Trastuzumab In HER2-positive Breast Cancer Research Articles

Neoadjuvant pyrotinib and trastuzumab in HER2-positive breast cancer with no early response (NeoPaTHer): Primary analysis of a prospective, multicenter, response-adapted study.

Neoadjuvant pyrotinib and trastuzumab in HER2-positive breast cancer with no early response (NeoPaTHer): Primary analysis of a prospective, multicenter, response-adapted study.

TRF-27 competitively Binds to G3BPs and Activates MTORC1 to Enhance HER2 Positive Breast Cancer Trastuzumab Tolerance.

About 20% of breast cancer patients are positive for HER2. The efficacy of current treatments is limited by primary and secondary resistance to trastuzumab. tRNA-derived fragments (tRFs) have shown crucial regulatory roles in various cancers. This study aimed to evaluate the role of tRF-27 in regulating the resistance of HER2-positive breast cancer against trastuzumab. tRF-27 was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of tRF-27 promoted the growth and proliferation of trastuzumab-exposed cells. RNA-pulldown assay and mass spectrometry were performed to identify Ras GTPase-activating protein-binding proteins 1 and 2 (G3BPs) (two proteins targeted by tRF-27); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and tRF-27.tRF-27 bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. tRF-27 relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. tRF-27 competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of tRF-27 inhibited phosphorylation of TSCs and promoted the activation of mechanistic target of rapamycin complex 1(MTORC1) to enhance cell proliferation and entice the resistance of HER2-positive breast cancer against trastuzumab.

Pertuzumab plus high-dose trastuzumab for HER2-positive breast cancer with brain metastases: PATRICIA final efficacy data

The PATRICIA study (NCT02536339) examined the efficacy and safety of pertuzumab plus high-dose trastuzumab in patients with HER2-positive metastatic breast cancer (MBC) with progressive central nervous system (CNS) metastases following radiotherapy. Primary analysis confirmed CNS objective response rate (ORR) was 11% (95% confidence interval [CI]: 3–25); clinical benefit rate (CBR) was 68% (4 months) and 51% (6 months). We report final efficacy data after a further 21-months of follow-up, updated safety, survival, and patient-reported outcomes (PROs). Patients received standard-dose pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. Primary endpoint: confirmed ORR (CNS) per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary endpoints were response duration, CBR, progression-free survival (PFS), overall survival (OS), safety, and PROs. By clinical cut-off, 39 patients had completed or discontinued treatment. Confirmed ORR (CNS) was 11% (95% CI: 3.0–25.4). Median CNS-PFS was 4.6 months (95% CI: 4.0–8.9), as was median CNS-PFS or systemic PFS (95% CI: 4.0–8.9); median OS was 27.2 months (95% CI: 16.1–not reached). CBR in the CNS was 51% (19 patients, 95% CI: 34.4–68.1) at 6 months. Two patients remained on treatment until study closure, achieving stable disease for 4.1 and 4.8 years. Treatment-related grade 3/4 adverse events occurred in 7.7% of patients. Patients with confirmed partial response or stable disease (≥4 months) in the CNS had stable PROs over time. Pertuzumab plus high-dose trastuzumab represents a reasonable non-chemotherapeutic treatment option for selected patients with HER2-positive MBC with CNS metastases.

Alternative trastuzumab dosing schedules and association with health care greenhouse gas emissions.

e13644 Background: Climate change due to greenhouse gas (GHG) emissions by humans imperils health. Health care is a major source of GHG emissions and thus reducing health care’s environmental impact should be a global priority. GHG emissions associated with the production and administration of cancer drugs, as well the downstream societal costs in human health terms, are undescribed. The extent to which a given cancer drug’s dosing frequency and duration impact GHG emissions is unknown. Methods: Using trastuzumab for HER2-positive breast cancer as a use case, we conducted a case-control simulation study of single, U.S. academic medical center data to estimate the expected reductions in GHG emissions with three alternative dosing strategies (6-month adjuvant treatment duration, extended-interval dosing, and both) using streamlined life-cycle analysis. We estimated the per-patient relative reduction in GHG emissions expected to occur with each of the alternative dosing strategies and, in exploratory analysis, the societal health costs ( e.g., disability-adjusted life-years [DALYs] and excess mortality per kg CO2) associated with therapy-related GHG emissions, using conventional versus alternative dosing strategies. Results: Adoption of 6-month adjuvant trastuzumab reduced expected per-patient GHG emissions in the adjuvant setting by 10%. Adoption of both 6-month adjuvant trastuzumab and pharmacokinetically-supported every 4-week trastuzumab dosing reduced GHG emissions by 4.5%, 18.7%, and 14.6% in the neoadjuvant, adjuvant, and metastatic settings, respectively. An estimated 8.1 DALYs and 4.6 excess lives are lost annually worldwide as a result of U.S.-based administration of conventionally dosed trastuzumab. Adoption of alternative dosing in the U.S. is estimated to enable avoidance of approximately 1.5 DALYs and 0.9 excess lives lost annually. Conclusions: Alternative dosing strategies, suggested to be noninferior by pharmacokinetic and clinical evidence, are estimated to reduce the societal health costs imposed on bystanders that arise from cancer care’s environmental impact. Environmental impact and its resultant societal health costs should be considered in clinical trial design, re-interpretation of previously conducted trials, regulatory decision-making, and health technology assessments of both new and existing cancer therapies.

Abstract P2-11-21: Outcomes and Treatment Pattern in Women With 1 cm or Smaller, Node-Negative Hormone Receptor-negative Breast Cancer in Fudan University Shanghai Cancer Center

Abstract Background: To evaluate the outcome the treatment pattern in women diagnosed with T1mic, T1a and T1b, node-negative, hormone receptor (HR) –negative breast cancer. Methods: This was a retrospective cohort study within the Fudan University Shanghai Cancer Center (FUSCC) that included 605 women with T1mic,a,bN0M0 breast cancer treated between 2010 and 2020. Tumors were grouped by size (T1mic, T1a, T1b), biologic subtype defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, and receipt of chemotherapy with or without trastuzumab. Kaplan-Meier product was used to calculate invasive disease-free survival (iDFS), breast cancer-specific survival (BCSS) and overall survival (OS). Results: Median follow-up time was 5.0 years. Seventy-three percent of patients with triple-negative breast cancer (TNBC) were treated with chemotherapy. For those with HER2- positive breast cancers, 82% received chemotherapy, and 71% received trastuzumab. The treatment pattern varied over the years, with a downward trend of chemotherapy in TNBC and an upward trend of trastuzumab in HER2-positive breast cancer. Survival outcomes diverged by subtype and size. In this retrospective cohort study, the 5-year DFS for treated patients with T1mic,a tumors ranged from 96.2% to 97.7%, and for patients with T1b tumors, it ranged from 92.1% to 95.0%. The 5-year DFS for patients with T1mic,a tumors untreated with chemotherapy or trastuzumab was 100%. The 5-year DFS for TNBC patients with T1b tumors untreated with chemotherapy was 90.5%, while for HER2-positive patients with T1b tumors untreated with chemotherapy or trastuzumab it was 87.5%, Conclusion: Women with T1mic,a tumors have an excellent prognosis without chemotherapy or trastuzumab, representing an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short- and long-term risks. Figure 1 Systematic Treatment Pattern of Patients With T1mic, a, b N0 Patients With Triple-negative or HER2-positive Breast Cancer from 2010 to 2020 Figure 1 Systematic Treatment Pattern of Patients With T1mic, a, b N0 Patients With Triple-negative or HER2-positive Breast Cancer from 2010 to 2020 Table 1. Patient Demographics and Clinicopathologic Characteristics for T1mic, a, b N0 Patients With Triple-negative or HER2-positive Breast Cancer, FUSCC 2010-2020 Table 2 Systematic Treatment of Patients With T1mic, a, b N0 Patients With Triple-negative or HER2-positive Breast Cancer, FUSCC 2010-2020 Citation Format: Xiyu Liu, Min He. Outcomes and Treatment Pattern in Women With 1 cm or Smaller, Node-Negative Hormone Receptor-negative Breast Cancer in Fudan University Shanghai Cancer Center [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 P2-11-21.

Claims-based cardiac monitoring (CM) in patients (Pts) receiving trastuzumab (TZ).

324 Background: TZ in HER2-positive breast cancer (BC) has established improved outcomes in certain Pts. TZ carries a black box warning and a recommendation for CM in all Pts prior to and during treatment (tx) Few studies have evaluated real-world CM compliance during tx. Methods: Retrospective, cross-sectional analysis was conducted to identify CM compliance among BC pts receiving TZ, using a limited data set of administrative claims data consisting of female Pts who were continuously insured over a 24-month period between Jan 1, 2019 and Dec 31, 2020, as provided through a secure portal by Blue Cross Blue Shield Association. [1] . BC diagnosis was confirmed by ICD-9 code, while tx with TZ or biosimilar was confirmed through Healthcare Common Procedure Coding System codes. A care episode spanned 14 months, including 123 days prior to first TZ dose (Index Date) and at least 307 days of follow up. Two cohorts (eligibility for both dx and continually insured status of female commercial Pts, 2018-2019 and 2019-2020) were analyzed across four tx Phases (Pre-Tx Phase [days -123-+ Index Date as day 1], Phase 1 [days 61-123], Phase 2 [days 153-215], Phase 3 [days 245-307]). Phase denominators were calculated independently, only including Pts with ongoing TZ tx for each Phase. [1] Blue Cross Blue Shield Association is an association of independent, locally operated Blue Cross and Blue Shield companies. Results: Pts in each Phase and cohort ranged from 2,304 (Full Compliance 2019-2020) to 3,263 (Pre-Tx 2019-2020). Similar results were seen in both cohorts, with highest proportion of Pts receiving CM in Pre-Tx phase. Overall compliance in Pre-Tx Phase and all subsequent Phases was low; nearly two-thirds of Pts missed one or more CM tests. Drop-off in CM testing occurred in each subsequent tx Phase (Table). Conclusions: Continued decline in CM over time suggests lack of awareness for potential late TZ cardiac toxicity. Further research regarding why Pts are not receiving recommended baseline and on-treatment CM is needed. Routine CM during TZ tx may be a quality indicator for practices, payers, and quality improvement programs.[Table: see text]

Quantification of methylation-specific cardiomyocyte cell-free DNA as an early marker of cardiotoxicity in patients with breast cancer receiving anthracyclines and trastuzumab.

12090 Background: There is currently no way to reliably predict which patients undergoing therapy for breast cancer will develop cardiotoxicity. An early biomarker of cardiotoxicity could provide opportunity for intervention prior to the appearance of gross abnormalities on echocardiogram (ECHO). A droplet digital PCR (ddPCR) assay for circulating cell-free DNA (cfDNA) can detect cfDNA released from dying cardiomyocytes with high sensitivity by differentiating cfDNA of cardiomyocyte origin based on the pattern of methylation specific to the cell type. Circulating cfDNA of cardiac origin was tested as an early biomarker of toxicity in patients who underwent breast cancer treatment while closely monitoring cardiac function in a prospective clinical trial. Methods: A cardiomyocyte methylation-specific quantitative ddPCR assay was tested in plasma samples from 29 patients who were part of a larger prospectively enrolled cohort of women who received anthracyclines and trastuzumab for HER2-positive breast cancer. Blood samples were tested from prior to doxorubicin and cyclophosphamide (AC) chemotherapy, two months later after completing AC and prior to trastuzumab, and every 3 months to 12 months post-treatment. Patients were assessed for clinical cardiotoxicity, defined as heart failure (NYHA class III/IV) or significant EF decline (> = 10% to below 53% or > = 16%) until completion of cancer therapy. The maximum detected level of cardiac cfDNA (copies per 500 µL plasma) was compared between those who experienced cardiotoxicity and those who did not by two-sided T-tests. Results are reported as mean +/- standard deviation. Results: At baseline, cardiac cfDNA levels were low (mean 1.1 +/- 2.4 copies). Of 29 patients, five developed clinical cardiotoxicity. The maximum number of cfDNA copies at any time point was elevated in patients who experienced cardiotoxicity compared to those who did not (mean of 20.6 +/- 7.3 copies versus 9.3 +/- 9.8 copies, p = 0.0216). Of the patients with cardiotoxicity, elevated cfDNA of greater than 10 copies was detected an average of 3.6 +/- 2.5 months prior to the onset of clinical cardiotoxicity. Conclusions: Methylation specific cardiac cfDNA shows promise as an early indicator of cardiotoxicity in patients treated with anthracyclines in this pilot study. A previously reported analysis in the levels of seven other biomarkers including high-sensitivity troponin I and NT-proBNP pre- versus post-treatment in the full cohort of 80 patients did not show any statistically significant associations with the development of cardiotoxicity, suggesting that cardiac cfDNA may be uniquely informative. Clinical trial information: NCT02177175.

Clinical observation of neoadjuvant chemotherapy with pyrotinib plus trastuzumab in HER2-positive breast cancer: a cohort study.

Pyrotinib is a new small-molecule tyrosine kinase inhibitor (TKI). However, the efficacy of pyrotinib in neoadjuvant therapy for HER2-positive breast cancer is unknown. This paper is a population-based cohort study, and the purpose is to evaluate the efficacy and safety of pyrotinib plus trastuzumab in a neoadjuvant setting for HER2-positive early or locally advanced breast cancers, and to compare it with that of pertuzumab plus trastuzumab. This cohort study included 166 patients with HER2-positive breast cancer who received neoadjuvant therapy and underwent surgery. Case groups: Group I: 63 patients received pyrotinib + trastuzumab; Group II: 50 patients received pertuzumab + trastuzumab. The control group consisted of 53 patients treated with trastuzumab alone in combination with neoadjuvant chemotherapy. Univariate logistic regression analysis was applied. Enumeration data were processed by Fisher's exact test. The total pathological complete response (tpCR) rate of Group I was 63.49% (40/63); the breast pathological complete response (bpCR) rate was 76.19% (48/63); and the objective response rate (ORR) was 100% (63/63). Compared with the tpCR rate of 54.00% (27/50), bpCR rate of 58.00% (29/50), and ORR 100% (50/50) of Group II, there was no statistical difference. Regarding adverse events (AEs), diarrhea (n=56, 88.89%) was the most frequent in the group I, including 7 participants who developed grade 3 diarrhea (11.11%), followed by leukopenia (n=48, 76.19%). In the meantime, there was only 1 patient experienced grade IV thrombocytopenia. Hormone receptor (HR)-negative patients were more likely to reach tpCR as compared to HR-positive patients (61.54% vs. 37.50%, P=0.002, 95% CI: 1.423 to 4.997), and the tpCR rate of tumor, node, metastasis (TNM) stage III 37.04% (20/54) was significantly lower than that of stage II 54.46% (61/112), which was statistically significant (P=0.048, 95% CI: 1.064 to 4.041). No recurrence or metastasis was found during short-term follow-up. Pyrotinib plus trastuzumab combined with neoadjuvant chemotherapy showed good short-term efficacy in HER2-positive breast cancer, and the AEs developed were all manageable. More sample data is required to further support the comparison with pertuzumab plus trastuzumab.

Alpha-smooth Muscle Actin Expression in the Stroma Predicts Resistance to Trastuzumab in Patients with Early-stage HER2-positive Breast Cancer.

The companion diagnostic test for trastuzumab has not changed much in the last 25 years. We used high-plex digital spatial profiling to identify biomarkers besides HER2 that can help predict response to trastuzumab in HER2-positive breast cancer. Fifty-eight protein targets were measured in three different molecularly defined compartments by the NanoString GeoMx Digital Spatial Profiler (DSP) in a tissue microarray containing 151 patients with breast cancer that received adjuvant trastuzumab as part of the Hellenic Cooperative Oncology Group 10/05 clinical trial. Promising candidate biomarkers were orthogonally validated with quantitative immunofluorescence (QIF). RNA-sequencing data from the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation Study (NeoALTTO) were accessed to provide independent cohort validation. Disease-free survival (DFS) was the main outcome assessed. Statistical analyses were performed using a two-sided test (α = 0.05) and multiple testing correction (Benjamini-Hochberg method, FDR < 0.1). By DSP, high expression of alpha-smooth muscle actin (α-SMA), both in the leukocyte and stromal compartments, was associated with shorter DFS in univariate analysis (P = 0.002 and P = 0.023, respectively). High α-SMA expression in the stroma was validated by QIF after controlling for estrogen receptor and progesterone receptor status [HR, 3.12; 95% confidence interval (CI), 1.12-8.68; P = 0.029] showing recurrence on trastuzumab in the same cohort. In the NeoALTTO cohort, elevated levels of ACTA2 were predictive for shorter DFS in the multivariate analysis (HR, 3.21; 95% CI, 1.14-9.05; P = 0.027). This work identifies α-SMA as a novel, easy-to-implement biomarker of resistance to trastuzumab that may be valuable in settings where trastuzumab is combined with other therapies.

Cardiotoxicity in patients on trastuzumab in HER2-positive breast cancer – A retrospective analysis from a center in North India

Objectives: Cardiotoxicity has been associated with trastuzumab for long and its relation with anthracyclines has also been well established. The study aims to assess the cardiotoxicity in patients on trastuzumab in human epidermal growth receptor 2-positive breast cancer. Material and Methods: This retrospective study consisting of a 3 years database of 112 patients with breast cancer from a tertiary care center in India. A total of 64 patients were scrutinized meeting the eligibility criteria. The primary eligibility criteria were availability of baseline, 3 monthly, end of treatment, and 3 months post-treatment left ventricular ejection fraction (LVEF) profile data. Results: 41/62 patients (66.1%) showed decrease in the LVEF profiles having mean reduction of 6%. Of these 41 patients, 34 (53.1%) patients exhibited a drop of 0–5%, 4 (6.2%) showed a drop of 6–10%, and 3 (4.6%) patients showed a drop of more than 10%. A significant drop (more than 10%) in the LVEF profile was observed in mean time of 6 months (8 cycles) which recovered to baseline value with the median follow-up of 3 months post-cessation of trastuzumab. Most of patients in the LVEF drop &gt;10% group (70%) had received an anthracyclines based regimen. Conclusion: Our study demonstrated a mean drop of &gt;10% in the LVEF profiles (4.6%) patients after mean follow-up of 6 months after starting therapy with trastuzumab and reverted back to baseline value after over a mean of 3 months post completing therapy with trastuzumab. This warrants regular and strict surveillance for the first 6 months and thereafter also after starting therapy with trastuzumab.

Simulating Costs of Intravenous Biosimilar Trastuzumab vs. Subcutaneous Reference Trastuzumab in Adjuvant HER2-Positive Breast Cancer: A Belgian Case Study.

This study aimed to compare drug costs and healthcare costs of a 1 year adjuvant course with intravenous biosimilar trastuzumab vs. subcutaneous reference trastuzumab in HER2-positive breast cancer from the Belgian hospital perspective. Our simulation is based on the methodology used by Tjalma and colleagues, and considered costs of drugs, healthcare professional time and consumables. We calculated intravenous drug costs for different body weights, and computed drug costs and healthcare costs to treat 100 patients with either trastuzumab formulation, assuming a binomial body weight distribution in this sample. Scenarios were run to account for drug discounts and intravenous vial sharing. Drug costs amounted to €1,431,282 with intravenous biosimilar trastuzumab and €1,522,809 with subcutaneous reference trastuzumab for a sample of 100 patients in the base case analysis. When healthcare professional time and consumables were also considered, healthcare costs with intravenous biosimilar trastuzumab were similar to those with subcutaneous reference trastuzumab. Differences in healthcare costs between intravenous biosimilar trastuzumab and subcutaneous reference trastuzumab depended on the level of discounts on these formulations and on intravenous vial sharing. Our case study demonstrates that comparing costs of intravenous vs. subcutaneous formulations is complex and multifactorial, and entails more than a simple cost comparison of products.

Clinical therapeutic effects of trastuzumab in HER2-positive breast cancer patients: A protocol for systematic review and meta-analysis.

Background:Despite the developments in diagnosis and treatment of HER2-positive metastatic breast cancer, there is a high likelihood in the development of resistance to trastuzumab. In general, HER2-positive patients with deteriorated health face negative clinical outcomes. The present study is conducted to systematically explore the medicinal properties of trastuzumab in HER2-positive breast cancer patients.Methods:Randomized controlled trials investigating the clinical properties of including trastuzumab to treat HER2-positive breast cancer cases will be sourced by exploring these online-based databases: MEDLINE, BIOSIS, China National Knowledge Infrastructure (CNKI), Cochrane Library, EMBASE, Central Register of Controlled Trials, and WanFang. Two independent authors will screen the literature, gather data, and assess the quality of selected studies. The significance of the relationship between the medical properties of trastuzumab when incorporated to treat HER2-positive breast cancer cases will be evaluated according to the relative risk, mean differences or standardized mean differences, and 95% confidence interval.Results:The outcomes from this review shall be issued in a journal that will be reviewed by peers.Conclusion:The conclusions presented in this review will serve as a reference for clinical practitioners and scholars to determine whether trastuzumab is an effective and safety intervention for treating HER2-positive breast cancer patients.Ethics and dissemination:Since this study is a systematic review of published studies, an ethical approval is not needed.Systematic review registration number:March 31, 2021.osf.io/wvqkf (https://osf.io/wvqkf/).

Clinical predictors of cardiac toxicity in HER2-positive early breast cancer patients treated with adjuvant s.c. versus i.v. trastuzumab

BackgroundFew data are available about real-life cardiotoxicity associated with s.c. versus i.v. trastuzumab treatment of early-stage, HER2-positive breast cancer, and little is known about its predisposing factors. Patients and methodsWe retrospectively reviewed data of 363 adult patients treated with adjuvant trastuzumab for HER2-positive breast cancer. Univariate statistical analysis was performed, and a multivariable logistic model was developed to identify independent risk factors of cardiac toxicity. ResultsWithin 5 years, the overall incidence of events meeting our criteria was 11.8%, and an early discontinuation of trastuzumab was recorded in 20 patients (5.5%). No cases of congestive heart failure occurred, neither multiple events per patient were observed. A total of 184 patients received i.v. and 179 received s.c. trastuzumab. Compared with the s.c. formulation, a higher cardiotoxicity rate for the i.v. administration (15.2% vs 8.4%) was found, and particularly in those patients with cardiovascular risk factors (19.3% vs 8.7%), at the univariate and multivariate analyses. Although more patients with prior anthracycline-based chemotherapy experienced cardiac events, the association of this therapy with cardiac events was not significant. The incidence of cardiac events was not influenced by anthropometric data (e.g. body mass index) or a diagnosis of diabetes mellitus. 5-year event-free survival was 91.7% in the overall population; event-free survival rates were similar between the s.c. and the i.v. groups. ConclusionOur study shows a more favorable safety profile of s.c. versus i.v trastuzumab administration. The use of s.c. trastuzumab could be advisable in at-risk patients.

Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments.

Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.

Abstract PS10-58: Cost effectiveness of routine cardiac imaging during adjuvant trastuzumab in HER2-positive breast cancer

Abstract Background: Guidelines recommend patients treated with trastuzumab (TRA) undergo a multiple gated-acquisition (MUGA) scan or echocardiogram (ECHO) at baseline and every 3 months thereafter. In this retrospective study, we evaluated the incidence of clinically significant cardiotoxicity and analyzed cost effectiveness of routine cardiac imaging during adjuvant TRA. Methods: HER2-positive breast cancer patients treated with adjuvant TRA between 2015 and 2019 were investigated. Information regarding comorbidities, clinical diagnosis of cardiotoxicity, and alterations in therapy were collected. ECHO and MUGA scans were reviewed to monitor trends in ejection fractions (EF). Data was analyzed via the FREQ procedure. We defined clinically significant cardiotoxicity as holding or discontinuing TRA regimen. Results: We found 108 patients. Median age was 57 years (interquartile range (IQR) of 47-68 years); 86% Caucasian and 12% African American. 3% had preexisting heart failure, 43% hypertension, 14% diabetes, 4% coronary artery diseases, 32% hyperlipidemia, 2% chronic kidney disease, 6% stroke, and 38% were smokers. No patients received anthracycline containing regimens. 30 patients (27.7%) had EF drop &amp;gt;10% from baseline. Six patients (5.5%) were identified with clinically significant cardiotoxicity; 4 (3.7%) had EF &amp;lt; 50% and 3 of those 4 were symptomatic (2.7% of total). Median time from initiation to decline in EF &amp;gt; 10% was 6 months (IQR of 4.5-7.5 months). Conclusions: Current practice for TRA cardiotoxicity monitoring consists of cardiac imaging every 3 months. The average cost for a MUGA scan and ECHO is approximately $3700 and $2500, respectively. We determined that clinically significant cardiotoxicity, occurred in 5.5% of the patients approximately 6 months into treatment. With TRA causing reversible cardiotoxicity and 2.7% of the patients being symptomatic, cardiac imaging every 3 months appears excessive, especially in patients without comorbidities. Baseline cardiac imaging with repeat assessment in 6 months appears sufficient in non-anthracycline containing regimen. This strategy allows cost savings of approximately $6000 per patient. Characteristics of patients with clinical cardiotoxicityClinically Significant Cardiotoxicity (N=6)StageChemotherapy RegimenHeart Failure SymptomsEF drop below 50%Initiation to Drop in EF &amp;gt;10% (months)Discontinuation to Recovery in EF (months)1IIBTCHPNoNo3.21.12IATCHPYesYes6.12.83IIATCHNoNo9.31.34IBTCHYesYes6.54.85IIATHYesYes6.12.66IIATCHPNoYes6.31.2 Citation Format: Vineeth Tatineni, Daniel Redle, Daljeet Singh, Arifa Abid, Sameer Mahesh. Cost effectiveness of routine cardiac imaging during adjuvant trastuzumab in HER2-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-58.

2D-echocardiography vs cardiac MRI strain using deep learning: a prospective cohort study in patients with HER2-positive breast cancer undergoing trastuzumab

Abstract Funding Acknowledgements Type of funding sources: Private hospital(s). Main funding source(s): Promotiefonds Albert Schweitzer Hospital Background Subclinical cardiotoxicity due to trastuzumab could be recognized by repeated measurements of global longitudinal/radial strain (GLS/GRS) which could be performed with cardiac magnetic resonance (CMR) or two-dimensional speckle tracking echocardiography (2DE-ST). Although CMR is the gold standard for cardiac function evaluation, it is not used for cardiac monitoring. 2DE-ST might be a reasonable alternative. Purpose To study the predictive value of early 2DE-ST for left ventricular ejection fraction (LVEF) changes during trastuzumab for HER2-positive breast cancer. Methods HER2-positive breast cancer patients receiving trastuzumab, with or without anthracycline, underwent 2DE-ST at baseline and after 3 and 6 months (m) trastuzumab. Cardiac magnetic resonance (CMR) imaging (with ST) was performed at baseline and 6m. We studied the correlation between 2DE-ST- and CMR-derived GLS and GRS. We then associated baseline and 3m 2DE-ST with later CMR-LVEF, and with cardiotoxicity, defined as CMR-LVEF &amp;lt;45% and/or absolute decline &amp;gt;10% during trastuzumab. Results 47 patients were included. GLS measurements based on 2DE-ST and CMR showed weak correlation (Pearson’s r = 0.33; P = 0.041); GRS measurements were uncorrelated (r = 0.09; P = 0.979). 2DE-LVEF at baseline and 3m, and 2DE-STE-GLS at 3m were predictive of CMR-LVEF at 6m (Table 1). In contrast, the change in 2DE-ST-GLS at 3m was predictive of the change in CMR-LVEF at 6m, whereas the change in 2DE-LVEF was not. Importantly, the 11 patients (28%) who developed cardiotoxicity had larger 2DE-ST-GLS change at 3m than those who did not (median 5.2% versus 1.7%; odds ratio 1.81, 95% confidence interval 1.11–2.93; P = 0.016). Conclusion Although correlations between 2DE-ST and CMR are weak, ST-measurements appeared useful to improve the performance of 2DE in predicting LVEF changes after 6m of trastuzumab. Table 1 2DE CMR-LVEF after 6m TZT Mean difference (95% CI) Change in CMR-LVEF after 6m TZT Mean difference (95% CI) Cardiotoxicity OR (95% CI) Before TZT LVEF, % 0.85 (0.42, 1.27)* 0.32 (-0.16, 0.80) 0.88 (0.75, 1.02) ST-GLS, % -0.42 (-1.31, 0.46) -0.28 (-1.14, 0.58) 1.13 (0.87, 1.46) 3 Months TZT LVEF, % 0.59 (0.30, 0.88)* 0.29 (-0.04, 0.61) 0.85 (0.74, 0.98)* ST-GLS, % -1.14 (-2.07, -0.19)* -0.62 (-1.54, 0.30) 1.36 (0.94, 1.84) Change at 3 months TZT LVEF, % 0.30 (-0.11, -0.71) 0.21 (-0.19, 0.61) 0.90 (0.80, 1.01) ST-GLS, % -1.17 (-2.14, -0.20)* -1.10 (-2.02, -0.18)* 1.81 (1.11, 2.93)* * P-value &amp;lt;0.05

Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy in combination with trastuzumab for HER2-positive breast cancer: the neoCARH phase II randomized clinical trial.

Background:Although dual blockade HER2-based neoadjuvant chemotherapy is associated with excellent outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, pertuzumab is not available to all patients due to cost. The optimal neoadjuvant chemotherapy for HER2-positive breast cancer in the presence of a single HER2 blockade is unknown. This study aimed to compare the efficacy and safety of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with docetaxel/carboplatin/trastuzumab (TCH) neoadjuvant setting for HER2-positive breast cancer under the single HER2 blockade.Methods:Patients with stage II-IIIC HER2-positive breast cancer were randomly assigned to either eight cycles of EC-TH every 3 weeks during all chemotherapy cycles, or six cycles of TCH every 3 weeks. The primary endpoint was pathological complete response (pCR) (defined as the absence of invasive tumor cells in breast and axilla, ypT0/is ypN0).Results:From May 2017 to November 2019, 140 patients were randomly assigned, and 135 patients were ultimately found evaluable for the primary endpoint. The pCR was recorded in 25 of 67 patients [37.3%; 95% confidence interval (CI), 25.8–50.0] in the EC-TH group and in 38 of 68 patients (55.9%, 95% CI, 43.3–67.9) in the TCH group (p = 0.032). The most common adverse events (AEs) were neutropenia in 24 of 67 (35.8%) patients in the EC-TH group versus 27 of 68 (39.7%) in the TCH group (p = 0.642), anemia in 33 of 67 (49.3%) patients in the EC-TH group versus 34 of 68 (50.0%) in the TCH group (p = 0.931), and thrombocytopenia in five of 67 (7.5%) patients in the EC-TH group versus 17 of 68 (25.0%) in the TCH group (p = 0.006).Conclusion:For patients receiving the single HER2 blockade trastuzumab for HER2-positive breast cancer, TCH regimen might be a preferred neoadjuvant therapy.Trial registration:This trial was registered with ClinicalTrials.gov identifier: NCT03140553) on 2 May 2017.

23 - Nine-year survival outcome of neoadjuvant lapatinib with trastuzumab for HER2-positive breast cancer (NeoALTTO, BIG 1-06): final analysis of a multicentre, open-label, phase 3 randomised clinical trial.

23 - Nine-year survival outcome of neoadjuvant lapatinib with trastuzumab for HER2-positive breast cancer (NeoALTTO, BIG 1-06): final analysis of a multicentre, open-label, phase 3 randomised clinical trial.

Nine weeks versus six months of adjuvant trastuzumab in HER2-positive breast cancer: 3-year disease-free survival results.

e12530 Background: A total of 12 months adjuvant trastuzumab is still the optimal choice for patients with HER2-positive early breast cancer. However, the shorter course of 9 weeks may be considered as a cost-effective and safe option in developing countries such as Syria. Purpose: We aimed at investigating whether short-course 9-week adjuvant Trastuzumab is non-inferior to 6-month treatment at Albairouni University Cancer Center. The primary endpoint was disease-free survival (DFS). The secondary objective was assessing toxicities, especially cardiotoxicity. Methods: Patients with HER2-positive stage I-IIIC breast cancer were assigned to receive either 9 weeks or 6 months of trastuzumab in combination with adjuvant chemotherapies (sequentially). The 9-week group; 90 patients received trastuzumab intravenously (loading dose 4 mg/kg; then 2mg/kg weekly), whereas in the 6-month group; 157 patients, trastuzumab was delivered every 3 weeks intravenously (loading dose 8 mg/kg then 6 mg/kg). The LVEF was measured pretreatment and every 3 months afterwards. Results: 3-year DFS was 71.87% in the 9-week group versus 76.43% in the 6-month group, (Non-significant). No obvious side effects have been noticed during the follow-up period in the 9-week group. Congestive heart failure was reported in 2.55% of patients in the 6-month group. Conclusions: Short-course 9-week adjuvant trastuzumab is less effective than 6 months of treatment, with less cardiotoxicity. The short course could be considered in patients with heart disease and low risk of recurrence.

The Hippo Pathway Transducers YAP1/TEAD Induce Acquired Resistance to Trastuzumab in HER2-Positive Breast Cancer.

Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer, leading to improved overall survival. However, acquired resistance inevitably occurs. We aimed to identify, quantify, and assess the mechanisms of acquired resistance to trastuzumab. We established an acquired trastuzumab-resistant model in vitro from BT-474, a trastuzumab-sensitive, HER2-amplified breast-cancer cell line. A multi-omic strategy was implemented to obtain gene, proteome, and phosphoproteome signatures associated with acquired resistance to trastuzumab in HER2-positive breast cancer, followed by validation in human clinical samples. YAP1 dephosphorylation and TEAD2 overexpression were detected as significant alterations in the Hippo pathway in trastuzumab-resistant breast cancer. Because of the emerging role of these proteins as mediators of normal growth and tumorigenesis, we assessed the exogenous modulation of their activity, either by in vitro gene silencing or by pharmacological inhibition of the YAP1/TEAD complexes, both in vitro and in vivo. Moreover, we identified increased signaling through the Hippo pathway in human samples after progression following trastuzumab treatment. Finally, YAP1/TAZ nuclear accumulation in malignant cells in HER2 breast tumor was significantly associated with worse progression-free and overall survival in metastatic HER2-positive breast-cancer patients. Our results suggest the involvement of Hippo signaling in acquired trastuzumab resistance in breast cancer. Additionally, we provide novel evidence for a potential breast-cancer treatment strategy based on dual targeting of HER2 and Hippo pathway effectors, which may improve the antitumor activity of trastuzumab and help overcome resistance.