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Regression of metastatic, radiation/chemotherapy-resistant uterine serous carcinoma overexpressing HER2/neu with trastuzumab emtansine (TDM-1).

ABSTRACT: The management of uterine-serous-carcinoma (USC) no longer amenable to treatment with surgery, radiation and/or chemotherapy remains dismal. Alternative therapeutic options are desperately needed.We describe the case of a heavily pretreated 74-year-old patient with a recurrent USC overexpressing HER2/neu at 3 + level by IHC treated with the anti-HER2/neu antibody-drug-conjugate (ADC) trastuzumab-emtansine (TDM-1-Kadcyla-Genentech/Roche). She experienced a remarkable clinical response to TDM-1 with a complete resolution of a large metastatic, radiation/chemotherapy resistant tumor deposit in her abdominal wall muscle confirmed by multiple CAT scans and a prolonged systemic control of her disease.TDM-1 may represent a novel treatment option for recurrent/metastatic HER2/neu-positive USC patients refractory to salvage-treatment.

SUBMITTER: Santin AD

PROVIDER: S-EPMC5175991 | biostudies-other | 2017 Feb

REPOSITORIES: biostudies-other

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Regression of metastatic, radiation/chemotherapy-resistant uterine serous carcinoma overexpressing HER2/neu with trastuzumab emtansine (TDM-1).

Santin Alessandro D AD Bellone Stefania S Buza Natalia N Schwartz Peter E PE

Gynecologic oncology reports 20161214

<h4>Background</h4>The management of uterine-serous-carcinoma (USC) no longer amenable to treatment with surgery, radiation and/or chemotherapy remains dismal. Alternative therapeutic options are desperately needed.<h4>Case</h4>We describe the case of a heavily pretreated 74-year-old patient with a recurrent USC overexpressing HER2/neu at 3 + level by IHC treated with the anti-HER2/neu antibody-drug-conjugate (ADC) trastuzumab-emtansine (TDM-1-Kadcyla-Genentech/Roche). She experienced a remarkab ...[more]

PMID: 28018954

Similar Datasets

PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas.

Project description:We evaluated the role of PIK3CA-mutations as mechanism of resistance to trastuzumab in primary HER2/neu-amplified uterine-serous-carcinoma (USC) cell lines.Fifteen whole-exome-sequenced USC cell lines were tested for HER2/neu-amplification and PIK3CA-mutations. Four HER2/neu-amplified USC (2-harbouring wild-type-PIK3CA-genes and 2-harbouring oncogenic-PIK3CA-mutations) were evaluated in in vitro dose-titration-proliferation-assays, cell-viability and HER2 and S6-protein-phosphorylation after exposure to trastuzumab. USC harbouring wild-type-PIK3CA were transfected with plasmids encoding oncogenic PIK3CA-mutations (i.e., H1047R/R93Q) and exposed to trastuzumab. Finally, trastuzumab efficacy was tested by using two USC xenograft mouse models.Seven out of fifteen (46%) of the USC cell lines were HER2/neu-amplified by fluorescence in situ hybridisation. Within these tumours four out of seven (57%) were found to harbour oncogenic PIK3CA-mutations vs two out of eight (25%) of the HER2/neu not amplified cell lines (P=0.01). HER2/neu-amplified/PIK3CA-mutated USC were highly resistant to trastuzumab when compared with HER2/neu-amplified/wild-type-PIK3CA cell lines (P=0.02). HER2/neu-amplified/PIK3CA wild-type cell lines transfected with oncogenic PIK3CA-mutations increased their resistance to trastuzumab (P<0.0001). Trastuzumab was effective in reducing tumour growth (P=0.001) and improved survival (P=0.0001) in mouse xenografts harbouring HER2-amplified/PIK3CA wild-type USC but not in HER2-amplified/PIK3CA-mutated tumours.Oncogenic PIK3CA mutations are common in HER2/neu-amplified USC and may constitute a major mechanism of resistance to trastuzumab treatment.

| S-EPMC4651122 | biostudies-literature

Trastuzumab tolerability in the treatment of advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress HER2/neu.

Project description:ObjectiveDue to previously reported trastuzumab safety concerns and the scant data available in endometrial cancer patients, we sought to assess the safety, tolerability and toxicity profile of trastuzumab in patients with advanced/recurrent uterine serous carcinoma (USC) that overexpress HER2/neu in our multicenter randomized phase II trial.MethodsPatients were randomized 1:1 to receive carboplatin/paclitaxel (C/P) for 6 cycles ± trastuzumab (T) with the experimental arm continuing to receive single agent trastuzumab maintenance treatment until disease progression/toxicity. Progression-free-survival was the primary endpoint; overall-survival and toxicity were secondary endpoints. Adverse events (AEs) were compared between treatment arms.ResultsThere were 28 patients in the C/P arm and 32 patients in the experimental (C/P + T) arm. Fifty-eight patients (97%) experienced 977 treatment-related AEs of which 875 (89.6%) were low-grade (grade 1-2) and 102 (10.4%) were high-grade (grade 3-5). The mean ± standard deviation of AEs per patient was 15.5 ± 16.3 in the C/P arm and 17.0 ± 16.0 in the C/P + T arm. Gastrointestinal AEs were the most common in both arms (n = 155, 15.7%) of which 94.2% were low-grade (n = 146). Importantly, no significant difference between treatment arms was detected in any system-organ class of AE including cardiac AE. Five (17%) of 29 patients who received prolonged trastuzumab maintenance therapy had no sign of cumulative toxicity after an average (range) of 5.1 (4.2-6.3) years.ConclusionsTrastuzumab appears to be safe and has a manageable toxicity profile both when used in combination with chemotherapy and when used for single agent maintenance in patients with HER2/neu positive USC. This safety profile is reassuring given the proven efficacy of trastuzumab in advanced/recurrent HER2/neu positive USC.

| S-EPMC8721852 | biostudies-literature

Downregulation of membrane complement inhibitors CD55 and CD59 by siRNA sensitises uterine serous carcinoma overexpressing Her2/neu to complement and antibody-dependent cell cytotoxicity in vitro: implications for trastuzumab-based immunotherapy.

Project description:BackgroundWe evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro.MethodsMembrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT-PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays.ResultsHigh expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean ± s.e.m.=6.8 ± 0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6 ± 0.8% and 10.7 ± 0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu.ConclusionUterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo.

| S-EPMC3341945 | biostudies-literature

Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer.

Project description:PurposeThe primary objectives of this phase I/II study were to evaluate the safety and immunogenicity of combination therapy consisting of concurrent trastuzumab and human epidermal growth factor receptor 2 (HER2)/neu-specific vaccination in patients with HER2/neu-overexpressing metastatic breast cancer.Patients and methodsTwenty-two patients with stage IV HER2/neu-positive breast cancer receiving trastuzumab therapy were vaccinated with an HER2/neu T-helper peptide-based vaccine. Toxicity was graded according to National Cancer Institute criteria, and antigen specific T-cell immunity was assessed by interferon gamma enzyme-linked immunosorbent spot assay. Data on progression-free and overall survival were collected.ResultsConcurrent trastuzumab and HER2/neu vaccinations were well tolerated, with 15% of patients experiencing an asymptomatic decline in left ventricular ejection fraction below the normal range during combination therapy. Although many patients had pre-existing immunity specific for HER2/neu and other breast cancer antigens while treated with trastuzumab alone, that immunity could be significantly boosted and maintained with vaccination. Epitope spreading within HER2/neu and to additional tumor-related proteins was stimulated by immunization, and the magnitude of the T-cell response generated was significantly inversely correlated with serum transforming growth factor beta levels. At a median follow-up of 36 months from the first vaccine, the median overall survival in the study population has not been reached.ConclusionCombination therapy with trastuzumab and a HER2/neu vaccine is associated with minimal toxicity and results in prolonged, robust, antigen-specific immune responses in treated patients.

| S-EPMC2754913 | biostudies-literature

Trastuzumab deruxtecan in recurrent uterine serous carcinoma resistant to trastuzmab based-chemotherapy.

Project description:BackgroundTreatment of uterine serous carcinoma (USC) is challenging; effective treatment options for metastatic and recurrent disease are needed.CaseA 68-year-old woman with recurrent, metastatic, USC overexpressing HER2/neu experienced durable response to the antibody drug conjugate (ADC) trastuzumab-deruxtecan (T-DXd), after failing multiple standard and experimental treatments targeting HER2/neu. She experienced a significant reduction in disease burden, disappearance of metastatic back bone pain as well as normalization of CA-125 quickly after starting treatment. Her disease continued to show response to treatment over 5 months and 7 cycles of T-DXd therapy. She did not experience any dose-limiting side effects and tolerated treatment with 5.4 mg/kg T-DXd without issue.ConclusionT-DXd may present a new treatment option for chemotherapy-resistant uterine serous carcinoma.

| S-EPMC10265462 | biostudies-literature

Proteomic characterization of Her2/neu-overexpressing breast cancer cells.

Project description:The receptor tyrosine kinase HER2 is an oncogene amplified in invasive breast cancer and its overexpression in mammary epithelial cell lines is a strong determinant of a tumorigenic phenotype. Accordingly, HER2-overexpressing mammary tumors are commonly indicative of a poor prognosis in patients. Several quantitative proteomic studies have employed two-dimensional gel electrophoresis in combination with MS/MS, which provides only limited information about the molecular mechanisms underlying HER2/neu signaling. In the present study, we used a SILAC-based approach to compare the proteomic profile of normal breast epithelial cells with that of Her2/neu-overexpressing mammary epithelial cells, isolated from primary mammary tumors arising in mouse mammary tumor virus-Her2/neu transgenic mice. We identified 23 proteins with relevant annotated functions in breast cancer, showing a substantial differential expression. This included overexpression of creatine kinase, retinol-binding protein 1, thymosin 4 and tumor protein D52, which correlated with the tumorigenic phenotype of Her2-overexpressing cells. The differential expression pattern of two genes, gelsolin and retinol binding protein 1, was further validated in normal and tumor tissues. Finally, an in silico analysis of published cancer microarray data sets revealed a 23-gene signature, which can be used to predict the probability of metastasis-free survival in breast cancer patients.

| S-EPMC4327899 | biostudies-literature

Silencing of the HER2/neu gene by siRNA inhibits proliferation and induces apoptosis in HER2/neu-overexpressing breast cancer cells.

Project description:In eukaryotes, double-stranded (ds) RNA induces sequence-specific inhibition of gene expression referred to as RNA interference (RNAi). We exploited RNAi to define the role of HER2/neu in the neoplastic proliferation of human breast cancer cells. We transfected SK-BR-3, BT-474, MCF-7, and MDA-MB-468 breast cancer cells with short interfering RNA (siRNA) targeted against human HER2/neu and analyzed the specific inhibition of HER2/neu expression by Northern and Western blots. Transfection with HER2/neu-specific siRNA resulted in a sequence-specific decrease in HER2/neu mRNA and protein levels. Moreover, transfection with HER2/neu siRNA caused cell cycle arrest at G0/G1 in the breast cancer cell lines SK-BR-3 and BT-474, consistent with a powerful RNA silencing effect. siRNA treatment resulted in an antiproliferative and apoptotic response in cells overexpressing HER2/neu, but had no influence in cells with almost no expression of HER2/neu proteins like MDA-MB-468 cells. These data indicate that HER2/neu function is essential for the proliferation of HER2/neu-overexpressing breast cancer cells. Our observations suggest that siRNA targeted against human HER2/neu may be valuable tools as antiproliferative agents that display activity against neoplastic cells at very low doses.

| S-EPMC1531682 | biostudies-literature

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.

Project description:PurposeUterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002.Patients and methodsEligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints.ResultsSixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28-0.76; P = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23-0.83; P = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03-0.48; P = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34-0.99; P = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25-0.97; P = 0.041). Toxicity was not different between arms.ConclusionsAddition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.

| S-EPMC8792803 | biostudies-literature

Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer.

Project description:BACKGROUND: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. METHODS: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. RESULTS: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. CONCLUSION: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.

| S-EPMC3304403 | biostudies-other

Combined Adjuvant Chemotherapy and Radiation Therapy Improves Disease-Free Survival for Uterine Serous Cancer.

Project description:PurposeUterine serous carcinoma (USC) is a rare but aggressive endometrial cancer histology. We reviewed outcomes for patients with USC to identify the best adjuvant treatment strategy.Methods and materialsWe retrospectively identified 162 patients with The International Federation of Gynecology and Obstetrics (FIGO) stage I-IVA USC treated at our institution. Baseline characteristics, treatment details, clinical outcomes, and toxicity data were recorded.ResultsMedian follow-up was 3.4 years (0.3-26 years). A variety of adjuvant therapy strategies were employed: 14% no adjuvant therapy, 28% radiation alone, 15% chemotherapy alone, and 43% combined chemotherapy and radiation. Distant metastasis was the most common type of recurrence (37% at 5 years). For patients with stage I-IVA disease, there were no significant differences in outcomes by treatment type. For patients with stage I-II disease (70% of the cohort), disease-free survival was significantly higher after chemotherapy (alone or with radiation therapy, P = .005) and after combined chemotherapy and radiation compared with all other treatments (P = .025). Toxicity outcomes were favorable, with minimal grade 3 and no grade 4 or 5 events.ConclusionsPatients with USC experience high rates of recurrence and mortality. Distant metastasis is the most common pattern of failure for all stages. For patients with early-stage disease, combined chemotherapy and radiation improves 5-year disease-free survival compared with either single adjuvant treatment alone or no adjuvant treatment. The relatively large group of patients with USC included in this study may account for our ability to detect this improvement whereas clinical trials have failed to do so, possibly owing to the relatively small percentages of patients with USC enrolled.

| S-EPMC7718545 | biostudies-literature

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