HER2-positive Invasive Breast Cancer Research Articles

Survival following adjuvant trastuzumab-based treatment among older patients with HER2-positive early invasive breast cancer: A national population-based cohort study using routine data

BackgroundRandomised controlled trials (RCTs) reported adjuvant trastuzumab-based treatment improved overall survival (OS) among patients with HER2-positive early invasive breast cancer (EIBC). Few RCTs included older patients or those with comorbidity/frailty. This study aimed to determine whether the effect of adjuvant trastuzumab-based treatment on survival outcomes varies by patient age and fitness, using national data from routine care. MethodsWomen (50+ years) newly-diagnosed with HER2-positive EIBC between 2014 and 2019 were identified from England Cancer Registry data. Registration records were linked to Systemic Anti-Cancer Therapy data for treatment details and ONS death register for mortality details. A propensity score analysis employing the inverse probability of treatment weighting method was used to balance the patient variables across treatment groups. Cox models were used to evaluate whether the effect of treatment on OS was associated with patient age and fitness; competing risks regression models were used for breast cancer-specific survival (BCSS). Results5238 women initiated adjuvant trastuzumab-based treatment. Median follow-up was 56.7 months. Comparison with 3421 women who did not receive adjuvant trastuzumab highlighted differences at diagnosis in relation to age, fitness, grade, nodal involvement, surgery type and use of radiotherapy. Weighted survival analysis found trastuzumab was associated with improved OS (hazard ratio HR 0.56, 95 %CI: 0.45–0.70) and improved BCSS (subHR 0.62, 95 %CI: 0.47–0.82). We found no evidence of a difference in effect by age or patient fitness for either outcome. ConclusionIn this national dataset, adjuvant trastuzumab was associated with improvements in survival, with an OS effect size similar to RCT evidence. The effect size was not found to vary by patient age or fitness. Chronological age and fitness alone should not be barriers to receipt of effective adjuvant targeted treatment.

Real-world analysis of inetetamab combined with pyrotinib plus chemotherapy for the treatment of HER2-positive advanced breast cancer: A multi-center retrospective study.

e13012 Background: Inetetamab combined with tyrosine kinase inhibitors exhibited stronger antitumor effects than inetetamab alone. At present, there was few studies on the efficacy and safety of inetetamab combined with pyrotinib in the treatment of advanced breast cancer (ABC) patients. The study aims to investigate the efficacy and safety of inetetamab combined with pyrotinib plus chemotherapy for HER2-positive ABC patients. Methods: We retrospectively investigated the medical records of eligible women who aged 18 years or older with pathologically confirmed HER2-positive recurrent or metastatic invasive breast cancer, and received at least two cycles of inetetamab combined with pyrotinib plus chemotherapy treatment regimens in multicenters in China between July 2020 and December 2022. The primary endpoint was progression-free survival (PFS) estimated by the Kaplan-Meier method. The secondary endpoints were the objective response rate (ORR), disease control rate (DCR), and safety. Cox regression model was used to identify predictive factors for PFS. Results: A total of 99 patients were included. Overall patient's median PFS was 12.3 (95% CI: 10.9-13.6) months. Of 99 evaluable patients, 53 (53.5%) patients achieved objective response, including 9 (9.1%) complete response and 44 (44.4%) partial response. The remaining 45 patients achieved stable disease as the best response, thus, the DCR was 99.0%. Patients who received Inetetamab combined with pyrotinib plus chemotherapy as first-line treatment (15.0 months [95% CI: 13.6-15.8]) provided longer median PFS than that as second-line treatment (10.3 months [95% CI:9.6-10.9], p<0.001). Furtherly, the Cox multivariate regression analysis indicated that patients who received inetetamab combined with pyrotinib plus albumin-bound paclitaxel for first-line treatment achieved longer median PFS. Grade 1-2 diarrhea (59.6%), vomiting (29.3%) and nausea (28.3%), hand-foot syndrome (23.2%) were the top four most common adverse events (AEs). The most common grade ≥3 AEs were leukopenia (19.2%), diarrhea (18.2%), myelosuppression (7.1%) and neutromenia (4.0%). Conclusions: The first-line treatment of inetetamab combined with pyrotinib plus chemotherapy was an effective and safe treatment for HER2-positive ABC patients. Inetetamab combined with pyrotinib plus albumin-bound paclitaxel might be the most effective combination therapies. All AEs were controllable and tolerable.

Preoperative Differentiation of HER2-Zero and HER2-Low from HER2-Positive Invasive Ductal Breast Cancers Using BI-RADS MRI Features and Machine Learning Modeling.

Accurate determination of human epidermal growth factor receptor 2 (HER2) is important for choosing optimal HER2 targeting treatment strategies. HER2-low is currently considered HER2-negative, but patients may be eligible to receive new anti-HER2 drug conjugates. To use breast MRI BI-RADS features for classifying three HER2 levels, first to distinguish HER2-zero from HER2-low/positive (Task-1), and then to distinguish HER2-low from HER2-positive (Task-2). Retrospective. 621 invasive ductal cancer, 245 HER2-zero, 191 HER2-low, and 185 HER2-positive. For Task-1, 488 cases for training and 133 for testing. For Task-2, 294 cases for training and 82 for testing. 3.0 T; 3D T1-weighted DCE, short time inversion recovery T2, and single-shot EPI DWI. Pathological information and BI-RADS features were compared. Random Forest was used to select MRI features, and then four machine learning (ML) algorithms: decision tree (DT), support vector machine (SVM), k-nearest neighbors (k-NN), and artificial neural nets (ANN), were applied to build models. Chi-square test, one-way analysis of variance, and Kruskal-Wallis test were performed. The P values <0.05 were considered statistically significant. For ML models, the generated probability was used to construct the ROC curves. Peritumoral edema, the presence of multiple lesions and non-mass enhancement (NME) showed significant differences. For distinguishing HER2-zero from non-zero (low + positive), multiple lesions, edema, margin, and tumor size were selected, and the k-NN model achieved the highest AUC of 0.86 in the training set and 0.79 in the testing set. For differentiating HER2-low from HER2-positive, multiple lesions, edema, and margin were selected, and the DT model achieved the highest AUC of 0.79 in the training set and 0.69 in the testing set. BI-RADS features read by radiologists from preoperative MRI can be analyzed using more sophisticated feature selection and ML algorithms to build models for the classification of HER2 status and identify HER2-low. Stage 2.

Abstract PO2-18-12: Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer

Abstract Background: Inetetamab is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity effect. However, robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) for neoadjuvant therapy is still lacking. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy for patients with locally advanced HER2-positive breast cancer. We now present the updated results of this trial. Methods: This phase II trial included female patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients received TCbIP treatment every three weeks for a maximum of six cycles followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease &amp;lt; 1cm) rate, objective response rate (ORR) and safety. Results: From November 2021 to July 2023, 40 patients were enrolled in the trial. One patient received one cycle of the study treatment but was lost to follow-up without surgery, and five patients received one cycle of the study treatment and were still undergoing treatment, leaving 34 patients in the intention-to-treat (ITT) population. Among these 34 patients (82.4% in stage III), 22 patients completed the study treatment and surgery (per-protocol [PP] population) and 12 patients were still undergoing neoadjuvant treatment. The ORR was 91.2% (31/34) in the ITT population and 86.4% (19/22) in the PP population. Among the 22 patients in the PP population, 12 patients (54.5%) achieved pCR, and18 patients (81.8%) achieved npCR. The pCR rates for patients with hormone receptor (HR) negative and positive tumors were 80.0% (8/10) and 33.3% (4/12), respectively. The most common grade 3 adverse event was neutropenia (17.6%). No significant reduction in the left ventricular ejection fraction was observed in any patient. Conclusions: Neoadjuvant therapy with TCbIP demonstrated promising efficacy and manageable toxicity in patients with HER2-positive locally advanced breast cancer. Registration number: NCT05749016 (www.clinicaltrials.gov). Citation Format: Yue Chai, Jiaxuan Liu, Mingxia Jiang, Maiyue He, Xin Wang, Yipeng Wang, Xue Yang, Jing Wang, Binghe Xu, Qiao Li. Updated Results of a Phase II Study: Neoadjuvant Inetetamab Combined with Pertuzumab, Paclitaxel and Carboplatin for Locally Advanced HER2-Positive Breast Cancer [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 PO2-18-12.

Abstract PO3-18-11: A011801 (CompassHER2 RD): Postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer

Abstract Background: Patients with HER2+ early breast cancer (EBC) and invasive residual disease (RD) after neoadjuvant therapy (NAT) have a higher risk of relapse than patients who have a pathologic complete response (pCR). Escalation of therapy in patients with RD using post-neoadjuvant T-DM1 has become the new standard of care, leading to improved invasive disease-free survival (iDFS), but patients with estrogen receptor (ER)-negative or nodal RD have suboptimal outcomes, and central nervous system recurrences are a challenge. More effective treatment strategies are urgently needed. Alliance A011801 (CompassHER2 RD) is an escalation trial for patients with high-risk HER2+ RD after neoadjuvant systemic therapy, evaluating the addition of the HER2 selective tyrosine kinase inhibitor (TKI) tucatinib to post-neoadjuvant T-DM1. Methods: Eligibility and Intervention: Patients with high-risk HER2+ RD (i.e., ER-, node-positive, or both) after a predefined course of neoadjuvant HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 + placebo, vs. T-DM1 and tucatinib with adjuvant RT +/- ET. Eligibility criteria include completion of ≥ 6 cycles of NAT, including ≥ 9 weeks of paclitaxel and trastuzumab +/- pertuzumab. All chemotherapy (CT) must be completed preoperatively unless participating in EA1181 (~15-30% will be participants in the CompassHER2 pCR de-escalation companion trial [NCT04266249]; these patients must receive postoperative CT to complete ≥ 6 cycles prior to enrollment on A011801). Patients who received prior HER2-targeted TKIs or antibody-drug conjugates are ineligible. Objectives: The primary objective is to determine if iDFS is improved with addition of tucatinib to T-DM1 in patients with HER2+ EBC with RD after neoadjuvant systemic therapy; secondary endpoints include overall survival, breast cancer free survival, distant recurrence-free survival, brain metastases-free survival and disease-free survival. Correlative objectives include the association of i) tumor infiltrating lymphocyte (TILs) levels in the primary tumor and RD with iDFS, ii) TILs with tucatinib benefit, iii) iDFS and circulating tumor cells (CTC) at serial timepoints and iv) the magnitude of benefit of tucatinib (iDFS) in patients with/without detectable pretreatment CTCs. Quality of life and pharmacokinetic endpoints are also being evaluated. Statistics: A011801 is a prospective, double-blind, randomized, phase III superiority trial; stratified by i) receipt of postoperative CT (Y/N), ii) hormone receptor-status (+/-), and iii) pathologic lymph node status (+/-). The study targets an absolute difference of 5% in iDFS (control vs. experimental arm 82% &amp; 87%, HR = 0.7), with a two-sided alpha of 0.05 and power of 80%. The sample size is 981; target accrual = 1031 patients; activation and estimated completion dates are 01/6/21 and ~ 01/2028. Accrual as of 7/10/2023: 438 patients. Support: U10CA180821, U10CA180882; Seagen Inc; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT04457596 Citation Format: Ciara O'Sullivan, Karla Ballman, Linda McCall, Tyler Zemla, Anna Weiss, Melissa Mitchell, Victoria Blinder, Nadine Tung, William Irvin, Myounghee Lee, Sailaja Kamaraju, Matthew Goetz, W. Fraser Symmans, Virginia Borges, Ian Krop, Ann Partridge, Lisa Carey. A011801 (CompassHER2 RD): Postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer [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 PO3-18-11.

Response to anti-HER2 neoadjuvant chemotherapy in HER2-positive invasive breast cancers with different HER2 FISH patterns

AimsHuman epidermal growth factor receptor 2 (HER2)-positive patients with breast cancer may have different HER2/CEP17 ratios and HER2 copy numbers, with inconsistent responses to anti-HER2 neoadjuvant chemotherapy (NACT). Our study...

Predictive markers for pathological complete response (pCR) after neo-adjuvant chemotherapy in HER2-positive breast carcinoma.

Patients with HER2-positive invasive breast cancer that is node-positive and/or larger than 3 cm are generally treated with neoadjuvant chemotherapy (NAC). We aimed to identify predictive markers for pathological complete response (pCR) after NAC in HER2-positive breast carcinoma. Hematoxylin/eosin-stained slides of 43 HER2-positive breast carcinoma biopsies were histopathologically reviewed. Immunohistochemistry (IHC) was performed on pre-NAC biopsies, comprising HER2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, epidermal growth factor receptor (EGFR), mucin-4 (MUC4), p53 and p63. Dual-probe HER2 in situ hybridization (ISH) was performed to study the mean HER2 and CEP17 copy numbers. ISH and IHC data were retrospectively collected for a validation cohort, comprising 33 patients. Younger age at diagnosis, 3+ HER2 IHC scores, high mean HER2 copy numbers and high mean HER2/CEP17 ratios were significantly associated with an increased chance of achieving a pCR, and the latter two associations were confirmed in the validation cohort. No other immunohistochemical or histopathological markers were associated with pCR. This retrospective study of two community-based NAC-treated HER2-positive breast cancer patient cohorts identified high mean HER2 copy numbers as a strong predictor for pCR. Further studies on larger cohorts are required to determine a precise cut-point for this predictive marker.

Multiparametric MRI-based radiomics nomogram for predicting the hormone receptor status of HER2-positive breast cancer

To investigate the value of multiparametric magnetic resonance imaging (MRI)-based radiomics nomograms for predicting the hormone receptor (HR) status of HER2-positive breast cancer. Patients with HER2-positive invasive breast cancer were divided randomly into training (68 patients) and validation (30 patients) sets. All were classified as either HR-positive (HR+) or negative (HR-) at histopathology. Two radiologists outlined the three-dimensional (3D) volumetric regions of interest (VOI) on the MRI images. Features (n=1,096) were extracted from the T2-weighted imaging (WI), apparent diffusion coefficient (ADC), and dynamic contrast-enhanced (DCE) images separately. Dimensionality was reduced using feature screening. Binary radiomics prediction models were established using a logistic regression classifier and were validated in the validation set. To construct a nomogram, independent predictors were identified using multivariate logistic regression analysis. The predictive efficacy of the model was assessed using the area under the receiver operating characteristic curve (AUC). Ten radiomics features were obtained after feature dimensionality reduction based on the merged T2WI, ADC, and DCE images. The diagnostic efficacy of the radiomics signature using the three sequences was better than that of any single sequence (training set AUC: 0.797; validation set AUC: 0.75). Using multivariate logistic regression analysis, the independent predictors for identifying HR status were combined radiomics signature and peritumoural oedema. Nomograms constructed by combining the radiomics signature and peritumoural oedema showed good discrimination in both the training and validation sets (AUC: 0.815 and 0. 805, respectively). A multiparametric MRI-based nomogram incorporating the radiomics signature and peritumoural oedema can assess the HR status of HER2-positive breast cancer. The resulting model can improve diagnostic accuracy, improving patient outcomes.

HER2-targeting two-dimensional black phosphorus as a nanoplatform for chemo-photothermal therapy in breast cancer

Trastuzumab (Tmab) targeted therapy or its combination with chemotherapy is normally insufficient to elicit a comprehensive therapeutic response owing to the inherent or acquired drug resistance and systemic toxicity observed in highly invasive HER2-positive breast cancer. In this study, we propose a novel approach that integrates photothermal therapy (PTT) with targeted therapy and chemotherapy, thereby achieving additive or synergistic therapeutic outcomes. We utilize PEGylated two-dimensional black phosphorus (2D BP) as a nanoplatform and photothermal agent to load chemotherapeutic drug mitoxantrone (MTO) and conjugate with Tmab (BP-PEG-MTO-Tmab). The in vitro and in vivo experiments demonstrated that the HER2-targeting BP-PEG-MTO-Tmab complexes exhibited desirable biocompatibility, safety and enhanced cancer cell uptake efficiency, resulting in increased accumulation and prolonged retention of BP and MTO within tumors. Consequently, the complex improved photothermal and chemotherapy treatment efficacy in HER2-positive cells in vitro and a subcutaneous tumor model in vivo, while minimized harm to normal cells and showed desirable organ compatibility. Collectively, our study provides compelling evidence for the remarkable efficacy of targeted and synergistic chemo-photothermal therapy utilizing all-in-one nanoparticles as a delivery system for BP and chemotherapeutic drug in HER2-positive breast cancer.

Treatment-related acute toxicity with adjuvant systemic treatment among patients with HER2-positive early invasive breast cancer: a national population-based cohort study

ObjectiveAlthough adjuvant trastuzumab-based treatment (TBT) improves survival for patients with HER2-positive early invasive breast cancer (EIBC), risk of toxicity grows as patient age increases. We examined use of TBT and...

Pathological complete response and survival of HER2-positive invasive breast cancer following docetaxel, carboplatin, and trastuzumab neoadjuvant therapy: a Vietnamese experience

Introduction. Neoadjuvant chemotherapy for HER2-positive breast cancer consists of a chemotherapy regimen plus trastuzumab with or without pertuzumab. The use of trastuzumab has been shown to improve pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS). Purposes: To evaluate the efficacy and safety of neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) in the treatment of HER2-positive breast cancer in Vietnamese patients. Material and methods. This retrospective study reviewed stage II–III HER2-positive breast cancer patients who received neoadjuvant docetaxel, carboplatin, and trastuzumab (TCH) at the Vietnamese National Cancer Hospital. The primary endpoint was the pCR rate which was defined as the absence of invasive tumor in the breast and axillary nodes (ypT0/is, ypN0). The secondary endpoints were DFS, OS, and toxicities. Results. The complete and partial clinical response of 51 patients were 33.3% and 58.8%, respectively. The pCR rate was 41.2%; there was a significantly higher response in cT1-2 patients compared to cT3-4 ones (61.1% vs. 39.3%, p = 0.033). Three-year estimated DFS and OS rates were 81.3% and 93.0%, respectively. Treatment was generally well tolerated. Grade 3/4 neutropenia and anemia were uncommon (21.6% and 7.8%). No symptomatic cardiac dysfunction occurred. Conclusions. Neoadjuvant TCH, non-anthracycline chemotherapy with single anti-HER2 regimen achieved high efficacy, with a good pCR rate and favorable tolerability in stage II or III HER2-positive breast cancer patients.

Pathologic complete response of ductal carcinoma in situ to neoadjuvant systemic therapy in HER2-positive invasive breast cancer patients: a nationwide analysis

PurposeDuctal carcinoma in situ (DCIS) is present in more than half of HER2-positive invasive breast cancer (IBC). Recent studies show that DCIS accompanying HER2-positive IBC can be completely eradicated by neoadjuvant systemic therapy (NST). Our aim was to determine the percentage of pathologic complete response of the DCIS component in a nationwide cohort and to assess associated clinicopathologic variables. Furthermore, the impact on surgical treatment after NST was investigated.MethodsWomen diagnosed with HER2-positive IBC, treated with NST and surgery, between 2010 and 2020, were selected from the Netherlands Cancer Registry. Pre-NST biopsy and postoperative pathology reports were obtained from the Dutch Nationwide Pathology Databank and assessed for the presence of DCIS. Clinicopathologic factors associated with DCIS response were assessed using logistic regression analyses.ResultsA DCIS component was present in the pre-NST biopsy in 1403 (25.1%) of 5598 included patients. Pathologic complete response of the DCIS component was achieved in 730 patients (52.0%). Complete response of DCIS occurred more frequently in case of complete response of IBC (63.4% versus 33.8%, p < 0.001). ER-negative IBC (OR 1.79; 95%CI 1.33–2.42) and more recent years of diagnosis (2014–2016 OR 1.60; 95%CI 1.17–2.19, 2017–2019 OR 1.76; 95%CI 1.34–2.34) were associated with DCIS response. Mastectomy rates were higher in IBC+DCIS compared to IBC (53.6% versus 41.0%, p < 0.001).ConclusionPathologic complete response of DCIS occurred in 52.0% of HER2-positive IBC patients and was associated with ER-negative IBC and more recent years of diagnosis. Future studies should investigate imaging evaluation of DCIS response to improve surgical decision making.

Association of HER2/CEP17 ratio with pCR after HER2-directed neoadjuvant treatments in the phase III NeoALTTO trial.

600 Background: HER2-directed therapies are approved for the treatment of patients with HER2-positive invasive breast cancer as defined by HER2 protein overexpression, or HER2 gene amplification based on HER2/chromosome enumeration probe (CEP17) ratio ≥ 2.2. Above this accepted HER2 status determination, however, it is still unknown whether the efficacy of HER2-directed therapy in early breast cancer increases with increasing HER2/CEP17 ratios. Therefore, the purpose of the presented work is to evaluate whether quantitative assessment of the HER2/CEP17 ratio predicts pathological complete response (pCR) and event-free survival (EFS) of patients treated with neo-adjuvant HER2-based regimen in the prospective phase III NeoALTTO trial. Methods: 455 women with HER2-positive early breast cancer, who had received neo-adjuvant trastuzumab and/or lapatinib for 6 weeks and then together with 12 cycles of weekly paclitaxel were included in this analysis. The HER2/CEP17 ratio in the primary tumor samples was correlated with pCR and survival outcome. Results: The Median HER2/CEP17 ratio in NeoALTTO was 5.1 (range: 1.1 – 100.0), and ratios were not associated with age, hormone receptor status, or any of the other clinicopathological variables analyzed. The log HER2/CEP17 ratio significantly predicted for pCR in both uni-variate (OR: 1.83; 95% CI: 1.11 - 3.01, p = 0.0176) and multivariate analysis (OR: 1.79; 95% CI: 1.07 - 2.99, p = 0.0257). Higher HER2/CEP17 ratios were, however, not associated with improved EFS (adjusted HR = 0.79; p = 0.3537). A pCR prediction model which included HER2/CEP17 ratio, treatment arm, and hormone receptor status improved the predictive strength of treatment arm alone from a ROC AUC value of 0.60 to 0.69. Conclusions: In patients treated with HER2-based neoadjuvant therapy, quantitative analysis of the readily available pre-treatment HER2/CEP17 ratio by FISH is predictive of pCR but not EFS.

Neoadjuvant inetetamab combined with pertuzumab, paclitaxel, and carboplatin (TCbIP) for locally advanced HER2-positive breast cancer: Primary analysis of a phase II study.

e12597 Background: Inetetamab (Cipterbin) is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity (ADCC) effect. Unfortunately, no robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) exists for neoadjuvant therapy. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy of patients with locally advanced (LA) HER2-positive breast cancer. Methods: This phase II trial included patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients receive TCbIP treatment every 3 weeks for a maximum of 6 cycles, followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease &lt; 1cm) rate, objective response rate (ORR) and safety. Efficacy was analyzed in the intention-to-treat (ITT) and per-protocol (PP) populations. The ITT population included patients who received at least 2 cycles of TCbIP treatment but excluded those who were lost to follow-up without surgery and those who received other targeted therapy. The PP population included patients who met all the trial criterias, complianted with the protocol, and did not violate any major protocol. The safety population included all patients who received at least one dose of the study drugs and had available safety data. Results: A total of 24 patients were enrolled from November 2021 to February 2023. Of 24 patients, 1 patient received 1 cycle of study treatment and was lost to follow-up without surgery, and 4 patients received 1 cycle of study treatment and were still in treatment, leaving 19 patients in the ITT population. Among 19 patients in the ITT population (median age, 50 years; 78.9% in stage III), 12 patients completed the study treatment and surgery (PP population) and 7 patients were still in neoadjuvant treatment. ORR was achieved 78.9% in the ITT population (15 of 19 patients) and 91.7% in the PP population (11 of 12 patients). Among 12 patients of PP population, 8 patients (66.7%) achieved pCR and 10 patients (83.3%) achieved npCR. For patients with hormone receptor negative and positive tumors, the pCR rates were 71.4% (5/7) and 60.0% (3/5) ( P = 0.771), and the npCR rates were 85.7% (6/7) and 80.0% (4/5) ( P = 0.793), respectively. The most common grade ³3 adverse events were hair loss (41.7%) and neutropenia (12.5%). No significant reduction in the left ventricular ejection fraction was observed in any patient. No patients withdrew from the treatment due to adverse drug reactions. Conclusions: TCbIP displays a promising efficacy (pCR rate of 66.7%) and manageable toxicity in patients with HER2-positive LA breast cancer in the neoadjuvant setting. Clinical trial information: NCT05749016 .

99P Exploratory analysis of differential gene expression (DGE) and non-negative matrix factorisation (NMF) clustering in KATHERINE: Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (H) in patients with HER2-positive residual invasive breast cancer after neoadjuvant treatment (NAT)

99P Exploratory analysis of differential gene expression (DGE) and non-negative matrix factorisation (NMF) clustering in KATHERINE: Adjuvant trastuzumab emtansine (T-DM1) vs trastuzumab (H) in patients with HER2-positive residual invasive breast cancer after neoadjuvant treatment (NAT)

Abstract P4-06-02: Complete response of ductal carcinoma in situ to neoadjuvant systemic therapy in HER2-positive invasive breast cancer patients: a nationwide analysis

Abstract Introduction Neoadjuvant systemic therapy (NST) is increasingly applied in breast cancer to increase breast-conserving surgery (BCS) rates and to improve oncological outcomes. Ductal carcinoma in situ (DCIS) can be present adjacent to invasive breast cancer (IBC), especially in HER2-positive IBC. DCIS was previously considered to be insensitive to NST. Consequently, mastectomy rates are higher in IBC with adjacent DCIS. Recent studies have shown that DCIS can be sensitive to NST, however, only small populations were investigated. Therefore, the aim of this study was to determine the rate of complete response of adjacent DCIS in HER2-positive IBC and to assess the potential influence of clinicopathological variables in a nationwide cohort. Methods All women diagnosed with HER2-positive IBC, treated with NST and surgery between January 2010 and December 2019, were selected from the Netherlands Cancer Registry (NCR). Of these patients, all pre-NST biopsy and postoperative specimen pathology reports were obtained from PALGA, the Dutch Pathology Registry, and assessed for presence of DCIS. Response of DCIS was defined as absence of DCIS in postoperative pathology when a DCIS component was present in the pre-NST biopsy. Clinicopathological factors associated with DCIS response were assessed using logistic regression analyses. Results In total, 5834 patients were included, of whom 1443 (24.7%) had a DCIS component in the pre-NST biopsy. Mastectomy rates were higher in IBC with adjacent DCIS compared to IBC without adjacent DCIS in the pre-NST biopsy (53.6% versus 41.0%, p&amp;lt; 0.001). Of these 1443 patients, 743 (51.5%) showed complete response of the DCIS component. Complete response of DCIS occurred more frequently in patients who also had a complete response of IBC (63.4% versus 33.8%, p&amp;lt; 0.001). Multivariable logistic regression analysis showed ER negative IBC (OR 1.79; 95% CI 1.33-2.42) and treatment with HER2-targeted therapy (OR 5.97; 95% CI 1.82-19.55) to be independently associated with complete response of DCIS. Conclusion More than half of HER2-positive IBC patients with adjacent DCIS in the pre-NST biopsy showed a complete response of the DCIS component to NST. Complete response of DCIS should be considered, especially in ER-negative HER2-positive IBC and in case of complete response of IBC. Future studies should investigate the evaluation of DCIS response by imaging and the possibility of increasing breast-conserving surgery rates. Citation Format: Roxanne Ploumen, Eva Claassens, Loes Kooreman, Kristien Keymeulen, Maartje van Kats, Suzanne Gommers, Sabine Siesling, Thiemo van Nijnatten, Marjolein Smidt. Complete response of ductal carcinoma in situ to neoadjuvant systemic therapy in HER2-positive invasive breast cancer patients: a nationwide analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-06-02.

Abstract P1-12-03: Antidiarrheal prophylaxis with loperamide for patients with lymph node-negative (N0) or micrometastatic (N1mi), HER2-positive breast cancer who received adjuvant pyrotinib plus nab-paclitaxel: a randomized sub-study of PHAEDRA

Abstract Background: Diarrhea is the most common adverse event of pan-HER tyrosine kinase inhibitors. There is no consensus on therapeutic or prophylactic strategy of pyrotinib-related diarrhea. PHAEDRA is an ongoing multicenter, single-arm, phase II trial conducted to evaluate adjuvant pyrotinib plus nab-paclitaxel for patients with low-risk HER2-positive breast cancer. Here, we reported the results from the sub-study of PHAEDRA, which investigated the effect of different prophylactic strategies with loperamide for diarrhea. Methods: In PHAEDRA, patients with N0/N1mi, HER2-positive invasive breast cancer and primary tumor ≤3 cm received nab-paclitaxel 260 mg/m2 once every 3 weeks for 12 weeks and pyrotinib 400 mg once daily for one year within 90 days after surgery. In the sub-study, patients were randomly assigned to receive loperamide 4 mg three times a day on days 1-7 and twice a day on days 8-21 (cohort A) or days 8-42 (cohort B) since the initiation of adjuvant therapy. The primary endpoint of the sub-study was the incidence of grade ≥3 diarrhea. Results: Between January 2021 and May 2022, the enrollment of 120 patients in the sub-study was completed. Grade ≥3 diarrhea was reported in 18 (30%) of 60 patients in cohort A and 19 (32%) of 60 patients in cohort B. The median time to first grade ≥3 diarrhea was 4.5 days (IQR, 1.0-6.5) in cohort A and 4 days (IQR, 1.0-6.0) in cohort B. The median number of grade ≥3 diarrhea episodes was 1 (IQR, 1-1) in both cohorts. Three (5%) patients in each cohort had constipation events, respectively, which were all grade 1 or 2. One (2%) patient in cohort A and two (3%) in cohort B had dose reductions of loperamide due to constipation, and no patients discontinued loperamide. One (2%) patient in cohort A had dose reduction of pyrotinib and one (2%) in each cohort discontinued pyrotinib due to diarrhea. Conclusions: The effects of both loperamide regimens on antidiarrheal prophylaxis were consistent with that of loperamide prophylaxis in the CONTROL trial, but with extremely fewer constipation events. Long-course and short-course loperamide prophylaxis showed numerically similar incidence of grade ≥3 diarrhea. Proactive diarrhea management can promote the full-dose and full-course treatment with pyrotinib. It is still necessary to develop more effective antidiarrheal prophylaxis regimens for pan-HER tyrosine kinase inhibitors. Citation Format: Changjun Wang, Yan Lin, Yidong Zhou, Feng Mao, Jinghong Guan, Songjie Shen, Xuejing Wang, Xiaohui Zhang, Yanna Zhang, Bo Pan, Ying Zhong, Li Peng, Yan Li, Xin Huang, Ying Xu, Qiang Sun. Antidiarrheal prophylaxis with loperamide for patients with lymph node-negative (N0) or micrometastatic (N1mi), HER2-positive breast cancer who received adjuvant pyrotinib plus nab-paclitaxel: a randomized sub-study of PHAEDRA [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-03.

Abstract P1-11-20: Trastuzumab (HLX02) plus Pertuzumab as Dual-target Neoadjuvant Therapy for HER2-positive Breast Cancer: A Real-World Study

Abstract Background: The effect of neoadjuvant therapy on tumor downstaging and breast-conserving during surgery is well documented. Pathologic complete response (pCR) after neoadjuvant treatment was associated with long-term survival. HLX02 (Zercepac®), a biosimilar of trastuzumab, showed the same efficacy, safety, and immunogenicity as the reference drug in human epidermal growth factor receptor-2 (HER2)-positive patients. Despite this, real-world evidence of its effectiveness when combined with pertuzumab in neoadjuvant treatment of HER-2 positive breast cancer still lacks. Methods: In this retrospective real-world study, women with confirmed invasive HER2-positive breast cancer who have received chemotherapy plus HLX02 and pertuzumab (Perjeta®) as neoadjuvant therapy were enrolled. Patients must be over 18 years old, have an Eastern Cooperative Oncology Group performance status score of 0 or 1, and have a baseline left ventricular ejection fraction of ≥ 55%. Patients without pathological assessment after neoadjuvant therapy were excluded. Pathologic complete response (pCR) was defined as no residual invasive tumors in mammary glands and axillary lymph nodes. Clinical response was assessed using RECIST1.1. To investigate the factors associated with pCR, univariate and multivariate logistic regression (forward stepwise) analyses were conducted. Results: A total of 85 patients were enrolled in this study, and 55 patients (64.71%) achieved pCR after neoadjuvant therapy. There were 84 (98.82%) patients with partial response (PR), one (1.18%) patient with stable disease (SD). According to the univariable analysis, when compared to those with a tumor diameter ≤ 5 cm, patients with a tumor diameter &amp;gt; 5 cm at baseline showed a lower pCR rate (odds ratio [OR] = 0.286; 95% confidence interval [CI]: 0.108-0.758, P = 0.01). Patients with preoperative PR positivity &amp;gt; 10% showed lower pCR rate than those with preoperative PR positivity &amp;lt; 1% (OR = 0.115, 95% CI 0.036-0.372, P = 0.02). Besides, pCR was more common in patients with preoperative hormone receptor (HR)-negative than in those with preoperative HR-positive (ER or PR positivity &amp;gt; 10%) (OR = 4.452, 95% CI 1.679-11.804, P &amp;lt; 0.01). Multivariable analyses showed that patients with tumor diameter &amp;gt; 5 cm had a lower pCR rate than those with tumor diameter ≤ 5cm (OR = 0.213; 95% CI 0.070-0.644, P = 0.01). Patients with preoperative HR-negative tumors were more likely to achieve pCR than those with preoperative HR-positive tumors (OR =5.649, 95% CI 1.927-16.556, P &amp;lt; 0.01) (Table 1). The treatment were well tolerated by patients, and no additional adverse events were reported. Conclusion: According to this real-world study, HLX02 in combination with pertuzumab as neoadjuvant therapy for HER2-positive breast cancer patients showed a similar pCR rate to that of dual-target neoadjuvant therapy reported in previous clinical trials. The treatment showed an encouraging effectiveness, and may become a novel neoadjuvant option for patients with HER2-positive breast cancer. The study was supported by the Natural Science Foundation of Shanghai (21ZR1414700). Table 1. Logistic regression for pCR. Citation Format: Yin Liu, Wen-Jia Zuo, Ruo-Xi Wang, Zhong-Hua Wang, Zhi-Ming Shao. Trastuzumab (HLX02) plus Pertuzumab as Dual-target Neoadjuvant Therapy for HER2-positive Breast Cancer: A Real-World Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-20.

HER2-positive invasive lobular carcinoma: a rare breast cancer which may not necessarily require anti-HER2 therapy. A population-based study.

HER2-positive (HER2 +) invasive lobular breast cancer (ILC) is rare and poorly characterised. In particular, patient outcomes compared to those associated with HER2 + invasive ductal cancer (IDC) and HER2-negative (HER2-) ILC, as well as the benefits of anti-HER2 therapy, are not well established. We analysed the data from the Côte d'Or Registry of Breast and Gynaecological Cancers (France) for all patients diagnosed with early-stage HER2 + ILC (62 cases), HER2 + IDC (833 cases) and HER2- ILC (685 cases) between 1998 and 2015 to compare overall and disease-free survival (OS and DFS) between these groups in correlation with anti-HER2 therapy. ILCs were associated with older age, larger tumours, lower histological grades, higher hormonal receptor positivity rates and multifocality, and more common endocrine therapy. OS and DFS between the three groups did not differ. We found that anti-HER2 therapy was associated with a survival benefit in patients with HER2 + IDC. In contrast, the survival of HER2 + ILC patients was not improved by anti-HER2 treatment, remaining close to that of HER2- ILC patients. HER2 + ILC seems not to be associated with better outcomes than HER2 + IDC but may not differ from HER2- ILC in terms of survival.

The efficacy and safety of epirubicin and cyclophosphamide combined with pyrotinib in neoadjuvant treatment for HER2-positive breast cancer: A real-world study.

Long-term survival benefit of anthracyclines for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is clear. In the neoadjuvant treatment, compared with the monoclonal antibody such as trastuzumab and pertuzumab, the clinical benefit of pyrotinib, a new small-molecule tyrosine kinase inhibitor (TKI), as the main anti-HER2 strategy currently requires more research to determine. Our real-world study is the first prospective observational study in China to evaluate the efficacy and safety of epirubicin (E) and cyclophosphamide (C) with pyrotinib as anti-HER2 therapy in the neoadjuvant setting of patients with stage II-III HER2-positive breast cancer. From May 2019 to December 2021, 44 untreated patients with HER2-positive nonspecific invasive breast cancer who received 4 cycles of neoadjuvant EC with pyrotinib. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included the overall clinical response, breast pathological complete response rate (bpCR), the rate of axillary lymph nodes pathological negativity and adverse events (AEs). Other objective indicators were the rate of surgical breast-conserving, the negative conversion ratios of tumor markers. Thirty-seven (84.1%) of 44 patients completed this neoadjuvant therapy, and 35 (79.5%) had surgery and were included in the primary endpoint assessment. The objective response rate (ORR) of 37 patients was 97.3%. Two patients reached clinical complete response, 34 obtained clinical partial response, 1 sustained stable disease, and no one had progressive disease. Eleven (31.4%) of 35 patients who had surgery achieved bpCR and the rate of axillary lymph nodes pathological negativity was 61.3%. The tpCR rate was 28.6% (95% CI: 12.8-44.3%). Safety was evaluated in all 44 patients. Thirty-nine (88.6%) had diarrhea, and 2 developed grade 3 diarrhea. Four (9.1%) patients had grade 4 leukopenia. All grade 3-4 AEs could be improved after symptomatic treatment. The regimen of 4 cycles of EC combined with pyrotinib presented some feasibility in the neoadjuvant setting for HER2-positive breast cancer with manageable safety. New regimens with pyrotinib should be evaluated for higher pCR in future. chictr.org Identifier: ChiCTR1900026061.