Trastuzumab Therapy Research Articles

Abstract P4-02-01: Efficacy of HER2 ADCs against HER2 inhibitor resistance alterations in the PI3K and MAPK pathways in HER2-positive breast cancer

Abstract Background: HER2 positive (HER2+) breast cancers harboring downstream MAPK or PI3K pathway alterations manifest persistent downstream signaling on anti-HER2 inhibitors with metastatic patients having worse outcomes on first line trastuzumab and pertuzumab (HP) therapy. However, HER2 antibody-drug conjugates (ADCs) are not as dependent upon potent signal transduction inhibition to exert their antitumor effects. To further investigate, we sought to determine whether MAPK and/or PI3K alterations affect the biologic or clinical outcomes of patients and models receiving HER2 ADCs. Methods: We performed prospective genomic sequencing using MSK-IMPACT on patients with advanced HER2+ breast cancer who received trastuzumab emtansine (T-DM1) in the metastatic setting between March 2013 and July 2021. We collected detailed information on clinical outcomes and correlates through our institutional IRB-approved retrieval process. HER2/ER/PR status at the time of metastatic recurrence were defined as per ASCO/CAP guidelines. Cox proportional hazard models were used to determine the association between MAPK and PI3K pathways alterations and progression-free survival (PFS) on T-DM1. Common mutations associated with outcomes were modeled in HER2+ breast cancer cell lines using short hairpin RNAs and CRISPR/Cas9, and the sensitivity to HER2 ADC was evaluated via cell proliferation and xenograft assays. Results: We identified 185 HER2+ breast cancer patients treated with T-DM1 at any line (median: 5) whose primary (N=65) or metastatic (N=120) tumor samples were sequenced. Median age was 55 (range: 20-87). The majority of the patients received T-DM1 in 2nd or 3rd line (52%) and received prior trastuzumab or HER2 TKI in metastatic setting (96%). 74/185 (40%) had de novo metastatic breast cancer and 119/185 (64%) had ER/PR+/HER2+ disease. Pathogenic activating alterations involving the MAPK pathway were observed in 14% of patients with the most frequent alterations being ERBB2 activating mutations (42%) and NF1 loss (34%). PI3K pathway alterations were identified in 42% of the patients, the majority being activating mutations of PIK3CA (87%). MAPK alterations were significantly enriched in the metastatic tumors compared to the treatment-naïve primaries (20% vs 3%, p=0.001), while PI3K alterations were not (44% vs 40%, p=0.6). To reduce the possible confounding resistance mechanisms induced by prior treatment, we restricted the survival analyses to patients who received T-DM1 up to 3rd line of therapy (N=100). On multivariable analysis adjusted for ER/PR status (positive vs negative), stage at the presentation of metastatic disease (de novo metastatic vs recurrence), treatment line and type of sequenced sample (primary vs metastatic), patients with MAPK (N=14) and PI3K (N= 38) alterations had similar PFS compared to wild type (HR 1.20, 95%CI 0.62-2.30, p=0.6 and HR 1.23, 95%CI 0.77-1.95, p=0.4, respectively). Similar results were found in the combined analysis including alterations in either pathway (N=48, HR 1.28, 95%CI 0.81-2.04, p=0.3). To verify the antiproliferative effect of HER2 ADCs on breast cancer cells with MAPK pathway activation, we depleted NF1 in a panel of HER2+ breast cancer cell lines. Consistently, MAPK-altered cell lines were sensitive to FDA-approved HER2 ADCs including trastuzumab deruxtecan (T-DXd). Conclusions: In contrast to H/P therapy, T-DM1 therapy was equally effective in tumors with downstream PI3K or MAPK alterations and wild type tumors. Expanded analysis on a larger cohort, including a subgroup of patients treated with novel HER2 ADCs such as T-DXd will be presented. The characterization of PI3K and MAPK pathways status in metastatic HER2+ breast cancer may inform prioritization of treatment options. Citation Format: Emanuela Ferraro, Anton Safonov, Yuan Chen, Charlie White, Antonio Marra, Mehnaj Ahmed, Barbara Acevedo, Chau T Dang, Shanu Modi, David B. Solit, Larry Norton, Mark E. Robson, Jorge Reis-Filho, Sarat Chandarlapaty, Pedram Razavi. Efficacy of HER2 ADCs against HER2 inhibitor resistance alterations in the PI3K and MAPK pathways in HER2-positive breast cancer [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 P4-02-01.

Abstract PD18-09: ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1

Abstract Background: Amplification of the human epidermal growth factor receptor 2 (HER2) gene with consequent HER2 protein overexpression occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. The HER2-targeted ADC trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive metastatic BC (mBC) after prior trastuzumab and taxane therapy. However, disease progression occurs in all patients requiring additional therapeutic options. The use of second-generation anti-HER2 ADCs using alternative molecules is being investigated to overcome drug resistance. ARX788 is a next-generation ADC using a technology platform whereby a HER2-specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 lead to its slow release and prolongation of the peak serum pAF-AS269 concentration, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Here, early evidence of activity of ARX788 in patients previously treated with T-DM1 is shown. Methods: ACE-Breast-03 (NCT04829604) is an ongoing global, phase 2, single-arm study evaluating ARX788 in patients with HER2+ mBC whose disease has progressed following T-DM1, T-DXd, and/or tucatinib-containing regimens. The ARX788 is administered with an initial dose of 1.5 mg/kg Q4W and subsequent doses of 1.3 mg/kg Q4W. Eligibility criteria included central laboratory confirmed HER2+ mBC per ASCO/CAP guidelines, measurable disease, and adequate organ function. Stable treated brain metastases are allowed. Patients with interstitial lung disease (ILD) or pneumonitis in prior 12 months; active ocular infections or any chronic corneal disorder; are excluded. The primary endpoint is overall response rate (ORR). Results: At the data cutoff of 11-Jul-2022, 7 patients were enrolled in ACE-Breast-03 (v1.0) who previously experienced disease progression on T-DM1 and had response-evaluable disease. Pts had a median age of 59 years and had received a median of 5 lines of prior anti-HER2 cancer therapy (range: 2-8). None of the pts in this subset had received T-DXd or tucatinib. 5 pts were previously treated with HER2-targeted TKIs (neratinib and lapatinib), as well as an investigational HER2 ADC and responded to ARX788 (3 PR; 2 SD). Two patients had hormone receptor (HR)-positive disease and 5 had HR-negative mBC. Treatment with ARX788 remains ongoing with the median time of ARX788 therapy of 4.5 months. The confirmed ORR was 57.1% (4/7 pts) and an unconfirmed ORR of 71.4% (5/7 pts) as one pt experienced an unconfirmed response with PR after 2 cycles. The disease control rate (DCR) was 100% (7/7 pts). No drug-related grade ≥3 AEs were reported; 57.1% (4/7 pts) reported ocular AEs including grade 1 events in 3 pts (i.e., dry eye, blurred vision) and a grade 2 event in one pt (lagophthalmos). No pneumonitis or ILD was observed. ARX788 was well-tolerated, and AEs were manageable. Conclusion: In this small cohort of patients previously treated with T-DM1, ARX788 had a manageable AE profile and demonstrated promising clinical activity (confirmed ORR 57%; DCR 100%). Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 ARX788 demonstrated promising clinical activity in patients previously treated with T-DM1. Citation Format: Sara Hurvitz, Kevin Kalinsky, Vinod Ganju, Kashif Ali, Laila Agrawal, William Gradishar, George Sledge, Anu Thummala, Arlene Chan, Sophia Frentzas, Joo Hyuk Sohn, Kyong-Hwa Park, Keon Uk Park, Catherine Shannon, Joshua Drago, Sara Tolaney, Hope Rugo, Michael F. Press, Alex Alika, Dong Xu, Janice Lu, Debu Tripathy. ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1 [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 PD18-09.

Abstract PD8-03: Beta blockers and/or ACE inhibitors as cardioprotective strategy for patients affected by nonmetastatic breast cancer who are receiving an anthracycline-based chemotherapy (SAFE - NCT02236806): final results of a randomized trial

Abstract Introduction. Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. However, the optimal approach still represents a controversial issue. We hypothesized whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with an anthracycline-based chemotherapy. Patients and methods. The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at eight oncology departments in Italy. The study recruitment was conducted between July 2015 and June 2020. A prespecified interim analysis on 174 women at 12 months was reported in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded. Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for one year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5mg, once daily), ramipril (5mg, once daily), and placebo, if tolerated. The primary end point was defined as detection of any subclinical impairment (worsening 10%) in myocardial function and deformation measured at 24 months using 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). ClinicalTrials.gov identifier: NCT2236806. Results. 262 women (median age, 48 years; range, 24-75 years) were enrolled and treated in the study. We analyzed patients who had completed the pre-planned cardiological assessment at 24 months. Baseline demographic, tumor, and cardiovascular profiles were similar between groups. All patients received an anthracycline-based chemotherapy, 215 patients received at least three cycles of anthracyclines (range 1-6), 223 patients received also a taxanes-based chemotherapy, and 84 cases were treated with adjuvant trastuzumab. Sixty patients were treated with neoadjuvant chemotherapy, 157 cases received adjuvant endocrine therapy, and 128 patients had postoperative radiation therapy. GLS worsened 10% or greater in 68% of patients enrolled in the placebo arm, 15%, 13%, and 13% in the ramipril, bisoprolol, and ramipril plus bisoprolol arms, respectively (P < 0.05). A reduction of 10% or greater in 3D-LVEF was observed in 19% in the placebo arm, 11% in the ramipril arm, 11% in the bisoprolol arm, and 7% in the ramipril plus bisoprolol arm (P < 0.05). Study drugs were well tolerated with no serious adverse events, the ramipril plus bisoprolol arm showed significantly more toxic effects and had a significantly higher rate of allocated treatment discontinuation as compared to the other arms. Conclusions. Cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and protect against cancer therapy–related LVEF decline and heart remodeling. Citation Format: Icro Meattini, Carlotta Becherini, Luca Visani, Calogero Saieva, Viola Salvestrini, Francesca Martella, Carlotta Bacci, Elena Molinara, Mario Airoldi, Maria Riccarda Del Bene, Domenico Amoroso, Luigi Coltelli, Isacco Desideri, Vieri Scotti, Marco Bernini, Lorenzo Orzalesi, Jacopo Nori, Simonetta Bianchi, Giuseppe Barletta, Lorenzo Livi. Beta blockers and/or ACE inhibitors as cardioprotective strategy for patients affected by nonmetastatic breast cancer who are receiving an anthracycline-based chemotherapy (SAFE - NCT02236806): final results of a randomized trial [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 PD8-03.

Nanoparticles (NPs)-mediated systemic mRNA delivery to reverse trastuzumab resistance for effective breast cancer therapy.

Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy. The first monoclonal antibody authorized for treating human epidermal growth receptor 2 (HER2)-positive breast cancer is trastuzumab. However, resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes. To address this issue, tumor microenvironment (TME) pH-responsive nanoparticles (NPs) were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer (BCa). This nanoplatform is comprised of a methoxyl-poly (ethylene glycol)-b-poly (lactic-co-glycolic acid) copolymer with a TME pH-liable linker (Meo-PEG-Dlink m -PLGA) and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction. When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously, they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface. With the intracellular mRNA release to up-regulate PTEN expression, the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells, thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.

Protocol for pyrotinib cardiac safety in patients with HER2-positive early or locally advanced breast cancer-The EARLY-MYO-BC study.

Cardiotoxicity has become the most common cause of non-cancer death among breast cancer patients. Pyrotinib, a tyrosine kinase inhibitor targeting HER2, has been successfully used to treat breast cancer patients but has also resulted in less well-understood cardiotoxicity. This prospective, controlled, open-label, observational trial was designed to characterize pyrotinib's cardiac impacts in the neoadjuvant setting for patients with HER2-positive early or locally advanced breast cancer. The EARLY-MYO-BC study will prospectively enroll HER2-positive breast cancer patients who are scheduled to receive four cycles of neoadjuvant therapy with pyrotinib or pertuzumab added to trastuzumab before radical breast cancer surgery. Patients will undergo comprehensive cardiac assessment before and after neoadjuvant therapy, including laboratory measures, electrocardiography, transthoracic echocardiography, cardiopulmonary exercise testing (CPET), and cardiac magnetic resonance (CMR). To test the non-inferiority of pyrotinib plus trastuzumab therapy to pertuzumab plus trastuzumab therapy in terms of cardiac safety, the primary endpoint will be assessed by the relative change in global longitudinal strain from baseline to completion of neoadjuvant therapy by echocardiography. The secondary endpoints include myocardial diffuse fibrosis (by T1-derived extracellular volume), myocardial edema (by T2 mapping), cardiac volumetric assessment by CMR, diastolic function (by left ventricular volume, left atrial volume, E/A, and E/E') by echocardiography, and exercise capacity by CPET. This study will comprehensively assess the impacts of pyrotinib on myocardial structural, function, and tissue characteristics, and, furthermore, will determine whether pyrotinib plus trastuzumab is a reasonable dual HER2 blockade regimen with regard to cardiac safety. Results may provide information in selecting an appropriate anti-HER2 treatment for HER2-positive breast cancer. https://clinicaltrials.gov/, identifier NCT04510532.

Clinical outcome of patients with isolated central nervous system progression on first-line pertuzumab and trastuzumab treatment for HER2-positive metastatic breast cancer in a real-life cohort.

More than 10% of HER2-positive metastatic breast cancer (mBC) will develop Central Nervous System (CNS) metastases as first and isolated site of relapse on trastuzumab and pertuzumab first-line therapy. However, few clinical data are available to guide the best strategy in this setting. Patients experiencing isolated CNS progression on trastuzumab and pertuzumab first-line therapy were retrospectively identified from the French Epidemiological Strategy and Medical Economics (ESME) real-life database between 2008 and 2016. Among 995 patients treated with first-line trastuzumab and pertuzumab for HER2-positive mBC, 132 patients (13%) experienced isolated CNS progression with a median time of 12months after mBC diagnosis. Twelves patients did not receive any treatment and were excluded from the analysis. Among the 120 patients considered, 76 (63%) received CNS-directed local therapy, 73 (60%) continued trastuzumab and pertuzumab, whereas 47 (39%) started another systemic treatment. After a median follow-up of 21months, there was no difference in progression-free survival for patient who continued trastuzumab-pertuzumab or switched to another systemic treatment. In multivariate analysis, trastuzumab-pertuzumab continuation was associated with longer OS (HR 0,28 IC 95%: 0,14-0,54 p < 0,001). mOS was not reached (95% 37.6-NE) and was 23.2months (95% CI 15.5-53.6) in patients who continued trastuzumab and pertuzumab therapy and in patients who switched for another systemic therapy, respectively. In this real-life cohort, trastuzumab-pertuzumab continuation after local treatment for isolated CNS progression did not negatively impact PFS and OS. Prospective trials and assessment of new strategies are warranted in this specific situation.

Effect of Electrocardiogram Observation on Chemotherapy and Radiotherapy Combined with Trastuzumab in Breast Cancer Postoperative Patients

In order to improve the therapeutic effect of breast cancer patients, trastuzumab combined with chemotherapy followed by radiotherapy was applied to breast cancer patients in this study and to observe the effect of this treatment on the abnormal rate of electrocardiogram and serum indexes of breast cancer patients. 60 patients received targeted therapy and chemotherapy during perioperative period. All patients received local radiotherapy after surgery. At the same time, for patients with poor peripheral blood vessels, jugular vein or subclavian vein catheterization should be performed before chemotherapy to avoid vein inflammation. The abnormal rate of electrocardiogram and serum indexes and rate of adverse reactions of 60 patients were examined. The results show that the abnormal electrocardiogram rate at T1, T2 and T3 was gradually increasing. The serum indexes after chemotherapy and radiotherapy are lower than those before chemotherapy and radiotherapy respectively. After chemotherapy and radiotherapy, there were 3 cases of radiation pneumonitis, 2 cases of pain and 2 cases of abnormal liver function. Postoperative chemotherapy and radiotherapy combined with trastuzumab can decrease serum levels in breast cancer patients. Meanwhile, the abnormal rate of electrocardiogram and cardiotoxicity were higher. Therefore, before trastuzumab therapy, cardiac function safety tests should be conducted in breast cancer patients and cardiac function should be closely monitored.

Real-world data of cardiotoxicity during long-term therapy with trastuzumab in human epidermal growth factor receptor-2-positive metastatic breast cancer

Introduction/Objective. This study aims to investigate the cardiotoxicity of long-term therapy with trastuzumab in patients with HER-2-positive metastatic breast cancer. Methods. A total of 48 patients with metastatic HER-2-positive breast cancer were analyzed. The patients received long-term trastuzumab (time of application was longer than 20 months). The analyzed characteristics of the patients were the following: age, initial stage of the disease, application of anti-HER-2 therapy and anthracyclines in the adjuvant setting, the number and type of applied systemic therapies concomitant with trastuzumab in the metastatic setting. Cardiac toxicity was assessed using left ventricular ejection fraction (LVEF) values at three time-points: at the beginning, in the middle, and at the end of treatment period for each patient separately. Results. In 17 (35.4%) patients the trastuzumab treatment was temporary discontinued. The average time of trastuzumab therapy interval was 52.2 ? 23.5 months. The mean LVEF values were 66.73 ? 7.02%, 64.62 ? 5.7%, and 63.44 ? 6.1%, respectively. The mean values of LVEF differed significantly in the three observed time-points (F = 4.9 p = 0.009). Post hoc pairwise comparison, using Bonferroni correction, confirmed significantly lower mean LVEF values at the end point (at the end of treatment) compared with the mean LVEF values at the beginning of anti-HER-2 treatment (p = 0.019), but within the reference range of LVEF ? 50%. Conclusion. The data confirm good safety profile of long-term trastuzumab therapy in HER-2 positive metastatic breast cancer patients considering cardiotoxicity.

Real-world data of triplet combination of pyrotinib, trastuzumab, and chemotherapy in HER2-positive metastatic breast cancer: a multicenter, retrospective study.

Pyrotinib, an irreversible pan-human epidermal growth (HER) inhibitor, has proven its antitumor efficacy as a second-line treatment for HER2-positive metastatic breast cancer (HER2+ MBC) when combined with capecitabine. However, real-world data concerning the pyrotinib, trastuzumab, and chemotherapy (PyroHC) combination remains scarce. Our study is to report the treatment patterns, efficacy, and safety of the PyroHC combination in a real-world setting. This study enrolled patients with HER2+ MBC from five institutions in China, treated with PyroHC between June 2017 and January 2023 (ClinicalTrials.gov, identifier: NCT05839288). We evaluated progression-free survival (PFS), objective response rate (ORR), toxicity profile, and utilized treatment regimens. Of the 135 patients in our cohort, 91.9% had prior trastuzumab exposure and 52.2% underwent at least two systematic therapy lines before receiving PyroHC. The most prevalent chemotherapies paired with PyroH were capecitabine (36.3%). Patients receiving PyroHC achieved a median PFS of 8.67 months [95% confidence interval (CI): 6.84-10.51] and an ORR of 51.3% (95% CI: 42.1-61.5%). The first-line treatment with PyroHC led to a median PFS of 14.46 months (95% CI: 6.35-22.56). Patients with brain metastases showed a median PFS of 9.03 months (95% CI: 6.56-11.50), achieving an ORR of 52.17% (95% CI: 51.74-83.39). Longer previous trastuzumab (⩾6.37 months) or lapatinib (⩾10.05 months) therapies could indicate improved PFS, while prior pyrotinib exposure negatively influenced PFS. Notably, the most common grade 3/4 adverse events were diarrhea (37.8%), which were generally manageable. PyroHC shows promising efficacy and a satisfactory safety profile for treating HER2+ MBC, both as a first-line option and for heavily treated patients, including those with brain metastasis. Our findings suggest the duration and history of anti-HER2 therapy as potential predictors for PyroHC efficacy in advanced settings.

Quantification of the growth suppression of HER2+ breast cancer colonies under the effect of trastuzumab and PD-1/PD-L1 inhibitor.

Immune checkpoint blockade (ICB)-based therapy is revolutionizing cancer treatment by fostering successful immune surveillance and effector cell responses against various types of cancers. However, patients with HER2+ cancers are yet to benefit from this therapeutic strategy. Precisely, several questions regarding the right combination of drugs, drug modality, and effective dose recommendations pertaining to the use of ICB-based therapy for HER2+ patients remain unanswered. In this study, we use a mathematical modeling-based approach to quantify the growth inhibition of HER2+ breast cancer (BC) cell colonies (ZR75) when treated with anti-HER2; trastuzumab (TZ) and anti-PD-1/PD-L1 (BMS-202) agents. Our data show that a combination therapy of TZ and BMS-202 can significantly reduce the viability of ZR75 cells and trigger several morphological changes. The combination decreased the cell's invasiveness along with altering several key pathways, such as Akt/mTor and ErbB2 compared to monotherapy. In addition, BMS-202 causes dose-dependent growth inhibition of HER2+ BC cell colonies alone, while this effect is significantly improved when used in combination with TZ. Based on the in-vitro monoculture experiments conducted, we argue that BMS-202 can cause tumor growth suppression not only by mediating immune response but also by interfering with the growth signaling pathways of HER2+BC. Nevertheless, further studies are imperative to substantiate this argument and to uncover the potential crosstalk between PD-1/PD-L1 inhibitors and HER2 growth signaling pathways in breast cancer.

PTEN rs701848 Polymorphism is Associated with Trastuzumab Resistance in HER2-positive Metastatic Breast Cancer and Predicts Progression-free Survival

BackgroundTrastuzumab is an effective therapeutic approach for HER2-positive metastatic breast cancer (BC). However, a considerable number of patients develop resistance along the course of the disease. PTEN rs701848 polymorphisms are associated with an increased risk of developing cancer and have a potential role in predicting drug resistance. ObjectiveWe studied the significance of PTEN rs701848 variants as significant predictors for trastuzumab resistance in HER2-positive metastatic BC patients. Therefore, considering their value in predicting clinical outcomes. Materials and MethodsThis case-control study was conducted among female patients with HER2-positive metastatic breast cancer who underwent Trastuzumab therapy during the period from March 2017 to December 2020. PTEN rs701848 genotypes were analyzed in 160 HER2-positive metastatic breast cancer who received Trastuzumab therapy and clinically monitored for therapeutic response. ResultsPTEN rs701848 is deemed a significant predictor of Trastuzumab resistance and an independent prognostic factor of progression-free survival (PPFS). In particular, the C allele is associated with increased risk for Trastuzumab resistance and shorter PFS as compared to the homozygous TT genotype. ConclusionPTEN rs701848 is significant predictor of trastuzumab resistance. Therefore, their value in predicting clinical outcomes is recommended

Additional effect of anthracycline in preoperative chemotherapy with a sequential anthracycline‑containing regimen preceded by pertuzumab, trastuzumab and docetaxel combination therapy.

The proper use of anthracycline-containing regimens in combination with anti-HER2-targeted therapy in a neoadjuvant setting for patients with HER2-positive breast cancer has not been resolved. Regimens preceded by anthracyclines have become the standard of care, and although the order has no significant impact on HER2-negative breast cancer, it is inconclusive as to whether a taxane-first sequence would have a similar effect on HER2-positive breast cancer. The present study aimed to investigate the benefit of a taxane-first sequence and of adriamycin and cyclophosphamide (AC) in patients with non-clinical complete response (non-cCR) to pertuzumab, trastuzumab and docetaxel (PTD). The present single-center prospective observational study was performed to investigate PTD followed by AC, and aimed to clarify the cCR rate after PTD alone and the pathological clinical response (pCR) rate after subsequent AC in patients without cCR after PTD alone. A total 24 patients were analyzed; of these, 14 achieved pCR (pCR rate, 58.3%). While four of 14 patients (28.6%) in the intention-to-treat population achieved pCR, nine of 14 patients (64.3%) achieved pCR with AC but not cCR after PTD. The median tumor reduction rate after four cycles of PTD was 58.9% (range, 20.8-100%) in all 24 patients, whereas the reduction rate after PTD-AC was 76.9% (range, 31.1-100%). Cardiac serious adverse events occurred in three patients (12.5%). In conclusion, a high pCR rate was observed for the taxane-first sequence. Patients were highly responsive to PTD, but some cases achieved additional antitumor effects after AC, which resulted in pCR without cCR after PTD alone. Since cardiotoxicity remains a significant problem, a higher risk-benefit treatment strategy is required to aim for AC omission. Trial registration number: UMIN000046338, name of registry: UMIN-CTR, date of registration: December 10, 2021.

Lapatinib and lapatinib plus trastuzumab therapy versus trastuzumab therapy for HER2 positive breast cancer patients: an updated systematic review and meta-analysis.

Trastuzumab, as the gold standard for HER2-positive BC treatment, was the first-line HER2 targeted drug. However, some studies reported patients benefited more from lapatinib and lapatinib plus trastuzumab therapy than standard trastuzumab therapy. This study presents an update of a systematic review and meta-analysis involving comparison of lapatinib and lapatinib plus trastuzumab therapy versus trastuzumab therapy. We determined whether trastuzumab plus lapatinib or lapatinib therapy is not inferior to trastuzumab therapy in HER2-positive breast cancer patients. Relevant trials were searched in CNKI, Wanfang, VIP, Sinomed, PubMed, Embase, and Cochrane CENTRAL databases from inception until October 25, 2021. Primary outcomes were OS, DFS/EFS, and PFS while secondary outcomes were pCR (ypT0/is ypN0), pCR (ypT0/is ypN0/+), ORR, DCR, rate of BCS, RFS, cardiac toxicities, and other toxicities. Thirteen randomized controlled trials were included in this study. Trastuzumab combined with lapatinib therapy was found to be superior to standard trastuzumab therapy alone with regard to overall survival, disease-free survival/event-free survival, pathologic complete response (ypT0/is ypN0), pathologic complete response (ypT0/is ypN0/+), recurrence-free survival, higher incidences of diarrhea, and rash/skin toxicity. Lapatinib therapy was established to be inferior to trastuzumab therapy in overall survival, progression-free survival, disease-free survival/event-free survival, pathologic complete response (ypT0/is ypN0) and pathologic complete response (ypT0/is ypN0/+), diarrhea, and rash/skin toxicity and had a low incidence of left ventricular ejection fraction decline. The efficacy of trastuzumab combined with lapatinib therapy is superior to standard trastuzumab therapy alone; however, it has more non-cardiac grade III/IV toxicities. Moreover, the efficacy of lapatinib therapy is inferior to that of standard trastuzumab therapy alone.

Association of Neurohormonal Antagonists on Incident Cardiotoxicity in Patients With Breast Cancer

Cardiovascular disease is the leading cause of mortality among breast cancer survivors. Anthracyclines and trastuzumab have been associated with an increased risk of cardiotoxicity, requiring close follow-up for signs of clinical heart failure or asymptomatic left ventricular systolic dysfunction. Whether neurohormonal antagonism with angiotensin-converting enzyme inhibitor (ACE-I), angiotensin receptor blockers (ARBs), or β-blockers can prevent the development of chemotherapy-induced cardiomyopathy in this population remains unknown. We studied 459 women who were diagnosed with breast cancer at our medical center from January 2014 to December 2021 and evaluated baseline characteristics, oncologic treatment, and outcomes. The primary end point was the development of cardiotoxicity, defined as symptomatic decline in ejection fraction of ≥5% below 55% or an asymptomatic decline of ≥10% after treatment with chemotherapy. Patients who were exposed to neurohormonal antagonists were more likely to have hypertension, hyperlipidemia, and diabetes. There was an increased risk of cardiotoxicity noted for patients who were older (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.01 to 1.1), smokers within the past 10years (HR 2.54, 95% CI 1.41 to 4.6), or who received a combination of both trastuzumab and anthracycline therapy (HR 2.52, 95% CI 1.01 to 6.3). Over a median follow-up of 12months, there were no significant protective benefits noted for patients who were taking ACE-I/ARBs (HR 0.49, 95% CI 0.17 to 1.4), β-blockers (HR 0.50, 95% CI 0.16 to 1.6), or both (HR 1.30, 95% CI 0.44 to 3.9). In conclusion, previous use of ACE-I/ARBs and β-blockers, separately or in combination, was not associated with a reduction in the development of cardiotoxicity in patients receiving anthracycline or trastuzumab therapies. Older age, smoking, and combination chemotherapy were found to be associated with an increased risk.

Syndecan-4 regulates the HER2-positive breast cancer cell proliferation cells via CK19/AKT signalling

Despite the use of the highly specific anti-HER2 receptor (trastuzumab) therapy, HER2-positive breast cancers account for 20–30% of all breast cancer carcinomas, with HER2 status a challenge to treatment interventions. The heparan sulfate proteoglycans (HSPGs) are prominently expressed in the extracellular matrix (ECM), mediate breast cancer proliferation, development, and metastasis with most studies to date conducted in animal models. This study examined HSPGs in HER2-positive human breast cancer cell lines and their contribution to cancer cell proliferation. The study examined the cells following enhancement (via the addition of heparin) and knockdown (KD; using short interfering RNA, siRNA) of HSPG core proteins. The interaction of HSPG core proteins and AKT signalling molecules was examined to identify any influence of this signalling pathway on cancer cell proliferation. Our findings illustrated the HSPG syndecan-4 (SDC4) core protein significantly regulates cell proliferation with increased BC cell proliferation following heparin addition to cultures and decreased cell number following SDC4 KD. In addition, along with SDC4, significant changes in CK19/AKT signalling were identified as mediators of BC HER2-positive BC cell proliferation. This study provides evidence for a cell growth regulatory axis involving HSPGs/CK19 and AKT that represents a potential molecular target to prevent proliferation of HER2-positive breast cancer cells.

Detecting the expression of HRs and BCL2 via IHC can help identify luminal A-like subtypes of triple-positive breast cancers.

Triple-positive breast cancer (TPBC) is a tumor that simultaneously expresses estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Luminal A-like TPBC is a special subtype with a favorable prognosis but benefits less from HER2-targeted therapy. However, little is known about how to identify luminal A-like TPBCs. Therefore, our study aims to explore a clinically feasible method to identify luminal A-like TPBCs using immunohistochemical (IHC) markers. Our cohort enrolled consecutive 190 patients with early-stage TPBCs diagnosed, treated and followed up in our hospital between 2013 and 2019. Patients whose IHC staining displayed ≥ 50% in both ER and PR scores and B-cell lymphoma 2 (BCL2) positivity were classified as cohort A (n = 64), and the rest were enrolled in cohort B (n = 126). Kaplan-Meier plotter and log-rank test were used to compare the survival difference between cohort A and cohort B and the efficacy of trastuzumab therapy in the two cohorts. The disease-free survival (DFS) of patients in cohort A was significantly better than in cohort B (p = 0.031). In cohort A, there was no statistically significant difference in DFS between patients treated with trastuzumab and those without trastuzumab (p = 0.663). While in cohort B, patients treated with trastuzumab had significantly better DFS than those without trastuzumab (p = 0.032). Multivariate survival analysis showed that cohort A was associated with better DFS(95%CI 1.046-11.776, p = 0.042). TPBCs consist of heterogeneous subtypes. Detecting the expression of ER, PR and BCL2 via IHC can help identify luminal A-like TPBCs. This study will enable individualized treatment of TPBCs.

Safety and Outcomes of a Plasmid DNA Vaccine Encoding the ERBB2 Intracellular Domain in Patients With Advanced-Stage ERBB2-Positive Breast Cancer

High levels of ERBB2 (formerly HER2)-specific type 1 T cells in the peripheral blood are associated with favorable clinical outcomes after trastuzumab therapy; however, only a minority of patients develop measurable ERBB2 immunity after treatment. Vaccines designed to increase ERBB2-specific T-helper cells could induce ERBB2 immunity in a majority of patients. To determine the safety and immunogenicity of 3 doses (10, 100, and 500 μg) of a plasmid-based vaccine encoding the ERBB2 intracellular domain (ICD). Single-arm phase 1 trial including 66 patients with advanced-stage ERBB2-positive breast cancer treated in an academic medical center between 2001 and 2010 with 10-year postvaccine toxicity assessments. Data analysis was performed over 2 periods: January 2012 to March 2013 and July 2021 to August 2022. Patients were sequentially enrolled to the 3 dose arms. The vaccine was administered intradermally once a month with soluble granulocyte-macrophage colony-stimulating factor as an adjuvant for 3 immunizations. Toxicity evaluations occurred at set intervals and yearly. Peripheral blood mononuclear cells were collected for evaluation of immunity. Biopsy of vaccine sites at weeks 16 and 36 measured DNA persistence. Safety was graded by Common Terminology Criteria for Adverse Events, version 3.0, and ERBB2 ICD immune responses were measured by interferon-γ enzyme-linked immunosorbent spot. Secondary objectives determined if vaccine dose was associated with immunity and evaluated persistence of plasmid DNA at the vaccine site. A total of 66 patients (median [range] age, 51 [34-77] years) were enrolled. The majority of vaccine-related toxic effects were grade 1 and 2 and not significantly different between dose arms. Patients in arm 2 (100 μg) and arm 3 (500 μg) had higher magnitude ERBB2 ICD type 1 immune responses at most time points than arm 1 (10 μg) (arm 2 compared with arm 1, coefficient, 181 [95% CI, 60-303]; P = .003; arm 3 compared with arm 1, coefficient, 233 [95% CI, 102-363]; P < .001) after adjusting for baseline factors. ERBB2 ICD immunity at time points after the end of immunizations was significantly lower on average in patients with DNA persistence at week 16 compared with those without persistence. The highest vaccine dose was associated with the greatest incidence of persistent DNA at the injection site. In this phase 1 nonrandomized clinical trial, immunization with the 100-μg dose of the ERBB2 ICD plasmid-based vaccine was associated with generation of ERBB2-specific type 1 T cells in most patients with ERBB2-expressing breast cancer, and it is currently being evaluated in randomized phase 2 trials. ClinicalTrials.gov Identifier: NCT00436254.

Cardiotoxicity in patients with early breast cancer treated with adjuvant trastuzumab

Introduction. Breast cancer is the most common cancer among women in Poland. The aim of this study was to evalu­ate the incidence of cardiotoxicity in patients treated with adjunctive trastuzumab, as well as to determine risk factors for cardiotoxicity. Material and methods. The study covered 100 patients who completed one year of trastuzumab therapy or discon­tinued treatment due to acute cardiac complications. They underwent an oncological, cardiological, questionnaire and laboratory follow-up. Results. Acute cardiac complications (CC(+)) occurred in 11 (11%) patients. Patients in the CC(+) group were more likely to have hypertension, ischemic heart disease, hypothyroidism, and were more likely to smoke compared to the gro­up without cardiac complications (CC(–)). They had a lower left ventricular ejection fraction before, during and after trastuzumab therapy, and larger left ventricular dimensions in systole and diastole after treatment. The CC(+) received a higher dose of anthracyclines compared to CC(–). The NT-proBNP value remained elevated in the CC(+) group after treatment, despite normal LVEF values, and was higher than in the CC(–) group. Conclusions. Based on the study, type II cardiotoxicity, diagnosed early and treated appropriately, was found to be reversible.

Trastuzumab-based regimens beyond progression: A crucial treatment option for HER2+ advanced/metastatic breast cancer

Upon its establishment for the treatment of metastatic breast cancer (mBC), continuing trastuzumab beyond disease progression was an important paradigm shift that became the recommendation by major guidelines. However, data supporting continuation of human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab beyond the second-line setting are limited, resulting in a lack of approval of, or access to, this therapeutic strategy in many countries. This study aimed to provide additional data on the continued use of trastuzumab and trastuzumab-based therapies in combination with chemotherapy (CT) as third-line treatment for patients with mBC. This open-cohort, retrospective, observational study used deidentified patient-level data from an electronic health record–derived database that included patients with mBC who initiated third-line treatment with trastuzumab-based therapy combined with CT (Tras + CT; n = 288) or CT alone (CT; n = 49). Patients who received Tras + CT had a longer weighted median overall survival vs those who received CT only: 20.6 months (95% CI, 18.3–26.4 months) vs 10.1 months (95% CI, 7.8–12.3 months), respectively (hazard ratio [HR], 0.29; 95% CI, 0.16–0.53). This study provides additional support for maintaining trastuzumab-based therapies for patients with HER2+ mBC beyond second-line treatment. This treatment option should be available for all patients with mBC worldwide.

Redox Status Response of Physical Exercise Training in Women with Breast Cancer during Trastuzumab Therapy.

Trastuzumab is indicated in the adjuvant setting for the early and intermediate stages of breast cancer (BC) positive for epidermal growth factor receptor 2 (HER2). Although HER2 in BC patients tends to disrupt pro-oxidant and inflammatory signaling, the influence of trastuzumab in modulating this process remains unknown. Due to the absence of any chemotherapeutic or chemoprophylactic agents for trastuzumab-induced side effects, this study investigated the potential role of regular physical exercise in modulating the antioxidant defenses, oxidative stress, and nitrosative damage in BC patients during trastuzumab treatment. Aim: The study aimed to analyze the relationship between regular physical activity and the redox status in women with BC during trastuzumab therapy. Materials and methods: We observed 50 BC patients during trastuzumab therapy in two groups: one that undertook moderately intensive supervised physical exercises, and a second that performed physical activity according to the recommendations for cancer patients, along with a third (control) group of healthy women. Results: The antioxidant enzyme and non-enzymatic antioxidant activities were significantly higher in the exercised group compared with the other participants. The concentrations of lipid and protein oxidative damage and nitrosative stress products were significantly higher in both BC groups than in the healthy controls. Conclusions: Trastuzumab treatment stimulates a redox response in BC patients. The results highlight the oxidative imbalance in parallel with regular physical training in women with BC during trastuzumab therapy. Further studies are needed to analyze different intensities and levels of physical training in women with BC during trastuzumab treatment.