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

doi:10.21203/rs.3.rs-4372638/v1

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

https://doi.org/10.21203/rs.3.rs-4372638/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

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

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.

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.

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.

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.

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.

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.

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.

Acknowledgements

The 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.

Rahib L, Wehner MR, Matrisian LM, Nead KT. Estimated Projection of US cancer incidence and death to 2040. JAMA Netw Open. 2021;4:e214708.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.
Lortet-Tieulent J, Ferlay J, Bray F, Jemal A. International patterns and trends in endometrial cancer incidence, 1978–2013. J Natl Cancer Inst. 2018;110:354-61.
Bogani G, Ray-Coquard I, Concin N, Ngoi NYL, Morice P, Enomoto T, et al. Uterine serous carcinoma. Gynecol Oncol. 2021;162:226-34.
Han Y, Liu C. Clinicopathological characteristics and prognosis of uterine serous carcinoma: A SEER program analysis of 1016 cases. J Obstet Gynaecol Res. 2021;47:2460-72.
Podratz KC, Mariani A. Uterine papillary serous carcinomas: The exigency for clinical trials. Gynecol Oncol. 2003;91:461-2.
Lin JF, Muñiz K, Sukumvanich P, Gehrig P, Beriwal S, Kelley JL, et al. Survival advantage associated with multimodal therapy in women with node-positive (stage-IIIC) uterine papillary serous carcinoma: A National Cancer Database study. BJOG. 2016;123:1846-52.
McGunigal M, Liu J, Kalir T, Chadha M, Gupta V. Survival differences among uterine papillary serous, clear cell and grade 3 endometrioid adenocarcinoma endometrial cancers: A National Cancer Database analysis. Int J Gynecol Cancer. 2017;27:85-92.
Boruta 2nd DM, Gehrig PA, Fader AN, Olawaiye AB. Management of women with uterine papillary serous cancer: A Society of Gynecologic Oncology (SGO) review. Gynecol Oncol. 2009;115:142-53.
Hoskins PJ, Swenerton KD, Pike JA, Wong F, Lim P, Acquino-Parsons C, et al. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: A phase II study. J Clin Oncol. 2001;19:4048-53.
Kiess AP, Damast S, Makker V, Kollmeier MA, Gardner GJ, Aghajanian C, et al. Five-year outcomes of adjuvant carboplatin/paclitaxel chemotherapy and intravaginal radiation for stage I–II papillary serous endometrial cancer. Gynecol Oncol. 2012;127:321-5.
Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17-48.
Raffone 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.
Berton-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.
Gonzalez 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.
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.

No competing interests reported.

Supplement.doc

Download PDF

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

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

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1