Adding trastuzumab to carboplatin and paclitaxel improves overall survival in patients with advanced-stage HER2/neu-overexpressing uterine serous carcinoma or carcinosarcoma

Adding trastuzumab to carboplatin and paclitaxel improves overall survival in patients with advanced-stage HER2/neu-overexpressing uterine serous carcinoma or carcinosarcoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Adding trastuzumab to carboplatin and paclitaxel improves overall survival in patients with advanced-stage HER2/neu-overexpressing uterine serous carcinoma or carcinosarcoma Ting-Fang Lu, Lou Sun, Yu-Hsiang Shih, Yen-Fu Chen, Chun-Ting Fan, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4372638/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Feb, 2025 Read the published version in BMC Medicine → Version 1 posted 11 You are reading this latest preprint version Abstract Background Uterine serous carcinomas and carcinosarcomas are aggressive forms of endometrial cancer with poor survival outcomes. Trastuzumab, a human epidermal growth factor receptor-2 (HER2)-directed monoclonal antibody, has demonstrated tumoricidal efficacy. However, clinical data regarding its efficacy in uterine serous carcinoma are limited, and there are no clinical data available for uterine carcinosarcoma. Therefore, this study aimed to ascertain the efficacy and safety of adding trastuzumab to carboplatin and paclitaxel as a frontline treatment for advanced-stage HER2-overexpressing uterine serous carcinoma and carcinosarcoma. Methods This retrospective study used deidentified data from electronic health records sourced from the TriNetX Research Network. Participants were identified using ICD codes, and HER2 positivity was confirmed by immunohistochemistry or fluorescence in situ hybridisation (FISH). Propensity score matching (PSM) was employed to reduce confounders, and survival outcomes and adverse events were assessed. Results Following PSM, 280 patients with advanced HER2-positive uterine serous carcinoma or carcinosarcoma were analysed. The group of patients treated with carboplatin/paclitaxel + trastuzumab (CP + T) showed a significantly extended median overall survival compared to those treated solely with CP (41 months versus 25.2 months, hazard ratio [HR] = 0.51, p = 0.002) in both advanced-stage uterine carcinosarcoma and serous carcinoma. Specifically, patients with uterine carcinosarcoma experienced an even longer survival benefit (HR = 0.39, p < 0.0001) when trastuzumab was added to their chemotherapy regimen, surpassing the survival benefit seen in patients with uterine serous carcinoma (HR = 0.56, p = 0.04). However, patients who received trastuzumab experienced higher rates of hypertension, diarrhoea, and left ventricular systolic dysfunction. Conclusions The addition of trastuzumab to frontline chemotherapy is effective for the treatment of HER2-overexpressing uterine serous carcinoma and carcinosarcoma, particularly uterine carcinosarcoma. However, careful monitoring of adverse cardiac events is needed. uterine serous carcinoma uterine carcinosarcoma human epidermal growth factor receptor 2 trastuzumab Figures Figure 1 Figure 2 Figure 3 Introduction Endometrial malignancy is the most prevalent gynaecological cancer in developed countries, and its incidence continues to increase. By 2040, it is projected to surpass colorectal cancer as the third most common cancer among women. [ 1 ] While the incidence and mortality rates of most solid tumours have either decreased or remained steady over the past three decades, those of endometrial cancer are increasing. [ 2 , 3 ] Among the histologic subtypes of endometrial cancer, uterine serous carcinoma is a particularly aggressive, high-grade variant with a high recurrence rate and poor survival outcomes. Although uterine serous carcinoma represents only a minority of endometrial cancer cases (up to 10%), it is responsible for 40% of endometrial cancer-related deaths, with a 5-year survival rate of 45%, compared to 91% for endometrioid adenocarcinoma. [ 4 , 5 ] A high proportion (60–70%) of patients with uterine serous carcinoma present with extrauterine spread at diagnosis. [ 6 , 7 ] Moreover, in patients with later-stage (III–IV) disease, the 5-year survival rate decreases to a mere 18–30%. [ 7 , 8 ] In this patient group, the initial response rates to carboplatin and paclitaxel, the standard chemotherapy regimen, are as low as 20–60%. [ 9 – 11 ] Therefore, new treatments are urgently needed for this subtype of endometrial cancer. Similar to uterine serous carcinoma, uterine carcinosarcoma is another rare tumour associated with a poor prognosis. Uterine carcinosarcoma, formerly known as malignant mixed Müllerian tumour, accounts for < 5% of all gynaecologic cancers but has a 1.5–1.6-fold increased risk of death compared with uterine serous carcinoma. [ 12 , 13 ] The 5-year survival rate of patients with this cancer subtype is < 30%. [ 14 , 15 ] Thus, the limited efficacy of current paclitaxel with carboplatin regimens in treating carcinosarcoma underscores the need for the development of novel, effective targeted therapies, especially for advanced and recurrent disease. [ 16 , 17 ] Furthermore, in uterine carcinosarcoma, the majority (more than 70%) of the carcinoma component is composed of serous carcinoma or a combination of serous carcinoma and high-grade endometrioid carcinoma. [ 13 , 14 ] Metastatic or recurrent tumours often consist of the carcinoma component, indicating that serous carcinoma may influence the clinical behaviour of uterine carcinosarcomas. [ 16 ] Uterine serous carcinoma and carcinosarcoma are molecularly distinct from endometrioid carcinoma. While uterine serous carcinomas are characterised by alterations in TP53 and dysregulation of human epidermal growth factor receptor-2 (HER2/neu), endometrioid cancers are characterised by aberrant PTEN. [ 18 ] The prevalence of HER2 expression is estimated to be approximately 30–35% in uterine serous carcinoma compared to 6–56% in uterine carcinosarcoma, depending on the interpretation and scoring criteria. [ 18 ] Similar to its role in many cancers, HER2 is a recognised marker of poor prognosis in uterine malignancies and is a potential target for novel therapeutic interventions. [ 19 , 20 ] Trastuzumab, the first HER2-directed monoclonal antibody approved by the Food and Drug Administration (FDA) in 1998 for the treatment of HER2-positive metastatic breast cancer, has demonstrated tumoricidal efficacy through antibody-dependent cellular cytotoxicity (ADCC) and inhibition of HER2-mediated signalling pathways, impeding cell proliferation and angiogenesis. [ 21 ] Additionally, the FDA approval for trastuzumab extends to the treatment of HER2-positive early-stage breast cancer as well as HER2-positive gastric and gastroesophageal junction adenocarcinoma. In 2018, Fader et al. conducted the only randomised controlled multicentre phase II trial to compare carboplatin + paclitaxel to carboplatin + paclitaxel + trastuzumab with the aim of evaluating the clinical effectiveness and safety of trastuzumab for advanced-stage (stage III–IV) or recurrent HER2-overexpressing uterine serous carcinoma. [ 22 ] Subsequently, in 2020, an updated survival analysis confirmed the initial progression-free survival (PFS) findings and reported overall survival (OS) differences, which favoured treatment with trastuzumab, particularly for stage III–IV disease. [ 23 ] According to the National Comprehensive Cancer Network (NCCN) guidelines, trastuzumab is recommended for the treatment of advanced stage or recurrent uterine carcinosarcoma with HER2 overexpression, in addition to stage III/IV or recurrent uterine serous carcinoma with HER2 overexpression. [ 24 ] However, to date, there have been no clinical trials or retrospective studies on the utility of trastuzumab for treating uterine carcinosarcoma. Therefore, the aim of this retrospective study was to examine the efficacy and safety of combining trastuzumab with carboplatin and paclitaxel as frontline treatment for stage III/IV HER2-overexpressing uterine serous carcinoma and carcinosarcoma using data from the TriNetX database. Methods This was a retrospective, multi-institutional study of deidentified data obtained from electronic health records sourced from the TriNetX Research Network in Cambridge, MA, USA. The TriNetX Research Network grants access to the electronic medical records of approximately 111 million patients across 80 healthcare organisations (HCOs), primarily in the United States and Europe. The platform is fully compliant with the Health Insurance Portability and Accountability Act and holds a waiver from the Western Institutional Review Board, given the deidentified and aggregate nature of the data. The data used in this study were collected on December 12, 2023, from the TriNetX Research Network. Eligible participants were identified using International Classification of Diseases (ICD) codes between January 2012 and December 2023 (Additional file 1). Only patients aged 18–90 years were included. Patients who were diagnosed with breast or ovarian cancer within 5 years prior to being diagnosed with endometrial cancer were excluded from the study to mitigate the potential inclusion of individuals with HER2-positive breast cancer and to ensure the accuracy of the cohort grouping. HER2-positive advanced uterine serous carcinoma or carcinosarcoma was identified based on an immunohistochemistry (IHC) staining score of 3 + or 2 + for HER2 positivity, and ERBB2 gene amplification was confirmed by fluorescence in situ hybridisation (FISH). This classification was confirmed using the TriNetX Curated and North American Association of Central Cancer Registries (NAACCR) and gene codes. Furthermore, corresponding ICD codes were subsequently used to identify metastasis to lymphatic systems and distant anatomical sites (such as International Federation of Gynaecology and Obstetrics (FIGO, 2009) stages III and IV). Chemotherapy and targeted therapy regimens were identified using RxNorm and Healthcare Common Procedure Coding System (HCPCS) codes. Surgical procedures and irradiation history were identified using Current Procedural Terminology (CPT) codes. All codes used in this study are listed in Additional file 1. All patients who were diagnosed with advanced HER2-positive uterine serous carcinoma or carcinosarcoma underwent primary staging/debulking surgery or interval staging/debulking surgery (after 3–4 cycles of neoadjuvant chemotherapy). Subsequently, they underwent six cycles of triweekly intravenous carboplatin and paclitaxel, optionally supplemented with trastuzumab. The index event for the carboplatin and paclitaxel (CP) group was defined as the initiation date of carboplatin and paclitaxel administration, which served as the primary first-line treatment. In contrast, for the trastuzumab (T) group, the index event was defined as the date when trastuzumab was initially administered within a 3-month timeframe following the commencement of CP treatment as the initial therapeutic approach. The primary outcome of this study was the median OS, estimated in each treatment group from the date of the index event to the date of death. The patients were censored after the last observation in their records. A secondary analysis was performed to assess haematological, hepatic, and systemic adverse events in the two study groups based on the index event date. Patients who experienced adverse events within 6 months before the start of the designated treatment were excluded from the analyses. Treatment toxicities were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). All statistical analyses were performed using SAS version 9.4 (SAS Institute). Baseline comorbidities and disease burden were assessed using the Charlson Comorbidity Index (CCI) (Additional file 2), which includes a list of 19 conditions, with each assigned a score of 1–6. We conducted 1:1 PSM with matched covariates, including age, race, irradiation, and CCI score, to reduce potential confounding factors between the treatment groups. The baseline characteristics of the treatment groups were compared using the Pearson chi-square test and an independent sample t test before PSM. The McNemar and paired t tests were used after PSM. A greedy nearest-neighbour matching algorithm with a 0.1 pooled standard deviation calliper was used, ensuring that patients with distinct propensity scores were not matched in this study (Additional file 3). Survival outcomes were compared using the stratified log-rank test to identify differences in OS between treatment groups. Hazard ratios (HRs) were generated using conditional Cox regression analysis after PSM. Statistical significance was defined as a two-sided p value < 0.05. Results We identified 603 patients aged 18–90 years who were newly diagnosed with advanced HER2-positive uterine serous carcinoma or carcinosarcoma across 23 HCOs between January 2012 and December 2023. According to the inclusion and exclusion criteria, 267 of the 603 patients received frontline CP, and 198 received CP + T. Following 1:1 PSM, the two cohorts were well balanced and contained 140 patients each (Additional file 3). The details of the CCI scores are provided in Additional file 2. Compared with the CP group, the CP + T group had a higher percentage of African American patients and those diagnosed with carcinosarcoma before the index date. However, the CP group had higher rates of radiotherapy, pelvic lymph node metastasis, and colorectal metastasis. A comparison of the baseline characteristics of the CP and CP + T groups is shown in Table 1 . Table 1 Baseline characteristics of patients in the CP and CP + T groups before and after PSM. Before PSM After PSM CP + T N = 198 CP N = 267 p value CP + T N = 140 CP N = 140 p value Age at index* 66.8 65.5 0.04 66.8 66.8 0.99 < 65 years 73 (37) 104 (39) 0.38 52 (37) 49 (35) 0.42 ≥ 65 years 125 (63) 163 (61) 0.38 88 (63) 91 (65) 0.42 Race* White 124 (63) 176 (66) 0.31 85 (61) 94 (67) 0.14 African American 38 (19) 37 (14) 0.04 27 (19) 22 (16) 0.19 Asian 12 (6) 13 (5) 0.39 8 (6) 6 (4) 0.29 Unknown 24 (12) 40 (15) 0.57 20 (14) 19 (14) 0.90 Charlson Comorbidity Index score* 8.4 8.8 0.06 8.6 8.7 0.82 History of irradiation* 53 (27) 96 (36) < 0.001 49 (35) 48 (34) 0.29 Histology* Serous carcinoma 73 (37) 112 (42) 0.04 45 (32) 45 (32) 1.00 Carcinosarcoma 125 (63) 155 (58) 0.03 95 (68) 95 (68) 1.00 Sites of metastasis Lymph node 160 (81) 211 (79) 0.46 106 (76) 105 (75) 0.70 Para-aortic LN 131 (66) 171 (64) 0.35 83 (59) 81 (58) 0.65 Pelvic LN 121 (61) 176 (66) 0.02 81 (58) 83 (59) 0.65 Lung 16 (8) 19 (7) 0.56 8 (6) 7 (5) 0.41 Liver 22 (11) 24 (9) 0.55 13 (9) 11 (8) 0.48 Peritoneum 30 (15) 43(16) 0.59 15 (11) 17 (12) 0.50 Colorectal 24 (12) 45 (17) 0.04 18 (13) 22 (16) 0.20 Data are presented as N (%). Demographic data were obtained from the TriNetX Research Network. Baseline characteristics were documented one day before the index date. Variables marked with * were selected for PSM. CP, carboplatin plus paclitaxel; T: trastuzumab; PSM: propensity score matching; LN, lymph node; NA, not available. In the study population, 31 and 93 deaths were noted in the CP + T and CP groups, respectively. The median OS times were significantly different in the CP group (25.2 months) and CP + T group (41 months) (hazard ratio [HR]: 0.51, 95% confidence interval [CI] 0.345–0.784, p = 0.002) (Fig. 1 ). In the subgroup of uterine carcinosarcoma, 63 patients in the CP group and 21 patients in the CP + T group died from the disease. This resulted in a notable contrast in the median overall survival time between the CP group (16.8 months) and the CP + T group (41.7 months) or uterine carcinosarcoma, with an HR of 0.39 (95% CI 0.221–0.560, p < 0.0001) (Fig. 2 ). Additionally, within the uterine serous carcinoma subgroup, 29 and 13 patients in the CP and CP + T groups respectively succumbed to the disease. Within the uterine serous carcinoma subgroup, the median OS time significantly differed between the CP (27.1 months) and CP + T (38.7 months) groups, with an HR of 0.56 (95% CI 0.294–0.869, p = 0.04) (Fig. 3 ). Regarding adverse events, compared with the CP group, the CP + T group had a higher incidence of hypertension (8% vs. 25%), diarrhoea (3% vs. 9%), and left ventricular systolic dysfunction (2% vs. 9%) (Table 2 ). However, the rates of haematological toxicities, electrolyte imbalances, fatigue, peripheral sensory neuropathy, gastrointestinal symptoms, and renal dysfunction were similar between the two groups. Table 2 Adverse events in the CP and CP + T groups after PSM CP + T N = 140 (%) CP N = 140 (%) HR (95% CI) P value Anaemia 35 (25) 32 (23) 0.571 (0.144–1.125) 0.723 Grade 3 anaemia 11 (8) 10 (7) 0.882 (0.439–1.769) 0.389 Thrombocytopenia 20 (14) 15 (11) 1.276 (0.578–2.821) 0.546 Grade 3 thrombocytopenia 7 (5) 6 (4) 1.206 (0.988–2.853) 0.643 Neutropenia 56 (40) 53 (38) 1.189 (0.351–2.062) 0.912 Grade 3 neutropenia 42 (30) 45 (32) 1.1 (0.436–2.294) 0.982 Sepsis 6 (4) 4 (3) 1.231 (0.626–2.419) 0.932 Acute kidney injury 25 (18) 22 (16) 0.706 (0.454–1.096) 0.117 Hyponatremia 36 (26) 42 (30) 0.862 (0.547–1.359) 0.522 Hypokalaemia 13 (9) 14 (10) 0.759 (0.433–1.109) 0.469 Left ventricular systolic dysfunction ＊ 13 (9) 3 (2) 0.329 (0.195–0.684) < 0.001 Hypertension 35 (25) 11 (8) 0.744 (0.624–0.886) 0.002 Grade 3 hypertension 7 (5) 3 (2) 1.476 (0.278–2.121) 0.562 Diarrhoea 13 (9) 4 (3) 0.681 (0.449–0.845) 0.007 Constipation 31 (22) 36 (26) 0.853 (0.550–1.348) 0.467 Nausea/vomiting 34 (24) 31 (22) 1.346 (0.760–2.386) 0.381 Bowel obstruction 11 (8) 14 (10) 1.296 (0.572–2.935) 0.534 Malaise and fatigue 69 (49) 60 (43) 1.119 (0.824–1.521) 0.472 Peripheral sensory neuropathy 125 (89) 126 (90) 0.899 (0.363–2.225) 0.817 ＊ As determined by an ejection fraction (EF) of less than 55% according to multigated acquisition scanning and/or conventional 2D-echocardiography. CP, carboplatin plus paclitaxel; T: trastuzumab; PSM: propensity score matching; HR, hazard ratio; CI, confidence interval. Discussion Our study represents a ground-breaking investigation of real-world data on the addition of trastuzumab to frontline chemotherapy for HER2-overexpressing uterine carcinosarcoma and uterine serous carcinoma, offering promising insights into its potential benefits. Although adding trastuzumab significantly improved OS, it is crucial to emphasise the importance of vigilant monitoring of cardiac health and the early recognition of cardiac-related symptoms in patients receiving trastuzumab. Based on the multicentre, randomised phase II trial by Fader et al. [ 22 , 23 ] , in which HER2 overexpression was identified based on an IHC score of 3 + or 2 + and ERBB2 amplification was confirmed by FISH testing, the NCCN put forward guidelines recommending trastuzumab for HER2/neu-overexpressing advanced or recurrent uterine serous carcinoma and carcinosarcoma. Despite these promising phase II findings, which showed that patients in the trastuzumab cohort, particularly those with stage III-IV disease, had a longer median survival time (not reached) than those in the control group (24.4 months) (HR 0.49, 90% CI, 0.25–0.97, p = 0.041), there had been no further clinical trials or investigations of real-world data on the efficacy and safety of trastuzumab for uterine carcinosarcoma. In the present study, the OS was 41 months in the CPT arm and 25.2 months in the CP arm (HR: 0.52, 95% CI 0.345–0.784, p = 0.002), consistent with findings from previous research. [ 22 , 23 ] Most patients in this study (164, 59%) were diagnosed with uterine carcinosarcoma. Subgroup analysis based on histological type revealed that the addition of trastuzumab significantly extended OS in the carcinosarcoma group (from 16.8 months to 41.7 months, HR: 0.39), outperforming the extension seen in the serous carcinoma group (from 27.1 months to 38.7 months, HR: 0.56). An ongoing phase II/III clinical trial (NCT05256225) is currently evaluating the addition of trastuzumab to frontline carboplatin and paclitaxel, either alone or in combination with pertuzumab (a monoclonal antibody that binds to different extracellular domains of HER2). Pertuzumab has been approved by the FDA for HER2 + breast cancer in combination with trastuzumab and chemotherapy. This ongoing trial is enrolling patients newly diagnosed with HER2-positive myoinvasive stage I–IV uterine serous carcinoma or carcinosarcoma and is expected to conclude on October 31, 2027. In addition to HER2-directed monoclonal antibodies such as trastuzumab or pertuzumab, antibody‒drug conjugates (ADCs) are a novel class of targeted therapies. ADCs are composed of a humanised monoclonal antibody specific for a tumour surface antigen, such as HER2; a cleavable or uncleavable linker; and a cytotoxic payload. Trastuzumab deruxtecan (T-DXd or DS-8201a), a prominent ADC, is internalised by tumour cells, wherein it releases the toxic payload of DXd, which can permeate neighbouring tumour cells regardless of their HER2 status. This unique mechanism has demonstrated clinical efficacy in the treatment of heterogeneous HER2-positive tumours. [ 25 ] The multicentre phase II STATICE trial, a single-arm study across several centres in Japan, evaluated T-DXd in 32 patients with advanced or recurrent uterine carcinosarcomas, encompassing a range of HER2 expression profiles. [ 26 ] Of the 32 patients, 22 had HER2-high and 10 had HER2-low carcinosarcomas. The overall response rate (ORR) was 54.5% (95% CI, 32.2–75.6) in the HER2-high cohort and 70% (95% CI, 45.1–86.1) in the HER2-low cohort. The median duration of response was 6.9 months in the HER2-high group and 8.1 months in the HER2-low group. [ 26 ] Another phase II, multicentre, open-label trial, DESTINY-PanTumor02, enrolled 267 patients with previously treated HER2-expressing solid tumours, including those with HER2-positive (IHC 3+/2+) bladder, biliary tract, cervical, endometrial, ovarian, or pancreatic cancer. [ 27 ] In the endometrial cohort, 77.5% of patients had ≥ two prior lines of therapy, yet this group had the highest ORR (84.6%) among the HER2 IHC 3 + patients. For all patients with endometrial cancer, the median PFS and OS were 11.1 months and 26.0 months, respectively. [ 27 ] Despite the promise of trastuzumab as targeted therapy for HER2-positive endometrial cancer, there are significant side effects associated with the addition of trastuzumab to carboplatin and paclitaxel for the treatment of late-stage HER2-overexpressing uterine cancer. In this study, adverse events included left ventricular systolic dysfunction, hypertension, and diarrhoea. Two percent of patients in the CP group and 9% of patients in the CP + T group experienced a decrease in the left ventricular ejection fraction (LVEF). Although the overall rate of hypertension was higher in patients who received trastuzumab, there was no significant difference in the incidence of Grade 3 hypertension between patients who did and did not receive trastuzumab. Furthermore, diarrhoea rates were higher in the trastuzumab group; however, this did not result in a significant increase in the rate of electrolyte imbalance (Table 2 ). This outcome aligns with that of the multicentre phase II trial conducted by Fader et al., which reported that 3% of patients in the CP + T group and no patients in the CP group experienced a decrease in LVEF. [ 22 ] Hence, these findings underscore the importance of monitoring cardiac function and related symptoms in patients receiving trastuzumab combined with carboplatin and paclitaxel. Early detection and intervention may help to mitigate the risk of severe cardiac complications. The mechanisms underlying trastuzumab-induced cardiotoxicity remain unclear. Recent studies have reported a direct association between impaired HER2 signalling and trastuzumab-induced cardiotoxicity. Trastuzumab disrupts HER signalling by inducing the phosphorylation of HER1 Tyr845 and HER2 Tyr1248, which triggers an autophagy-inhibitory Erk/mTOR/Ulk 1 signalling cascade, thereby compromising the ability of cardiomyocytes to recycle toxic cellular substrates and leading to cardiotoxicity. [ 28 ] To further underscore the concerns surrounding trastuzumab-induced cardiac effects, a comprehensive meta-analysis of cardiac dysfunction in seven trials found that while cardiac dysfunction occurred in 3–7% of patients treated with trastuzumab alone, this incidence increased to 13% when trastuzumab and paclitaxel were combined and further increased to 27% when trastuzumab was combined with anthracyclines, as opposed to < 7% in the anthracycline-only group. [ 29 , 30 ] These findings highlight the increased risk of cardiac toxicity when trastuzumab is administered in conjunction with other chemotherapeutic agents. Although our study has the advantage of including the largest cohort of patients with late-stage HER2-overexpressing uterine serous carcinoma and carcinosarcoma, it is crucial to recognise certain limitations. First, the study did not have a randomised controlled design, and detailed dosage information for each treatment was not available. Nevertheless, efforts were made to minimise selection bias through PSM of baseline characteristics. Second, our reliance on coding systems, such as ICD, RxNorm, HCPCS, and CPT, to identify patient diagnoses, adverse events, lines of chemotherapy, and treatment regimens may have introduced misclassifications or reporting delays that potentially affected the analysis outcomes. However, the TriNetX data originated from developed countries in Europe and America, where the personnel responsible for data entry are typically well trained, which reduces the likelihood of errors. Therefore, further clinical study is required to corroborate and validate our findings, and a deeper understanding of trastuzumab-induced cardiotoxicity is crucial for optimising treatment strategies and ensuring the best possible patient outcomes within the evolving landscape of targeted therapies for HER2-overexpressing cancers. Conclusion The addition of trastuzumab to frontline treatment with carboplatin and paclitaxel for patients with stage III/IV HER2-overexpressing uterine serous carcinoma or carcinosarcoma significantly improved OS. Although this finding highlights the potential benefits of incorporating trastuzumab into treatment regimens for this patient population, it is crucial to emphasise the importance of routine, careful monitoring of cardiac function and signs of congestive heart failure when administering trastuzumab. The increased risk of adverse cardiac events associated with trastuzumab underscores the need for early detection methods and intervention to manage these potential complications effectively. Abbreviations ADC, antibody‒drug conjugate; ADCC, antibody-dependent cellular cytotoxicity; CCI, Charlson Comorbidity Index; CI, confidence interval; CPT, Current Procedural Terminology; CTCAE, Common Terminology Criteria for Adverse Events; FDA, the Food and Drug Administration; FIGO, International Federation of Gynaecology and Obstetrics; FISH, fluorescence in situ hybridisation; HCO, healthcare organisation; HCPCS, Healthcare Common Procedure Coding System; HER-2, human epidermal growth factor receptor-2; HR, hazard ratio; ICD, International Classification of Diseases; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction; NCCN, National Comprehensive Cancer Network; NAACCR, North American Association of Central Cancer Registries; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching. Declarations This manuscript presents original work and has not been previously published, nor is it under consideration for publication elsewhere. All authors have significantly contributed to the conception, design, analysis, or interpretation of the data presented in this manuscript. Ethics approval and consent to participate The TriNetX Research Network is fully compliant with the Health Insurance Portability and Accountability Act and holds a waiver from the Western Institutional Review Board, given the deidentified and aggregate nature of the data. Consent for publication The consent for publication of the subjects in this study was not applicable, as the data collected is sourced from electronic health records obtained from the TriNetX Research Network in Cambridge, MA, USA. Availability of data and materials Deidentified participant data will be made available upon request to the corresponding author according to the regulations of Taichung Veterans General Hospital. Competing interests The authors of this manuscript have no conflicts of interest to disclose. Funding This work was supported by Taichung Veterans General Hospital (grant number: TCVGH-1126401C). No external funding was used for this research. Authors' contributions Ting-Fang Lu analyzed and interpreted the data from TriNetX and made significant contributions to writing the manuscript. Chien-Hsing Lu contributed to conceptualization, supervision, and major revisions of the paper. Lou Sun, Sheau-Feng Hwang, Yu-Hsiang Shih, and Yen-Fu Chen conducted data analysis and participated in methodological discussions aimed at minimizing possible biases from the database. Chin-Ku Liu, Chun Ting Fan, Shao-Jing Wang, and Shih-Tien Hsu contributed to the validation and visualization of the benefits of trastuzumab to carboplatin and paclitaxel in patients with advanced-stage HER2/neu-overexpressing uterine serous carcinoma or carcinosarcoma. All authors have read and approved the final manuscript. 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The impact of multi-modal therapy on survival for uterine carcinosarcomas. Gynecol Oncol. 2010;116:419-23. Rottmann D, Snir OL, Wu X, Wong S, Hui P, Santin AD, et al. HER2 testing of gynecologic carcinosarcomas: Tumor stratification for potential targeted therapy. Mod Pathol. 2020;33:118-27. Powell MA, Filiaci VL, Hensley ML, Huang HQ, Moore KN, Tewari KS, et al. A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I). In: chemotherapy-naïve patients with stage I-IV, persistent, or recurrent uterine or ovarian carcinosarcoma: An NRG Oncology trial. J Clin Oncol. 2019;40:968-77. Zhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, et al. The landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A. 2013;110:2916-21. Luo H, Xu X, Ye M, Sheng al B, Zhu X. The prognostic value of HER2 in ovarian cancer: A meta-analysis of observational studies. PLoS One. 2018;13:e0191972. Erickson BK, Najjar O, Damast S, Blakaj A, Tymon-Rosario J, Shahi M, et al. Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study. Gynecol Oncol. 2020;159:17-22. Hudis CA. Trastuzumab–mechanism of action and use in clinical practice. N Engl J Med. 2007;357:39-51. Fader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol. 2018;36:2044-51. Fader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, et al. Randomized phase II trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (Stage III–IV) or recurrent uterine serous carcinomas that overexpress Her2/Neu (NCT01367002): Updated overall survival analysis. Clin Cancer Res. 2020;26:3928-35. Abu-Rustum N, Yashar C, Arend R, Barber E, Bradley K, Brooks R, et al. Uterine neoplasms. version 1.2023, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21:181-209. Andrikopoulou A, Zografos E, Liontos M, Koutsoukos K, Dimopoulos MA, Zagouri F. Trastuzumab deruxtecan (DS-8201a): The latest research and advances in breast cancer. Clin Breast Cancer. 2021;21:e212-9. Nishikawa T, Hasegawa K, Matsumoto K, Mori M, Hirashima Y, Takehara K et al. Trastuzumab deruxtecan for human epidermal growth factor receptor 2-expressing advanced or recurrent uterine carcinosarcoma (NCCH1615): The STATICE trial. J Clin Oncol. 2023;41:2789-99. Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, González-Martín A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: Primary results from the DESTINY-PanTumor02 Phase II trial. J Clin Oncol. 2024;42:47-58. Mohan N, Shen Y, Endo Y, ElZarrad MK, Wu WJ. Trastuzumab, but not pertuzumab, dysregulates HER2 Signaling to mediate inhibition of autophagy and increase in reactive oxygen species production in human cardiomyocytes. Mol Cancer Ther. 2016;15:1321-31. Wilcken N, Zdenkowski N, White M, Snyder R, Pittman K, Mainwaring P, et al. Systemic treatment of HER2-positive metastatic breast cancer: A systematic review. Asia Pac J Clin Oncol. 2014;10 Suppl S4:1-14. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215-21. Additional Declarations No competing interests reported. Supplementary Files Supplement.doc Cite Share Download PDF Status: Published Journal Publication published 21 Feb, 2025 Read the published version in BMC Medicine → Version 1 posted Editorial decision: Revision requested 05 Nov, 2024 Reviews received at journal 05 Oct, 2024 Reviewers agreed at journal 23 Sep, 2024 Reviews received at journal 10 Jul, 2024 Reviews received at journal 07 Jul, 2024 Reviewers agreed at journal 25 Jun, 2024 Reviewers agreed at journal 20 Jun, 2024 Reviewers invited by journal 06 Jun, 2024 Editor assigned by journal 07 May, 2024 Submission checks completed at journal 07 May, 2024 First submitted to journal 05 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4372638","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":301814363,"identity":"a6e68372-54a7-44f9-92dc-8830a9c9b3b9","order_by":0,"name":"Ting-Fang Lu","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ting-Fang","middleName":"","lastName":"Lu","suffix":""},{"id":301814364,"identity":"f90c20f3-3b3d-44ed-8b13-449db3690b70","order_by":1,"name":"Lou Sun","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lou","middleName":"","lastName":"Sun","suffix":""},{"id":301814365,"identity":"df900bab-7b53-4a44-ae67-08ae8e8e486d","order_by":2,"name":"Yu-Hsiang Shih","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yu-Hsiang","middleName":"","lastName":"Shih","suffix":""},{"id":301814366,"identity":"d2577807-9cf6-440c-819d-8398395c4c9e","order_by":3,"name":"Yen-Fu Chen","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yen-Fu","middleName":"","lastName":"Chen","suffix":""},{"id":301814367,"identity":"afa35819-1c1e-49dd-aafd-51dcd229cb2d","order_by":4,"name":"Chun-Ting Fan","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chun-Ting","middleName":"","lastName":"Fan","suffix":""},{"id":301814368,"identity":"eb97b977-e626-4e1c-9e29-c3871943c469","order_by":5,"name":"Shao-Jing Wang","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shao-Jing","middleName":"","lastName":"Wang","suffix":""},{"id":301814369,"identity":"a4bf44ee-1b2d-4a99-9ec0-23305baa071b","order_by":6,"name":"Shih-Tien Hsu","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shih-Tien","middleName":"","lastName":"Hsu","suffix":""},{"id":301814370,"identity":"270bfdfc-d4f1-4aae-911c-9977908e7b0b","order_by":7,"name":"Chih-Ku Liu","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chih-Ku","middleName":"","lastName":"Liu","suffix":""},{"id":301814371,"identity":"fb6baef6-5274-4862-be5d-01bafc88fcaf","order_by":8,"name":"Sheau-Feng Hwang","email":"","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sheau-Feng","middleName":"","lastName":"Hwang","suffix":""},{"id":301814372,"identity":"31340692-aa9f-4a00-929f-24b2632d961a","order_by":9,"name":"Chien-Hsing Lu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYDACCeYGhg8MDAmkaGFsYJwB1MID4xOlhZmHJC38sxvbpG3bavPs2Q8wv/jYxlBncICQJXcOtknnth0v5uFJYLOc2cYgQVCLgURim3TOmWOJPRIMbMY8ZxgkzIjSYkG6FoaKGpAW5sc8FURokbiR2GzZU3EgsedMYhvjjAoJyf2EtPDPSD5444dBXWJ7++HDHz4Y2PBLNhDQAgWHgZixTYKomISCOhDB/IFo9aNgFIyCUTCiAADeNT0tWp/dUwAAAABJRU5ErkJggg==","orcid":"","institution":"Taichung Veterans General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Chien-Hsing","middleName":"","lastName":"Lu","suffix":""}],"badges":[],"createdAt":"2024-05-05 17:27:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4372638/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4372638/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12916-025-03916-3","type":"published","date":"2025-02-21T15:57:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56563571,"identity":"d16c5f4f-fa68-4573-b553-f9d9ecd7961f","added_by":"auto","created_at":"2024-05-15 22:39:58","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":223066,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival (OS) of all HER2-positive uterine cancer patients who were treated with CP or CP+T\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eCP, carboplatin plus paclitaxel; T: trastuzumab\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4372638/v1/80263c9299dcbc2013fbb1c0.jpeg"},{"id":56563572,"identity":"7222b358-35c0-4c18-915e-37705b8f278f","added_by":"auto","created_at":"2024-05-15 22:39:58","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":209658,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival (OS) of patients with HER2-positive uterine carcinosarcoma who were treated with CP or CP+T\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCP, carboplatin plus paclitaxel; T: trastuzumab\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4372638/v1/511f02f188fd6038b2a09210.jpeg"},{"id":56563574,"identity":"9ec0f896-e08c-4903-8387-f0cf3bc8a7c3","added_by":"auto","created_at":"2024-05-15 22:39:59","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":199470,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival (OS) of patients with HER2-positive uterine serous carcinoma who were treated with CP or CP+T\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCP, carboplatin plus paclitaxel; T: trastuzumab\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4372638/v1/173439ac5678feef64b6e858.jpeg"},{"id":77052484,"identity":"71f3bc1c-700e-43aa-8847-9fab549fb209","added_by":"auto","created_at":"2025-02-24 16:09:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1450016,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4372638/v1/32175ed4-d961-48ca-9930-6ed61b6a49ca.pdf"},{"id":56564469,"identity":"c681acc9-6423-4077-a80d-5d12a4aa3847","added_by":"auto","created_at":"2024-05-15 22:47:59","extension":"doc","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":338432,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement.doc","url":"https://assets-eu.researchsquare.com/files/rs-4372638/v1/2b97097137967995ff650481.doc"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adding trastuzumab to carboplatin and paclitaxel improves overall survival in patients with advanced-stage HER2/neu-overexpressing uterine serous carcinoma or carcinosarcoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEndometrial malignancy is the most prevalent gynaecological cancer in developed countries, and its incidence continues to increase. By 2040, it is projected to surpass colorectal cancer as the third most common cancer among women.\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e While the incidence and mortality rates of most solid tumours have either decreased or remained steady over the past three decades, those of endometrial cancer are increasing.\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e Among the histologic subtypes of endometrial cancer, uterine serous carcinoma is a particularly aggressive, high-grade variant with a high recurrence rate and poor survival outcomes. Although uterine serous carcinoma represents only a minority of endometrial cancer cases (up to 10%), it is responsible for 40% of endometrial cancer-related deaths, with a 5-year survival rate of 45%, compared to 91% for endometrioid adenocarcinoma.\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e A high proportion (60\u0026ndash;70%) of patients with uterine serous carcinoma present with extrauterine spread at diagnosis.\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e Moreover, in patients with later-stage (III\u0026ndash;IV) disease, the 5-year survival rate decreases to a mere 18\u0026ndash;30%.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e In this patient group, the initial response rates to carboplatin and paclitaxel, the standard chemotherapy regimen, are as low as 20\u0026ndash;60%.\u003csup\u003e[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e Therefore, new treatments are urgently needed for this subtype of endometrial cancer.\u003c/p\u003e \u003cp\u003eSimilar to uterine serous carcinoma, uterine carcinosarcoma is another rare tumour associated with a poor prognosis. Uterine carcinosarcoma, formerly known as malignant mixed M\u0026uuml;llerian tumour, accounts for \u0026lt;\u0026thinsp;5% of all gynaecologic cancers but has a 1.5\u0026ndash;1.6-fold increased risk of death compared with uterine serous carcinoma.\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e The 5-year survival rate of patients with this cancer subtype is \u0026lt;\u0026thinsp;30%.\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e Thus, the limited efficacy of current paclitaxel with carboplatin regimens in treating carcinosarcoma underscores the need for the development of novel, effective targeted therapies, especially for advanced and recurrent disease.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e Furthermore, in uterine carcinosarcoma, the majority (more than 70%) of the carcinoma component is composed of serous carcinoma or a combination of serous carcinoma and high-grade endometrioid carcinoma.\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e Metastatic or recurrent tumours often consist of the carcinoma component, indicating that serous carcinoma may influence the clinical behaviour of uterine carcinosarcomas.\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eUterine serous carcinoma and carcinosarcoma are molecularly distinct from endometrioid carcinoma. While uterine serous carcinomas are characterised by alterations in TP53 and dysregulation of human epidermal growth factor receptor-2 (HER2/neu), endometrioid cancers are characterised by aberrant PTEN.\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e The prevalence of HER2 expression is estimated to be approximately 30\u0026ndash;35% in uterine serous carcinoma compared to 6\u0026ndash;56% in uterine carcinosarcoma, depending on the interpretation and scoring criteria.\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e Similar to its role in many cancers, HER2 is a recognised marker of poor prognosis in uterine malignancies and is a potential target for novel therapeutic interventions.\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e Trastuzumab, the first HER2-directed monoclonal antibody approved by the Food and Drug Administration (FDA) in 1998 for the treatment of HER2-positive metastatic breast cancer, has demonstrated tumoricidal efficacy through antibody-dependent cellular cytotoxicity (ADCC) and inhibition of HER2-mediated signalling pathways, impeding cell proliferation and angiogenesis.\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e Additionally, the FDA approval for trastuzumab extends to the treatment of HER2-positive early-stage breast cancer as well as HER2-positive gastric and gastroesophageal junction adenocarcinoma.\u003c/p\u003e \u003cp\u003eIn 2018, Fader et al. conducted the only randomised controlled multicentre phase II trial to compare carboplatin\u0026thinsp;+\u0026thinsp;paclitaxel to carboplatin\u0026thinsp;+\u0026thinsp;paclitaxel\u0026thinsp;+\u0026thinsp;trastuzumab with the aim of evaluating the clinical effectiveness and safety of trastuzumab for advanced-stage (stage III\u0026ndash;IV) or recurrent HER2-overexpressing uterine serous carcinoma.\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e Subsequently, in 2020, an updated survival analysis confirmed the initial progression-free survival (PFS) findings and reported overall survival (OS) differences, which favoured treatment with trastuzumab, particularly for stage III\u0026ndash;IV disease.\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e According to the National Comprehensive Cancer Network (NCCN) guidelines, trastuzumab is recommended for the treatment of advanced stage or recurrent uterine carcinosarcoma with HER2 overexpression, in addition to stage III/IV or recurrent uterine serous carcinoma with HER2 overexpression.\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e However, to date, there have been no clinical trials or retrospective studies on the utility of trastuzumab for treating uterine carcinosarcoma.\u003c/p\u003e \u003cp\u003eTherefore, the aim of this retrospective study was to examine the efficacy and safety of combining trastuzumab with carboplatin and paclitaxel as frontline treatment for stage III/IV HER2-overexpressing uterine serous carcinoma and carcinosarcoma using data from the TriNetX database.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This was a retrospective, multi-institutional study of deidentified data obtained from electronic health records sourced from the TriNetX Research Network in Cambridge, MA, USA. The TriNetX Research Network grants access to the electronic medical records of approximately 111\u0026nbsp;million patients across 80 healthcare organisations (HCOs), primarily in the United States and Europe. The platform is fully compliant with the Health Insurance Portability and Accountability Act and holds a waiver from the Western Institutional Review Board, given the deidentified and aggregate nature of the data.\u003c/p\u003e \u003cp\u003eThe data used in this study were collected on December 12, 2023, from the TriNetX Research Network. Eligible participants were identified using International Classification of Diseases (ICD) codes between January 2012 and December 2023 (Additional file 1). Only patients aged 18\u0026ndash;90 years were included. Patients who were diagnosed with breast or ovarian cancer within 5 years prior to being diagnosed with endometrial cancer were excluded from the study to mitigate the potential inclusion of individuals with HER2-positive breast cancer and to ensure the accuracy of the cohort grouping. HER2-positive advanced uterine serous carcinoma or carcinosarcoma was identified based on an immunohistochemistry (IHC) staining score of 3\u0026thinsp;+\u0026thinsp;or 2\u0026thinsp;+\u0026thinsp;for HER2 positivity, and ERBB2 gene amplification was confirmed by fluorescence in situ hybridisation (FISH). This classification was confirmed using the TriNetX Curated and North American Association of Central Cancer Registries (NAACCR) and gene codes. Furthermore, corresponding ICD codes were subsequently used to identify metastasis to lymphatic systems and distant anatomical sites (such as International Federation of Gynaecology and Obstetrics (FIGO, 2009) stages III and IV). Chemotherapy and targeted therapy regimens were identified using RxNorm and Healthcare Common Procedure Coding System (HCPCS) codes. Surgical procedures and irradiation history were identified using Current Procedural Terminology (CPT) codes. All codes used in this study are listed in Additional file 1.\u003c/p\u003e \u003cp\u003eAll patients who were diagnosed with advanced HER2-positive uterine serous carcinoma or carcinosarcoma underwent primary staging/debulking surgery or interval staging/debulking surgery (after 3\u0026ndash;4 cycles of neoadjuvant chemotherapy). Subsequently, they underwent six cycles of triweekly intravenous carboplatin and paclitaxel, optionally supplemented with trastuzumab. The index event for the carboplatin and paclitaxel (CP) group was defined as the initiation date of carboplatin and paclitaxel administration, which served as the primary first-line treatment. In contrast, for the trastuzumab (T) group, the index event was defined as the date when trastuzumab was initially administered within a 3-month timeframe following the commencement of CP treatment as the initial therapeutic approach.\u003c/p\u003e \u003cp\u003eThe primary outcome of this study was the median OS, estimated in each treatment group from the date of the index event to the date of death. The patients were censored after the last observation in their records. A secondary analysis was performed to assess haematological, hepatic, and systemic adverse events in the two study groups based on the index event date. Patients who experienced adverse events within 6 months before the start of the designated treatment were excluded from the analyses. Treatment toxicities were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using SAS version 9.4 (SAS Institute). Baseline comorbidities and disease burden were assessed using the Charlson Comorbidity Index (CCI) (Additional file 2), which includes a list of 19 conditions, with each assigned a score of 1\u0026ndash;6. We conducted 1:1 PSM with matched covariates, including age, race, irradiation, and CCI score, to reduce potential confounding factors between the treatment groups. The baseline characteristics of the treatment groups were compared using the Pearson chi-square test and an independent sample t test before PSM. The McNemar and paired t tests were used after PSM. A greedy nearest-neighbour matching algorithm with a 0.1 pooled standard deviation calliper was used, ensuring that patients with distinct propensity scores were not matched in this study (Additional file 3). Survival outcomes were compared using the stratified log-rank test to identify differences in OS between treatment groups. Hazard ratios (HRs) were generated using conditional Cox regression analysis after PSM. Statistical significance was defined as a two-sided p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe identified 603 patients aged 18\u0026ndash;90 years who were newly diagnosed with advanced HER2-positive uterine serous carcinoma or carcinosarcoma across 23 HCOs between January 2012 and December 2023. According to the inclusion and exclusion criteria, 267 of the 603 patients received frontline CP, and 198 received CP\u0026thinsp;+\u0026thinsp;T. Following 1:1 PSM, the two cohorts were well balanced and contained 140 patients each (Additional file 3). The details of the CCI scores are provided in Additional file 2. Compared with the CP group, the CP\u0026thinsp;+\u0026thinsp;T group had a higher percentage of African American patients and those diagnosed with carcinosarcoma before the index date. However, the CP group had higher rates of radiotherapy, pelvic lymph node metastasis, and colorectal metastasis. A comparison of the baseline characteristics of the CP and CP\u0026thinsp;+\u0026thinsp;T groups is shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics of patients in the CP and CP\u0026thinsp;+\u0026thinsp;T groups before and after PSM.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBefore PSM\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eAfter PSM\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCP\u0026thinsp;+\u0026thinsp;T\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;198\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCP\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;267\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCP\u0026thinsp;+\u0026thinsp;T\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;140\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCP\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;140\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge at index*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e65.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.99\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt; 65 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e104 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49 (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge; 65 years\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e125 (63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e163 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.38\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e88 (63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e91 (65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.42\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eRace*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWhite\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e124 (63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e176 (66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e85 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e94 (67)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAfrican American\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37 (14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.19\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAsian\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.39\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.57\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.90\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCharlson Comorbidity\u003c/p\u003e\n\u003cp\u003eIndex score*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.82\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHistory of irradiation*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53 (27)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96 (36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49 (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.29\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHistology*\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"6\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSerous carcinoma\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73 (37)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112 (42)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCarcinosarcoma\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e125 (63)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e155 (58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95 (68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e95 (68)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" align=\"left\"\u003e\n\u003cp\u003eSites of metastasis\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLymph node\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e160 (81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e211 (79)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.46\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e106 (76)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e105 (75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.70\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePara-aortic LN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e131 (66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e171 (64)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83 (59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e81 (58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePelvic LN\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e121 (61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e176 (66)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e81 (58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e83 (59)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.65\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLung\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.56\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.41\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLiver\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.48\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeritoneum\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43(16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.50\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eColorectal\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (13)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.20\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eData are presented as N (%). Demographic data were obtained from the TriNetX Research Network. Baseline characteristics were documented one day before the index date. Variables marked with * were selected for PSM. CP, carboplatin plus paclitaxel; T: trastuzumab; PSM: propensity score matching; LN, lymph node; NA, not available.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIn the study population, 31 and 93 deaths were noted in the CP\u0026thinsp;+\u0026thinsp;T and CP groups, respectively. The median OS times were significantly different in the CP group (25.2 months) and CP\u0026thinsp;+\u0026thinsp;T group (41 months) (hazard ratio [HR]: 0.51, 95% confidence interval [CI] 0.345\u0026ndash;0.784, p\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). In the subgroup of uterine carcinosarcoma, 63 patients in the CP group and 21 patients in the CP\u0026thinsp;+\u0026thinsp;T group died from the disease. This resulted in a notable contrast in the median overall survival time between the CP group (16.8 months) and the CP\u0026thinsp;+\u0026thinsp;T group (41.7 months) or uterine carcinosarcoma, with an HR of 0.39 (95% CI 0.221\u0026ndash;0.560, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Additionally, within the uterine serous carcinoma subgroup, 29 and 13 patients in the CP and CP\u0026thinsp;+\u0026thinsp;T groups respectively succumbed to the disease. Within the uterine serous carcinoma subgroup, the median OS time significantly differed between the CP (27.1 months) and CP\u0026thinsp;+\u0026thinsp;T (38.7 months) groups, with an HR of 0.56 (95% CI 0.294\u0026ndash;0.869, p\u0026thinsp;=\u0026thinsp;0.04) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eRegarding adverse events, compared with the CP group, the CP\u0026thinsp;+\u0026thinsp;T group had a higher incidence of hypertension (8% vs. 25%), diarrhoea (3% vs. 9%), and left ventricular systolic dysfunction (2% vs. 9%) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). However, the rates of haematological toxicities, electrolyte imbalances, fatigue, peripheral sensory neuropathy, gastrointestinal symptoms, and renal dysfunction were similar between the two groups.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAdverse events in the CP and CP\u0026thinsp;+\u0026thinsp;T groups after PSM\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCP\u0026thinsp;+\u0026thinsp;T\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;140 (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCP\u003c/p\u003e\n\u003cp\u003eN\u0026thinsp;=\u0026thinsp;140 (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHR (95% CI)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAnaemia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.571 (0.144\u0026ndash;1.125)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.723\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 3 anaemia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 (7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.882 (0.439\u0026ndash;1.769)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.389\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eThrombocytopenia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.276 (0.578\u0026ndash;2.821)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.546\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 3 thrombocytopenia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.206 (0.988\u0026ndash;2.853)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.643\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNeutropenia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e56 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e53 (38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.189 (0.351\u0026ndash;2.062)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.912\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 3 neutropenia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (32)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.1 (0.436\u0026ndash;2.294)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.982\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSepsis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.231 (0.626\u0026ndash;2.419)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.932\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAcute kidney injury\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25 (18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.706 (0.454\u0026ndash;1.096)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.117\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHyponatremia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e42 (30)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.862 (0.547\u0026ndash;1.359)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.522\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypokalaemia\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.759 (0.433\u0026ndash;1.109)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.469\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eLeft ventricular systolic dysfunction\u003csup\u003e＊\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.329 (0.195\u0026ndash;0.684)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (25)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.744 (0.624\u0026ndash;0.886)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGrade 3 hypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.476 (0.278\u0026ndash;2.121)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.562\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiarrhoea\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4 (3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.681 (0.449\u0026ndash;0.845)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u003cstrong\u003e0.007\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eConstipation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31 (22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e36 (26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.853 (0.550\u0026ndash;1.348)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.467\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNausea/vomiting\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e34 (24)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31 (22)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.346 (0.760\u0026ndash;2.386)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.381\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBowel obstruction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 (8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.296 (0.572\u0026ndash;2.935)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.534\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMalaise and fatigue\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69 (49)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60 (43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.119 (0.824\u0026ndash;1.521)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.472\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeripheral sensory neuropathy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e125 (89)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e126 (90)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.899 (0.363\u0026ndash;2.225)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.817\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"5\"\u003e\u003csup\u003e＊\u003c/sup\u003eAs determined by an ejection fraction (EF) of less than 55% according to multigated acquisition scanning and/or conventional 2D-echocardiography. CP, carboplatin plus paclitaxel; T: trastuzumab; PSM: propensity score matching; HR, hazard ratio; CI, confidence interval.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study represents a ground-breaking investigation of real-world data on the addition of trastuzumab to frontline chemotherapy for HER2-overexpressing uterine carcinosarcoma and uterine serous carcinoma, offering promising insights into its potential benefits. Although adding trastuzumab significantly improved OS, it is crucial to emphasise the importance of vigilant monitoring of cardiac health and the early recognition of cardiac-related symptoms in patients receiving trastuzumab.\u003c/p\u003e \u003cp\u003eBased on the multicentre, randomised phase II trial by Fader et al.\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, in which HER2 overexpression was identified based on an IHC score of 3\u0026thinsp;+\u0026thinsp;or 2\u0026thinsp;+\u0026thinsp;and ERBB2 amplification was confirmed by FISH testing, the NCCN put forward guidelines recommending trastuzumab for HER2/neu-overexpressing advanced or recurrent uterine serous carcinoma and carcinosarcoma. Despite these promising phase II findings, which showed that patients in the trastuzumab cohort, particularly those with stage III-IV disease, had a longer median survival time (not reached) than those in the control group (24.4 months) (HR 0.49, 90% CI, 0.25\u0026ndash;0.97, p\u0026thinsp;=\u0026thinsp;0.041), there had been no further clinical trials or investigations of real-world data on the efficacy and safety of trastuzumab for uterine carcinosarcoma.\u003c/p\u003e \u003cp\u003eIn the present study, the OS was 41 months in the CPT arm and 25.2 months in the CP arm (HR: 0.52, 95% CI 0.345\u0026ndash;0.784, p\u0026thinsp;=\u0026thinsp;0.002), consistent with findings from previous research.\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e Most patients in this study (164, 59%) were diagnosed with uterine carcinosarcoma. Subgroup analysis based on histological type revealed that the addition of trastuzumab significantly extended OS in the carcinosarcoma group (from 16.8 months to 41.7 months, HR: 0.39), outperforming the extension seen in the serous carcinoma group (from 27.1 months to 38.7 months, HR: 0.56).\u003c/p\u003e \u003cp\u003eAn ongoing phase II/III clinical trial (NCT05256225) is currently evaluating the addition of trastuzumab to frontline carboplatin and paclitaxel, either alone or in combination with pertuzumab (a monoclonal antibody that binds to different extracellular domains of HER2). Pertuzumab has been approved by the FDA for HER2\u0026thinsp;+\u0026thinsp;breast cancer in combination with trastuzumab and chemotherapy. This ongoing trial is enrolling patients newly diagnosed with HER2-positive myoinvasive stage I\u0026ndash;IV uterine serous carcinoma or carcinosarcoma and is expected to conclude on October 31, 2027.\u003c/p\u003e \u003cp\u003eIn addition to HER2-directed monoclonal antibodies such as trastuzumab or pertuzumab, antibody‒drug conjugates (ADCs) are a novel class of targeted therapies. ADCs are composed of a humanised monoclonal antibody specific for a tumour surface antigen, such as HER2; a cleavable or uncleavable linker; and a cytotoxic payload. Trastuzumab deruxtecan (T-DXd or DS-8201a), a prominent ADC, is internalised by tumour cells, wherein it releases the toxic payload of DXd, which can permeate neighbouring tumour cells regardless of their HER2 status. This unique mechanism has demonstrated clinical efficacy in the treatment of heterogeneous HER2-positive tumours.\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e The multicentre phase II STATICE trial, a single-arm study across several centres in Japan, evaluated T-DXd in 32 patients with advanced or recurrent uterine carcinosarcomas, encompassing a range of HER2 expression profiles.\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e Of the 32 patients, 22 had HER2-high and 10 had HER2-low carcinosarcomas. The overall response rate (ORR) was 54.5% (95% CI, 32.2\u0026ndash;75.6) in the HER2-high cohort and 70% (95% CI, 45.1\u0026ndash;86.1) in the HER2-low cohort. The median duration of response was 6.9 months in the HER2-high group and 8.1 months in the HER2-low group.\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e Another phase II, multicentre, open-label trial, DESTINY-PanTumor02, enrolled 267 patients with previously treated HER2-expressing solid tumours, including those with HER2-positive (IHC 3+/2+) bladder, biliary tract, cervical, endometrial, ovarian, or pancreatic cancer.\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e In the endometrial cohort, 77.5% of patients had\u0026thinsp;\u0026ge;\u0026thinsp;two prior lines of therapy, yet this group had the highest ORR (84.6%) among the HER2 IHC 3\u0026thinsp;+\u0026thinsp;patients. For all patients with endometrial cancer, the median PFS and OS were 11.1 months and 26.0 months, respectively.\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDespite the promise of trastuzumab as targeted therapy for HER2-positive endometrial cancer, there are significant side effects associated with the addition of trastuzumab to carboplatin and paclitaxel for the treatment of late-stage HER2-overexpressing uterine cancer. In this study, adverse events included left ventricular systolic dysfunction, hypertension, and diarrhoea. Two percent of patients in the CP group and 9% of patients in the CP\u0026thinsp;+\u0026thinsp;T group experienced a decrease in the left ventricular ejection fraction (LVEF). Although the overall rate of hypertension was higher in patients who received trastuzumab, there was no significant difference in the incidence of Grade 3 hypertension between patients who did and did not receive trastuzumab. Furthermore, diarrhoea rates were higher in the trastuzumab group; however, this did not result in a significant increase in the rate of electrolyte imbalance (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). This outcome aligns with that of the multicentre phase II trial conducted by Fader et al., which reported that 3% of patients in the CP\u0026thinsp;+\u0026thinsp;T group and no patients in the CP group experienced a decrease in LVEF.\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e Hence, these findings underscore the importance of monitoring cardiac function and related symptoms in patients receiving trastuzumab combined with carboplatin and paclitaxel. Early detection and intervention may help to mitigate the risk of severe cardiac complications.\u003c/p\u003e \u003cp\u003eThe mechanisms underlying trastuzumab-induced cardiotoxicity remain unclear. Recent studies have reported a direct association between impaired HER2 signalling and trastuzumab-induced cardiotoxicity. Trastuzumab disrupts HER signalling by inducing the phosphorylation of HER1 Tyr845 and HER2 Tyr1248, which triggers an autophagy-inhibitory Erk/mTOR/Ulk 1 signalling cascade, thereby compromising the ability of cardiomyocytes to recycle toxic cellular substrates and leading to cardiotoxicity.\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e To further underscore the concerns surrounding trastuzumab-induced cardiac effects, a comprehensive meta-analysis of cardiac dysfunction in seven trials found that while cardiac dysfunction occurred in 3\u0026ndash;7% of patients treated with trastuzumab alone, this incidence increased to 13% when trastuzumab and paclitaxel were combined and further increased to 27% when trastuzumab was combined with anthracyclines, as opposed to \u0026lt;\u0026thinsp;7% in the anthracycline-only group.\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e These findings highlight the increased risk of cardiac toxicity when trastuzumab is administered in conjunction with other chemotherapeutic agents.\u003c/p\u003e \u003cp\u003eAlthough our study has the advantage of including the largest cohort of patients with late-stage HER2-overexpressing uterine serous carcinoma and carcinosarcoma, it is crucial to recognise certain limitations. First, the study did not have a randomised controlled design, and detailed dosage information for each treatment was not available. Nevertheless, efforts were made to minimise selection bias through PSM of baseline characteristics. Second, our reliance on coding systems, such as ICD, RxNorm, HCPCS, and CPT, to identify patient diagnoses, adverse events, lines of chemotherapy, and treatment regimens may have introduced misclassifications or reporting delays that potentially affected the analysis outcomes. However, the TriNetX data originated from developed countries in Europe and America, where the personnel responsible for data entry are typically well trained, which reduces the likelihood of errors. Therefore, further clinical study is required to corroborate and validate our findings, and a deeper understanding of trastuzumab-induced cardiotoxicity is crucial for optimising treatment strategies and ensuring the best possible patient outcomes within the evolving landscape of targeted therapies for HER2-overexpressing cancers.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe addition of trastuzumab to frontline treatment with carboplatin and paclitaxel for patients with stage III/IV HER2-overexpressing uterine serous carcinoma or carcinosarcoma significantly improved OS. Although this finding highlights the potential benefits of incorporating trastuzumab into treatment regimens for this patient population, it is crucial to emphasise the importance of routine, careful monitoring of cardiac function and signs of congestive heart failure when administering trastuzumab. The increased risk of adverse cardiac events associated with trastuzumab underscores the need for early detection methods and intervention to manage these potential complications effectively.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADC, antibody‒drug conjugate; ADCC, antibody-dependent cellular cytotoxicity; CCI, Charlson Comorbidity Index; CI, confidence interval; CPT, Current Procedural Terminology; CTCAE, Common Terminology Criteria for Adverse Events; FDA, the Food and Drug Administration; FIGO, International Federation of Gynaecology and Obstetrics; FISH, fluorescence in situ hybridisation; HCO, healthcare organisation; HCPCS, Healthcare Common Procedure Coding System; HER-2, human epidermal growth factor receptor-2; HR, hazard ratio; ICD, International Classification of Diseases; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction; NCCN, National Comprehensive Cancer Network; NAACCR, North American Association of Central Cancer Registries; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThis manuscript presents original work and has not been previously published, nor is it under consideration for publication elsewhere. All authors have significantly contributed to the conception, design, analysis, or interpretation of the data presented in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe TriNetX Research Network is fully compliant with the Health Insurance Portability and Accountability Act and holds a waiver from the Western Institutional Review Board, given the deidentified and aggregate nature of the data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe consent for publication of the subjects in this study was not applicable, as the data collected is sourced from electronic health records obtained from the TriNetX Research Network in Cambridge, MA, USA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDeidentified participant data will be made available upon request to the corresponding author according to the regulations of Taichung Veterans General Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors of this manuscript have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Taichung Veterans General Hospital (grant number: TCVGH-1126401C). No external funding was used for this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTing-Fang Lu analyzed and interpreted the data from TriNetX and made significant contributions to writing the manuscript. Chien-Hsing Lu contributed to conceptualization, supervision, and major revisions of the paper. Lou Sun, Sheau-Feng Hwang, Yu-Hsiang Shih, and Yen-Fu Chen conducted data analysis and participated in methodological discussions aimed at minimizing possible biases from the database. Chin-Ku Liu, Chun Ting Fan, Shao-Jing Wang, and Shih-Tien Hsu contributed to the validation and visualization of the benefits of trastuzumab to carboplatin and paclitaxel in patients with advanced-stage HER2/neu-overexpressing uterine serous carcinoma or carcinosarcoma. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all the staff of the obstetrics and gynaecology department of VGHTC for their technical assistance. Last but not least, we would like to thank the reviewers and the editor for their comments.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US cancer incidence and death to 2040. JAMA Netw Open. 2021;4:e214708.\u003c/li\u003e\n\u003cli\u003eSiegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.\u003c/li\u003e\n\u003cli\u003eLortet-Tieulent J, Ferlay J, Bray F, Jemal A. International patterns and trends in endometrial cancer incidence, 1978\u0026ndash;2013. 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Gynecol Oncol. 2012;127:321-5.\u003c/li\u003e\n\u003cli\u003eSiegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17-48.\u003c/li\u003e\n\u003cli\u003eRaffone A, Travaglino A, Raimondo D, Maletta M, De Vivo V, Visiello U, et al. Uterine carcinosarcoma vs endometrial serous and clear cell carcinoma: A systematic review and meta-analysis of survival. Int J Gynaecol Obstet. 2022;158:520-7.\u003c/li\u003e\n\u003cli\u003eBerton-Rigaud D, Devouassoux-Shisheboran M, Ledermann JA, Leitao MM, Powell MA, Poveda A et al. Gynecologic Cancer InterGroup (GCIG) consensus review for uterine and ovarian carcinosarcoma. Int J Gynecol Cancer. 2014;24:S55-60.\u003c/li\u003e\n\u003cli\u003eGonzalez Bosquet J, Terstriep SA, Cliby WA, Brown-Jones M, Kaur JS, Podratz KC, et al. The impact of multi-modal therapy on survival for uterine carcinosarcomas. Gynecol Oncol. 2010;116:419-23. \u003c/li\u003e\n\u003cli\u003eRottmann D, Snir OL, Wu X, Wong S, Hui P, Santin AD, et al. HER2 testing of gynecologic carcinosarcomas: Tumor stratification for potential targeted therapy. Mod Pathol. 2020;33:118-27.\u003c/li\u003e\n\u003cli\u003ePowell MA, Filiaci VL, Hensley ML, Huang HQ, Moore KN, Tewari KS, et al. A randomized phase 3 trial of paclitaxel (P) plus carboplatin (C) versus paclitaxel plus ifosfamide (I). In: chemotherapy-na\u0026iuml;ve patients with stage I-IV, persistent, or recurrent uterine or ovarian carcinosarcoma: An NRG Oncology trial. J Clin Oncol. 2019;40:968-77.\u003c/li\u003e\n\u003cli\u003eZhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, et al. The landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A. 2013;110:2916-21.\u003c/li\u003e\n\u003cli\u003eLuo H, Xu X, Ye M, Sheng al B, Zhu X. The prognostic value of HER2 in ovarian cancer: A meta-analysis of observational studies. PLoS One. 2018;13:e0191972.\u003c/li\u003e\n\u003cli\u003eErickson BK, Najjar O, Damast S, Blakaj A, Tymon-Rosario J, Shahi M, et al. Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort study. Gynecol Oncol. 2020;159:17-22.\u003c/li\u003e\n\u003cli\u003eHudis CA. Trastuzumab\u0026ndash;mechanism of action and use in clinical practice. N Engl J Med. 2007;357:39-51.\u003c/li\u003e\n\u003cli\u003eFader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. J Clin Oncol. 2018;36:2044-51.\u003c/li\u003e\n\u003cli\u003eFader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, et al. Randomized phase II trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (Stage III\u0026ndash;IV) or recurrent uterine serous carcinomas that overexpress Her2/Neu (NCT01367002): Updated overall survival analysis. Clin Cancer Res. 2020;26:3928-35.\u003c/li\u003e\n\u003cli\u003eAbu-Rustum N, Yashar C, Arend R, Barber E, Bradley K, Brooks R, et al. Uterine neoplasms. version 1.2023, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21:181-209.\u003c/li\u003e\n\u003cli\u003eAndrikopoulou A, Zografos E, Liontos M, Koutsoukos K, Dimopoulos MA, Zagouri F. Trastuzumab deruxtecan (DS-8201a): The latest research and advances in breast cancer. Clin Breast Cancer. 2021;21:e212-9.\u003c/li\u003e\n\u003cli\u003eNishikawa T, Hasegawa K, Matsumoto K, Mori M, Hirashima Y, Takehara K et al. Trastuzumab deruxtecan for human epidermal growth factor receptor 2-expressing advanced or recurrent uterine carcinosarcoma (NCCH1615): The STATICE trial. J Clin Oncol. 2023;41:2789-99.\u003c/li\u003e\n\u003cli\u003eMeric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, Gonz\u0026aacute;lez-Mart\u0026iacute;n A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: Primary results from the DESTINY-PanTumor02 Phase II trial. J Clin Oncol. 2024;42:47-58.\u003c/li\u003e\n\u003cli\u003eMohan N, Shen Y, Endo Y, ElZarrad MK, Wu WJ. Trastuzumab, but not pertuzumab, dysregulates HER2 Signaling to mediate inhibition of autophagy and increase in reactive oxygen species production in human cardiomyocytes. Mol Cancer Ther. 2016;15:1321-31.\u003c/li\u003e\n\u003cli\u003eWilcken N, Zdenkowski N, White M, Snyder R, Pittman K, Mainwaring P, et al. Systemic treatment of HER2-positive metastatic breast cancer: A systematic review. Asia Pac J Clin Oncol. 2014;10 Suppl S4:1-14.\u003c/li\u003e\n\u003cli\u003eSeidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215-21.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"uterine serous carcinoma, uterine carcinosarcoma, human epidermal growth factor receptor 2, trastuzumab","lastPublishedDoi":"10.21203/rs.3.rs-4372638/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4372638/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eUterine serous carcinomas and carcinosarcomas are aggressive forms of endometrial cancer with poor survival outcomes. Trastuzumab, a human epidermal growth factor receptor-2 (HER2)-directed monoclonal antibody, has demonstrated tumoricidal efficacy. However, clinical data regarding its efficacy in uterine serous carcinoma are limited, and there are no clinical data available for uterine carcinosarcoma. Therefore, this study aimed to ascertain the efficacy and safety of adding trastuzumab to carboplatin and paclitaxel as a frontline treatment for advanced-stage HER2-overexpressing uterine serous carcinoma and carcinosarcoma.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study used deidentified data from electronic health records sourced from the TriNetX Research Network. Participants were identified using ICD codes, and HER2 positivity was confirmed by immunohistochemistry or fluorescence in situ hybridisation (FISH). Propensity score matching (PSM) was employed to reduce confounders, and survival outcomes and adverse events were assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFollowing PSM, 280 patients with advanced HER2-positive uterine serous carcinoma or carcinosarcoma were analysed. The group of patients treated with carboplatin/paclitaxel\u0026thinsp;+\u0026thinsp;trastuzumab (CP\u0026thinsp;+\u0026thinsp;T) showed a significantly extended median overall survival compared to those treated solely with CP (41 months versus 25.2 months, hazard ratio [HR]\u0026thinsp;=\u0026thinsp;0.51, p\u0026thinsp;=\u0026thinsp;0.002) in both advanced-stage uterine carcinosarcoma and serous carcinoma. Specifically, patients with uterine carcinosarcoma experienced an even longer survival benefit (HR\u0026thinsp;=\u0026thinsp;0.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) when trastuzumab was added to their chemotherapy regimen, surpassing the survival benefit seen in patients with uterine serous carcinoma (HR\u0026thinsp;=\u0026thinsp;0.56, p\u0026thinsp;=\u0026thinsp;0.04). However, patients who received trastuzumab experienced higher rates of hypertension, diarrhoea, and left ventricular systolic dysfunction.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe addition of trastuzumab to frontline chemotherapy is effective for the treatment of HER2-overexpressing uterine serous carcinoma and carcinosarcoma, particularly uterine carcinosarcoma. However, careful monitoring of adverse cardiac events is needed.\u003c/p\u003e","manuscriptTitle":"Adding trastuzumab to carboplatin and paclitaxel improves overall survival in patients with advanced-stage HER2/neu-overexpressing uterine serous carcinoma or carcinosarcoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-15 22:39:54","doi":"10.21203/rs.3.rs-4372638/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-05T13:14:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-06T02:16:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"23956620747831295483958645290090786378","date":"2024-09-23T13:11:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-10T11:48:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-07T21:05:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"39985596942548331968681599676262004637","date":"2024-06-25T12:51:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"88879757166054501383845005243194693836","date":"2024-06-20T12:48:57+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-06T11:11:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-07T09:49:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-07T08:43:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2024-05-05T17:26:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c1813273-5760-4421-adbd-d5fe6c1d44e6","owner":[],"postedDate":"May 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-24T15:59:24+00:00","versionOfRecord":{"articleIdentity":"rs-4372638","link":"https://doi.org/10.1186/s12916-025-03916-3","journal":{"identity":"bmc-medicine","isVorOnly":false,"title":"BMC Medicine"},"publishedOn":"2025-02-21 15:57:02","publishedOnDateReadable":"February 21st, 2025"},"versionCreatedAt":"2024-05-15 22:39:54","video":"","vorDoi":"10.1186/s12916-025-03916-3","vorDoiUrl":"https://doi.org/10.1186/s12916-025-03916-3","workflowStages":[]},"version":"v1","identity":"rs-4372638","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4372638","identity":"rs-4372638","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}