Abstract The years 2024–2025 has marked a period of profound evolution in the management of breast cancer, characterized by the consolidation of established therapies and the emergence of transformative new strategies across all subtypes. The field of locoregional management is undergoing a paradigm shift towards surgical de-escalation, with landmark trials questioning the necessity of long-held axillary procedures. For hormone receptor-positive (HR +) breast cancer, the narrative has shifted from the initial adoption of CDK4/6 inhibitors (CDK4/6i) to refining their use in the adjuvant setting and, critically, defining the complex therapeutic landscape following their progression. The rise of antibody–drug conjugates (ADCs) continues to blur traditional subtype boundaries, particularly with the expansion of trastuzumab deruxtecan into the HER2-low and even “HER2-ultralow” populations. In HER2-positive (HER2 +) breast cancer, ADCs are challenging the long-standing first-line standards, while de-escalation strategies in early-stage disease are gaining robust evidence. For triple-negative breast cancer (TNBC), long-term data has solidified the role of immunotherapy, while molecular subtyping is finally translating into tangible clinical benefits in first-line precision trials. This commentary synthesizes the pivotal data from 2024–2025, exploring the clinical implications and future directions of these advancements.

Axillary management in breast cancer has evolved toward de-escalation to reduce complications, particularly breast cancer-related lymphedema (BCRL). This study aimed to assess current practices and trends of axillary surgery and BCRL management in China. A nationwide survey was conducted across hospitals performing ≥ 200 breast cancer surgeries annually in 2022. The questionnaire evaluated institutional characteristics, clinical practices of axillary surgery and BCRL care. Data were compared with those from the 2017 national survey involving 110 hospitals to assess temporal changes in hospital-reported practice patterns. The 198 hospitals surveyed performed a total of 123,237 breast cancer surgeries in 2022. SLNB for cN0 patients was routine practice, with 59.6

BACKGROUND:We aimed to investigate potential biomarkers for predicting pathological complete response (pCR) to neoadjuvant therapy in HER2-positive breast cancer, with a focus on early-stage indicators. METHODS:We conducted a comprehensive analysis incorporating genomic and PET imaging data from 61 patients undergoing neoadjuvant treatment. Genomic profiling and PET/CT scans were performed at baseline (T1) and after one treatment cycle (T2). Various clinical and molecular parameters were assessed, including HER2 gene status, maximum standardized uptake value, and genomic alterations. RESULTS:Our findings revealed several candidate biomarkers associated with treatment response. Early changes in 18 F-FDG PET/CT and baseline 68 Ga-HER2 PET/CT emerged as potential predictors for pCR. Genomic analysis identified differences in mutation frequencies, with notable changes after one treatment cycle. A multivariate predictive model, incorporating PET imaging and clinical characteristics, demonstrated excellent performance in forecasting treatment response. CONCLUSIONS:The study underscores the significance of early biomarkers in predicting neoadjuvant treatment outcomes for HER2-positive breast cancer. Integrating genomic and imaging data provides a comprehensive approach for tailoring therapeutic strategies. The identified biomarkers hold promise for guiding treatment escalation or de-escalation, presenting a step forward in personalized management for HER2-positive breast cancer patients.

INTRODUCTION:Endoscopy-assisted breast surgery is gaining popularity in the treatment of breast cancer owing to its minimally access nature. However, its application in Mainland China varies significantly across regions. We aimed to evaluate the current practices and challenges of endoscopy-assisted breast surgery in Mainland China using a nationwide cross-sectional survey. MATERIAL AND METHODS:In 2022, we conducted a comprehensive questionnaire survey across Mainland China regarding the clinical practices of breast surgery in 215 hospitals, 198 responded fully before September 2024 and included for analysis. Data on hospital characteristics, types of EABS performed, agreements on indications and contraindications, complications, and surgeon preferences were collected and analyzed. RESULTS:Of 198 hospitals with complete responses in the endoscopy-assisted breast surgery section, 93 (47.0 %) could perform endoscopy-assisted breast surgery, and 7 (3.5 %) could perform robot-assisted breast surgeries. Hospitals performing endoscopy-assisted breast surgery had more developed breast surgery departments, higher numbers of inpatient beds, and a greater patient population. The median annual number of endoscopy-assisted breast surgery procedures per hospital was 55, with significant variability. Common procedures included endoscopy-assisted breast-conserving surgery and lumpectomy (15.5 % and 30.7 %, respectively). Breast reconstructions constituted 15.5 %. The most commonly reported complications were seroma formation and bleeding. Despite these complications, endoscopy-assisted breast surgery was considered safe and effective, with positive aesthetic and functional outcomes. CONCLUSIONS:To the best of our knowledge, this is the largest cross-sectional study on endoscopy-assisted breast surgery-related clinical practices in China, highlighting regional disparities and the need for standardized training and procedures.

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.

To investigate the treatment pattern, adverse events, and quality of life of Chinese patients treated with CDK4/6 inhibitors (CDK4/6i) for hormone receptor (HR)+/HER2- advanced breast cancer. This multicenter cross-sectional survey enrolled patients with HR+/HER2- advanced breast cancer currently treated with CDK4/6i. The patients reported adverse events and quality of life during CDK4/6i treatment with a questionnaire and EORTC QLQ-BR23. Meanwhile, the oncologists collected the treatment information, adverse events and patient characteristics from medical record. The analysis included 1254 patients. Most patients received only one CDK4/6i, of which 38.92

Revision surgery is an integral component of post-mastectomy breast reconstruction, aimed at enhancing breast aesthetics and improving patient satisfaction. While developed countries have established high rates of revision surgery, its implementation in China remains limited. We aimed to evaluate the current practices and challenges of revision surgery in Mainland China using a nationwide cross-sectional survey. A nationwide questionnaire authorized by the Chinese Anti-Cancer Association and related committees was distributed to 215 hospitals in China performing over 200 annual breast cancer surgeries, with 198 hospitals completed the survey. Data on nipple-areola complex reconstruction (NAR), autologous fat grafting (AFG), and contralateral breast symmetry surgery were collected and analyzed. Of the 198 surveyed hospitals, 23.2 www.springer.com/00266 .

Background:. Implant-based breast reconstruction (IBBR) is widely used globally and in China, but regional disparities and concerns about complications persist. This nationwide survey evaluates current IBBR practices and trends. Methods:. A cross-sectional survey was conducted in 215 hospitals in 2022, collecting data on surgical volume, reconstruction types, mesh usage, and complications. A total of 198 hospitals provided complete responses, with 122 offering IBBR. Results:. IBBR hospitals had higher surgical volumes, greater bed capacity, more breast specialists, and higher reconstruction rates. In these hospitals, IBBR accounted for a median of 93.5% of reconstructions, with a median annual volume of 24.5 (interquartile range [IQR]: 9–59.3). High-volume hospitals (≥100 IBBR/y) performed 69.4% of cases. TiLOOP Bra was available in 76.2% of hospitals, with 45.9% using it in more than 50% of cases. Prepectoral reconstruction comprised a median of 30% of IBBR cases. Most IBBR procedures used a single mesh (median 95%, IQR: 60%–100%), whereas 2-mesh usage was rare. Direct-to-implant reconstruction with mesh was the most common immediate approach (54.1%), increasing from 23.2% in 2017. Radiation therapy (62.3%), capsular contracture (62.3%), and infection (61.5%) were the leading concerns. Estimated median complication rates were 5% (IQR: 0%–10%) for contracture, 3% (IQR: 1%–10%) for infection, and 2% (IQR: 0%–5%) for implant loss. Conclusions:. IBBR adoption is increasing in China, particularly with mesh-assisted techniques such as TiLOOP Bra. However, disparities in access and concerns over complications highlight the need for standardized care and further research.

e12596 Background: Patients with early-stage HER2-positive breast cancer need more effective neoadjuvant treatment choices. Disitamab vedotin is a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E via a cleavable linker. This phase 2 trial was conducted to evaluate the safety and efficacy of neoadjuvant disitamab vedotin + pertuzumab (group A) or disitamab vedotin + pertuzumab + toripalimab (group B) in patients with previously untreated HER2-positive breast cancer. Methods: Patients with invasive breast cancer (T2-3N0-3M0) and central lab-confirmed HER2-positive status (IHC 3+, or IHC 2+/ISH+) were randomized (stratified by hormone receptor (HR) status [HR+ vs HR-], and clinical N stage [N+ vs N-]) at 1:1 to receive disitamab vedotin (2.0 mg/kg, IV, Q2W) + pertuzumab (initial dose of 840 mg followed by 420 mg, IV, Q3W) or disitamab vedotin + pertuzumab + toripalimab (3.0 mg/kg, IV, Q2W) for up to 18 weeks. Radical surgery (RS) was performed within 3-6 weeks after the last neoadjuvant treatment. Radiological tumor assessment was performed every 6 weeks and assessed by investigators per RECIST v 1.1 during neoadjuvant treatment. The primary endpoint was total pathological complete response (tpCR, defined as ypT0/Tis and ypN0) rate; secondary endpoints included breast pathological complete response (bpCR, ypT0/Tis) rate, objective response rate (ORR) and safety. Data cutoff date for this analysis was December 30, 2024. Results: Thirty-one patients were enrolled with 16 patients in group A (median age: 47.0 years; clinical stage III: 50.0%; clinical stage T3: 12.5%; N+: 100%; HR+: 81.3%; IHC 3+: 56.3%) and 15 in group B (median age: 50.0 years; clinical stage III: 60.0%; clinical stage T3: 20.0%; N+: 100%; HR+: 86.7%; IHC 3+: 73.3%). Among the 15 patients in group A and 14 in group B who underwent RS, the tpCR rate was 20.0% (95% CI: 4.33-48.09) and 50.0% (23.04-76.96), respectively. The bpCR rates were consistent with tpCR rates. ORR was 73.3% (95% CI: 44.9-92.2) and 93.3% (68.1-99.8) for groups A and B, respectively. Up to 20.0% (95% CI: 4.33-48.09) patients had residual cancer burden score 0-1 in group A and 64.3% (35.14-87.24) in group B. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in eight (50.0%) patients in group A and six (40.0%) patients in group B; no grade 5 TRAEs occurred in either group. Conclusions: The combination of disitamab vedotin, pertuzumab and toripalimab showed promising antitumor activity and manageable safety profiles. This regimen may offer a potential chemotherapy-free treatment option for patients in this population. The synergistic effects between HER2-directed antibody-drug conjugates (ADCs), immune checkpoint inhibitors and HER2-directed monoclonal antibodies are worthy of further exploration. Clinical trial information: NCT06178159 .

Breast cancer diagnosed in premenopausal women tends to be more aggressive and the benefit of ovarian function suppression (OFS), at least in certain groups of patients, is well known. There is hesitancy in using OFS in some groups of patients who may otherwise benefit from the treatment. For instance, it is clear that in premenopausal patients with hormone receptor-positive (HR + ), high-risk, early-stage breast cancer, gonadotropin-releasing hormone agonists (GnRHa) should be given in the adjuvant setting; however, confusion remains whether premenopausal patients with intermediate-risk disease benefit from GnRHa, given the lack of consensus on its definition in guidelines and clinical practice. Most recent evidence on the long-term efficacy of GnRHa, with up to 20-years of follow-up, reinforced its benefits in premenopausal patients with early-stage breast cancer. In this comprehensive review, we reviewed the long-term efficacy in terms of improvement in DFS and OS for early-stage HR + breast cancer and examined evidence from multiple randomized clinical studies to identify the clinicopathological characteristics that correlated with improved disease-free survival (DFS) and overall survival with the addition of OFS to adjuvant endocrine therapy. Other aspects of GnRHa, including its efficacy in advanced breast cancer, safety profile, evidence in ovarian function preservation, and the advantages of long-acting formulations were also discussed. By addressing the existing gaps and grey areas regarding the inclusion of OFS as a crucial treatment component for premenopausal breast cancer patients, physicians are more aware of who to administer and the potential impact on survival outcomes.

Objective:To review the development of endoscopic techniques in breast surgery, focusing on their use in benign breast lump resection and breast-conserving surgery for cancer, and also summarize the development and application of these techniques in China, highlighting promotion and homogenization challenges and future directions. Methods:A systematic review of relevant literature was conducted to trace the historical evolution, clinical applications, and related research of endoscopic techniques in breast surgery, emphasizing their advantages and disadvantages of endoscopic benign breast lump resection and breast-conserving surgery for cancer. Results:Endoscopic benign breast lump resection and breast-conserving surgery for cancer have improved patients' postoperative psychological health and quality of life, particularly in scar-free surgery. However, challenges such as limited intraoperative visibility and prolonged surgery time lead to controversy in clinical practice. Conclusion:Despite significant advancements, endoscopic techniques in breast surgery also face challenges. Future efforts should focus on technological improvements and clinical research to address these issues, promoting widespread application and standardization. The key to future development lies in the promotion and homogenization of these technologies.

Abstract Background: Gene mutations and copy number variations (CNVs) are associated with the occurrence and development of tumors. Neoadjuvant therapy (NAT) has shown greater clinical benefit in the treatment of HER2-positive breast cancer (BC). The impact of genetic mutations on NAT efficacy in BC has been frequently reported, but the relationship between genetic mutations and NAT efficacy and the long-term prognosis in HER2-positive BC patients still requires more high-quality studies. Methods: This retrospective cohort study was conducted patients receiving NAT between September 2017 and March 2021 in the Department of Breast Surgery of Fudan University Shanghai Cancer Center (FUSCC). The genomic characteristics of 513 cancer-related genes from the archived tumour blocks were assessed by next-generation sequencing (NGS). The relationship between tumour mutated gene and the postoperative pathological complete response (pCR) as well as prognosis of the disease-free survival (DFS) were further explored.Statistical methods included Chi-square test, fisher's exact test, Kaplan-Meier survival analysis, all of which were completed by SPSS 20.0. Results: 208(47.8%) patients achieved pCR after HER2-targeted NAT and 40(9.2%) patients encountered DFS events. The frequency of somatic alterations in TP53(60%), PIK3CA (15%) and ERBB2(11%) was highest in women with HER2-positive breast cancer. KMT2C (P= 0.036) and TP53(P=0.037) mutations were significantly increased in patients with DFS events. In the HER2+/HR- cohort, patients who achieved pCR had significantly benefit in prognosis (HR=3.605, P=0.002), and CCND1 amplifications(p=0.014), ATM(p=0.016) and GATA3(p=0.016) mutations were more frequent. ERBB2 mutations were significantly associated with younger ages of diagnosis(p=0.018). TP53 mutations were associated with worse DFS (HR=3.242, P=0.0110) as well as more DFS events(p=0.048). Furthermore, TP53 mutations had significant prognostic importance in HER2-positive BC patients with HR-negative (HR=3.712, P=0.0266), pCR (HR=6.253, P=0.0268) and who received trastuzumab-only targeted therapy (HR=4.145, P=0.0105). Conclusions: Regard to diverse hormone receptor status or neoadjuvant efficacy, the genetic mutation maps of Chinese HER2+ patients receiving NAT are disparate. Our study found that TP53 mutations have significant prognostic value in patients with NAT for HER2-positive BC and patients benefit differently depending on HR status, neoadjuvant regimens and response. Citation Format: Min Xiong, Liren Wangxu, Jingyan Xue, Benlong Yang, Jiong Wu. Somatic mutations of a multigene panel in Chinese HER2-positive patients undergoing neoadjuvant therapy and impact on prognosis based on TP53 status:a single-institution retrospective cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-10.

Background: Gene mutations play a crucial role in the occurrence and development of tumors, particularly in breast cancer (BC). Neoadjuvant therapy (NAT) has shown greater clinical benefit in HER2-positive breast cancer. However, further clinical investigation is needed to fully understand the correlation between genetic mutations and NAT efficacy and the long-term prognosis in HER2-positive BC. Methods: This was a retrospective cohort study of 222 patients receiving NAT between 2017 and 2021 in the Department of Breast Surgery of Fudan University Shanghai Cancer Center. Tumor samples from these patients were subjected to Next Generation Sequencing (NGS) to analyze mutations in 513 cancer-related genes. This study aimed to investigate the association between these genetic mutations and postoperative pathological complete response (pCR), as well as their impact on disease-free survival (DFS). Results: In total, 48.65% patients reached pCR, ER-negative status (p < 0.001), PR-negative status (p < 0.001), Ki67 >= 20 (p = 0.011), and dual-targeted therapy (p < 0.001) were all associated with enhanced pCR rates. The frequency of somatic alterations in TP53 (60%), PIK3CA (15%), and ERBB2 (11%) was highest. In the HER2+/HR- cohort, patients who achieved pCR had a significant benefit in prognosis (HR = 3.049, p = 0.0498). KMT2C (p = 0.036) and TP53 (p = 0.037) mutations were significantly increased in patients with DFS events. Moreover, TP53 mutations had prognostic significance in HER2-positive BC patients with HR-negative (HR = 3.712, p = 0.027) and pCR (HR = 6.253, p = 0.027) status and who received herceptin-only targeted therapy (HR = 4.145, p = 0.011). Conclusions: The genetic mutation profiles of Chinese HER2+ patients who received NAT were discrepant with respect to HR status or DFS events. TP53 mutations have significant prognostic value in patients with NAT for HER2-positive BC and patients benefit differently depending on HR status, the neoadjuvant regimen and response, which highlights the significance of genetic factors in treatment customization based on individual genetic and clinical characteristics.

Abstract Background: The use of TiLOOP@ Bra in implant-based breast reconstruction (IBBR) becomes standard of care in mainland China. But evidence is limited about complication of one-stage and two-stage IBBR using TiLOOP@ Bra. A prospective randomized trial was conducted to compare the safety of immediate IBBR with that of immediate-delayed IBBR, both with TiLOOP@ Bra. Methods: We did an open label, randomized, controlled trial in eleven hospitals in the mainland China. Inclusion criteria: Women aged above 18 with cT0-T2N0M0 breast carcinoma which requires to undergo nipple or skin-sparing mastectomy (NSM or SSM) and immediate IBBR. Randomization was done electronically, stratified per center and in blocks of four of six to achieve approximately balanced groups of patients assigned to undergo one-stage or two-stage IBBR. Both procedures were undergone pectoralis major and TiLOOP@ Bra to build pockets. The primary endpoint of the present study was the incidence of postoperative complications (within 90 days after surgery), while the secondary endpoints were the quality of life at 18 months after surgery, satisfaction with breast appearance, aesthetic scores of reconstructed breasts, type of reoperation and TiLOOP@ Bra angiopathological assessment. This study is registered at clinicaltrials.gov, number NCT03589924. Findings: Between June 2018 and May 2022, a total of 418 eligible patients were randomly assigned to either two-stage implant reconstruction (n=194) group or immediate one-stage implant reconstruction (n=224) group. In terms of surgical procedures, NSM was more commonly (72.7%) chosen, with the two-stage implant reconstruction group having a lower proportion compared to the immediate one-stage implant reconstruction (66.3% vs. 78.3%; p=0.010). At 3 months after breast reconstruction surgery, the incidence of complications was lower in the two-stage implant reconstruction group than that in the immediate one-stage implant reconstruction group, with significant difference of 14.5% vs 23%; p=0.038. The incidence of nipple or areola necrosis was lower in the two-stage implant reconstruction group compared to the immediate one-stage implant reconstruction group, with statistically significant difference of 9.8% vs 17.1%; p=0.048. The implant loss rate was only 0.7%. It was discovered that the incidence of severe complications was lower in the two-stage implant reconstruction group than in the immediate one-stage implant reconstruction group (2.6% vs. 3.7%), and the difference was not statistically significant. Patients who experienced complications had a higher proportion of chemotherapy (69.2% vs. 38.9%; p< 0.001), endocrine therapy (74.4% vs. 53.9%; p=0.002), and targeted therapy (24.4% vs. 9.6%; p=0.001), and the differences were statistically significant. In terms of surgical procedures, 67 (85.9%) patients who experienced complications underwent NSM, while the proportion of NSM in patients who did not experience complications was lower at 69.6%, which were 231 patients, and the difference was statistically significant (p=0.011). In addition, the complication incidence of patients who received implants sizes of 300-400ml was higher than that of the group that did not (32.1% vs. 17.8%; p=0.012). Conclusion: Both one-stage and two-stage TiLOOP@-assisted IBBR demonstrated perioperative safety. The complication rate within three month of two-stage is lower than one-stage. The implant loss rate was only 0.7% perioperatively. Our results suggest that use of TiLOOP@ Bra be considered carefully for one-stage NSM with IBBR but can be considered for SSM patients. Citation Format: Benlong Yang, Jian Liu, Haibo Wang, Yiding Chen, Cuizhi Geng, Nanyan Rao, Siyuan Han, Antai Zhang, Jinping Shi, Qiang Zhang, Wenhe Zhao, Jiong Wu. Study to Compare the Safety of Immediate One-stage IBBR With Expander-Implant Two-stage IBBR Augmented With TiLoop® Bra(COSTA) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-22-11.

Abstractp95HER2 isoform is a truncated form of HER2 that retains the C terminal domain but lacks an N terminal trastuzumab binding site. From 2014 to 2016, we assessed the expression of p95HER2 expression in 59 HER2‐positive breast cancer patients from FUSCC. The median follow‐up was 54 months. In our study, 19 patients (32.2%) were p95HER2 positive. p95HER2‐positive expression rate is higher in premenopausal patients than in postmenopausal patients (68.4% vs. 31.6%, P = .026). p95HER2 positive was found more in premenopausal patients and was associated with worse DFS (hazard ratio, 2.21; 95% CI, 1.06–4.61; P = .034), indicating that p95HER2 expression tends to be a more aggressive isoform type of HER2‐positive breast cancer.

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The immunomodulatory (IM) subtype of triple negative breast cancer (TNBC) exhibits high expression of immune cell signaling genes and is more responsive to immunotherapy. However, the specific mechanism underlying this phenomenon remains unclear. One of the potential key genes appears to be the cytotoxic and regulatory T cell molecule (CRTAM). A cohort of 360 previously untreated TNBC patients from Fudan University Shanghai Cancer Center (FUSCC) underwent RNA sequencing analysis of their primary tumor tissue. Combined with three RNA-seq datasets obtained from the GEO database, a LASSO regression analysis was conducted to identify genes specific to the IM type of TNBC. Our findings revealed elevated CRTAM expression in the IM-type TNBC, which correlated with a favorable overall survival and recurrence-free survival in TNBC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated a strong association between CRTAM and immune responses as well as immune system processes. Notably, CRTAM overexpression induced STAT1 phosphorylation and upregulation of interferon-stimulated genes. We also found that CRTAM enhanced tumor-associated immune cell infiltration, especially CD8+ T cells, which may be related to the increased expression of MHC class I molecules caused by CRTAM overexpression. These results suggest that CRTAM may serve as a potential biomarker for predicting the efficacy of immunotherapy in TNBC.

Abstract Background: Pathological complete response (pCR) has been demonstrated as a surrogate endpoint for disease-free and overall survival in HER2-positive early-stage breast cancer (EBC). Trastuzumab (H) plus pertuzumab (P) improved pCR rates in patients with HER2-positive early-stage breast cancer. Nevertheless, biomarkers to assess the effectiveness of this treatment in the neoadjuvant setting are still unclear. This study aims to evaluate the effectiveness of fluorodeoxyglucose positron emission tomography (18F-FDG-PET) and 68 Ga-Affibody HER2 Imaging PET (HER2-PET) in HER2 EBC neoadjuvant therapy, and to identify novel biomarkers for this regimen. Methods: HER2-positive EBC patients were prospectively recruited at Fudan University Shanghai Cancer Center between April 2020 and March 2022. All patients received the 1 dose of HP, followed by 6 cycles of docetaxel (T), carboplatin (Cb), and HP. We use FoundationOne to evaluate the genomic alterations before treatment. In addition, 18F-FDG-PET and HER2 PET were performed at baseline, after 1 cycle of HP, and after 6 cycles of TCbHP, to assess the effectiveness of these examinations in the prediction of pCR and correlation to disease burden. All patients were received surgery and completed 1 year of HP-based regimen in the adjuvant setting. Results: A total of 61 patients with a median age of 49 years were included. Among them, 93.5% of patients are node positive. 75.8% of the patients reported adverse events (AEs), primarily grade 1 and 2. The incidence of serious AEs was 6.6%. Patients exhibiting a greater than 40% reduction in SUVmax of 18-FDG-PET or HER2-PET scans from baseline to the fifth day after the initial HP treatment were classified as the treatment-sensitive group. The pCR rate for the 18-FDG-PET-sensitive group was 79.3%, while for the insensitive group was 48.1%. For HER2-PET scans, the pCR rate was 70.0% in the sensitive group and 59.3% in the non-sensitive group. To evaluate the potential biomarkers, 25 patients (13 pCR and 12 non-pCR) were evaluated with FoundationOne, with the identification of 1,321 somatic alterations. The most frequently altered genes were ERBB2 (100%), TP53 (96%), CDK12 (76%), MYC (56%), CCND1 (44%), PIK3CA (40%), and SRSF2 (36%). In the pCR group, we found PPM1D (38.5%) and RAD21 (38.5%) were altered more frequently than the non-pCR group. PIK3CA alterations were significantly reduced in pCR group, only 23% of cases are affected compared to 58.3% in non-pCR group. Patients were non-pCR had more MDM4 (41.7%) and ZNF217 (41.7%) alterations than pCR patients. Conclusion: The SUVmax value of 18-FDG-PET and HER2-PET scans are correlated well with the tumor burden and the residual disease in the HER2 EBCs. The reduction of SUVmax could predict pCR but need further exploration. Patients with alterations in PPM1D and RAD21 have a favorable response to the TCbHP regimen. Conversely, alterations in PIK3CA, MDM4, and ZNF217 are associated with treatment resistance. These results indicate the significance of 18-FDG-PET and HER2-PET in monitoring treatment effectiveness. The biomarker analysis in this study will help us understand the mechanism of HER2 positive breast cancer treatment resistance and assisting in tailoring personalized therapy. Clinical trial information: NCT04281641. Citation Format: Ming Chen, Benlong Yang, Sun Yuyun, Linxiaoxi Ma, Song Shaoli, Min He, Zhi-Ming Shao, Bingqiu Xiu, Jiong Wu. An Open-label, Single-center Study Assessing the Efficacy of PH-based Regimen as Neoadjuvant Therapy for HER2-positive Early-stage Breast Cancer: Integrating Genomic Features and Functional Imaging [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-05.