Trastuzumab-based Treatment Research Articles

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

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

HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments.

Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.

Identification of ADME genes polymorphic variants linked to trastuzumab-induced cardiotoxicity in breast cancer patients: Case series of mono-institutional experience

BackgroundLong-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced. MethodsWe selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients (“case series”), who experienced TIC, were compared to 37 “control group” matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity. ResultsIn this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC. ConclusionReal-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren’t available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.

Abstract 2484: Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC)

Abstract Background: Although trastuzumab plus chemotherapy is the treatment of choice for HER2-positive mGC, not all patients respond to the therapy. To date, there is no reliable and efficient biomarker that can predict the response to trastuzumab-based treatment. Methods: Clinical data and pathology slides from HER2-positive mGC patients treated with first-line trastuzumab and capecitabine/5-fluorouracil plus cisplatin were retrospectively collected. HER2 positivity was confirmed using standard methods with immunohistochemistry (IHC) and/or in situ hybridization. An AI-based model was applied to a single HER2 IHC-stained whole slide image (WSI) of each patient to identify and quantify the tumor cells with HER2 IHC staining intensity categories of 0, 1+, 2+, or 3+ on the slide. The proportion of tumor cells with 3+ staining intensity among total tumor cells (h3 percentage) in each slide was calculated and analyzed in relation to clinical outcomes. Results: A total of 160 cases were included in this analysis. Overall, the median progression-free survival (PFS) was 9.2 mo, and the overall survival (OS) was 18.9 mo. By standard IHC HER2 grading, 107 (66.9%) 3+ and 53 (33.1%) 2+ cases were included. The median AI-estimated h3 percentage in these patients was 14.8% (range 0 - 99.5%). The patients with their best tumor response of complete (CR) or partial response (PR) (44.4%) exhibited significantly higher h3 percentages (mean h3 percentage 46.6% in CR/PR vs. 29.4% in stable or progressive disease, p = 0.018). The h3 percentage exhibited strong associations as a continuous variable with longer PFS (hazard ratio [HR] 0.94 [95% confidence interval (CI) 0.90 - 0.99] for 10% change of h3 percentages, p = 0.015) or OS (HR 0.93 [95% CI 0.89 - 0.98] for 10% change of h3 percentages, p = 0.004). Notably, patients having a proportion of 3+ tumor cells at ≥ 90% (27/160, 16.9%) showed particularly longer PFS (median PFS 21.4 mo in ≥ 90% vs. 8.5mo in < 90%, p = 0.006) and OS (median OS 40.3 mo in ≥ 90% vs. 16.6 mo in < 90%, p = 0.004). Conclusion: AI-based models interpreting WSI can provide additive predictive information to HER2-positive mGC patients treated with trastuzumab plus chemotherapy. Citation Format: Minsu Kang, Yoojoo Lim, Hyeon Jeong Oh, Ji Ae Lee, Jin Won Kim, Ji-Won Kim, Sanghoon Song, Heon Song, Keun-Wook Lee. Association of artificial intelligence (AI)-based HER2 scoring with clinical outcomes to first-line trastuzumab plus chemotherapy in HER2-positive metastatic gastric cancer (mGC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2484.

Thioridazine reverses trastuzumab resistance in gastric cancer by inhibiting S-phase kinase associated protein 2-mediated aerobic glycolysis.

Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2 (HER-2)-positive gastric cancer (GC). However, the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance. While S-phase kinase associated protein 2 (Skp2) overexpression has been implicated in the malignant progression of GC, its role in regulating trastuzumab resistance in this context remains uncertain. Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products, there has been a lack of successful commercialization of drugs specifically targeting Skp2. To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment. Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells. Q-PCR, western blot, and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression. A cell counting kit-8 assay, flow cytometry, a amplex red glucose/glucose oxidase assay kit, and a lactate assay kit were utilized to measure the proliferation, apoptosis, and glycolytic activity of GC cells in vitro. A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo. The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab. Thioridazine demonstrated the ability to directly bind to Skp2, resulting in a reduction in Skp2 expression at both the transcriptional and translational levels. Moreover, thioridazine effectively inhibited cell proliferation, exhibited antiapoptotic properties, and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways. The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo, surpassing the efficacy of either monotherapy. Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance, particularly when used in conjunction with lapatinib. This compound has potential benefits for patients with Skp2-proficient tumors.

Neratinib as Extended Adjuvant Treatment of HER2-Positive/HR-Positive Early Breast Cancer Patients in Germany, Austria, and Switzerland: Interim Results of the Prospective, Observational ELEANOR Study

Introduction: Prognosis of patients diagnosed with HER2+ early breast cancer (eBC) has substantially improved, but distant recurrences impacting quality of life and survival still occur. One treatment option for extended adjuvant treatment of patients with HER2+/HR+ eBC is neratinib, available in Europe for patients who completed adjuvant trastuzumab-based therapy within 1 year. The ELEANOR study is investigating the real-world use of neratinib in Germany, Austria, and Switzerland. Results from an interim analysis of the first 200 patients observed for ≥3 months are reported. Methods: The primary objective of this prospective, multicenter, observational study is to assess patient adherence to neratinib (defined as the percentage of patients taking neratinib on ≥75% prescribed days). Secondary objectives are patient characteristics and treatment outcomes. Results: At cut-off (May 2, 2022), a total of 202 patients had been observed for ≥3 months, with neratinib treatment documented for 187 patients (median age: 53.0 years; 67.9% at increased risk of disease recurrence). In total, 151 (80.7%) patients had received prior neoadjuvant treatment; of these, 82 (54.3%) patients achieved a pathologically complete response. Neratinib was initiated at a median 3.6 months after trastuzumab-based treatment, with 36.4% starting at a dose <240 mg/day. Treatment is ongoing for 46.0% of patients, with median treatment duration of 11.2 (interquartile range 0.9–12.0) months. Diarrhea was the most common adverse event (78.6% any grade, 20.3% grade ≥3); pharmacologic prophylaxis was used in 85.6% of patients. Conclusions: The pattern of anti-HER2 pretreatment observed reflected the current treatment for HER2+/HR+ eBC in Germany, Austria, and Switzerland. These interim results suggest that neratinib as an extended adjuvant is a feasible option after various anti-HER2 pretreatments and that its tolerability can be managed and improved with proactive diarrhea management.

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

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

A Review and Meta-analysis on Trastuzumab Resistance in Patients with HER2+ Breast Cancer.

Trastuzumab is a monoclonal antibody that revolutionized the treatment of HER2+ breast cancer. However, about 30% of patients demonstrate resistance to this drug. The purpose of this study is to identify the mechanisms involved in resistance to treatment. with trastuzumab in women undergoing HER2+ breast cancer treatment. A wide review and meta-analysis were performed in the PubMed and Scielo databases up to January 2022. All articles that analyzed the efficacy of the drug in HER2+ human patients treated with trastuzumab were selected, except reviews, meta-analyses, and reports. Egger's test was applied to verify publication bias. Forest plot and PRISMA flowchart were employed. 60 articles were selected for the review and 15 included in the meta-analysis. A total of 102 resistance mechanisms were identified, 73 of which are different from each other. The mechanisms have been classified into 5 different categories. The main resistance mechanisms found are in the PI3K/Akt/mTOR pathway or related to low HER2, often resulting from failure to assess HER2 status. Both groups presented statistical significance. The two groups were not significantly different from each other. Drug resistance is the main challenge of trastuzumab-based treatment. To overcome this challenge, it is important to continue efforts to understand the mechanisms of cancer drug resistance, identify therapies that can treat refractory cancer to current therapies, and possibly create a panel of genes that predict resistance, avoiding symptomatic and economic costs. The main limitation of this study was the selection and population bias.

Termination of trastuzumab in HER2-positive metastatic breast cancer patients who received trastuzumab beyond progression

The purpose of the study was to assess the prognosis of HER2-positive metastatic breast cancer patients who received trastuzumab beyond progression and investigate the predictors of complete response. HER2-positive metastatic breast cancer patients who received long-term trastuzumab were included in the study. Predictors of complete response were analyzed with binary regression analysis. The prognosis of patients who had their trastuzumab-based treatment terminated was assessed. Eighty patients were involved in the study. The patients were received with trastuzumab for a median of 62 months (12–191). A complete response was observed in 60 (75%) patients. The median duration to development of complete response was found as 14.8 months (2.4–55). In logistic regression analysis: using endocrine therapy with trastuzumab (p = 0.04), menopausal status (p = 0.03), and the number of metastatic sites (p = 0.01) were found to be statistically significant factors for a complete response. Trastuzumab-based therapy of fifteen patients was terminated, six (40%) patients continued to receive an aromatase inhibitor, and nine (60%) patients were followed up without treatment. After termination of trastuzumab, at a median follow-up of 32 months (11–66), recurrence was detected in two (13.3%) patients. We detected that menopausal status, the number of metastatic sites, and using endocrine therapy with trastuzumab were predictors of complete response in HER2-positive metastatic breast cancer patients who received long-term trastuzumab-based therapy. We observed that HER2-positive metastatic breast cancer patients may be completely cured with trastuzumab-based therapy. There are no defined criteria for termination of trastuzumab treatment in this selected patient group. It is necessary to confirm our data with multicenter studies involving a large number of patients.

Identification of genetic and immune signatures for the recurrence of HER2-positive breast cancer after trastuzumab-based treatment

To determine the genetic and immune features associated with the recurrence of human epidermal growth factor receptor2-positive (HER2 +) breast cancer (BC) after trastuzumab-based treatment. A retrospective cohort study of 48 patients who received trastuzumab-based treatment was divided into recurrent and non-recurrent groups according to clinical follow-up. Baseline samples from all 48 patients were analyzed for genetic variation, HLA allele type, gene expression, and immune features, which were linked to HER2 + BC recurrence. Statistics included logistic regression models, Kaplan-Meier plots, and Univariate Cox proportional hazards models. Compared with the non-recurrent group, the extracellular matrix-related pathway and 3 Hallmark gene sets were enriched in the recurrent group. The infiltration levels of immature B cells and activated B cells were significantly increased in the non-recurrent group, which correlated remarkably with improved overall survival (OS) in two other published gene expression datasets, including TCGA and METABRIC. In the TCGA cohort (n = 275), activated B cells (HR 0.23, 95%CI 0.13-0.43, p < 0.0001), and immature B cells (HR 0.26, 95%CI 0.12-0.59, p < 0.0001). In the METABRIC cohort (n = 236), activated B cells (HR 0.60, 95%CI 0.43-0.83, p = 0.002), and immature B cells (HR 0.65, 95%CI 0.47-0.91, p = 0.011). Cox regression suggested that immature B cells and activated B cells were protective factors for outcome OS. Aberrant activation of multiple pathways and low baseline tumor-infiltrating B cells are related to HER2 + BC trastuzumab-based recurrence, which primarily affects the antitumor activity of trastuzumab.

Abstract P1-13-15: Elevated TCEAL9 Expression Is Correlated With Trastuzumab-based Neoadjuvant Chemotherapy Resistance In HER2-positive Breast Cancer

Abstract Background: -Trastuzumab-based neoadjuvant chemotherapy has shown to have remarkable clinical benefits for HER2-positive breast cancer patients who had higher tumor burden. -Patients who achieved pathological complete response (pCR) are known to have better prognosis. -However, certain patients have little response or are not sensitive to trastuzumab-based treatment regimens. -Understanding the mechanism of trastuzumab resistance is crucial for the development of new therapeutic strategy. Objectives: To investigate the role of TCEAL9 in developing trastuzumab resistance in HER2-positive breast cancer Methods: A total of 83 patients who received paclitaxel, carboplatin and trastuzumab neoadjuvant chemotherapy in Fudan University Shanghai Cancer Center(FUSCC) from 2016 to 2018 were enrolled in this study. After completed neoadjuvant chemotherapy and surgery, gene expressions were compared between the pCR and non-pCR groups. Total RNA from formalin-fixed paraffin-embedded tissue sections was isolated and RNA-sequencing was performed. Gene sets from GEO dataset GSE52707 were used to analyze TCEAL9 expression in resistant and non-resistant cell lines. Gene expression levels were converted into log2 values and row-wised standardized. BT-474 and SK-BR-3 cell lines were transduced with each expression lentivirus, followed by selection with puromycin for stable expression. TCEAL9 mRNA and protein level evaluation was evaluated by qPCR and western blot. The influence of TCEAL9 expression on proliferation and sensitivity to HER2-targeted therapy was evaluated by CCK8. BT-474 and SK-BR-3 transfected cells were plated in 96-well plates with 4,000 cells per well. After 3 or 5 days of incubation with trastuzumab, pertuzumab or lapatinib, the viability of cells was measured using Cell Proliferation Assay. Comparisons between Kaplan-Meier curves were performed using the long-rank test. Results: TCEAL9 was elevated significantly (P&amp;lt; 0.05) in non-pCR patients in the FUSCC cohort and was associated with lapatinib resistance in GSE52707 from GEO datasets. Patients with elevated TCEAL9 expression had worse recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and progression-free survival (PPS) (all P&amp;lt; 0.05)by using KM-plotter. Overexpression of TCEAL9 was associated with lapatinib(IC50= 5.56 vs 10.90nM) and trastuzumab + pertuzumab(IC50= 745 vs 635nM) resistance in BT-474 and SK-BR-3 respectively, but has no influence in proliferation. In this study, we found that TCEAL9 could induce HER2-positive breast cancer cells resistance to HER2-targeted therapy through the activation of mTOR signaling pathway. After EGFR stimulation, TCEAL9 has a higher mTOR phosphorylation level in BT-474 cells. TCEAL9 elevation also increased HER2 and mTOR phosphorylation after lapatinib treatment in SK-BR-3 cells. In addition, the elevation of TCEAL9 has a positive correlation with HER2 signaling pathways such as EGFR, PIK3R1, FOXO1 and AKT3 in TCGA datasets. Conclusions: TCEAL9 expression correlates with trastuzumab resistance and high TCEAL9 expression is associated with poor prognosis in HER2-positive breast cancer patients. Citation Format: Chih Wan Goh, Wei-Ru Chi, Liyi Zhang, Qi Zhang, Ming Chen, Min Xiong, Douwaner Liu, Hengyu Ren, Bingqiu Xiu, Jingyan Xue, Yayun Chi, Jiong Wu. Elevated TCEAL9 Expression Is Correlated With Trastuzumab-based Neoadjuvant Chemotherapy Resistance 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 P1-13-15.

Abstract P4-01-27: Prognosis and treatment landscape of HER2-positive metastatic breast cancer (MBC) before the availability of tucatinib and trastuzumab-deruxtecan: Results from the Austrian AGMT_MBC-Registry

Abstract Background: New anti-HER2 drugs such as tucatinib and trastuzumab deruxtecan (T-DXd) have shown to improve survival of HER2+ MBC in clinical phase III trials. To allow a future confirmation of this survival advantage in real world, we evaluated the prognosis of HER2+ MBC patients before the availability of tucatinib and T-DXd in Austria. Furthermore, we analyzed the treatment landscape and the drop-out rate between subsequent lines of therapy as documented in the MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT). Patients and methods: The AGMT-MBC-Registry is a multicenter nationwide ongoing retrospective and prospective registry for MBC patients in Austria. In this analysis, patients with known HER2 status, available survival data, at least one treatment line and diagnosis of metastatic disease after 01/04/2013 (pertuzumab available) were included. Follow-up was censored at Dec 31, 2020, when tucatinib und T-DXd became available. Results: As of 04/05/2022, 2,235 patients have been included in the registry. Out of 2,000 evaluable patients, 362 (18.1%) were HER2+, of which 171 (47.2%) fulfilled the inclusion criteria. Out of them 69.0% were hormone-receptor positive. In patients with metachronous metastatic disease (53.2%), 61.5% had received trastuzumab-based treatment for early breast cancer. Median overall survival (OS) for all patients was 50.1 months (95%CI 40.7-73.0), and 66.1 months (95%CI 50.1-NA) for those who received a pertuzumab combination as first-line treatment. The drop-out rate from 1st- to 5th-line was 26.9%, 24.4%, 28.3% and 36.7%, respectively. This yields an estimated percentage of patients that received at least 3, 4, and 5 treatment lines for advanced disease of 55.2%, 39.6% and 25.1%, respectively. In first line, 50.9% received trastuzumab plus pertuzumab and 11.1% T- DM1. In second line, 38.9% were treated with T-DM1 and 35.6% with trastuzumab-based chemotherapy or endocrine therapy. In third line, 11.3%, 17.0% and 49.1% received T-DM1, lapatinib-based and trastuzumab-based therapy, respectively. Outcomes according to treatment line are shown in Table 1. Conclusion: Median overall survival of HER2+ MBC in Austria who received a pertuzumab combination treatment is comparable to the results reported in the registration CLEOPATRA trial. In this analysis, only ~40% of patients are estimated to receive more than three treatment lines and treatment benefit diminished from line to line. This underlines the importance of investigating and ultimately using the most effective compounds in early treatment lines in order to allow more patients to benefit from these life prolonging drugs. Table 1: Outcome according to treatment line Citation Format: Simon P. Gampenrieder, Gabriel Rinnerthaler, Christoph Tinchon, Andreas Petzer, Marija Balic, Sonja Heibl, Margit Sandholzer, August F. Zabernigg, Daniel Egle, Christopher Hager, Petra Pichler, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Michael Knauer, Michael Hubalek, Christian F. Singer, Richard Greil. Prognosis and treatment landscape of HER2-positive metastatic breast cancer (MBC) before the availability of tucatinib and trastuzumab-deruxtecan: Results from the Austrian AGMT_MBC-Registry [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 P4-01-27.

End-of-neoadjuvant treatment circulating microRNAs and HER2-positive breast cancer patient prognosis: An exploratory analysis from NeoALTTO.

The absence of breast cancer cells in surgical specimens, i.e., pathological complete response (pCR), is widely recognized as a favorable prognostic factor after neoadjuvant therapy. In contrast, the presence of disease at surgery characterizes a prognostically heterogeneous group of patients. Here, we challenged circulating microRNAs (miRNAs) at the end of neoadjuvant therapy as potential prognostic biomarkers in the NeoALTTO study. Patients treated within the trastuzumab arm (i.e., pre-operative weekly trastuzumab for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks; post-operative FEC for 3 cycles followed by trastuzumab up to complete 1 year of treatment) were randomized into a training (n= 54) and testing (n= 72) set. RT-PCR-based high-throughput miRNA profile was performed on plasma samples collected at the end of neoadjuvant treatment of both sets. After normalization, circulating miRNAs associated with event free survival (EFS) were identified by univariate and multivariate Cox regression model. Starting from 23 circulating miRNAs associated with EFS in the training set, we generated a 3-circulating miRNA prognostic signature consisting of miR-185-5p, miR-146a-5p, miR-22-3p, which was confirmed in the testing set. The 3-circulating miRNA signature showed a C-statistic of 0.62 (95% confidence interval [95%CI] 0.53-0.71) in the entire study cohort. By resorting to a multivariate Cox regression model we found a statistical significant interaction between the expression values of miR-194-5p and pCR status (p.interaction =0.005) with an estimate Hazard Ratio (HR) of 1.83 (95%CI 1.14- 2.95) in patients with pCR, and 0.87 (95%CI 0.69-1.10) in those without pCR. Notably, the model including this interaction along with the abovementioned 3-circulating miRNA signature provided the highest discriminatory capability with a C-statistic of 0.67 (95%CI 0.58-0.76). Circulating miRNAs are informative to identify patients with different prognosis among those with heterogeneous response after trastuzumab-based neoadjuvant treatment, and may be an exploitable tool to select candidates for salvage adjuvant therapy.

EE291 Economic Evaluation of Metastatic Breast Cancer Following Trastuzumab-Based Treatment of HER2+ Early Breast Cancer in Hong Kong

EE291 Economic Evaluation of Metastatic Breast Cancer Following Trastuzumab-Based Treatment of HER2+ Early Breast Cancer in Hong Kong

Phase 1 multicenter, dose-expansion study of ARX788 as monotherapy in HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma

ARX788 is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate with AS269 as cytotoxic payload. In this phase 1 multicenter dose-expansion clinical trial, patients with HER2-positive advanced gastric/gastroesophageal junction adenocarcinoma failing to respond to prior trastuzumab-based standard treatment were enrolled. Between July 15th, 2019, and March 14th, 2022, 30 participants were enrolled. Twenty-eight (93.3%) patients experienced at least one drug-related adverse event (AE) and 13.3% experienced grade 3 ARX788-related AEs. The confirmed objective response rate is 37.9% (95% confidence interval [CI]: 20.7%-57.7%) and the disease control rate is 55.2% (95% CI: 35.7%-73.6%). With a median follow up of 10months, the median progression-free survival and overall survival are 4.1 (95% CI: 1.4-6.4) and 10.7months (95% CI: 4.8-not reached), respectively. The median duration of response is 8.4 (95% CI: 2.1-18.9) months. ARX788 is well tolerated and has promising anti-tumor activity in patients with HER2-positive advanced gastric adenocarcinoma (ChinaDrugTrials.org.cn: CTR20190639).

The Impact of the Hippo Pathway and Cell Metabolism on Pathological Complete Response in Locally Advanced Her2+ Breast Cancer: The TRISKELE Multicenter Prospective Study.

Simple SummaryPathological complete response (pCR) is a key outcome in locally advanced Her2+ breast cancer (BC) patients treated with anti-Her2−based neoadjuvant therapy. Several clinical and biological features may affect pCR rate, but reliable predictors are needed for clinical practice. The Hippo pathway and its main transducers, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), play a relevant role in treatment outcomes. We herein present evidence concerning the impact of the immunohistochemical expression of key Hippo transducers and their regulators, namely AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR), on the pCR rate of 65 Her2+ BC patients receiving neoadjuvant trastuzumab-based therapy. Low expression of TAZ, especially if concomitant with low expression of YAP and HMGCR and high expression of SCD1, was a negative predictor of pCR, although not confirmed in the multivariate analysis. However, our findings were concordant with overall survival data from the TCGA cohort.The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies.

Prognostic Value of the Serum HER2 Extracellular Domain Level in Breast Cancer: A Systematic Review and Meta-Analysis.

Simple SummaryWe performed a systematic review and meta-analysis evaluating the predictive value of the serum HER2 extracellular domain (sHER2 ECD) for breast cancer prognosis. Our review investigated 40 studies (12,229 patients) that assessed the impact of the sHER2 ECD levels on breast cancer prognosis and explored the clinical significance of sHER2 ECD levels in different treatment modalities. Our findings indicated that an elevated sHER2 was an unfavorable prognostic factor in breast cancer. More interestingly, sHER2 ECD was found to be a promising biomarker for predicting adverse clinical outcomes of trastuzumab-based treatment but did not affect the efficacy of tyrosine kinase inhibitors. In addition, the baseline cutoff value of sHER2 ECD in different treatment stages of breast cancer remains to be further explored. Overall, our study suggested that sHER2 ECD levels have important prognostic value in breast cancer and may be helpful for clinicians to select the appropriate anti-HER2 therapy for HER2-positive breast cancer, providing more evidence for guiding clinical practice.An elevated serum HER2 extracellular domain is associated with poor prognosis in breast cancer, but the relationship between sHER2 and the efficacy of different modalities remains controversial. Herein, we aimed to evaluate the prognostic value of serum HER2 extracellular domain (sHER2 ECD) in breast cancer and to identify its correlation with the efficacy of different treatment regimens. A systematic search of the PubMed, Embase, Cochrane Library, Web of Science, and Scopus databases was conducted to identify studies exploring the association between HER2 ECD level and clinical outcomes among patients with breast cancer. Using the random effects models, pooled hazard ratios (HRs), and odds ratios (ORs) with 95% confidence intervals (CI), were calculated for progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), and the objective response rate (ORR). Heterogeneity was further evaluated by subgroup and sensitivity analysis. Overall, 40 studies comprising 12,229 patients were included in this systematic review and meta-analysis. Elevated HER2 ECD levels were associated with worse PFS (HR 1.74, 95% CI 1.40–2.17; p < 0.001), and this effect was observed in patients treated with chemotherapy (HR 1.81, 95% CI 1.37–2.39; p < 0.001), endocrine therapy (HR 1.91, 95% CI 1.57–2.32; p < 0.001), and trastuzumab (HR 1.74, 95% CI 1.31–2.30; p < 0.001). However, this association was not present in patients treated with tyrosine kinase inhibitors (TKIs) (HR 1.44, 95% CI 0.85–2.43, p = 0.17). The HRs/ORs for an elevated HER2 ECD level for DFS, OS, and ORR were 2.73 (95% CI 2.17–3.42; p < 0.001), 2.13 (95% CI 1.77–2.57; p < 0.001), and 0.80 (95% CI 0.49–1.31; p = 0.381), respectively. An elevated sHER2 ECD was an unfavorable prognostic factor in breast cancer but did not affect the efficacy of tyrosine kinase inhibitors such as lapatinib. Detection of sHER2 ECD may be helpful for clinicians selecting the appropriate anti-HER2 therapy for patients with HER2-positive breast cancer.

Evaluation of Prognostic Factors and Trastuzumab-based Treatments in HER2/Neu-positive Metastatic Gastric Cancer.

To determine the efficacy of trastuzumab-based treatment in patients with HER2/neu-positive metastatic gastric cancer. Observational study. Department of Medical Oncology, Istanbul University, Institute of Oncology, Istanbul, Turkey, between January 2014 and December 2020. The clinicopathological characteristic and treatment data of patients with HER2/neu-positive metastatic gastric cancer were recorded retrospectively. Kaplan-Meier analysis was performed to compare the chemotherapy regimens. Sixty-three patients were included in the study. The average age was 61. Female patients accounted for 27% of the total, while male patients accounted for 73%. De novo metastatic cases accounted for 44 (69.8%) of the total number of patients. The median survival time was 13.6 (8-19.3) months. Complete response was 6.3%, partial response was 39.7%, and the stable response was 9.5% with trastuzumab-based chemotherapy. The overall survival (p= 0.45) and progression-free survival (p=0.893) were similar for different chemotherapy regimens. The grade 1-2 to grade 3-4 toxicity ratio was 79.6% and 20.6%, respectively. The patients' performance (p<0.001) and the number of metastatic sites (p=0.001) were both shown to be unfavourable predictive variables for OS in multivariate analysis. The addition of taxane to trastuzumab-based combinations (with platinum and fluoropyrimidine) did not affect overall and progression-free survival in this research. Three or more metastatic sites and poor performance status were found as the unfavourable prognostic variables for overall survival. Gastric cancer, Trastuzumab, Chemotherapy, Prognostic factors.

Survival of elderly patients with HER2+/HR- metastatic breast cancer in clinical practice: SEER-Medicare data 2012-2016.

1039 Background: Older patients with human epidermal growth factor 2-positive (HER2+) metastatic breast cancer(mBC) are underrepresented in clinical trials. We aim to assess the overall survival (OS) and breast cancer-specific survival of elderly women with de novo HER2+/hormone receptor-negative (HR-) mBC in a real-world setting. Methods: Elderly women with HER2+/HR- mBC treated with chemotherapy and/or HER2-targeted agents and with continuous Medicare Part A, B, and D coverage 1-year before diagnosis were identified from the SEER-MEDICARE database 2012-2016. Patients were retrospectively followed from metastatic diagnosis until death, disenrollment from Medicare A, B, or D, or end of the observation period. Patients' year and month of diagnosis and death were retrieved from SEER. Death dates were verified with Medicare records reported by the Social Security Administration (SSA). For all-cause deaths, Kaplan-Meier analysis was used to estimate overall survival. The cumulative incidence competing risk (CICR) method based on cumulative incidence function (CIF) was used to estimate breast cancer-specific death incidence. Results: Seventy-three patients (mean age at diagnosis, 75.0±7.7 years) met the inclusion criteria. Among them, 56 were treated with trastuzumab ± pertuzumab /chemotherapy as first-line treatment, and 17 were treated with chemotherapy only. The median time to initiate trastuzumab-based treatment from diagnosis was 2.5 months, and the longest trastuzumab treatment length was over 44 months. The median follow-up for OS was 13 months. One patient developed stomach cancer 6 months after breast cancer diagnosis. In Kaplan-Meier analysis, censoring or not censoring this patient after second cancer development resulted in a median OS of 19 months (95% CI, 9-24 months) and 18 months (95% CI, 9-22 months). The OS at the end of 46 months was approximately 25%. Five patients died from other causes, including lung cancer, cerebrovascular diseases, aortic aneurysm and dissection, pneumonia and influenza, and heart diseases during treatment. Considering these competing risks, 50% (95% CI, 36%-64%) of patients specifically died from breast cancer between 21 and 22 months, estimated by the CICR method. Conclusions: Our study observed a shorter OS among HER2+/HR- mBC elderly patients in clinical practice than the OS of 40.8 and 56.5 months among younger patients in the CLEOPATRA trial, suggesting that age is an important prognostic factor for breast cancer survival. The presence of second cancer and other competing risks led to overestimating the probabilities of breast cancer-specific death and resulted in a shorter OS using the Kaplan-Meier method. The CICR method is more relevant to estimate the breast-cancer-specific death incidence.

Temporal dynamics from phosphoproteomics using endoscopic biopsy specimens provides new therapeutic targets in stage IV gastric cancer

Phosphoproteomic analysis expands our understanding of cancer biology. However, the feasibility of phosphoproteomic analysis using endoscopically collected tumor samples, especially with regards to dynamic changes upon drug treatment, remains unknown in stage IV gastric cancer. Here, we conducted a phosphoproteomic analysis using paired endoscopic biopsy specimens of pre- and post-treatment tumors (Ts) and non-tumor adjacent tissues (NATs) obtained from 4 HER2-positive gastric cancer patients who received trastuzumab-based treatment and from pre-treatment Ts and NATs of 4 HER2-negative gastric cancer patients. Our analysis identified 14,622 class 1 phosphosites with 12,749 quantified phosphosites and revealed molecular changes by HER2 positivity and treatment. An inhibitory signature of the ErbB signaling was observed in the post-treatment HER2-positive T group compared with the pre-treatment HER2-positive T group. Phosphoproteomic profiles obtained by a case-by-case review using paired pre- and post-treatment HER2-positive T could be utilized to discover predictive or resistant biomarkers. Furthermore, these data nominated therapeutic kinase targets which were exclusively activated in the patient unresponded to the treatment. The present study suggests that a phosphoproteomic analysis of endoscopic biopsy specimens provides information on dynamic molecular changes which can individually characterize biologic features upon drug treatment and identify therapeutic targets in stage IV gastric cancer.