BACKGROUND:Phase II and III trials have demonstrated progression-free survival (PFS) benefits of pyrotinib plus capecitabine over lapatinib plus capecitabine in HER2-positive metastatic breast cancer (MBC). However, long-term overall survival (OS) data from a single-center cohort remain limited. This pooled analysis compared OS between the two regimens and explored outcomes across prespecified subgroups. METHODS:We included patients with HER2-positive MBC from our center enrolled in a Phase Ic study, a Phase II study, or the Phase III PHOEBE trial. The primary endpoint was OS. OS was analyzed using Kaplan-Meier estimates, log-rank tests, and a multivariable Cox model adjusted for ECOG performance status, pathological grade, prior anti-HER2 therapy, trastuzumab exposure duration, trastuzumab resistance, and prior chemotherapy lines. The proportional hazards assumption was assessed using Schoenfeld residuals. Exploratory subgroup analyses used prespecified categories. RESULTS:At data cutoff, 82 patients were included; 53 received pyrotinib plus capecitabine and 29 received lapatinib plus capecitabine. Baseline characteristics were comparable between groups. Median OS was 74.61 months (95% CI 41.10-not reached) with pyrotinib plus capecitabine and 30.98 months (26.12-50.76) with lapatinib plus capecitabine (log-rank p = 0.0053). Cox models suggested a reduced risk of death with pyrotinib plus capecitabine. Subgroup analyses were exploratory and should be interpreted cautiously because several subgroup estimates were imprecise. CONCLUSION:In this single-center pooled analysis, pyrotinib plus capecitabine was associated with significantly longer OS than lapatinib plus capecitabine in patients with HER2-positive MBC. These exploratory results are consistent with prior Phase II/III trials and provide evidence supporting the OS benefit of pyrotinib.

Purpose:The study aims to explore the predictive value of the Ki67 index for everolimus efficacy in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Materials and Methods:We collected data on 2,518 cancer patients who received everolimus treatment from three cancer centers in China. Their clinicopathologic characteristics were retrospectively collected. A training cohort and a validation cohort were developed. Results:A total of 300 patients with HR+/HER2- ABC were included in the study, with 200 patients in the training cohort and 100 patients in the validation cohort. When analyzing the Ki67 index from 14% to 50%, only the Ki67 cut-off of 40% was found to be significantly correlated with progression-free survival (PFS) for patients in the training cohort. Multivariate Cox analyses further showed that Ki67 index of 40% (p=0.03) was significantly associated with PFS in patients treated with everolimus. Patients with Ki67 less than 40% had an improved PFS of 7.0 months, significantly better than 4.6 months for patients with Ki67 more than 40% (p=0.03, HR=0.67, 95CI%=0.46-0.97). In the validation cohort, patients with a Ki67 index of less than 40% had a significantly longer PFS of 4.3 months (2.1 months versus 4.3 months, p<0.001, HR=0.29, 95CI%=0.17-0.51). Conclusion:The Ki67 cut-off value of 40% was identified as an optimal index for predicting the efficacy of everolimus, which may help with the management of everolimus in Chinese patients with HR+/HER2- ABC.

Circulating cell-free DNA (cfDNA) has emerged as a valuable non-invasive biomarker that provides unique insights into the spatial and temporal heterogeneity of tumors, serving a key role in cancer precision medicine. Applications of cfDNA include detecting disease progression before clinical and radiological confirmation, identifying actionable genomic alterations, monitoring treatment response, revealing mechanisms of treatment resistance and assessing prognosis. The latest progress in research on the biological characteristics of cfDNA has provided unprecedented molecular insights into cancer diagnosis and treatment, thereby markedly expanding its clinical application scope. The present review explored the latest findings in cfDNA biology and its applications in early diagnosis, treatment monitoring and prognostic assessment of breast cancer. The present review proposed a novel staged transformation strategy guided by the disease progression stage of breast cancer and the maturity of cfDNA technology. The present review aimed to systematically and efficiently promote the application of cfDNA in the full-cycle management of breast cancer. Furthermore, the present review predicted cutting-edge directions such as multi-omics integration, artificial intelligence assistance and ethical considerations. Although cfDNA holds notable promise, its clinical translation is still limited by low-abundance signals in early-stage tumors, insufficient detection standardization and the complexity of bioinformatics interpretation. The present review was based on the integration of existing evidence; however, majority of studies are still retrospective or small-sample prospective, indicating a need to elevate the evidence level. Future research should focus on developing ultra-high-sensitivity multi-omics technology, establishing an international standardization system and verifying the actual effectiveness of cfDNA in guiding clinical decisions through large-scale prospective clinical trials. The ultimate goal is to realize the comprehensive application of cfDNA in early screening and personalized treatment of breast cancer.

ABSTRACT Objective To examine factors influencing breast cancer liver metastases (BCLM) and assess the impact of underlying liver diseases (nonalcoholic fatty liver and HBsAg infection) on BCLM development. Methods Patients diagnosed with breast cancer at four affiliated hospitals in China between 2014 and 2024 were included. Logistic regression was used to identify factors associated with BCLM. Propensity score matching (PSM) and Kaplan–Meier analyses were performed to evaluate the prognostic impact of underlying liver diseases. Results A total of 3653 breast cancer patients were included, among whom 387 (11%) were identified with liver metastasis (LM). Factors including nonalcoholic fatty liver (NAFL) and HBsAg (hepatitis B surface antigen) infection were independently associated with a lower risk of BCLM (NAFL: p < 0.001; HBsAg: p = 0.011). Subsequent analysis stratified by the severity of NAFL indicated that mild NAFL was associated with a lower risk of BCLM, whereas moderate‐to‐severe NAFL was associated with a higher risk of BCLM (p = 0.01 and p = 0.02, respectively). Survival analysis showed that HBsAg infection was associated with significantly longer liver metastasis‐free survival (LMS) and overall survival (OS) (both p < 0.01). Further survival analysis, stratified by the presence of NAFL, revealed that mild NAFL could prolong both LMS and OS, while moderate‐to‐severe NAFL not only shortened LMS, but also shortened OS after LM (OSLM), so that OS was significantly shortened (p < 0.01 for mild NAFL; p < 0.05 for LMS and p < 0.01 for OSLM and OS in moderate‐to‐severe NAFL). Furthermore, consistent results on OS and OSLM were obtained even after employing 1:1 PSM to account for other covariate interferences (both p < 0.01). Conclusion Mild NAFL may be associated with reduced LM and improved prognosis, while moderate‐to‐severe NAFL appears to correlate with increased LM risk and worse clinical outcomes. Furthermore, HBsAg infection may be linked to suppressed LM and extended OS for patients with BCLM.

Breast cancer is the most commonly diagnosed cancer in women globally. Our previous MIRACLE trial (NCT02313051) demonstrated that everolimus plus letrozole (E + L) significantly improves progression-free survival compared with letrozole (L) monotherapy in premenopausal patients with endocrine therapy-resistant, hormone receptor-positive, HER2-non-amplified advanced breast cancer. This study aims to investigate spatially resolved biomarkers linked to survival benefits from E + L to guide precision therapies. Patients from MIRACLE were stratified by overall survival (OS ≤ 3 vs. >3 years). Spatial Whole Transcriptome Atlas analysis was used to evaluate tumor-, immune-, and stroma-specific gene expression, co-expression network patterns, and survival correlations. Among patients with shorter survival (OS ≤ 3 years), we identified a distinctive gene interaction network characterized by tumor-derived S100A9 and CALML5, which is associated with mTORC1 activation. This finding suggests that tasquinimod, an S100A9 inhibitor, could be a viable therapeutic option. Additionally, an interaction between CALML5 and SLPI across tumor and immune areas indicated a potential role in maintaining tumor integrity and mitigating immune-mediated damage. Conversely, patients with longer survival (OS > 3 years) exhibited SERPINA1 as a hub gene linked to estrogen receptor activation, and an interaction between FKBP5 and SESN3 associated with AKT/mTORC1 inhibition within tumor-rich regions. Furthermore, the interaction between MMP11 and COL16A1 in stroma-rich regions suggests that cancer-associated fibroblasts may contribute to improved outcomes. Our study underscores the critical role of spatial gene expression analysis in elucidating the tumor microenvironment and its impact on prognosis in patients undergoing E + L treatment, thereby opening new avenues for targeted interventions.

Background:The efficacy and safety of poly (ADP-ribose) polymerase inhibitors (PARPis) in the Chinese real-world setting have not been well characterized. Design:This is a retrospective analysis of PARPis efficacy in metastatic breast cancer (MBC) patients with homologous recombination repair (HRR) gene pathogenic variants (PVs). Objectives:We aimed to evaluate the efficacy and toxicities of PARPis in real-world MBC patients. Methods:Patients who received PARPi for MBC at the National Cancer Center and two other centers between January 1, 2019, and December 31, 2024, were consecutively included. The primary endpoint was progression-free survival (PFS). Univariable and multivariable Cox proportional hazard models were used to evaluate the predictive impact of clinicopathologic characteristics on PFS. Results:In total, 62 MBC patients treated with olaparib (N = 55), talazoparib (N = 4), pamiparib (N = 2), and fluzoparib (N = 1) were enrolled. The median PFS (mPFS) in all patients was 6.0 months (95% confidence interval: 4.1-7.9). mPFS in the germline BRCA1 (gBRCA1; N = 19), gBRCA2 (N = 30), gBRCA (N = 4), somatic BRCA2 (sBRCA2; N = 1), gPALB2 (N = 4), and other HRR gene (N = 4) PVs carriers were 3.7, 8.0, 2.8, 2.7, 5.3, and 7.1 months, respectively (p = 0.334). In multivariate analysis, ⩽40 years old (hazard ratio (HR): 2.281, p = 0.008), third-line or later therapy (HR: 2.429, p = 0.019), and prior platinum-based treatment (HR: 2.172, p = 0.014) were independently associated with shorter PFS. The incidence of adverse events (AEs) of all grades was 62.5% (35/56). The most common AEs in all grades were anemia (30.4%), nausea (21.4%), and leukopenia (17.9%). Hematologic toxicity was the most common grade ⩾3 AEs. Conclusion:PARPis showed promising PFS and tolerable toxicity in the real-world treatment of Chinese MBC patients with HRR-related gene mutations.

Malignant phyllodes tumor of the breast (MPTB) is a rare interstitial neoplasm, accounting for less than 1

Despite the established benefit of adjuvant trastuzumab emtansine (T-DM1) over trastuzumab in HER2-positive early breast cancer (eBC) with residual disease after neoadjuvant chemotherapy plus HER2-targeted therapy, comparison of efficacy between T-DM1 and dual HER2 blockade (trastuzumab plus pertuzumab, HP) remains undetermined. This study evaluates survival outcomes with adjuvant T-DM1 versus HP in a multicenter real-world cohort. Breast cancer patients with residual disease after neoadjuvant treatment from 3 centers in China who received either T-DM1 or HP from 2018 to 2024 were included. To analyze treatment effects, multivariable Cox regression was utilized as the primary analysis, with sensitivity analyses employing Firth’s penalized method, inverse probability of treatment weighting (IPTW), and propensity score matching (PSM) in the anthracycline (AC)-naïve cohort (N = 212). Totally 230 patients were enrolled. Among them, 203 received TCbHP, 9 received THP, and 18 received AC-containing chemotherapy plus HP before surgery. In the AC-naïve cohort, 89 had T-DM1 as adjuvant treatment and 123 had HP instead. More iDFS events were observed in HP group than T-DM1 group (19 vs. 2 events respectively). Multivariable Cox regression demonstrated superior iDFS with T-DM1 compared with HP (2-year iDFS: 97.6

BACKGROUND:A growing number of antibody‒drug conjugates (ADCs) have been approved for breast cancer treatment. However, the proper sequential strategies of ADCs remain uncertain. Our study aimed to explore the ideal ADC sequential treatment strategies in human epidermal growth factor receptor 2 (HER2)-expressing metastatic breast cancer (MBC). METHODS:Our multi-centre retrospective study enrolled MBC patients who received at least 2 lines of different types of ADCs between Jan 1, 2018, and Jul 1, 2024. The efficacy of both ADC1 and ADC2 was evaluated. RESULTS:A total of 111 patients (83 HER2-positive and 28 HER2-low) were included. In HER2-positive populations, Patients who received ADC2 with a different payload from ADC1 exhibited significantly longer progression-free survival 2 (PFS2) (6.8 vs. 2.7 months, p < 0.001) and overall PFS (progression-free Interval 1 (PFI1) + PFS2) (15.0 vs. 8.5 months, p = 0.043) compared to those treated with ADC2 containing a similar payload with ADC1. Patients received ADC2 immediately after ADC1 progression showed longer PFS2 ADC2 delayed sequential patients (median PFS2: 6.0 vs. 3.0 months, p = 0.004). In HER2-low patients, the efficacy of ADC2 tended to be lower than ADC1 (median PFI1 vs. PFS2: 3.1 vs. 2.4 months, p = 0.078). No significant differences of efficacy were observed, no matter what ADC sequential treatment strategy used. CONCLUSIONS:Sequential treatment with ADCs showed clinical benefit especially for HER2-positive patients treated with ADC2 which have different types of payloads from ADC1. In HER2-low patients, the benefit of ADC sequential therapy seemed to be limited.

PURPOSE:This study aimed to evaluate the impact of postoperative adjuvant chemotherapy (AC) on survival outcomes in breast cancer (BC) patients who have already undergone neoadjuvant chemotherapy (NAC) followed by surgery. MATERIALS AND METHODS:Data from a population-based cohort (2010-2020) were analyzed for BC patients treated with NAC and surgery. Univariate and multivariate Cox regression identified prognostic factors for overall survival (OS), and a nomogram was developed and validated. Personalized scores from the nomogram were used for risk stratification to assess the effect of postoperative AC. RESULTS:A total of 15,921 BC patients were analyzed, with 11,144 in the training cohort and 4,777 in the validation cohort. The key prognostic indicators for OS included age, race, marital status, histological grade, BC subtype, T category, N category, type of surgery, and response to NAC (all p < 0.05). The nomogram effectively predicted individualized OS rates and stratified patients into various risk categories. Postoperative AC was found to significantly enhance OS in the high-risk subgroup (p=0.011 in the training cohort, p=0.012 in the overall population). However, for the low-risk subgroup, there was no significant survival benefit from postoperative AC (p=0.130 for the training cohort, p=0.588 for the overall population), suggesting that some patients might safely forgo unnecessary postoperative AC. CONCLUSION:This study efficiently differentiates between varying levels of risk, enabling clinicians to identify patients unlikely to benefit from postoperative AC and thus reduce the likelihood of overtreatment.

Objective:A subset of patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer shows insensitivity to neoadjuvant therapy (NAT), often evidenced by imaging results indicating stable disease (SD) or progressive disease (PD), which may reflect intrinsic resistance to treatment. We aimed to investigate the factors associated with NAT insensitivity and its prognostic value in HER2+ breast cancer. Methods:This study included consecutive patients with HER2+ breast cancer who received NAT consisting of chemotherapy combined with anti-HER2 monoclonal antibodies. NAT insensitivity was defined as SD or PD on the basis of treatment response evaluations. Statistical analyses were conducted on the collected clinical data, and HER2 heterogeneity was subsequently assessed. Results:A total of 541 patients were included in the study, among whom 63 (11.6%) were categorized as NAT-insensitive group and 478 (88.4%) as NAT-sensitive group. Hormone receptor (HR) status (P=0.033), HER2 status (P=0.036) and anti-HER2 therapy (P=0.007) were associated with NAT sensitivity. NAT-insensitive group had a significantly shorter event-free survival (EFS) (3-year: 69.4% vs. 94.3%; P<0.001) and remained an independent prognostic factor according to Cox models [hazard ratio (HR)=8.637; 95% confidence interval (95% CI), 3.091-24.136; P<0.001]. Exploratory analysis revealed a greater proportion of HER2 heterogeneity in the NAT-insensitive group (19.4% vs. 4.3%; P=0.035). Conclusions:HR positivity, HER2 2+/fluorescence in situ hybridization (FISH)+ status, and trastuzumab monotherapy are associated with NAT insensitivity, and NAT insensitivity independently indicates poor EFS. This study also highlights the need for prospective studies to clarify the role of HER2 heterogeneity and other mechanisms involved in predicting the response to NAT.

BackgroundProgrammed death-1 (PD-1) inhibitors plus tyrosine kinase inhibitors (TKIs) combination therapy are considered as a first-line treatment recommendation for advanced hepatocellular carcinoma (HCC). However, patients with hyperbilirubinemia are excluded from this therapeutic option due to limitations in indications. There is a notable absence of published studies evaluating the safety and efficacy of the PD-1 inhibitors plus TKIs combination therapy in patients with HCC combined with hyperbilirubinemia.MethodsPatients with HCC complicated with hyperbilirubinemia who received combination therapy with PD-1 inhibitors and TKIs were retrospectively analyzed. Adverse events, tumor response, and laboratory parameters were recorded to assess the safety and efficacy of the treatment, as well as to identify potential risk factors influencing survival.ResultsA total of 108 participants were included in the study, with 56 patients (51.9%) reporting at least one adverse event, the majority of which were mild. The objective response rate (ORR) for the enrolled participants was 11.9%, and the disease control rate(DCR) reached 61.2%. The median overall survival (OS) for the entire cohort was 5.03 months, while the median progression-free survival (PFS) was 3.63 months. Multifactorial analysis showed that MELD score >18 and increased total bilirubin (TBIL) levels within one week were significant risk factors for OS. Patients with a decrease in TBIL levels within one week had significantly prolonged median OS (not reached vs 3.3months, P =0.013) and median PFS (7.03 months vs 2.77 months, P =0.010).ConclusionCombination therapy demonstrated favorable safety and tolerability among patients with HCC combined with hyperbilirubinemia. Patients who experienced a rapid decline in TBIL levels during the early phase of treatment with PD-1 inhibitors and TKIs were observed to derive clinical benefits. Early initiation of aggressive interventions aimed at reducing TBIL levels is recommended to optimize treatment outcomes.

Background: The selection of appropriate chemotherapy backbone agents in combination with neoadjuvant immunotherapy for triple-negative breast cancer (TNBC) remains unclear. Herein, we aimed to evaluate the efficacy and safety of anthracycline-free and anthracycline-containing regimens coupled with neoadjuvant immunotherapy. Method: This retrospective study included 87 patients with TBNC who received neoadjuvant immunotherapy combined with various chemotherapy regimens at three research centers from November 2020 to November 2023. The primary objective was pathological complete response (pCR), while secondary objectives included overall response rates, event-free survival (EFS), and the incidence of adverse events. A subgroup analysis was performed to delineate patients who may substantially benefit from distinct therapeutic strategies. Results: Coupled with immunotherapy, anthracycline-free regimens achieved comparable pCR rates (55.1 % vs. 51.4 %; Odds ratio, 1.16; 95 % confidence interval [CI], 0.49-2.74; p = 0.73) and EFS (Hazard ratio, 0.66; 95 % CI, 0.18-2.45; p = 0.53) to anthracycline-containing regimens. According to subgroup analyses, the tumor stage (p = 0.017) and lymph node stage (p = 0.011) exhibit contradictory predictive power for the pCR rate of anthracycline-free regimens when compared with that of anthracycline-containing regimens. Specifically, anthracycline-free regimens yielded significantly higher pCR rates in patients without lymph node metastasis than anthracycline-containing regimens (p = 0.021). Pooled analyses further confirmed the results of both total and subgroup analyses. Most adverse events were grades 1-2, and no new adverse reactions were observed. Conclusion: Anthracycline-free neoadjuvant chemotherapy regimens could serve as an effective and safe alternative immunotherapy partner for patients with TNBC, particularly in those without lymph node metastasis.

Lerociclib (GB491), a highly selective oral CDK4/6 inhibitor, has displayed anti-tumor activity and differentiated safety and tolerability profile in previous ph1/2 clinical trials. The LEONARDA-1, a randomized, double-blind, phase III study, was conducted to evaluate the efficacy and safety of lerociclib in HR+/HER2− locally advanced or metastatic breast cancer patients, who had relapsed or progressed on prior endocrine therapy. A total of 275 patients were randomized at 1:1 ratio to receive lerociclib (137 patients, 150 mg twice daily) or placebo (138 patients) plus fulvestrant. Progression-free survival (PFS) assessed by investigators was significantly improved in lerociclib arm versus placebo arm (11.07 vs 5.49 months; hazard ratio, 0.451, 95

e12518 Background: The clinicopathological and prognostic features of HER2-low female breast cancer (BC) have been widely studied. Current knowledge suggests that HER2-low could be identified as a special entity for treatment. However, limited research has focused on the HER2-low subtype in early-stage male breast cancer. Methods: This retrospective study screened male BC cases from all breast cancer patients at a single institution between January 2010 and September 2023. Early-stage cases with non-HER2-positive tumors were included and categorized into HER2-low and HER2-zero groups. Clinicopathological features were collected and compared between the two groups. The primary endpoints were disease-free survival (DFS) and overall survival (OS). Statistical analysis was conducted using descriptive statistics, the Kaplan-Meier method with the Log-rank test, and the Cox proportional hazards model to evaluate differences in DFS and OS between the groups. Results: A total of 99 early-stage non-HER2-positive male BC cases were identified, with 41 classified as HER2-low and 58 as HER2-zero, and these cases were included in the final analysis. Regarding the clinicopathological features, the HER2-low subgroup exhibited higher androgen receptor (AR) expression (P = 0.003). Regarding survival outcomes, no significant difference was observed in DFS (P = 0.1), but the HER2-low subgroup had a significantly longer OS compared to the HER2-zero subgroup (P = 0.01). Multivariate analysis identified age and TNM stage as independent prognostic factors for DFS, while age and HER2-low were independent prognostic factors for OS. Conclusions: HER2-low population in early-stage male BC had a different clinicopathological feature and prognostic role compared to HER2-zero counterparts. The HER2-low subgroup had a better OS compared to the HER2-zero subgroup, and HER2-low was determined as an independent prognostic factor for OS, but not for DFS.

ABSTRACT Everolimus (EVE) combined with letrozole is an approved treatment for hormone receptor‐positive/human epidermal growth factor receptor 2‐negative (HR+/HER2−) advanced breast cancer (ABC). However, predictive biomarkers for EVE efficacy remain undefined. In the phase 2 MIRACLE trial, we performed digital spatial profiling (DSP) on pretreatment tumor samples from 21 patients receiving EVE plus letrozole. Patients were divided into resistant and sensitive groups based on their best response to EVE. A total of 119 regions across three compartments—tumor, leukocytes, and stroma—were profiled for immune and transcriptomic markers. Responders had significantly higher fibroblast infiltration in PANCK+ (p = 0.011) and CD45−/PANCK− (p = 0.043) regions, whereas non‐responders exhibited increased neutrophils in CD45+ (p = 0.0061) and PANCK+ (p = 0.03) regions. Prolactin‐induced protein (PIP) mRNA expression was significantly elevated in non‐responders in both PANCK+ (p < 0.0001) and CD45−/PANCK− (p = 0.0006) regions. PIP mRNA expression was found to be associated with EVE resistance and unfavorable progression‐free survival (PFS). PIP mRNA expression and specific immune‐stromal features are associated with resistance to EVE. These findings suggest the potential of PIP as a spatially resolved predictive biomarker for patient stratification in HR+/HER2− ABC.

Background: Pathological complete response (pCR) has been proven to be related to prognosis. pCR can be further classified as pCR of the breast (bpCR), pCR of axillary lymph nodes (apCR) or pCR of both tumors. The aim of this study was to elucidate the outcomes and clinicopathological characteristics associated with different patterns of pCR. Methods: Patients with node-positive disease who received neoadjuvant chemotherapy between August 2009 and July 2016 and who achieved pCR in axillary lymph nodes, breast or both were included. Multivariate logistic regression was used to identify factors related to different patterns of pCR. Results: Among the 271 patients who were included in the study, 42.1% achieved total pCR, 46.1% achieved ApCR, and 11.8% achieved BpCR. Disease-free survival (DFS) was significantly better in the total pCR group than in the limited pCR groups throughout the entire cohort (p=0.042). Univariate and multivariate analyses indicated that patients with HR-negative disease and a high Ki-67 proliferation index were more likely to achieve total pCR. Patients with earlier T stage disease were more likely to achieve pCR only in the breast. Among patients who achieved limited pCR, there was no significant difference in terms of whether these patients received intensified adjuvant chemotherapy. Conclusions: Total pCR is still the best marker for predicting survival benefit in patients receiving neoadjuvant chemotherapy, and total pCR is more likely to be achieved in patients with HR-negative disease and a high Ki-67 proliferation index. T stage and N stage may predict apCR and bpCR, respectively.

AIMS:This study compared pathologic complete response (pCR) rates to neoadjuvant chemotherapy (NAC) in HER2-negative early breast cancer patients with versus without homologous recombination repair (HRR) mutation, focusing on BRCA1/2. METHODS:This retrospective cohort study included HER-2-negative breast cancer patients who completed HRR genetic testing and received NAC. The primary endpoint was the pCR rate among HRR mutation carriers and noncarriers. RESULT:Among 211 HER2-negative breast cancer patients analyzed, 64 (30.3%) harbored pathogenic/likely pathogenic HRR mutations, predominantly in BRCA1 (42.2%), BRCA2 (31.3%), and other HRR genes (26.6%). Hormone receptor positive patients accounted for 55.9% (118/211). Half of the patients (51.2%) treated with platinum-containing regimens. pCR rates were comparable between HRR mutation carriers and noncarriers (26.6% vs. 24.5%, p = 0.750), regardless of hormone receptor status. However, BRCA1 carriers achieved significantly higher pCR rates than BRCA2 carriers (40.7% vs. 10.0%, p = 0.001). Platinum-containing regimens (51.2% of patients) yielded greater benefit in BRCA1 carriers (pCR 61.1% vs. 12.5% in BRCA2; p = 0.022). CONCLUSION:These data indicated that HRR mutations had no effect on pCR in HER-2 negative patients receiving NAC regardless of hormone receptor status. BRCA1 mutation carriers have a higher rate of pCR and are more benefit from platinum-containing regimen than BRCA2 mutation carriers.

Previous studies often combined double hormone receptor-positive (dHR +) and single HR-positive (sHR +) tumors, thus not accounting for the distinct characteristics of sHR + , particularly in the neoadjuvant setting. Moreover, adding immunotherapy to cytotoxic chemotherapy has shown encouraging efficacy in certain HR-positive early breast cancers. This study sought to assess pathological complete response (pCR) and survival outcomes in sHR + /HER2- breast cancer after neoadjuvant chemotherapy, while also investigating its specific biological traits and immune profile. Clinical data were sourced from the Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS, n = 1049), and the Surveillance, Epidemiology, and End Results (SEER, n = 21,092) database to examine neoadjuvant chemosensitivity and survival outcomes. Additionally, clinicopathological and subtype data from CHCAMS, SEER, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1052), and Fudan University Shanghai Cancer Center (FUSCC, n = 570) were analyzed to identify biological features that correlate with pCR rates and prognosis in sHR + /HER2- breast cancer. Further genomic and transcriptomic data from METABRIC, The Cancer Genome Atlas (TCGA, n = 741), and MSK-IMPCAT (n = 1535) were reviewed to uncover their potential links with endocrine and immunotherapy responses. In comparison to dHR + (ER + and PR +)/HER2- breast cancer, sHR + (ER + /PR- or ER-/PR +)/HER2- breast cancer displayed a higher pCR rate (20.2