The ROOT-CTRCD study: exploring the relationship of oral health to cancer therapy-related cardiac dysfunction in HER2-positive breast cancer patients.

SY10-1 - The Upfront Therapy for HER2 Positive Breast Cancer Patients

Background: Tumor-associated macrophages (TAMs) are considered to be one of the key players in the tumor microenvironment, which regulates cancer invasion and metastases. TAMs can be divided into two phenotypes with opposite functions. While M1 macrophages are known to exert anti-tumor activity by promoting pro-inflammatory effects and immune responses such as intereukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), M2 macrophages influence an anti-inflammatory response, wound healing, and pro-tumorigenic properties. A bioactive lipid mediator, sphingosine-1-phosphate (S1P) has emerged as a key regulatory molecule in cancer progression. We previously demonstrated that S1P generated by sphingosine kinase 1 (SPHK1), is a crucial mediator of breast cancer-induced angiogenesis and lymphangiogenesis, and promotes its metastasis. In particular, we found that SPHK1 is highly expressed in HER2 negative breast cancer, and the patients who developed lymph node metastasis demonstrated significantly higher levels of S1P (J Surg Res 2016). Although we have previously reported the role of S1P in recruitment of TAMs in vivo (Cancer Res 2018), its relevance in patients is yet to be uncovered. Here, we test our hypothesis that S1P signaling affects TAMs in human patients with breast cancer. Materials and Methods: The expression level of each enzyme-encoding gene involved in S1P production was evaluated by retrieving RNA sequencing and gene expression quantification data using the Genomics Data Commons (GDC) data portal of the The Cancer Genome Atlas cohort. Gene expression levels were derived using normalization methods provided in the DESeq2 package. We compared the difference in expression levels of tumor associated macrophage related genes, including CD68, CD163, IL-6, andTNF-α between SPHK1-high breast tissue, and SPHK1-low breast tissue in the group of HER2 negative or positive patients. Unpaired t-tests were performed to compare expression differences between SPHK1-high and SPHK1-low breast tissue. All tests were two-sided and P values < 0.05 were considered statistically significant. Results: CD68, pan-macrophage marker, is significantly increased in SPHK1-high breast cancer tissues both in HER2 negative and positive breast cancer patients (p=<0.001, <0.01). CD163 which is a scavenger receptor that is regarded as highly specific for M2 macrophages is significantly increased in SPHK1-high breast cancer tissues in HER2 negative breast cancer patients, but not in HER2 positive breast cancer patients (p=<0.001, 0.2). IL-6, which characterize M1 phenotype is significantly increased in SPHK1-high breast cancer tissues both in HER2 negative and positive breast cancer patients (p=<0.001, <0.001). TNF-α, which also characterizes M1 phenotype, is significantly increased in SPHK1-high breast cancer tissues in HER2 negative breast cancer patients, but not in HER2 positive breast cancer patients (p=<0.001, 0.05). Conclusion: Our results suggest that S1P affects TAMs in breast cancer patients, which implicate the important roles of S1P in the complicated immune system related to tumor progression. Our results also indicate that S1P have a large role in HER2 negative breast cancer patients. Further investigations are needed to understand the underlying mechanisms. Citation Format: Tsuchida J, Nagahashi M, Moro K, Ikarashi M, Koyama Y, Sakata J, Kobayashi T, Kameyama H, Qi Q, Yan L, Takabe K, Wakai T. Sphingosine-1-phosphate affects tumor-associated macrophages in breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-19.

587 Background: IGF receptor (IGF1R) signalling has been implicated in resistance to trastuzumab in HER2 positive breast cancer in vitro. However, two previous studies on HER2 positive breast tumors showed that IGF1R expression does not correlated with response to trastuzumab. The relationship between activation of the IGF1R and response to trastuzumab has not been examined in HER2 positive tumours. The aims of this study were to examine IGFIR and phosphorylated IGFIR (pIGF1R) in HER2 positive breast tumours, and to correlate IGFIR and pIGFIR with response to trastuzumab. Methods: Formalin-fixed paraffin-embedded tumour samples were obtained from 160 HER-2 positive breast cancer patients. Tissue microarrays were constructed using 4 cores from each specimen. Antigen retrieval was performed using pH6 antigen retrieval buffer (DAKO) and immunohistochemical (IHC) staining was performed on an autostainer (DAKO) using an IGF1R antibody and an antibody which detects phosphorylated IGF1R or insulin receptor (pIGF1R/IR). IHC results were correlated with tumor characteristics using Chi Square tests. Survival data was available for 94 HER2 positive early stage breast cancer patients who received trastuzumab, (median follow up 5.1 yrs). Survival analysis was performed using Kaplan Meier curves. Results: Membrane staining for IGF1R (mIGF1R) was detected in only 13.8 % of tumors (22/16), while varying degrees of cytoplasmic IGF1R (cIGF1R) staining were detected in all samples. mIGF1R was detected more frequently in larger tumors (>2 cm) (p=0.0414) and was detected in Grade 2 and 3 tumors but not in Grade 1 tumors (p=0.0239). pIGF1R/IR was detected in 48.8 % of tumors tested (78/160). pIGF1/IR was detected more frequently in node negative (57.6%) than node positive tumors (41.9%) although this difference did not achieve statistical significance (p=0.0592). In the trastuzumab treated cohort of HER2 positive early stage breast cancer patients (n=94), mIGF1R, cIGF1R and pIGF1R/IR did not correlate with patient survival (mIGF1R: p = 0.319; cIGF1R: p = 0.686; pIGF1R/IR: p = 0.504). Conclusions: Phosphorylated IGF1R/IR is detected in 49% of HER2 positive breast tumors but does not seem to predict response or resistance to trastuzumab in early stage breast cancer.

BackgroundBrain metastasis (BM) frequently occurs in HER2-positive breast cancer (BC) patients, but the risk factors of BM in this type of patients are still unknown. Our study aims to assess the risk factors of BM and prognostic analysis in HER2-positive BC patients.MethodsUnivariate analysis used t-test, chi-square test, and Fisher’s exact test to find out the risk factors for BM, and multivariable analysis was done with stepwise logistic regression analysis. Prognostic data analysis was estimated by the Kaplan–Meier method.ResultsA total of 228 HER2-positive BC patients were included, of whom 214 patients were postoperative metastatic patients and 14 patients were de novo stage IV patients. Through comparing the stratified variables between 51 postoperative metastatic patients with BM and 163 postoperative metastatic patients without BM, the multivariate analysis showed that age ≤40 years (OR 2.321, 95% CI: 1.089 to 4.948) and first metastatic site with lung metastasis (OR 2.168, 95% CI: 1.099 to 4.274) were independent risk factors for BM in HER2-positive BC patients. Prognostic data of all 65 HER2-positive BC patients with BM showed that the time from the diagnosis of BC to the development of breast cancer brain metastasis (BCBM) was 36.3 months (95% CI: 30.0 to 42.1 months). The time from the diagnosis of first recurrence and metastasis stage to the diagnosis of BCBM was 11.35 months (95% CI: 7.1 to 18.4 months). The time from the diagnosis of BCBM to the time of follow-up was 24.1 months (95% CI: 13.9 to 37.5 months). Up until the time of follow-up data, a total of 38 patients had died, and the time from the diagnosis of BM of these 38 patients to death was 11.0 months (95% CI: 9.0 to 20.4 months).ConclusionThe prognosis of HER2-positive BC patients with BM was poor due to the lack of effective treatments for BM. Age ≤40 years and first metastatic site with lung metastasis were the independent risk factors for BM in HER2-positive BC patients. Future research about pre-emptive medical interventions may help to improve the prognosis of HER2-positive BC patients with high risk to develop BM.

Background Although trastuzumab has benefits in treatment of HER2 positive breast cancer, it also carries the risk of cardiotoxicity. It is very important to evaluate the cardiac status before and after therapy with trastuzumab, as well as monitoring of electrocardiografic and echocardiographic parameters. The aim of this study was to assess of cardiac function during trastuzumab therapy in HER2 positive breast cancer patients. Method Ninety six HER2 positive female breast cancer patients (mean age, 59.57 ± 9.6 years) were enrolled in the study. At the time, they were on sequential therapy with anthracyclines (IV to VI cycles) within the FAC regimen (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) on day 22, and after that trastuzumab therapy (6 mg/kg of body weight on day 21, for the period of one year). In all patients (pts) blood pressure (BP), heart rate (HR), electrocardiografic and echocardiographic parameters (left ventricular ejection fraction–LVEF(%); fractional shortening–FS(%); end-diastolic diameter–EDD(mm); left ventricular mass – LVM (g)) were assesed at the beginning and after the therapy with trastuzumab. Results There was no significant changes in arterial BP before and after trastuzumab in examined pts (systolic BP119.90 ± 16.04 mmHg vs 121.30 ± 13.06 mmHg; diastolic BP 75.89 ±7.25 mmHg vs 76.30 ± 7.65 mmHg) ns and HR (68.78 ± 7.69/min vs 67.92 ± 7.90/min) ns. All pts at the beginning and after the last therapy with trastuzumab on the electrocardiogram (ECG) were in sinus rhythm, one pts has LBBB and one RBBB. During therapy ectopic beats were registred in 11 pts, SVES in 7 (7.29%), VES in 4(4.16%). In the most of this patients with PSR in the middle of treatment period with trastuzumab sinus tachycardia was recorded as well. At the end of trastuzumab therapy in examined group LVEF was decreased by 1.73% (from 65.49 ± 5.82% to 63.76 ± 6.43%; p = 0.007), FS by 0.86% (from 36.18 ± 5.10% to 35.32 ± 4.91%; p = 0.123) ns, EDD increased by 1.26 mm (from 47.53 ± 4.48 mm to 48.80 ± 5.19 mm; p = 0.005) and LVM increased by 173.68 g (from 161.55 ± 43.76 g to171.15 ± 47.88 g; p = 0.031). Cardiotoxicity is registred in 4 (4.17%) patients, according to the criteria of EACVI and ASE. Results Tratsuzumab has not significant effect on BP and ECG changes.The rate of cardiotoxicity after trastuzumab therapy was low and was expressed through reduction of left ventricle ejection fraction, the increase in the end-diastolic diameter and the left ventricular mass.

Background: Pertuzumab (P) has been aproved in neoadjuvant setting for HER2 positive early breasta cancer patients in association with Trastuzumab (T) and chemotherapy. Diverse studies support this combination as NeoSphere, Tryphaena, GeparSepto or Berenice trial. Some of these studies combine P - T with taxanes and sequencing anthracyclines, and other use antraciclines-free regimen as Carboplatine-Docetaxel-P-T. The patologic complete response (pCR) showed achieve percentages from 45.8 % to 66.6% depending on chemotherapy combination. In Spain, the approval of new drugs is a national issue, but sometimes regional regulatory agencies could modify some indications. We have carry out this study in routine patients as our daily clinical practice. Aims: This is a retrospective and multicentric study that has investigated the clinical characteristics, treatment patterns, safety and clinical outcomes for patient with HER-2 positive early breast cancer patients. Methods: We have collected all HER2 positive early breast cancer patients treated with P in neoadjuvant setting in our hospitals. The effect of adding Pertuzumab on pCR was analyzed, as well as other predictive factors of response using logistic regression analyses. Results: A total of 298 patients met the selection criteria. The median age was 50 years (range 24-88 years), 54,2% were premenopausic. 4 patients were stage I, 194 patients stage II, 95 patients were stage III and one patient was stage IV. 76,3% of the patient had a ki67 >20%. The majority of the patient received anthracyclines and taxanes with P and T regimen (80,7%), 13,2% received carboplatin-docetaxel-P-T combination and only 6,1% received taxane-P-T. 292 patients were analysed for response. pCR was seen in 61,7 % of the patients, dividing by hormonal receptor (HR) status, pCR was 53,29% in HR-positive and 72,14% in HR-negative. 63,4% of the patients received breast conservative surgery. Grade 3-4 chemo-related toxicity was presented in 14,2% of patients, 3 patients presented cardiac toxicity. Different treatments patterns were seen between hospitals: only 15 patients (5,1%) complete adjuvant Pertuzumab, 4 patients (1,4%) received adjuvant Neratinib and 2 patients (0,7%) received adjuvant TDM1. Only 12 patients (4,1%) has presented a distant recurrence, 6 of them (50%) had achieved a previous pCR. Conclusion: In our knowledge, this is the biggest real-world-data presented until this year, for Pertuzumab in the neoadjuvant setting of HER2 positive breast cancer patients. Our results are consistent with those published in previous clinical trial. pCR by subtypepCR NOpCR YESTotalLuminal B HER2+7181152HER2+39101140Total110182292 Citation Format: Alejandro Falcón González, Rocío Álvarez Ambite, Elisenda Llabrés Valenti, Rocío Urbano Cubero, Maria del Carmen Álamo de la Gala, Antonia Martínez Guisado, Carlos José Rodríguez González, Marta Amérigo Góngora, Encarnación González Flores, Salvador Gámez Casado, María Valero Arbizu, Alicia Quilez Cutillas, Josefina Cruz Jurado, Pedro Sánchez Rovira, Fernando Henao Carrasco, Javier Salvador Bofill, Manuel Ruiz Borrego. Neopersur: Neoadjuvant pertuzumab in a real world data population in the south of Spain [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-29.

Background: Human epidermal growth factor receptor 2 (HER2) positive breast cancer represented approximately 15%-20% of all breast cancers. Liver metastasis was commonly observed in patients treated with trastuzumab and tyrosine kinase inhibitor (TKI), thereby further reducing the overall survival to only 8-14 months. MRG002 is a novel antibody-drug conjugate composed of recombinant humanized anti-HER2 monoclonal antibody MAB802 and potent cytotoxic small molecule MMAE linked by the vc-linker. This study was designed to evaluate the efficacy and safety of MRG002 in liver metastases breast cancer patients after the treatment failure of trastuzumab and TKI. Method: This single-armed, open-label, multicenter, phase II study enrolled patients who had received ≥2 lines of anti-HER2 treatment (including trastuzumab and TKI) and had confirmed tumor progression during or after the most recent treatment. MRG002 was administered at a dose of 2.6 mg/kg every 3 weeks until the end of treatment, initiation of new anti-tumor therapy, withdrawal of informed consent, or death. Result: A total of 102 females were enrolled in this study, with a median age of 53 years (range: 26-73). Forty-four patients had an ECOG score of 0, and 58 scored 1. Forty-one patients (40.2%) were immunohistochemistry (IHC) 3+, and 61 (59.8%) were IHC 2+/ISH+. All patients had liver metastasis, 55 (53.9%) had bone metastasis, and 37 (36.3%) had lung metastasis. All patients had received HER2-mAb and anti-HER2-TKI drug treatment (Pyrotinib 94 cases, 92.2%). The median treatment line was 3 (range: 2-10), wherein 39 patients (38.2%) received two treatment lines, 28 (27.5%) received three, and 35 (34.3%) received ≥ four lines. As of July 19, 2024, the median follow-up time was 14.8 months (range: 0.4-27.2), and 7 patients (6.9%) had a treatment duration of nearly 2 years. The Independent Review Committee (IRC) evaluated the objective response rate (ORR) based on RECIST v1.1 as 60.8% (95% CI: 50.6-70.3), the disease control rate (DCR) as 86.3% (95% CI: 78.0-92.3), the median progression-free survival (mPFS) as 8.6 months (95% CI: 6.9-11.9), and the median duration of response (mDoR) as 9.4 months (95% CI: 6.2-16.8). The investigator assessed the ORR as 56.9% (95% CI: 46.7-66.6), the mPFS as 7.5 months (95% CI: 5.7-8.0), and the mDoR as 6.8 months (95% CI: 6.0-8.9). Subgroup analysis showed that the ORR of IHC 3+ and IHC 2+/FISH+ patients were 70.0% and 60.7%, respectively. The mPFS were 11.9 months and 7.7 months, respectively. The most common treatment-related adverse events (TRAEs) included 70.6% white blood cell count decreased, 64.7% neutrophil count decreased, 62.7% AST increased, and 54.9% ALT increased. TRAEs were mainly Grade 1-2 and recovered after treatment. TRAEs ≥ Grade 3 included 31.4% neutrophil count decreased, 13.7% white blood cell count decreased, and 6.9% peripheral neuropathy. No new safety signals were found, and the adverse events were manageable. Conclusion: MRG002 showed a potential efficacy in trastuzumab and anti-HER2-TKI treatment failed HER2-positive liver metastasis breast cancer patients with a good tolerance and safety profile. The emergence of MRG002 presented a promising treatment option for patients. Clinical trial information: NCT05263869 Citation Format: Qiang Liu, Shaohua Zhang, Yaping Yang, Quchang Ouyang, Tao Sun, Yongsheng Wang, Min Yan, Yongmei Yin, Xiaoyu Liu, Shusen Wang, Xinhong Wu, Qingyuan Zhang, Changlu Hu, Hui Li, Wei Li, Fuming Qiu, Jun Qian, Li Sun, Xiaojia Wang, Zefei Jiang. Efficacy and Safety of MRG002 in Prior TKI-Treated HER2 Positive Breast Cancer Patients: A Single Arm, Open Label, Multicenter, Phase II Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-12-21.

Brain relapse is a common occurrence in HER2-positive breast cancer patients. However, the factors determining the risk of brain metastasis in these patients remain to be established. The aim of this study was to assess the impact of particular clinical and pathological factors on the risk of brain relapse in HER2-positive advanced breast cancer patients. The study group included 264 consecutive HER-2 positive metastatic breast cancer patients, most of whom (210; 80%) were administered trastuzumab, usually in combination with chemotherapy. Time from the diagnosis to distant relapse ranged from 0 to 142 months (median 16 months). The most common dominant site of metastatic disease was viscera (80%), followed by soft tissue (11%) and bones (10%). After a median follow-up of 3.1 years, the symptomatic brain relapse occurred in 103 patients (39%). Median time from treatment dissemination to brain relapse was 15 months (range, 0-81 months), and the cumulative 1-year, 3-year and 5-year risk of brain relapse was 17, 42 and 55%, respectively. The average annual risk of brain relapse for surviving patients during consecutive 7 years of follow-up was 10.0% (95% CI, 6.6-13.5%). In the univariate analysis the only variable significantly related to the increased risk of brain relapse was time from initial diagnosis to distant relapse shorter than 2 years (HR = 1.55, 95% CI, 1.03-2.33, P = 0.034). Patients with dominant site of disease in soft tissue or bones tended to have lower risk of relapse (HR = 0.54 and 0.62; P = 0.098 and 0.203, respectively) compared to patients with visceral metastases. Treatment with trastuzumab was not associated with reduced risk of brain relapse (HR = 0.91, 95% CI, 0.47-1.77, P = 0.78). In the multivariate analysis, time from initial diagnosis to distant relapse shorter than 2 years remained the only significant variable related to increased risk of brain relapse (adjusted HR = 1.62, 95% CI, 1.07-2.44; P = 0.022). HER2-positive breast cancer patients remain at high and continuous risk of brain relapse for a prolonged period of time after diagnosis of disease dissemination. Short time from initial diagnosis to distant relapse is related to increased risk of brain relapse. Molecular predictors are sorely needed to better characterize patients with high probability of early brain relapse.

Abstract #2014 Problem Statement: Radiation therapy followed by Trastuzumab-based therapy is the standard of care for Her-2 positive breast cancer (BC) patients, but the molecular basis of this sequential treatment has not been investigated. Fifty percent of early BC patients show primary resistance to Trastuzumab (Tz) and 70% of metastatic breast cancer patients develop Tz resistance within one year. Our in vitro pre-clinical data suggests the role of ß1-integrin, a cell adhesion molecule involved in cell survival, invasion and drug resistance, in Tz resistance. Because ionizing radiation (IR) increases the expression of several integrin subunits in endothelial and tumor cells, we hypothesized that radiation induced ß1-integrin expression could be a potential mechanism of Tz resistance in Her-2 positive BC patients.
 Methods: We use Her-2 positive Tz-senstive BC cell lines, SKBR-3 and BT474, which express lower levels of ß1- integrin, than the Tz-resistant cell line JIMT-1.
 We analyzed by Immunoblotting the expression of ß1-integrin, phosphorylation and expression of Her-2 and common downstream signaling pathways, PI3-K/Akt and Erk1/2 before and after exposure to IR.
 Results: Exposure to IR increased ß1-integrin expression in SKBR-3 and BT474 cells, but not in JIMT-1. Increased ß1-integrin expression in BT474 cells was associated with a substantial increase in phosphorlyation of Her-2, suggesting that ß1-inetgrin may induce transactivation of Her-2. Phosphorylation of Erk 1/2 and Akt, important signal transducers for cell proliferation and survival were also increased.
 We will further, investigate Tz sensitivity of SKBR-3 and BT474 following exposure to IR using a blocking antibody for ß1-integrin, and clonogenic survival and XTT assays to evaluate cellular viability and proliferation.
 Conclusion: Our results show that IR increased ß1-integrin expression and activation of the PI3-K/Akt pro-survival pathway and suggest that increased b1-integrin expression by IR may confer resistance to Trastuzumab in Her-2 positive cell lines. The physiological relevance of radiation-induced ß1-inetgrin expression in Trastuzumab resistance needs to be further investigated in vivo. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2014.

BackgroundLapatinib has been approved for the treatment of patients with advanced stage HER2-positive breast cancer (BC) patients with moderate survival rates.PurposeTo analyse the prescription profile used and the demographic and...

Simple SummaryThe goal of this study was to find circulating proteins that can be easily sampled and incorporated into a clinical setting to improve predictive treatment response in HER2-positive breast cancer patients receiving neoadjuvant chemotherapy. We looked for potential biomarkers in serum, which we identified using two proteomics techniques: qualitative LC-MS/MS and a quantitative assay that assessed protein expression between responders and non-responders HER2-positive breast cancer patients to neoadjuvant chemotherapy.Despite the increasing use of neoadjuvant chemotherapy (NAC) in HER2-positive breast cancer (BC) patients, the clinical problem of predicting individual treatment response remains unanswered. Furthermore, the use of ineffective chemotherapeutic regimens should be avoided. Serum biomarker levels are being studied more and more for their ability to predict therapy response and aid in the development of personalized treatment regimens. This study aims to identify effective protein networks and biomarkers to predict response to NAC in HER2-positive BC patients through an exhaustive large-scale LC-MS/MS-based qualitative and quantitative proteomic profiling of serum samples from responders and non-responders. Serum samples from HER2-positive BC patients were collected before NAC and were processed by three methods (with and without nanoparticles). The qualitative analysis revealed differences in the proteomic profiles between responders and non-responders, mainly in proteins implicated in the complement and coagulation cascades and apolipoproteins. Qualitative analysis confirmed that three proteins (AFM, SERPINA1, APOD) were correlated with NAC resistance. In this study, we show that serum biomarker profiles can predict treatment response and outcome in the neoadjuvant setting. If these findings are further developed, they will be of significant clinical utility in the design of treatment regimens for individual BC patients.

Background: In HER2-positive breast cancer patients, timing from the end of (neo)adjuvant trastuzumab (T)-based therapy to diagnosis of metastatic breast cancer is the key factor in determining the optimal first-line treatment. There is currently lack of clear evidence to support the possible prognostic role of this interval and 12 months has been mostly empirically used. The present analysis aimed to investigate patterns of relapse, first-line choice and survival outcomes of patients with HER2-positive early breast cancer who relapsed after adjuvant T-based therapy depending on T-free interval (TFI, i.e. timing from end of adjuvant T to diagnosis of distant metastases). Methods: In ALTTO, HER2-positive early breast cancer patients were randomized to 1 year of either T alone, lapatinib (L) alone, their sequence (T–>L) or their combination (T+L). This exploratory analysis included only pts in the T or T+L arms who experienced a distant disease-free survival (DDFS) event. Two cohorts of patients were defined depending on TFI: group A (TFI of <12 months) and group B (>12 months). Baseline characteristics, patterns of relapse, first-line choice and overall survival (OS) were compared. OS was defined as time between date of DDFS event to death; age at diagnosis, tumor size and hormone receptor status were the variables included in the final multivariate models. Results: Out of 8,381 patients included in ALTTO, 404 patients in the T and T+L arms developed a DDFS event, of whom 201 occurred <12 months (group A) and 203 >12 months (group B) after the end of adjuvant T. Patients in group A were older (p=0.013), had larger tumors (p=0.004) and more frequently hormone receptor-negative disease (p<0.001). No significant difference in patterns of first DDFS event was observed (p=0.073); however, a numerically higher number of patients in group A compared to group B developed brain metastasis (26% vs. 15%). First-line anti-HER2 therapy was received by 57% of the patients. Choice of first-line anti-HER2 therapy was different between the two groups (p=0.022): the majority of patients received T in both groups (61% vs. 65% in groups A and B, respectively), while more patients in group A received L (25% vs. 11%) and less received pertuzumab (8% vs. 17%). OS survival was significantly shorter in group A compared to group B: median OS was 18.4 and 29.3 months in groups A and B, respectively (adjusted HR 0.69; 95% CI 0.54-0.89; p=0.004). Similar results were observed after the exclusion of patients treated with first-line pertuzumab-based therapy (n=29): median OS was 18.2 and 26.8 months in groups A and B, respectively (adjusted HR 0.66; 95% CI 0.51-0.86; p=0.002). Better outcomes in terms of OS for patients in group B was observed across all analyzed subgroups with no interaction according to hormone receptor status (p=0.814) nor type of adjuvant anti-HER2 treatment (p=0.233): hormone receptor-positive (adjusted HR 0.69; 95% CI 0.48-0.99), hormone receptor-negative (adjusted HR 0.68; 95% CI 0.48-0.98), T+L arm (adjusted HR 0.55; 95% CI 0.38-0.80) and T arm (adjusted HR 0.80; 95% CI 0.55-1.17). Conclusions: In the ALTTO trial, HER2-positive early breast cancer patients who experienced shorter TFI (i.e. <12 months vs. >12 months) following adjuvant T-based therapy had inferior OS after the diagnosis of distant recurrence. Given its prognostic value, TFI can help to individualize clinical recommendations and to design future trials in the metastatic setting for patients relapsing after prior exposure to anti-HER2 therapy for early disease. Citation Format: Matteo Lambertini, Dominique Agbor-Tarh, Otto Metzger-Filho, Noam Ponde, Francesca Poggio, Florentine Hilbers, Larissa A Korde, Saranya Chumsri, Olena Werner, Lucia Del Mastro, Rafael Caparica, Volker Moebus, Alvaro Moreno-Aspitia, Martine Piccart, Evandro de Azambuja. Prognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-04.

Background: Pyrotinib, a newly-developed irreversible pan-ErbB inhibitor, has shown promising antitumor activity and acceptable tolerability in phase 1-3 studies. However, findings from randomized clinical trials may have limited generalizability to patients treated in routine clinical practice. Herein, we conducted this multicenter real-world study to examine the treatment patterns, effectiveness and safety of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients in China.Methods: This is a China-based, observational study of HER2-positive BC patients receiving pyrotinib-based therapy (NCT04158505). Both early stage and advanced disease were included. Demographics, treatment patterns, and diarrhea management were summarized. The data cutoff date was April 30, 2021, and the study is ongoing to enroll. Real-world progression-free survival (PFS) and overall survival (OS) will be analyzed. Results: Between October 2019 and April 2021, a total of 907 patients (45 in the neoadjuvant setting [median age, 51 years] and 862 in the advanced setting [median age, 54 years]) from 65 sites received at least one dose of pyrotinib. Considering the limited sample size of early stage patients so far, we focused on advanced BC patients in this report. Of 862 patients with advanced disease, 44.2% had visceral metastases, 12.5% had brain metastases, 31.1%, 35.7%, and 33.2% received pyrotinib-based therapy as first-line, second-line, and third- or later-line treatment, respectively. The majority of patients (82.5%) were trastuzumab-exposed, and 10.2% were lapatinib-treated before receiving pyrotinib. Among 744 patients with available treatment information, 75.8% started with standard dose of pyrotinib (400 mg). Pyrotinib plus capecitabine (372 [50.0%]) was the most commonly used regimen for advanced disease, followed by pyrotinib plus chemotherapy other than capecitabine (189 [25.4%]), pyrotinib plus trastuzumab and chemotherapy (100 [13.4%]), and pyrotinib alone (77 [10.3%]). At the time of data cutoff, there were 164 (19.0%) progression or death events in 862 patients with advanced disease, and the median PFS and OS was not mature for the whole population. The median PFS for patients receiving second-line pyrotinib-based therapy was 11.7 months (95% CI, 8.8-not reached). The most common adverse event was diarrhea. Any grade and grade ≥3 diarrhea occurred in 70.5% and 14.9% of 907 patients, respectively. Diarrhea in eight (0.9%) patients with advanced disease were deemed as serious adverse events. Eighty-nine (9.8%) patients received diarrhea prophylaxis, and 436 (48.1%) used antidiarrhea drugs after diarrhea occurred. Montmorillonite powder (6.0% and 33.6%) were the most commonly used drug for both diarrhea prophylaxis and treatment, followed by loperamide (3.9% and 27.9%).Conclusions: In real world, a high percentage of physicians chose to use pyrotinib-based therapy in front lines when treating HER2-positive advanced BC patients, which might maximize its antitumor activity. Diarrhea is manageable in the real-world setting. Citation Format: Yiqun Li, Zhongsheng Tong, Quchang Ouyang, Xinhong Wu, Wei Li, Li Cai, Zhiyong Yu, Zhengxiang Han, Xiaojia Wang, Man Li, Jin Yang, Li Li, Zhaofeng Niu, Haibo Wang, Qitang Wang, Yi Li, Yuee Teng, Shiguang Zhu, Binghe Xu. Treatment patterns and adverse events of pyrotinib-based therapy in HER2-positive breast cancer patients in China: Results from a multicenter, real-world study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-40.

The main purpose of this study is to explore the predictive value of HER3 expression level and PIK3CA mutation for the efficacy of neoadjuvant therapy in HER2 positive breast cancer patients. The clinicopathological data of HER2 positive non-specific invasive breast cancer patients who received neoadjuvant treatment in the Second Affiliated Hospital of Anhui Medical University from June 2017 to June 2024 were retrospectively analyzed. The correlation between HER3 expression level detected by immunohistochemistry and PIK3CA gene mutation detected by ARMS-PCR and pathological complete response rate (pCR) was analyzed. Among 51 patients, 29 (56.86%) had positive HER3 expression, 15 (29.41%) had PIK3CA mutation, and 19 (37.25%) had pCR. The expression level of HER3 was correlated with the pCR rate (χ2=7.905, p=0.019). The PIK3CA mutation status was not correlated with the pCR rate (χ2=0.140, p=0.708). The HER3 expression level combined with PIK3CA mutation status affected the pCR rate (p=0.036). Multivariable regression further identified HER3 positivity as an independent negative predictor of pCR (OR=0.08, 95% CI: 0.01-0.50, p=0.008), underscoring its role in therapeutic resistance. HER3 expression may serve as a critical biomarker for guiding therapeutic strategies in HER2-positive breast cancer patients. The combinatorial effect of HER3 overexpression and PIK3CA mutations may exacerbate therapeutic resistance, while dual-targeted strategies against the HER3/PI3K pathway could potentially improve clinical outcomes in treatment-resistant populations.

e12609 Background: Neoadjuvant therapy is an important treatment strategy for HER-2 positive early breast cancer and Trastuzumab combined with Pertuzumab (HP) plus chemotherapy is the current standard treatment scheme. In recent years, multiple studies have revealed that the combination of Trastuzumab and Pyrotinib (HPy) has satisfactory efficacy and controllable toxic side effects. In clinical practice, how to choose a target regimen (HP or HPy) for HER-2 positive breast cancer patients is one of the key problems to be solved urgently. Methods: In this prospective, multicenter, observational real-world study (ChiCTR220056467), patients with stage II-III HER-2 positive breast cancer were assigned to the HP group or the HPy group according to the doctor's recommendation and their own wishes (specific programs include: 6 * TCbHP/6 * TCbHPy, 4 * EC-4 * THP/4 * EC-4 * THPy and 6 * THP/6 * THPy). The primary endpoint was total pathological complete response rate (tpCR, ypT0/isypN0), while the secondary endpoints were safety indicators, EFS and OS. Results: From January 2022 to December 2024, 687 patients from 10 hospitals were enrolled in the real-world study. As of now, 386 patients have completed neoadjuvant therapy and surgery with complete data, including 204 in the HP group and 182 in the HPy group, respectively. Statistical difference were observed in neoadjuvant chemotherapy and the expression levels of Ki-67. To reduce selection bias and ensure comparability of baseline data between two groups, propensity score matching (PSM) was performed in a 1:1 ratio. After PSM, 136 patients were equally divided and there was no statistically significant difference in baseline characteristic between the two groups. Before PSM, there was a statistically significant difference in tpCR rates between the HP group and the HPy group (63.24% vs 48.35%, P = 0.003); After PSM, the tpCR rate of the HPy group was consistent with that of the HP group, with no statistically significant difference (60.29% vs 61.76%, P = 0.860). Subgroup analysis showed that there was no statistically significant difference in tpCR rates between the HPy group and the HP group in each subgroup (all P interactions > 0.05). In terms of safety, 386 cases were included in the analysis, among which the most common adverse reactions in the HPy group were diarrhea (82.7%), nausea (80.4%), and vomiting (78.1%), while the most common adverse reactions in the HP group were anemia (66.7%), vomiting (55.9%), and leukopenia (49.3%). Conclusions: In the real-world study, HER-2 positive early breast cancer patients are more likely to use HP as neoadjuvant therapy, and HP are more likely to be used in combination with platinum drugs. Our study has confirmed that there is no significant difference in tpCR rates between HPy or HP. Clinical trial information: ChiCTR220056467 .