HER2-positive Breast Cancer Research Articles

ASO Author Reflections: Evolving Multidisciplinary Decision Making for Early-Stage, HER2-Positive Breast Cancer.

ASO Author Reflections: Evolving Multidisciplinary Decision Making for Early-Stage, HER2-Positive Breast Cancer.

Clinicopathological Factors Predicting Pathological Complete Response to Neoadjuvant Anti-HER2 Therapy in HER2-Positive Breast Cancer

Plain Language SummaryNeoadjuvant treatment is the standard approach for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Especially, pathologic response is an important prognostic factor and the adjuvant treatment is dependent on the response. Therefore, predicting the response is important for modulating the treatment sequence, especially in the initial stage of treatment decision. Therefore, we aimed to identify factors that can predict the effectiveness of neoadjuvant chemotherapy, and our results suggest that factors such as tumor size, grade, hormone receptor, and HER2 status should be considered in the treatment of breast cancer.

Bioconjugated clicked chitosan/alginate nanocarriers with trastuzumab: Unlocking curcumin's potential in targeting breast cancer

Curcumin (Cur) has shown potential anticancer effects against various cancers, including colorectal and breast cancers. The aim of this study was to develop nanocarriers (NCs) bioconjugated with trastuzumab (Tras) using click reactions. Chitosan-maleimide (CHI-Mal) and thiolated alginate (SH-ALG) were synthesized to prepare CS-Mal/SH-ALG NCs, which were then conjugated with Tras as a receptor-targeting ligand via click chemistry. The characteristics of the NCs, including Cur loading and release profiles, were examined. Biocompatibility, anticancer effects, targetability, and cell death analysis were conducted on HER2-positive breast cancer cell line (SK-BR-3). The developed NCs exhibited a nano-scaled size, relatively spherical shape, and positive surface charge. The 7-day release of Cur from the Cur-loaded CHI-Mal/SH-ALG NCs (Cur-NCs) was significantly higher in the cancer environment (pH 5.5; 98%) compared to body fluid (pH 7.4; 57%). Tras-conjugated Cur-NCs (Tras-Cur-NCs) demonstrated superior anticancer effects, receptor-targeting efficiency, and cellular uptake compared to free Cur and non-targeted Cur-NCs. Additionally, Tras-Cur-NCs enhanced apoptotic cell death, indicating a non-inflammatory cell death with strong anticancer effect against HER2-positive SK-BR-3 cells. The spontaneous click reaction successfully formed pH-responsive Tras-conjugated NCs for targeted Cur delivery to HER2-positive breast cancer cells.

Tumor enhancement and shrinkage pattern in dynamic contrast-enhanced magnetic resonance imaging for predicting pathologic complete response after human epidermal growth factor receptor 2 (HER2)-targeted therapy in breast cancer.

Targeted therapy with neoadjuvant chemotherapy for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer has increased the rates of pathological complete response (pCR) and breast preservation surgery and improved the overall disease-free survival rate. This study aimed to determine whether tumor enhancement and shrinkage patterns in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can predict the efficacy of targeted therapy in patients with HER2-positive breast cancer and differentiate pCR from non-pCR. The data of 64 patients with HER2-positive breast cancer who received targeted therapy prior to surgery were retrospectively collected. All patients had complete postoperative pathological data. The pretreatment evaluation of the tumor enhancement pattern and the shrinkage pattern after two treatment cycles were assessed. The difference in the enhancement and shrinkage patterns between the pCR and non-pCR groups was evaluated via the χ2 test. Logistic regression analysis was used to assess the value of enhancement and shrinkage patterns for predicting pCR in patients with HER2-positive breast cancer. There were statistically significant differences in tumor size, estrogen receptor (ER) status, lymph node metastasis, enhancement pattern, and shrinkage pattern between the pCR and non-pCR cases. Patients with a tumor size ≤20 mm were likely to achieve pCR. ER status, lymph node metastasis, and enhancement and shrinkage patterns each had good precision for predicting pCR, and the combination of enhancement and shrinkage patterns had the highest prediction accuracy. Multivariate logistic regression analysis indicated that only enhancement pattern had a significant predictive value. Among patients with HER2-positive breast cancer, those with tumor size ≤20 mm, ER-negative status, no lymph node metastases, and mass enhancement and concentric shrinkage patterns are more likely to achieve pCR. Mass enhancement combined with concentric shrinkage had the highest accuracy in predicting pCR, indicating that preoperative imaging may be useful for guiding clinical decisions regarding targeted treatments.

Development and Validation of a Prognostic Nomogram Model for HER2-Positive Male Breast Cancer Patients.

HER2-positive male breast cancer (MBC) is a rare condition that has a poor prognosis. The purpose of this study was to establish a nomogram model for predicting the prognosis of HER2-positive MBC patients. 240 HER2-positive MBC patients from 2004 to 2015 were retrieved from the surveillance, epidemiology, and end results (SEER) database. All HER2-positive MBC patients were divided randomly into training (n = 144) and validation cohorts (n = 96) according to a ratio of 6:4. Univariate and multivariate Cox regression analyses were used to determine the prognostic factors associated with HER2-positive MBC patients. A clinical prediction model was constructed to predict the overall survival of these patients. The nomogram model was assessed by using receiver operating characteristics (ROC) curves, calibration plots and decision curve analysis (DCA). The Cox regression analysis showed that T-stage, M-stage, surgery and chemotherapy were independent risk factors for the prognosis of HER2-positive MBC patients. The model could also accurately predict the Overall survival (OS) of the patients. In the training and validation cohorts, the C indexes of the OS nomograms were 0.746 (0.677-0.815) and 0.754 (0.679-0.829), respectively. Calibration curves and DCA verified the reliability and accuracy of the clinical prediction model. In conclusion, the predictive model constructed had good clinical utility and can help the clinician to select appropriate treatment strategies for HER2-positive MBC patients.

Nomograms for predicting recurrence of HER2-positive breast cancer with different HR status based on ultrasound and clinicopathological characteristics.

This study aimed to identify ultrasound and clinicopathological characteristics related to recurrence in HER2-positive (HER2+) breast cancer, and to develop nomograms for predicting recurrence. In this dual-center study, we retrospectively enrolled 570 patients with HER2+ breast cancer. The ultrasound and clinicopathological characteristics of hormone receptor (HR)-/HER2+ patients and HR+/HER2+ patients were analyzed separately according to HR status. Eighty percent of the original samples from HR-/HER2+ and HR+/HER2+ patients were extracted by bootstrap sampling as the training cohorts, while the remaining 20% were used as the external validation cohorts. Informative characteristics were screened through univariate and multivariable Cox regression in the training cohorts and used to develop nomograms for predicting recurrence. The predictive accuracy was calculated using Harrell's C-index and calibration curves. Three informative characteristics (axillary nodal status, calcification, and Adler degree) were identified in HR-/HER2+ patients, and another three (histological grade, axillary nodal status, and echogenic halo) in HR+/HER2+ patients. Based on these, two separate nomograms were constructed to assess recurrence risk. In the training cohorts, the C-index was 0.740 (95% CI: 0.667-0.811) for HR-/HER2+ nomogram, and 0.749 (95% CI: 0.679-0.820) for HR+/HER2+ nomogram. In the validation cohorts, the C-index was 0.708 (95% CI: 0.540-0.877) for HR-/HER2+ group, and 0.705 (95% CI: 0.557-0.853) for HR+/HER2+ group. The calibration curves also indicated the excellent accuracy of the nomograms. Ultrasound performance of HER2+ breast cancers with different HR status was significantly different. Nomograms integrating ultrasound and clinicopathological characteristics exhibited favorable performance and have the potential to serve as a reliable method for predicting recurrence in heterogeneous breast cancer.

Quercetin inhibits truncated isoform of dopamine- and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer

Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC). The truncated isoform of dopamine- and cAMP-regulated phosphoprotein (t-DARPP) has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression. To evaluate the t-DARPP expression in BC, paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+ BC tumor tissues. We established 2 patient-derived xenografts (PDX) mice models to test the efficacy of trastuzumab, named model 1 (non-responder) and model 2 (responder). t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays. Instead, there is no response from the responder. Furthermore, mechanistic studies using transwell and Western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins, enhance p95-HER2 expression and promote cell migration. We found that quercetin effectively reduced t-DARPP expression in HER2+ BC cells. In t-DARPP ShRNA-suppressed cells, quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest. In conclusion, the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+ BC patients has the potential as a biomarker for mitigating drug resistance.

277P Long term follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of trastuzumab in patients with HER2-positive breast cancer

277P Long term follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of trastuzumab in patients with HER2-positive breast cancer

Changes in Mitochondrial Function and Cell Death Patterns in Peripheral Blood Mononuclear Cells during Trastuzumab Treatment Following Doxorubicin Chemotherapy.

Trastuzumab, a monoclonal antibody which works against human epidermal growth factor receptor 2 (HER2), possibly causes cardiotoxicity through mitochondrial dysfunction. The usefulness of isolated peripheral blood mononuclear cells (PBMCs) in the assessment of trastuzumab-induced cardiotoxicity remains uncertain. This study aimed to determine the temporal changes in mitochondrial function, oxidative stress, and cell death in the isolated PBMCs of HER2-positive breast cancer patients during breast cancer treatment and to compare the changes with HER2-negative breast cancer patients who did not receive trastuzumab therapy. Eighteen newly diagnosed HER2-positive breast cancer women who received sequential doxorubicin and trastuzumab were consecutively recruited. Age- and gender-matched controls with HER2-negative breast cancer were selected. Echocardiography was carried out, and blood samples for the study of cardiac biomarkers and PBMCs were collected periodically during treatment. Only one patient in our cohort developed asymptomatic left ventricular dysfunction during trastuzumab treatment. However, trastuzumab following doxorubicin aggravated subclinical cardiac injury, determined by cardiac troponin and echocardiography. Cellular and mitochondrial oxidative stress in isolated PBMCs remained unchanged throughout breast cancer treatment. Regarding mitochondrial respiration, the maximal respiration and spare respiration capacity was significantly increased in controls after doxorubicin treatment but not in patients who received trastuzumab therapy. Moreover, the percentage of apoptosis and necroptosis in isolated PBMCs was dramatically decreased in the control, compared to patients with trastuzumab treatment. In conclusion, trastuzumab caused subtle myocardial injury and impaired mitochondrial respiration and cell viability in isolated PBMCs.

233MO Ovarian function suppression in HR-positive, HER2-positive breast cancer: An exploratory analysis from the HERA trial

233MO Ovarian function suppression in HR-positive, HER2-positive breast cancer: An exploratory analysis from the HERA trial

A pooled analysis of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with brain metastases

This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. The endpoints included intracranial objective response rate (ORR; complete or partial response in the brain) per blinded independent central review (BICR) by RECIST version 1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. A total of 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median intracranial DoR was 12.3 [95% confidence interval (CI) 9.1-17.9] months, and for those with untreated/active BMs, it was 17.5 months (95% CI 13.6-31.6 months). The median CNS-PFS and OS were 12.3 months (95% CI 11.1-13.8 months) and not reached (95% CI 22.1 months-not estimable) in those with treated/stable BMs, and 18.5 months (95% CI 13.6-23.3 months) and 30.2 months (95% CI 21.3 months-not estimable) in those with untreated/active BMs, respectively. Drug-related treatment-emergent adverse events grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

378P Updated data on real-world efficacy and safety of inetetamab-based therapy in HER2-positive metastatic breast cancer patients with prior exposure to trastuzumab

378P Updated data on real-world efficacy and safety of inetetamab-based therapy in HER2-positive metastatic breast cancer patients with prior exposure to trastuzumab

382P Pyrotinib combined with metronomic oral etoposide (VP-16) in heavily pretreated HER2-positive metastatic breast cancer: A single-arm, phase II study

382P Pyrotinib combined with metronomic oral etoposide (VP-16) in heavily pretreated HER2-positive metastatic breast cancer: A single-arm, phase II study

373P Quality-of-life outcomes in patients with HER2-positive, locally advanced or metastatic breast cancer treated with eribulin mesylate in combination with trastuzumab and pertuzumab in the phase III JBCRG-M06/EMERALD study

373P Quality-of-life outcomes in patients with HER2-positive, locally advanced or metastatic breast cancer treated with eribulin mesylate in combination with trastuzumab and pertuzumab in the phase III JBCRG-M06/EMERALD study

Trastuzumab-Deruxtecan: Redefining HER2 as a Tumor Agnostic Biomarker.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2-positive malignancies across various tumor types. Through its unique composition, T-DXd achieves selective payload delivery, inducing cell death and halting tumor progression. Clinical trials initially investigated T-DXd's efficacy in HER2-positive advanced or metastatic breast, gastric, lung, and colorectal cancers; however, recent results from the DESTINY-PanTumor02 trial further underscore T-DXd's versatility, prompting T-DXd's US FDA approval for HER2-positive (immunohistochemistry [IHC] 3+) solid tumors. Moreover, in addition to T-DXd's efficacy against brain metastasis, T-DXd is showing promising results in HER2-low and HER2-ultra-low metastatic breast cancer, indicating a broader population of patients who may benefit.

438TiP Trastuzumab deruxtecan with pyrotinib in first-line HER2-positive unresectable or metastatic breast cancer: An exploratory, multi-center, single-arm, phase II study (TROPHY, trial in progress)

438TiP Trastuzumab deruxtecan with pyrotinib in first-line HER2-positive unresectable or metastatic breast cancer: An exploratory, multi-center, single-arm, phase II study (TROPHY, trial in progress)

Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: An expert consensus in China.

Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.

A randomized, double-blind, placebo-controlled phase II study of olanzapine-based prophylactic antiemetic therapy for delayed and persistent nausea and vomiting in patients with HER2-positive or HER2-low breast cancer treated with trastuzumab deruxtecan: ERICA study (WJOG14320B)

Nausea and vomiting are common adverse events associated with trastuzumab deruxtecan (T-DXd). We evaluated the efficacy of an olanzapine-based triplet regimen for preventing nausea and vomiting in patients receiving first cycle T-DXd. This multi-institutional, randomized, double-blind, placebo-controlled (ERICA) phase II study enrolled patients with HER2-positive/HER2-low metastatic breast cancer receiving their first cycle of T-DXd. Patients were randomized to olanzapine 5 mg or placebo once daily (1:1 ratio) from Day 1 to 6, plus a 5-hydroxytryptamine type 3-receptor antagonist (5-HT3RA) and dexamethasone 6.6 mg intravenously or 8 mg orally on Day 1. The total observation period was 504 hours (21 days) from the first T-DXd administration. The primary endpoint was complete response (CR), defined as no emetic events and no rescue medications, in the delayed phase (24-120 hours post-T-DXd), with the type I error rate of 0.2 (one-sided) for the comparison. Secondary endpoints included no nausea rate in the delayed and persistent phases (120-504 hours), adverse event by CTCAE and PRO-CTCAE. In total, 168 patients were enrolled at 43 sites in Japan (Nov 2021-Sep 2023) with 162 patients (olanzapine, n = 80; placebo, n = 82) included in the per protocol set. The primary endpoint was met as the delayed phase CR rate was significantly greater with olanzapine than placebo (70.0% versus 56.1%, P = 0.047). Efficacy was maintained in the persistent phase (63.9% versus 44.4%). No nausea rate was also greater with olanzapine (delayed phase: 57.5% versus 37.8%; persistent phase: 51.4% versus 31.9%). CR rates in the delayed phase favored olanzapine across subgroups. Appetite loss was also decreased with olanzapine. Hyperglycemia and somnolence were mostly of low-grade severity. Olanzapine 5mg for 6 days with 5-HT3RA and dexamethasone appears effective for T-DXd-treated patients to prevent delayed and persistent nausea and vomiting.

Can neoadjuvant systemic therapy provide additional benefits for T1 HER2+ breast cancer patients: a subgroup analysis based on different high-risk signatures.

Neoadjuvant systemic therapy (NAST) is vital in the management of HER2-positive (HER2+) breast cancer. Nevertheless, the indications for NAST in tumors <2cm remain controversial. A total of 7961 patients were screened from the Surveillance, Epidemiology, and End Result database. Independent prognostic factors were identified using multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were used to simulate whether NAST would provide a survival benefit with different high-risk characteristics. Nomograms were constructed, and an internal validation cohort was employed. Of the 7961 included patients, 1137 (14.3%) underwent NAST. In the total population, NAST was associated with poorer overall survival (OS) and breast cancer-specific survival (BCSS) (OS: P=0.00093; BCSS: P < 0.0001). Multivariate Cox analysis confirmed that NAST markedly affected the prognosis of enrolled patients. Besides, a direct association between T, N, age, subtype, and prognosis was observed. Subgroup analyses yielded in these three subgroups, T1c, hormone receptor-negative, and 61-69years of age, NAST and AST had comparable OS, while NAST possessed worse BCSS. Notably, even in the N3, we still did not observe any additional benefit of NAST. The calculated C-index of 0.72 and 0.73 confirmed the predictability of the nomograms. The AUCs exhibit consistency in the training and validation cohorts. Our findings suggest that NAST does not provide additional benefit to patients with T1 HER2+ breast cancer, even in the presence of lymph node metastasis, T1c, or hormone receptor negativity. This study facilitates the implementation of individualized management strategies.

331P Neoadjuvant intetamab in combination with standard chemotherapy for locally advanced HER2-positive breast cancer

331P Neoadjuvant intetamab in combination with standard chemotherapy for locally advanced HER2-positive breast cancer