Treatment Of HER2-positive Breast Cancer Research Articles

Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer.

Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20-30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer.

Prediction of Cardiac Toxicity by Measurement of Coronary Artery Calcium Scoring Method Using Chest Computed Tomography in Early Breast Cancer Patients Treated with Trastuzumab

Background: In human epidermal growth factor receptor 2 (HER2)-positive early stage breast cancer, prediction of trastuzumab-related cardiac toxicity remains a challenge. The coronary calcium artery (CAC) reflects the total coronary plaque burden, which predicts the risk of atherosclerosis. We investigated the prediction of left ventricular ejection fraction (LVEF) decline in breast cancer according to CAC scores. Methods: A total of 347 patients were enrolled from Seoul St Mary’s Hospital between January 2010 and December 2019. Chest computed tomography (CT) was performed at a single tertiary center. Patients who received trastuzumab for HER2-positive early breast cancer were included in this study. Results: Of the 347 patients, 312 and 35 had CAC scores of 0 and ≥1, respectively. The CAC ≥1 group was associated with older age, body mass index, and receipt of left breast irradiation. The CAC ≥1 group was significantly associated with LVEF decline (absolute value, ≤50%) (hazard ratio [HR] 12.038, 95% confidence interval [CI] 2.845–50.937, p = 0.001), LVEF decline (absolute value, ≤55%) (HR 4.439, 95% CI: 1.787–11.028, p = 0.001), and decline in LVEF of ≥10% points compared with baseline echography (HR 5.083, 95% CI: 1.658–15.582, p = 0.004). Even after adjusting for other clinical factors, CAC ≥1 remained a significant predictor of decreased LVEF. Conclusion: Our findings suggest that the CAC score is a significant predictor of cardiac toxicity following trastuzumab treatment in HER2-positive breast cancer. Therefore, CAC measurement could reduce cardiac toxicity by distinguishing patients at high risk for trastuzumab.

218 (PB-042) Poster - Impact of subcutaneous versus intravenous administration of pertuzumab and trastuzumab (PH) for the treatment of HER2-positive breast cancer in Montenegro

Background: Both PH are approved for use in patients with HER2-positive breast cancer and are available as intravenous formulations (PH IV) and subcutaneous fixed-dose combination of both drugs (PH FDC SC). SC formulations showed similar efficacy as IV counterparts, providing additional economic value to patients, physicians and health systems due to shorter administration and observation time.

180 (PB060) - Neratinib plus dasatinib has pre-clinical efficacy against HER2-positive breast cancer

Background: HER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. The aim of this study was to investigate neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, as a new treatment option for patients with HER2-targetted therapy resistant HER2-positive breast cancer.

Evaluation of biosimilar trastuzumab MYL-1401O in HER2-positive breast cancer.

The trastuzumab biosimilar MYL-1401O has demonstrated equivalent efficacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) as HER2 monotherapy. Here, we present the first real-world comparison of MYL-1401O vs RTZ as single/dual HER2-targeted therapy for the neoadjuvant, adjuvant, and palliative treatment of HER2-positive breast cancer in the first and second lines. We retrospectively investigated medical records. We identified patients with HER2-positive early-stage breast cancer (EBC) (n = 159) who had received neoadjuvant chemotherapy with RTZ or MYL-1401O ± pertuzumab (n = 92) or adjuvant chemotherapy with RTZ or MYL-1401O plus taxane (n = 67) between January 2018 and June 2021, as well as patients with MBC (n = 53) who had received palliative first-line treatment with RTZ or MYL-1401O and docetaxel ± pertuzumab or second-line treatment with RTZ or MYL-1401O and taxane between January 2018 and June 2021. The rate of achieving pathologic complete response in patients receiving neoadjuvant chemotherapy was similar between those receiving MYL-1401O and RTZ (62.7% [37/59] and 55.9% [19/34], respectively; P = .509). Progression-free survival (PFS) at 12, 24, and 36 months was similar in the 2 cohorts of the EBC-adjuvant group: 96.3%, 84.7%, and 71.5%, respectively, in patients receiving MYL-1401O, and 100%, 88.5%, and 64.8% in patients receiving RTZ (P = .577). Median PFS was also similar in MBC, at 23.0 months (95% CI, 9.8-26.1) in patients receiving MYL-1401O and 23.0 months (95% CI, 19.9-26.0) in patients receiving RTZ (P = .270). The overall response rate, disease control rate, and cardiac safety profiles did not show significant differences in efficacy outcomes between the 2 groups. These data suggest that biosimilar trastuzumab MYL-1401O has similar effectiveness and cardiac safety to RTZ in patients with HER2-positive EBC or MBC.

Systemic Therapy for HER2-Positive Metastatic Breast Cancer: Moving Into a New Era.

Patients with HER2-positive breast cancer account for approximately 15% to 20% of all breast cancers and represent one of the most aggressive breast cancer subtypes. Survival rates of patients with metastatic disease have improved dramatically and progressively. Many new agents have been developed, and long-term follow-up from trials of anti-HER2 agents has shown long-term responses. The availability of novel, highly active anti-HER2 treatments, together with the ongoing development of promising diagnostic tools, will offer the unprecedented opportunity to raise cure rates. Our ultimate goal is to tailor treatment intensity to disease and patient characteristics, hopefully increasing the fraction of cured patients while minimizing the risk for overtreatment. If conducted rationally and carefully, this plan has the potential to break a decades-long paradigm, leading to a new, precise era of treatment of HER2-positive breast cancer.

Abstract 1787: Statin therapy enhances the efficacy of HER2 directed antibody-drug conjugates in breast cancer

Abstract Antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) are a widely successful strategy for the treatment of HER2-positive breast cancer. Despite the demonstrated efficacy, intrinsic and acquired resistance to anti-HER2 ADCs remains a major challenge. The activity of ADCs is dependent upon the internalization of the HER2-ADC complex into specific subcellular compartments permissive for release of the chemotherapeutic payload. Previous studies have demonstrated that statins, a commonly used cholesterol-lowering medication, could increase plasma membrane-bound HER2 and improve trastuzumab efficacy in HER2-positive gastric cancer. In this study, we sought to characterize the impact of statins on the efficacy of HER2 ADCs. We performed in vitro internalization assays with trastuzumab emtansine (T-DM1) labeled with a pH-sensitive pHrodo fluorogenic dye to monitor T-DM1 entering lysosome whereupon payload DM1 is released, and found that combined treatment of T-DM1 and lovastatin potently enhanced T-DM1 internalization of T-DM1 into lysosome in HER2-amplified and HER2-low models. Consistent with the internalization assays, lovastatin increased cell death caused by T-DM1 and sensitized the HER2-low ZR75-1 cells to T-DM1 treatment in vitro. Using HER2-positive xenograft models, we found orally administrated lovastatin promoted T-DM1 uptake in tumors and enhanced T-DM1 efficacy in vivo. To investigate whether these results might be observed in the clinic, we conducted retrospective analyses on a cohort of 164 HER2 positive metastatic breast cancer patients treated at MSKCC who received T-DM1. Among these patients, 21 (12.8%) were taking statins concurrently with T-DM1, and the median progression-free survival in the patients who received statins was 14 months (95% confidence interval, 3.5-24 months) compared to 5.4 months (95% confidence interval, 3.9-7.0 months) in those who had no record of statin use (p=0.1). Overall, our findings demonstrate that statins potentiate the susceptibility of breast cancer cells to anti-HER2 ADCs by modulating HER2 membrane dynamics and HER2-ADC internalization, suggesting statin as a rational therapeutic partner for anti-HER2 ADC in HER2-positive breast cancer, especially those with relatively low HER2 expression. Citation Format: Bo Liu, Joshua Z. Drago, Yi Rao, Patricia R. Pereira, Anton Safonov, Antonio Marra, Mehnaj S. Ahmed, Shanu Modi, Jorge S. Reis-Filho, Filippo Montemurro, Pedram Razavi, Jason S. Lewis, Sarat Chandarlapaty. Statin therapy enhances the efficacy of HER2 directed antibody-drug conjugates in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1787.

Cost of illness of HER2-positive and metastatic and recurrent HER2-positive breast cancer – a Danish register-based study from 2005 to 2016

BackgroundInformation and knowledge about cost of illness and labour productivity in patients with HER2-positive early-stage and metastatic breast cancer treated with trastuzumab is limited. The aim of this study was to estimate the direct and indirect costs associated with treatment of HER2-positive breast cancer among patients with early-stage and metastatic breast cancer, treated with trastuzumab, in a 10-year period after diagnosis.Materials and methodsThis study included all Danish HER2-positive breast cancer patients (≥ 18 years) treated with trastuzumab between 2005 and 2016 identified in The Danish Patient Register and the Danish Cancer Register. Furthermore, we identified patients experiencing metastatic or recurrent breast cancer. For the study populations, we estimated total direct costs and indirect costs for one year prior to the breast cancer diagnosis and up to 10 years after diagnosis compared with a group of matched controls free of breast cancer. In addition to The Danish Patient Register and Cancer Register, we applied patient level data from The Civil Registration System, The National Pathology Register, National Health Service Register for Primary Care, Register of Medicinal Product Statistics, Register of Municipal Services, The DREAM database, and Population’s Education Register.ResultsWe identified 4,153 HER2-positive breast cancer patients, whereof 27% were identified with metastatic or recurrent breast cancer. During the follow-up period of 10 years, we estimated excess direct costs of EUR 115,000 among the total study population compared to controls; EUR 211,000 among patients with metastases or recurrence; and EUR 89,000 among patients without metastases or recurrence. Direct costs were found to be highest in the first year after diagnosis and also peaked in the year after recurrence. Labour productivity was significantly lower among patients with recurrence 10 years after breast cancer diagnosis compared with controls.ConclusionsIn this study, we estimated the direct and indirect cost associated with HER2-positive breast cancer. The costs were significantly higher during the 10 years after diagnosis compared to the control group, specifically among patients experiencing metastases or recurrence of breast cancer.

A prospective real-world study to assess the effectiveness and safety of trastuzumab biosimilar in the adjuvant treatment of HER2-positive breast cancer: Preliminary safety results.

e12524 Background: The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) defines a biosimilar as a biological molecule product that is highly similar to and has no clinically meaningful differences from an existing approved reference product. The trastuzumab biosimilar was the first oncology biosimilar approved in Brazil for HER2-positive breast cancer (BC) and advanced gastric cancer treatment. This study aimed to assess the effectiveness and safety of trastuzumab biosimilar (named as Zedora in Brazil) in the adjuvant setting among HER2-positive BC patients treated in Brazil. Methods: This is a national, multicentric, observational, and prospective real-world study. Patients with early-stage HER2-positive BC who received at least one dose of trastuzumab biosimilar as adjuvant therapy were eligible. At the present date, 126 of 170 planned patients were recruited. Here, we present the preliminary safety data of the first 42 patients recruited in the study. The safety endpoint is the occurrence of adverse events (AEs), and the safety population included all patients who received at least one dose of trastuzumab biosimilar. We analyzed the AEs collected from the signature of the consent form until the end of adjuvant treatment. Results: Baseline patient characteristics among the 42 evaluated patients included a median age of 48.5 years, with 78.6% of them having a node-negative disease. Most patients had hormone-receptor-positive tumors (71.4% estrogen-receptor-positive and 57.1% progesterone-receptor-positive). The number of patients undergoing conservative surgery (59.5%) was higher than mastectomy (40.5%). The most frequent histological BC subtype was invasive ductal carcinoma (97.6%). Neoadjuvant therapy included the trastuzumab biosimilar administration (25%) and the dual anti-HER2 block (trastuzumab biosimilar + pertuzumab) (68.8%). Only 6.3% of patients received the reference trastuzumab in neoadjuvant therapy. In total, 25/42 (59,5%) patients had at least one AE, two of them were serious AEs (4.8%). The incidence of grade 3 or 4 AEs was 35.7%, and no death occurred. The table lists the most reported AEs according to SOC (System Organ Class). Conclusions: The nature and severity of AEs observed were consistent with the known safety profile of trastuzumab. Clinical trial information: NCT03892655. [Table: see text]

Neoadjuvant pegylated liposomal doxorubicin (PLD) plus cyclophosphamide followed by nab-paclitaxel (Nab-P) as primary chemotherapy continuously combined with dual HER2 blockage for HER2-positive breast cancer: A single-arm phase 2 trial (Brecan Trial).

e12622 Background: Despite that AC-THP regimen is one of the commonly used regimens for neoadjuvant treatment of HER2-positive breast cancer, previous studies showed that pCR rate rarely exceeds 70%. We hypothesized that prolonged dual anti-HER2 therapy can increase pCR rate in neoadjuvant therapy. In this study, we designed a single-arm trial of ACHP-THP regimen (continuous dual anti-HER2 therapy of trastuzumab and pertuzumab) in neoadjuvant therapy of HER2 positive breast cancer. To minimize adverse cardiovascular events, we used pegylated liposomal doxorubicin (PLD) and Nab-Paclitaxel (Nab-P) instead of doxorubicin and paclitaxel. We aimed to examine whether continuous dual anti-HER2 therapy can boost pCR rate in the neoadjuvant therapy. The cardiotoxicity was closely monitored when the anti-HER2 therapy was combined with PLD and Nab-P respectively. Methods: Upon approval by the Medical Ethics Committee of Xijing Hospital, patients with HER2-positive breast cancer (cT2-3/N0-1/M0) receiving neoadjuvant therapy, were enrolled. The patients were treated with PldCHP (pegylated liposomal doxorubicin 35mg/m2, cyclophosphamide 600mg/m2, trastuzumab 8 mg/kg loading, then 6 mg/kg, pertuzumab 840 mg loading, then 420 mg, iv, q3w) for 4 cycles followed by Nab-PHP (Nab-Paclitaxel 260mg/m2, trastuzumab 6 mg/kg, pertuzumab 420 mg, iv, q3w) for 4 cycles, with strict monitoring of cardiotoxicity. The primary endpoint was pCR rate, and secondary endpoint was cardiotoxicity during neoadjuvant therapy. Results: From January 2020 to October 2021, a total of 96 patients were recruited. Among the 96 patients with a median age of 49 (21-71), 58 patients were HR positive and 42 patients had positive lymph node status. Overall, the pCR rate was 80.2% (77/96). The ER-positive tumor achieved a higher pCR rate than ER-negative tumor (82.8% vs 76.3%, p=0.439), but the difference was statistically insignificant. Multivariate regression analysis showed that for participants older than 30, HER2 3+ (IHC) showed a statistically significant positive influence on pCR rate. The common adverse reactions of grade ≥3 were neutropenia (30.2%), asthenia (8.3%), and peripheral sensory neuropathy (7.3%). Left ventricular insufficiency was detected in 4 patients, and no cardiotoxic events higher than grade 2 occurred during the neoadjuvant therapy. There was no treatment-related death. Conclusions: The PldCHP---Nab-PHP regimen is a feasible and effective neoadjuvant therapy for early stage HER2-positive breast cancer, showing high pCR rate and acceptable cardiotoxicity. These results support a further random controlled trial testing for continuous dual anti-HER2 therapy combined with PLD in neoadjuvant or adjuvant therapy of HER2 positive breast cancer.

Primary analysis of MUKDEN 01: A multicenter, single-arm, prospective, phase 2 study of neoadjuvant treatment with pyrotinib and letrozole plus dalpiciclib in triple-positive breast cancer.

588 Background: Despite the use of multiple lines of targeted therapy has revolutionized treatment for HER2-positive breast cancer, these methods still have limited efficacy for triple-positive breast cancer (TPBC), which calls for persistent exploration for optimized treatment strategy. This MUKDEN-01 prospective trial aimed to evaluate the efficacy of oral, chemo-sparing neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib, which also meet the need for treatment convenience under COVID-19 pandemic, for patients with TPBC. Methods: The MUKDEN 01 was an investigator-initiated, multicentre, single arm, prospective phase II trial, which was performed at twelve hospitals in China(NCT04486911). Treatment-naïve patients with stage II-III tumors that according to the AJCC 8th edition criteria were eligible. Patients were treated with each cycle of 4 weeks with oral administration of pyrotinib 320 mg, and letrozole 2.5mg once daily for 4 weeks, and dalpiciclib 125 mg once daily for three weeks, followed by one week off, for five cycles. The primary endpoint was pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). Secondary endpoints included pCR in the breast (ypT0/is). residual cancer burden (RCB) score, Ki67 index change at surgery compared with baseline, and safety. Safety was analyzed in all patients, who received treatment. The study is still ongoing, and the enrollment has been completed. Results: Between June 20, 2020 and Sep. 6, 2021, 68 patients were screened for eligibility and 61 patients were recruited into this first stage of study. After surgery, 18 (29.5%, 95% CI 18.5-42.6) out of 61 patients achieving tpCR(ypT0/is ypN0), 21 (34.4%, 95% CI 22.7-47.7) patients achieved bpCR(ypT0/is). The patients with excellent pathologic response (RCB 0-1) to the combined therapy accounted for 54.1% (33/61, 95% CI 40.9-66.9). Mean Ki67 expression was reduced from 38.7% (95%CI: 31.3-46.0) at baseline to 19.3% (95% CI:13.6-25.0; p=0.0001) in the surgical samples. The most frequent grade 3 AE were neutropenia (35 [57%]), leukopenia (13 [21%]), diarrhea (9 [15%]) and oral mucositis (4 [7%]). There were five grade 4 neutropenia (8%) and one grade 4 increased AST (2%), but without other SAE and death throughout the study. Conclusions: Neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib yielded a pCR rate comparable to standard chemotherapy plus dual HER2 blockade in TPBC patients. The combined therapy was also well-tolerated and provided a chemo-sparing neoadjuvant approach for TPBC patients. To our knowledge, this is the first study to evaluate the therapeutic efficacy of a chemo-free neoadjuvant treatment with HER2 TKI pyrotinib and letrozole plus CDK4/6 inhibitor dalpiciclib for TPBC patients. Further validation in a large-scale randomized controlled trial is warranted. Clinical trial information: NCT04486911.

Antibiotic treatment targeting gram negative bacteria prevents neratinib-induced diarrhea in rats

BackgroundNeratinib is a pan-ErbB tyrosine kinase inhibitor used for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the main adverse event associated with neratinib treatment. We aimed here to determine whether antibiotic-induced gut microbial shifts altered development of neratinib-induced diarrhea. MethodsFemale Albino Wistar rats (total n = 44) were given antibiotics (vancomycin, neomycin, or a cocktail of vancomycin, neomycin and ampicillin) in drinking water for four weeks, and then treated daily with neratinib (50 mg/kg) for 28 days. Diarrhea, along with markers of gastrointestinal damage and microbial alterations were measured by histopathology and 16S sequencing, respectively. ResultsRats treated with vancomycin or neomycin had significantly lower levels of diarrhea than rats treated with neratinib alone. In the distal ileum, neratinib was associated with a statistically significant increase in histological damage in all treatment groups expect the antibiotic cocktail. Key features included villous blunting and fusion and some inflammatory infiltrate. Differences in microbial composition at necropsy in vehicle control, neratinib and neratinib + neomycin groups, were characterized by a neratinib-induced increase in gram-negative bacteria that was reversed by neomycin. Neomycin shifted bacterial composition so that Blautia become the dominant genus. ConclusionsNarrow spectrum antibiotics reduced neratinib-induced diarrhea. This suggests that the microbiome may play a key role in the development and prolongation of diarrhea following neratinib treatment, although further research is required to understand the key bacteria and mechanisms by which they reduce diarrhea, as well as how this may impact presentation of diarrhea in clinical cohorts.

Cardiotoxicity monitoring of pyrotinib in combination with nab-paclitaxel, doxorubicin, and cyclophosphamide in HER2-positive breast cancer: a single-armed clinical trial.

Human epidermal growth factor receptor 2 (HER2) inhibitors play a vital role in the treatment of HER2-positive breast cancer. Numerous studies have shown that traditional HER2 inhibitors and chemotherapeutics such as albumin-paclitaxel, liposomal doxorubicin, and cyclophosphamide (TAC regimen) have different degrees of cardiotoxicity. Pyrotinib is a novel small-molecule HER2 inhibitor and has no cardiotoxicity. Here, the purpose of this study was to investigate the cardiac safety of pyrotinib with TAC regimen for HER2-positive breast cancer. In this study, 22 patients with stage I-IIIA HER2-positive breast cancer were screened, enrolled, and assigned to receive either neoadjuvant or postoperative adjuvant treatment with pyrotinib (320-400 mg, once daily) combined with TAC (albumin-paclitaxel 260 mg/m2, liposomal doxorubicin 20 mg/m2, cyclophosphamide 600 mg/m2) from December 2019 to May 2021. Patients' heart function was monitored using electrocardiogram, echocardiogram, and serological indicators. ST segment and T wave change, left ventricular ejection fraction (LVEF, %), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), creatine kinase (CK), creatine kinase myoglobin band (CK-MB), together with patients' weight, white blood cells (WBC), red blood cells (RBC), platelets, plasma lipid, and glucose were recorded. Before and after the 2nd, 4th, and 6th cycles of treatment, the incidence of abnormal electrocardiogram of patients enrolled in the neoadjuvant treatment group was 36.4%, 27.3%, 27.3%, and 27.3%, respectively, while in the postoperative adjuvant treatment, the incidence was 45.5%, 36.4%, 36.4%, and 36.4%, respectively. LVEF before and after treatment in the neoadjuvant chemotherapy group was 65.36%±2.25% and 65.00%±2.15% (t=1.305, P=0.221), while in the postoperative adjuvant treatment group, LVEF was 66.27%±2.69% and 65.18%±1.89% (t=1.359, P=0.204). Pyrotinib combined with a TAC regimen may have induced a decrease in RBC. No obvious abnormality was found in the level of NT-pro-BNP, CK, CK-MB, patients' weight, WBC, platelets, plasma lipid, or glucose in all enrolled patients during the entire treatment process. Our findings indicated that neither neoadjuvant nor postoperative adjuvant treatment using pyrotinib combined with a TAC regimen to treat patients with HER2-positive breast cancer increased cardiotoxicity. However, the treatment may have induced a decrease in RBC and further research is needed.

Targeted Nanoparticle for Co‐delivery of HER2 siRNA and a Taxane to Mirror the Standard Treatment of HER2+ Breast Cancer: Efficacy in Breast Tumor and Brain Metastasis (Small 11/2022)

Breast Cancer Treatment In article number 2107550, Wassana Yantasee and co-workers develop polymer-decorated mesoporous silica nanoparticles for HER2-positive breast cancer treatment. This patented versatile platform can co-deliver multiple therapeutic classes to ensure that they reach the target cells at the same time to fully realize their synergy. Illustrated herein are nanoparticles with three drug cargos: HER2 antibody, HER2 siRNA, and chemotherapeutic docetaxel.

Abstract P2-13-36: Comparative time course analysis of the effects of neratinib, lapatinib and tucatinib in an in vitro HER2+ breast cancer model

Abstract Introduction: Human epidermal growth factor 2 (HER2/ErbB2) is overexpressed in approximately 20% of breast cancers. The HER2-targeted tyrosine kinase inhibitors (TKIs) neratinib, lapatinib and tucatinib are all FDA-approved for the treatment of HER2-positive breast cancer. All three inhibit the HER2 kinase domain but differ in binding characteristics (the irreversible neratinib vs reversible lapatinib and tucatinib) and their affinity for other HER family members. The aim of this study was to carry out kinetic analysis of the effect of the three TKIs on HER family signalling, cellular proliferation, and apoptosis induction in a cell model of breast cancer. Methods: In this study, the anti-proliferative effects of the three TKIs were assessed in the HER2-amplified breast cancer cell line SKBR3 by acid phosphatase assay (5-day endpoint assay) and with the IncuCyte→ live-cell imaging system over 120 hours. TKI IC50 values were calculated using CalcuSyn software. Apoptotic cells were detected every 3 hours for 5 days using the Incucyte→ Caspase 3/7 dye. Western blotting was used to investigate the time course effects (15 min, 6 h, 24 h, 72 h) of the TKIs on the expression and phosphorylation of EGFR, HER2 and on their downstream effectors ERK1/2 and Akt. Results: All three TKIs displayed nanomolar activity against SKBR3 cells. Neratinib showed the greatest anti-proliferative effect (IC50 = 3.4 ± 1.1 nM), followed by tucatinib (IC50 = 37.5 ± 18.4 nM) and lapatinib (IC50 = 51.0 ± 23.0 nM). 50 nM neratinib induced higher activation of caspase 3/7 than 500 nM lapatinib or 500 nM tucatinib. Total levels of HER2 and EGFR were increased in the presence of lapatinib and tucatinib, but decreased in the presence of neratinib. The three drugs (500 nM) significantly inhibited the activation of EGFR and HER2 at 15 min. From 6 h to 72 h, treatment with 5 nM and 50 nM neratinib resulted in greater inhibition of phosphorylated HER2 and EGFR, compared to the equivalent concentration of lapatinib or tucatinib. All three TKIs (500 nM) inhibited the activity of phospho-Akt at the earliest timepoint (15 min), but a strong impact on downstream ERK1/2 phosphorylation was not observed until the 6h timepoint. 50 and 500 nM neratinib was more effective at preventing reactivation of ERK1/2 and Akt phosphorylation than either 500 nM lapatinib or tucatinib at 72 h. Conclusion: These data highlight the differences in in vitro efficacy of the three HER2-targeting TKIs currently approved for the treatment of HER2+ breast cancer in the clinic. Neratinib inhibits HER2 and EGFR at lower concentrations and for longer compared to lapatinib and tucatinib, resulting in increased apoptosis induction. This may be due to the irreversible nature of neratinib binding, as opposed to the reversible nature of lapatinib and tucatinib binding. Further comparative studies between neratinib, lapatinib and tucatinib are warranted to explore the impact of varied pre-clinical characteristics on the emergence of therapeutic resistance. Citation Format: Myra E Castel, Neil T Conlon, Naomi Walsh, Irmina Diala, Lisa Eli, John Crown, Denis M Collins. Comparative time course analysis of the effects of neratinib, lapatinib and tucatinib in an in vitro HER2+ breast cancer model [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 P2-13-36.

Abstract P2-13-37: A prospective, open, multi-center clinical study of pyrotinib combined with trastuzumab and nab-paclitaxel in neoadjuvant treatment for stage II-III HER2-positive breast cancer patients

Abstract Background: Targeted therapy has significant efficacy in adjuvant and advanced treatment of HER2-positive breast cancer, and it has also promoted its development in neoadjuvant therapy. For HER2-positive breast cancer, chemotherapy with anthracyclines and taxanes combined with trastuzumab targeted therapy is currently the standard regimen for adjuvant or neoadjuvant therapy. On the basis of the preliminary clinical trials, we carried out this study to confirmed efficacy and safety of pyrotinib combined with trastuzumab and nab-paclitaxel as neoadjuvant treatment regimen in patients(pts) with stage II- III HER2-positive breast cancer. Method: In this multicenter, single arm, prospective, open-label phase II study, 46pts with stage II-III HER2-positive breast cancer will be enrolled (in Simon twostages model, 16 pts will be enrolled in the first stage) to receive pyrotinibcombined with trastuzumab and nab-paclitaxel. The inclusion criteria are asflows. (1) female aging from 18 to 75; (2) Eastern Cooperative Oncology Group(ECOG) performance score of 0-1; (3) Life expectancy is no less than 12weeks;(4) Pathologically confirmed HER-2 positive breast cancer;(5) earlystage (T2-3, N0-1, M0) or locally advanced (T2-4, N2, or N3), with tumor sizeno less than 2cm in diameter. All pts will receive pyrotinib (400mg qd) andtrastuzumab: 8 mg/kg for cycle 1 and 6 mg/kg for cycles 2-6, intravenousinfusion, 21 days for 1 cycle, a total of 6 cycles and nab-paclitaxel: 260mg/m2,intravenous infusion, 21 days as a cycle, a total of 6 cycles. The primaryendpoint is pathological complete response rate (pCR: ypT0/is, ypN0), and thesecondary endpoints are disease-free survival time (DFS), objective responserate (ORR), and survival time without distant metastasis (DDFS). Findings: From Nov 2020 to May 2021, a total of 11 pts were enrolled, 4 pts havecompleted surgery and 6 pts could be evaluated for ORR. The pCR rate was50%, ORR was 100% (5 PR, 1CR). Adverse events (AEs) of any garde werediarrhea 11 (100.0%), anorexia and vomiting 8 (72.7%) and rash 4 (36.4%).Garde 3 AEs were diarrhea 3 (27.3%), and there was no grade 4 AEs. Conclusion: Pyrotinib combined with trastuzumab and nab-paclitaxel in neoadjuvanttreatment for pts with stage II-III HER2-positive breast cancer showedacceptable toxicity and promising efficacy. Citation Format: Bin Shao, Zhengyan Yu, Yu Wang, Guangcai Zhao, Fei Zhou, Ranmei Wei. A prospective, open, multi-center clinical study of pyrotinib combined with trastuzumab and nab-paclitaxel in neoadjuvant treatment for stage II-III HER2-positive breast cancer patients [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 P2-13-37.

Abstract P2-13-17: A phase III, randomized, multicenter, double-blind study to compare efficacy and safety of EG12014 (EirGenix trastuzumab) with Herceptin® as neoadjuvant treatment in combination with anthracycline/paclitaxel-based systemic therapy in patients with HER2-positive early breast cancer - a multinational phase III study conducted during the COVID-19 pandemic

Abstract Amplification and/or overexpression of HER2 in breast cancer (BCa) patients is associated with aggressive disease and poor prognosis. Herceptin® (trastuzumab), a monoclonal antibody targeting HER2, has an established role in the treatment of HER2 positive BCa. Addition of trastuzumab to anthracycline- and taxane-based neoadjuvant treatment in women with HER2-positive BCa has resulted in improvements in pathological complete response (pCR, a strong predictor for long-term clinical outcome), event-free survival (EFS) and overall survival (OS). This study is designed to compare efficacy (pCR) and safety between the originator Herceptin and the proposed trastuzumab biosimilar EG12014. The study is conducted during the COVID-19 pandemic (last patient in: March 2020, last patient last visit: planned Jan 2022) in Belarus, Chile, Colombia, Georgia, India, Russia, South Africa, South Korea, Taiwan, and the Ukraine. Methods: Neoadjuvant phase: 807 patients were randomized (1:1) into 2 arms receiving epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) every 3 weeks for 4 cycles, followed by EG12014 (arm 1) or Herceptin (arm 2) (both at loading dose: 8 mg/kg and maintenance dose: 6 mg/kg) and paclitaxel (175 mg/m2) every 3 weeks for 4 cycles. Subsequently, the patients underwent surgery, and primary endpoint (pCR [ypT0/is ypN0]) was assessed. Adjuvant phase: After surgery, the patients received EG12014 or Herceptin (both at loading dose: 8 mg/kg and maintenance dose: 6 mg/kg) to complete 12 months of overall trastuzumab treatment. COVID-19 infections in the study population were not expected to affect primary endpoint analysis; thus, no sensitivity analysis was performed regarding COVID-19 status (symptomatic/asymptomatic). Differences between the 2 arms regarding delays in study treatments and procedures due to COVID-19 were assessed. Results (at interim data base lock, blinded as study is ongoing): Study population: the mean age was 50 years, the majority were white Europeans with tumor stage II, estrogen receptor positive and progesterone receptor negative. The median time from date of first diagnosis was 0.5 months. Primary endpoint pCR (ypT0/is ypN0) was reached with relative risk ratio (RR) for the full analysis set: 0.992 (90% CI 0.880 to 1.118) between the 2 treatment arms. Secondary pCR endpoints (defined as ypT0 ypN0 and ypT0/is) were also reached, with RR between the treatment arms: 0.917 and 0.992, respectively. Objective clinical response prior to surgery was similar for the 2 treatment arms: 83.8% and 83.6%, respectively. EFS, OS, safety endpoints (e.g., adverse events [most frequently reported: alopecia], serious adverse events, and deaths), and toxicity assessments, supported similarity between EG12014 and Herceptin. Sixty-two patients (7.7%) were infected with COVID-19; the infections were equally distributed between the 2 treatment arms. COVID-19 did not cause any discontinuations or deaths in the study. Among all reported COVID-19 events, 13 (21%) were asymptomatic, 11 (18%) were graded as 3 (severe), and 1 (1.6%) was graded as grade 4 (life threatening). Conclusion: EG12014 has shown equivalent efficacy to Herceptin in regard to clinical response (pCR) and has also demonstrated a similar safety profile. The impact of the COVID-19 pandemic has been comparable between the two treatment arms. The influence of the pandemic on this clinical study has been relatively low considering timing and the participating countries. For further information, visit ClinicalTrials.gov (NCT03433313). Citation Format: Barbara Grohmann-Izay, Chiun-Sheng Huang, Giorgi Dzagnidze, Nestor Llinas, Anand Misra, Denys Pominchuk, Alexander Prokhorov, Bernardo Rapoport, Vladimir Semiglazov, Ling-Ming Tseng, Eduardo Yanez Ruiz, Sibylle Loibl. A phase III, randomized, multicenter, double-blind study to compare efficacy and safety of EG12014 (EirGenix trastuzumab) with Herceptin® as neoadjuvant treatment in combination with anthracycline/paclitaxel-based systemic therapy in patients with HER2-positive early breast cancer - a multinational phase III study conducted during the COVID-19 pandemic [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 P2-13-17.

Abstract ES1-2: Genomics of HER2+ breast cancer

Abstract Human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in about 20% ofall breast cancers and, when untreated, is the most aggressive breast cancer phenotype. The prognosis of patients with HER2-positive breast cancer has been markedly improved thanks to the effectiveness of anti-HER2 therapies. However, we still overtreat a high proportion of patients with toxic chemotherapy +antiHER2 combinations, while others still develop recurrent disease despite these complex regimens. Both the intrinsic complexity of HER2-positive tumors and the properties of its tumor microenvironment likely contribute to differences in response toanti-HER2 targeted therapies. HER2-positive breast cancer is highly heterogeneous, and all the intrinsic molecular subtypes can be identified within HER2-positive tumors by gene expression. HER2-enriched subtype has been systematically associated with higher pCR rates to anti-HER2 targeted therapies across multiple trials in early stages. Genomically, the HER2-enriched subtype is the most HER2 oncogene addicted of the subtypes, which likely explains the high sensitivity to anti-HER2 therapies. However, this may also explain why a HER2-enriched tumor with residual disease after anti-HER2 treatments carries a particularly poor prognosis. Conversely, both tumor-infiltrating lymphocytes (TILs) and RNA-based immune-signatures are significantly and independently associated with a higher likelihood of pCR and better survival outcomes in patients with HER2-positive disease. Thus, integrating the prognostic information provided by clinical factors, genomic subtype, and immune-related signatures is essential to improve the design of future clinical trials and establish new and better treatment algorithms for HER2-positive breast cancer treatment. Citation Format: C Perou. Genomics of HER2+ breast cancer. [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 ES1-2.

Inhibition of Cytochrome P450 Enzyme and Drug-Drug Interaction Potential of Acid Reducing Agents Used in Management of CDK Inhibitors for Breast Cancer Chemotherapy.

Concurrent usage of proton pump inhibitors and their effect on survival and medication termination has been found in individuals receiving protein kinase inhibitor chemotherapy. To investigate the drug-drug interaction mechanism between CDK inhibitors and proton pump inhibitors, the in-silico docking approach was designed by applying computer simulation modules to predict the binding and inhibitory potential. The interaction potential of proton pump inhibitors and CDK inhibitors was predicted utilising molecular docking techniques that employed Schrödinger algorithms to capture the dynamics of the CYP450 enzyme-inhibitor interaction between proton pump inhibitors and CDK inhibitors. Additionally, the human liver microsomes assay was used to determine the in vitro half-maximal inhibitory concentration (IC50) of proton pump inhibitors and the inactivation of CDK inhibitors via CYP3A4. Proton pump inhibitors alter the conformation of the CYP3A4 and CYP2C19 enzymes and interact with the heme prosthetic group, as determined by docking studies. It may result in the suppression of CDK inhibitors' metabolism via competitive inhibition at the binding site of an enzyme. Omeprazole and rabeprazole both significantly block midazolam's 1'-hydroxylation by CYP3A4 in vitro, with IC50 values of 9.86μM and 9.71μM, respectively. When omeprazole and rabeprazole are co-incubated in human liver microsomes at a 30μM concentration equivalent to the Cmax of omeprazole and rabeprazole, rabeprazole significantly prolongs the metabolic clearance of palbociclib, whereas omeprazole affects the ribociclib CYP3A4-mediated metabolism. Using dynamic models, we determined that proton pump inhibitors such as rabeprazole and omeprazole indeed have the potential to cause clinically significant drug-drug interactions with CDK inhibitors in the treatment of estrogen receptor (ER) positive and HER2-positive breast cancer. As a result, it is suggested to use caution when prescribing proton pump inhibitors to these individuals.

Circulating metabolites serve as diagnostic biomarkers for HER2-positive breast cancer and have predictive value for trastuzumab therapy outcomes.

Human epidermal growth factor receptor 2 (HER2)‐positive is a particularly aggressive type of the breast cancer. Trastuzumab‐based therapy is a standard treatment for HER2‐positive breast cancer, but some patients are resistance to the therapy. There are no known diagnostic biomarkers to improve the early diagnosis of HER2‐positive breast cancer and the clinical utility of trastuzumab therapy. Using ultrahigh‐performance liquid time of flight mass spectrometry (UPLC‐TOF‐MS)‐based serum metabolomics and multivariate statistical analysis, we investigated and identified the circulating metabolites L‐arginine and arachidonic acid were elevated in trastuzumab‐responsive and trastuzumab‐resistant HER2‐positive breast cancer patients, and increased until reaching their peaks in trastuzumab‐resistant HER2‐positive breast cancer patients. Moreover, an equation for assessing the risk scores based on linear logistic regression models involving L‐arginine and arachidonic acid was created, which was beneficial for revealing metabolic changes in HER2‐positive breast cancer and enhancing current trastuzumab‐based therapy. In summary, we develop serum‐based metabolic biomarkers for diagnosis of HER2‐positive breast cancers and predicts the therapeutic effects of trastuzumab therapy.