic agent docetaxel. Collectively, these findings uncover a previously unknown role of the BPNT1-STUB1-LIMA1 axis in progression and docetaxel resistance in TNBC, and highlight BPNT1 as a potential therapeutic target for patients with TNBC.

591 Background: Standard neoadjuvant regimens for HER2-positive breast cancer include trastuzumab and pertuzumab combined with chemotherapy, and the efficacy and safety of third-generation HER2-direted antibody-drug conjugate (ADC) is unknown. TQB2102 is an anti-HER2 antibody-drug conjugate that targets two non-overlapping epitopes of HER2 (ECD2 and ECD4). It consists of a humanized HER2 IgG1 bispecific antibody conjugated to a topoisomerase I inhibitor via a cleavable linker, and the DAR value is 6. Methods: This open-label, randomized, multi-centre phase 2 study enrolled HER2-positive patients aged 18-75 years with stage II–III disease. Patients were randomly assigned to receive neoadjuvant TQB2102 6mg/kg every 3 weeks for 6 cycles or for 8 cycles. The primary endpoint was pathological complete response (pCR). Safety was analysed in patients who received at least one dose of study medication. Results: Between 05 February 2024 and 24 Sep 2024, we randomly assigned 52 patients to neoadjuvant TQB2102 6 cycles (Arm A, n=26), 8 cycles (Arm B, n=26). The baseline characteristics were well balanced; approximately 50% of the patients were hormone receptor (HR)-positive, and 63% of the patients were stage III. The pCR rate was 57.7% in Arm A (95%CI 36.9%-76.7%), 76.9% in TQB2102 Arm B (95%CI 56.3%-91%). In patients with HR positive disease, the pCR rate was 53.8% in Arm A and 58.3% in Arm B; in patients with HR negative disease, the pCR rate was 61.5% and 92.9%. Grade 3 or higher adverse events occurred 23.1% in Arm A, and 30.8% in 8 Arm B, 7.69% with increased alanine aminotransferase and aspartate transferase. Dose reduction rate and discontinuation was 3.8% and 19.2% in Arm A, 3.8% and 23.1% in Arm B, and no treatment-related deaths occurred. Conclusions: This is the first study to report the efficacy and safety of third-generation duel-HER2-directed ADC in the neoadjuvant setting for HER2-positive breast cancer. TQB2102 is highly efficient and well tolerated. Clinical trial information: NCT06198751 . pCR in All patients and by HR status. 6 cycles 8 cycles All 57.7% 76.9% HR positive 53.8% 58.3% HR negative 61.5% 92.9%

To report the results of a single-arm, prospective partial breast irradiation (PBI) trial from China mainland using a dose of 40.05 Gy in 15 fractions delivered with intensity-modulated radiation therapy (IMRT) technique for patients with early stage breast cancer. Patients aged ≥ 50 years who underwent breast-conserving surgery for unifocal non-lobular invasive breast cancer, with pathological T1 disease, clear margins, negative axillary nodes, and positive hormonal receptors, were recruited. The primary endpoint was 3-year cosmetic deterioration, and secondary endpoints included adverse events, ipsilateral breast tumor recurrence (IBTR), regional recurrence, and survivals. This trial is registered with ClinicalTrials.gov (registration No. NCT03411174). From Jan of 2015 to July of 2018, 208 out of 222 patients recruited were evaluable and included in final analysis. The median follow-up was 66.3 (range: 42.0-105.4) months. The 3-year overall cosmetic deterioration rate was 3.5%. The rates of grade 2 radiation dermatitis and breast induration was 5.8% and 1.5%, respectively. No one experienced ≥ grade 2 breast pain, edema, or telangiectasia. The 5-year cumulative incidence of IBTR and RR was 0.5%. No one developed DM. The 5-year DFS was 99.0%. Four patients died from non-breast cancer causes, and the 5- year OS was 97.9%. In conclusion, we observed lower rates of cosmetic deterioration, IBTR, and ≥ grade 2 acute/late normal tissue effects following PBI with a moderately hypofractionated regimen delivered with IMRT technique. Therefore, this regimen represents an attractive option when an external beam PBI approach is chosen to treat a patient with low-risk early breast cancer.

Introduction Autologous breast reconstruction (ABR) provides distinct aesthetic and functional advantages; however, its adoption in China remains relatively limited. This nationwide survey evaluated the current status, trends and institutional disparities in ABR practice across the country. Materials and methods A national cross-sectional survey was conducted in 2022 among 215 hospitals, with 198 valid responses (response rate = 92%). Data on institutional characteristics, reconstruction techniques, complications and influencing factors were collected and analysed. Results Among the hospitals performing breast reconstruction (n = 169), 110 (65.1%) offered ABR. The most common techniques were latissimus dorsi flaps (LDFs) (28.9%), LDF with implants (28.0%), pedicled transverse rectus abdominis myocutaneous (TRAM) (15.7%) and free abdominal flaps (12.9%). Compared with 2017, the use of LDF and pedicled TRAMs declined, whereas perforator-based procedures showed a notable rise. ABR was more prevalent in economically developed eastern regions and in hospitals equipped with plastic surgery departments. Considerable regional and institutional disparities persist in the availability and implementation of ABR. Conclusions ABR is steadily increasing in China, accompanied by a gradual shift towards perforator-based techniques such as deep inferior epigastric artery perforator flaps. However, its provision remains concentrated in tertiary centres with strong surgical capacity and multidisciplinary support. Addressing regional disparities through targeted training, resource allocation, and standardised practice guidelines will be key to improving equity and quality in breast reconstruction nationwide.

We report the results of LINUX (NCT05594095), a multicenter, randomized, controlled phase II platform trial aiming to identify effective precision treatments for hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer after resistance to cyclin-dependent kinase 4/6 inhibitor. A total of 105 patients were categorized into four similarity network fusion (SNF) subtypes by artificial intelligence-assisted classification and randomly assigned to receive subtyping-based precision therapy (N = 70) or treatment of physician's choice (N = 35). Results demonstrate superior primary endpoint of objective response rates in the subtyping-based groups compared to controls: 10% versus 0% for SNF1, 65% versus 30% for SNF2, 40% versus 30% for SNF3, and 70% versus 20% for SNF4. Grade 3-4 treatment-related adverse events occurred in 37% of both groups. These findings highlight the clinical benefits of subtyping-based precision therapies, particularly for SNF2 and SNF4 subtypes, warranting further validation in phase III trials.

Background: Endocrine therapy combined with CDK4/6 inhibitor represents the first-line standard treatment for HR+/HER2- metastatic breast cancer. However, there is no well-defined standard of care following resistance to CDK4/6 inhibitors. In previous study, we innovatively classified HR+/HER2- breast cancers into four subtypes using large-scale multi-omics data and similarity network fusion (SNF) (Nat Genet. 2023) : SNF1 for canonical luminal, SNF2 for immunogenic, SNF3 for proliferative and SNF4 for receptor tyrosine kinase (RTK)-driven. This platform trial aimed to evaluate the efficacy and safety of precision therapy based on SNF subtyping in patients with HR+/HER2- metastatic breast cancer who have failed CDK4/6 inhibitors treatment. Methods: The Linux trial was an ongoing, multi-center, open-label, randomized controlled phase II platform trial utilizing a Bayesian Optimal Interval design. Eligible participants had histologically confirmed HR+/HER2- breast cancer that had progressed with a CDK4/6 inhibitors treatment for metastatic disease. Participants were categorized into four SNF subtypes and randomly assigned (2:1) to receive either subtyping-based precision therapy or physician’s choice of chemotherapy (TPC) . The subtyping-based precision therapies included: everolimus (10 mg orally daily) + fulvestrant for SNF1, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (10 mg orally daily) + TPC for SNF2, fuzuloparib (100 mg orally bid) + TPC for SNF3, and apatinib (250mg orally daily) + TPC for SNF4. The primary endpoint was the objective response rate (ORR) for precision treatment group versus the control group in the intention-to-treat (ITT) population. Safety was analyzed in all patients who received at least one dose of the study drugs and had safety records. Results: Between Jan 16, 2023 and May 23, 2024, 110 female participants were enrolled and randomly assigned to the subtyping-based group (n=70) or control group (n=40), with a median of two previous lines of therapy (range, 1-6). At the data cutoff, the median follow-up was 9.1 months. The ORR was 48.6% (34/70, 95% CI: 36.6%–60.6%) in the subtyping-based group compared to 17.5% (7/40, 95% CI: 5.2%–29.8%) in the control group in ITT patients. The subgroup ORRs of subtyping-based groups vs. control groups were 10.0% vs. 10.0% for SNF1, 70.0% vs. 30.0% for SNF2, 30.0% vs. 20.0% for SNF3, 65.0% vs. 10.0% for SNF4. Treatment-related adverse events were well managed. Grade 3-4 treatment-related adverse events occurred in 24 participants (34.3%) in the subtyping-based group, compared to 11 participants (27.5%) in the control group. No treatment-related deaths were reported in either group. Conclusions: Our findings highlight the potential clinical benefits of SNF subtyping guided precision medicine in patients with HR+/HER2- breast cancer, suggesting a direction for further clinical investigation. Phase III randomized clinical trials for SNF2 and SNF4 assessing the efficacy of SNF subtyping-based strategies are now underway. (Linux, ClinicalTrials.gov, NCT05594095) Citation Format: Wenjuan Zhang, Xi Jin, Huiping Li, Xiaohua Zeng, Peng Ji, Xiyu Liu, Li Chen, Xinyi Sui, Linxiaoxi Ma, Yue Gong, Chao Chen, Yuee Teng, Jing Shi, Aodi Li, Lei Zhao, Jin Yang, Nan Wang, Yaxin Liu, Hanfang Jiang, Ran Ran, Ruyan Zhang, Bin Shao, Xinyu Gui, Linhui Zhang, Wenyan Chen, Yun Wang, Qiang Peng, Tao Sun, Yujun Jiang, Yangyang Duan, Yufeng Jia, Fangyuan Dong, Dan Lv, Ningning Zhang, Xinrui Liang, Zhigang Zhuang, Shusen Wang, Deyuan Fu, Sujie Ni, Zhixian He, Jiong Wu, Keda Yu, Guangyu Liu, Xin Hu, Yizhou Jiang, Zhonghua Wang, Lei Fan. Precision medicine based on similarity network fusion (SNF) subtypes of multi-omics in CDK4/6 inhibitor failed HR+/ HER2- advanced breast cancer: the Linux trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-09-17.

Background Early prediction of response to neoadjuvant chemotherapy (NACT) in breast cancer is critical for optimizing treatment strategies and improving outcomes. This study assessed the prognostic value of early Ki67 change (ΔKi67 %) via on-treatment core needle biopsy (CNB) in stratifying event-free survival (EFS) and informing potential treatment escalation. Methods In this prospective cohort study, 1388 breast cancer patients treated from 2013 to 2021 were randomly divided into training and validation sets (7:3 ratio). ΔKi67 % was calculated as the percentage change from baseline to on-treatment CNB after a median of two NACT cycles. K-means clustering determined an optimal 40 % cutoff classifying patients as poor (≤40 %) or good responders (>40 %). EFS was analyzed using Kaplan-Meier estimates, multivariable Cox models, and restricted mean survival time (RMST). Results Good responders had significantly superior 5-year EFS compared to poor responders in both training (78.8 % versus 62.4 %, p < 0.001) and validation (78.6 % versus 60.9 %, p = 0.001) sets. ΔKi67 % showed stronger stratification than imaging-based metrics in RMST analysis and remained an independent predictor after adjustment. Subgroup analyses suggested poor responders in the ER-negative/HER2-negative subgroup derived a 32.0 % 3-year EFS benefit from chemotherapy intensification. The 3-year survival benefit was 14.1 % in poor responders in the HER2-positive subtype with dual HER2 blockade, though these findings require further validation. Conclusion Early ΔKi67 % change using a 40 % cutoff via on-treatment CNB is a reliable prognostic predictor supporting response-adapted treatment tailoring, particularly in ER-negative/HER2-negative and HER2-positive populations.

Background: Blockade of the PD-L1/programmed cell death protein 1 checkpoint improves the efficacy of classical chemotherapy in the neoadjuvant treatment of triple-negative early breast cancer (TNBC) but results in adverse events. Treatment approaches for immune-sensitive diseases and the efficacy of adding camrelizumab to chemotherapy regimens is unclear, especially in TNBC patients with a high tumor burden. Methods: This open-label, randomized, phase 2 study randomly assigned (1:1) 90 patients ≥ 18 years with stage II–III histologically documented immunomodulatory TNBC (CD8 ≥10%) were randomly assigned (1:1) to receive chemotherapy with or without intravenous 200 mg camrelizumab every 2 weeks. Chemotherapy comprised nab-paclitaxel (100 mg/m2)and carboplatin at a dose based on an area under the concentration–time curve of 1.5 mg per milliliter per minute once every week for 3 weeks for a 28 days per cycle within the first 12 weeks, followed by epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 2 weeks for 8 weeks, followed by surgery. The primary endpoint ( pathological complete response, pCR) was evaluated using an intention-to-treat approach. This study is registered with ClinicalTrials.gov (NCT05582499). Findings: Between October 2022 and September 2023, 156 patients were recruited and assessed for eligibility. Of the 90 eligible patients, 45 were randomly assigned to receive camrelizumab plus chemotherapy, and 45 was assigned to receive chemotherapy, with 76.7% having stage III disease. At the data cutoff (March 30, 2024), the pCR rate was 62.2% (28/45 patients) in the camrelizumab–chemotherapy group and 42.2% (19/45 patients) in the chemotherapy group (rate difference: 20.0% [95% CI, -0.8 to 39.2]; P=0.058). Treatment-related adverse events of grade 3 or higher occurred in 33 patients (73.3%) in the camrelizumab-chemotherapy group and in 32 patients (71.1%) in the chemotherapy group. Bulk transcriptomic analysis indicated that patients who received immunotherapy and achieved pCR had significantly greater baseline levels of CD8+ T cells than did those who did not achieve pCR(non-pCR). Interpretation: In immunomodulatory TNBC patinets with a high tumor burden, neoadjuvant treatment with camrelizumab in combination with nab-paclitaxel plus carboplatin and anthracycline-based chemotherapy significantly improved pCR rates with an acceptable safety profile. Citation Format: Li Chen, Shu-hao Jiang, Guang-Yu Liu, Ke-Da Yu, Jiong Wu, Gen-Hong Di, Wen-Juan Zhang, Xiao-xi Ma-lin, Qian-nan Liang, Yu Shen, Zhong-Hua Wang, Jun-Jie Li, Zhi-Ming Shao. Neoadjuvant chemotherapy plus camrelizumab vs. chemotherapy in patients with locally advanced immunomodulatory triple-negative breast cancer: a prospective, randomized, open-label, phase 2 trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-11-06.

Introduction Despite its therapeutic advantages, postmastectomy radiotherapy (PMRT) increases the risk of complications and often leads to poor cosmesis in women undergoing breast reconstruction. Preoperative radiotherapy followed by skin-sparing mastectomy and deep inferior epigastric perforator (DIEP) flap reconstruction is technically feasible, with low rates of surgical complications and good short-term oncological outcomes. Further evaluation in a randomised trial comparing preoperative radiotherapy versus conventional PMRT in breast reconstruction is required to assess both oncological and patient-reported outcomes (PROs).Methods and analysis The CAPPELLA trial is a prospective, multicentre, open-label, randomised controlled trial across nine centres comparing PROs and safety outcomes between preoperative and postoperative radiotherapy in patients with locally advanced breast cancer requiring immediate DIEP flap reconstruction. Female patients aged >18 years with breast cancer who are treated with neoadjuvant systemic treatment, require both mastectomy and radiotherapy and are suitable for DIEP flap reconstruction will be included. Patients will be randomly assigned (1:1) to a preoperative radiotherapy group or a postoperative radiotherapy group. Stratification will be performed by cancer centre at initial diagnosis. The radiation volumes will include the ipsilateral breast/chest wall, supraclavicular lymph nodes, undissected axilla and internal mammary nodes. The dose regimen will be 42.56 Gy in 16 fractions. The primary endpoint will be satisfaction with the breast domain of the BREAST-Q at 2 years postoperatively. The secondary endpoints will include PROs at 3, 12 and 24 months postoperatively in both groups, aesthetic assessment, complication rates, rates of total pathological complete response (tpCR) and tumour safety. All patients will be followed up for 36 months postoperatively. The app software will be used to collect all data prospectively. Data will be analysed using SPSS and Stata software. The target sample size will be 80 participants.Ethics and dissemination This study will be performed according to the Helsinki Declaration. All patients will be asked to provide informed consent before enrolment. Approval for this study was provided by the independent ethics committee and institutional review board of Fudan University Shanghai Cancer Centre. We will present the study results at national and international meetings and publish them in a scientific peer-reviewed journal.Trial registration number NCT05512286.

Blockade of the programmed cell death 1 ligand 1 (PD-L1) enhances the efficacy of standard chemotherapy in the neoadjuvant treatment of triple-negative early breast cancer (TNBC) but is associated with adverse events. This phase 2 trial evaluated camrelizumab (anti-PD-1) combined with chemotherapy in locally advanced immunomodulatory TNBC (CD8+ T cell infiltration ≥10%). From October 2022 to September 2023, 90 stage II-III TNBC patients were randomized to receive neoadjuvant chemotherapy ± camrelizumab (200 mg biweekly). The camrelizumab plus chemotherapy group (n = 45) achieved a pathological complete response (pCR) rate of 62.2% (95% confidence interval [CI]: 46.5%-76.2%) versus 42.2% (95% CI: 27.7%-57.8%) in the chemotherapy-alone group (n = 45), with a 20.0% absolute increase (p = 0.059). Grade ≥3 adverse events occurred in 88.9% (40/45) and 82.2% (37/45) of patients, respectively. Multi-omics analyses demonstrated significantly elevated CD8+ T cell infiltration in camrelizumab-treated pCR patients, alongside strong correlations between PD-L1 expression, stromal tumor-infiltrating lymphocytes, and CD8+ density. These results indicate that CD8-guided immunochemotherapy with camrelizumab improves pCR rates in high-tumor-burden TNBC with manageable toxicity, supporting CD8+ T cell levels as a predictive biomarker for immunotherapy response.

PURPOSE:To evaluate the efficacy and safety of the bispecific human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC) TQB2102 in the neoadjuvant treatment of HER2-positive breast cancer. PATIENTS AND METHODS:This randomized, open-label, multicenter, phase II study (ClinicalTrials.gov identifier: NCT06198751) enrolled HER2-positive patients with stage II and III disease. Patients were stratified by hormone receptor status and randomly assigned (1:1) to receive 6.0 mg/kg once every 3 weeks of TQB2102 for six (cohort 1) or eight cycles (cohort 2) or 7.5 mg/kg once every 3 weeks for six (cohort 3) or eight cycles (cohort 4). The primary end point was total pathologic complete response (tpCR) rate across all four cohorts (n = 26 per cohort). When the lower limit of the 90% CI (Clopper-Pearson exact binomial test) for tpCR rate exceeded 40%, efficacy was considered better than that of the historical control. RESULTS:Between February 5, 2024, and September 24, 2024, 104 patients were enrolled, with 26 patients in each cohort. The tpCR rates were 57.7% (15 of 26 [90% CI, 43.2 to 71.3]; P = .04) for cohort 1, 76.9% (20 of 26 [90% CI, 62.3 to 87.6]; P < .01) for cohort 2, 61.5% (16 of 26 [90% CI, 46.5 to 74.8]; P = .02) for cohort 3, and 69.2% (18 of 26 [90% CI, 54.6 to 81.3]; P < .01) for cohort 4. The incidence rates of grade ≥3 treatment-related adverse events were 23.1% (6 of 26) for cohort 1, 30.8% (8 of 26) for cohort 2, 30.8% (8 of 26) for cohort 3, and 26.9% (7 of 26) for cohort 4. No treatment-related deaths occurred in any groups. CONCLUSION:To our knowledge, this was the first study to report the efficacy and safety of the bispecific HER2-directed ADC TQB2102 in the neoadjuvant setting for HER2-positive breast cancer. TQB2102 showed robust activity and was well-tolerated.