Uterine Serous Carcinoma

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Alessandro D. Santin - One of the best experts on this subject based on the ideXlab platform.

  • minimal Uterine Serous Carcinoma and endometrial polyp a close clinicopathological relationship
    Human Pathology, 2021
    Co-Authors: Hisham Assem, Alessandro D. Santin, Natalia Buza, Elena Ratner, Douglas Rottmann, Alexander Finkelstein, Minhua Wang, Pei Hui
    Abstract:

    Summary Frequently involving an endometrial polyp, minimal Uterine Serous Carcinoma (MUSC) represents the earliest recognizable forms of endometrial Serous Carcinoma. The aim of this study was to provide a comprehensive morphological and clinical outcome assessment of MUSC involving endometrial polyp. A total of 77 fully staged MUSCs involving endometrial polyp were identified, including 53 MUSCs confined to polyp and 24 nonpolyp confined tumors. ExtraUterine disease was found in 17% (9/53) of polyp-confined MUSCs compared to 41.7% (10/24) of nonpolyp confined tumors (p = 0.02). Lymphovascular invasion was observed in 3.8% (2/53) of polyp-confined cases compared to 25% (6/24) of nonpolyp confined cases (p = 0.047). Lymph node metastasis was observed in 11.3% (6/53) of polyp-confined cases, compared to 29.2% (7/24) of nonpolyp confined cases (p = 0.058). Positive pelvic washing cytology was seen in 18.9% (10/53) of polyp-confined versus 37.5% (9/24) of nonpolyp confined tumors (p = 0.078). Overall, 58 of 77 (75.3%) patients had low tumor stage (57 stage I cases and 1 stage II case) and only two patients (3.5%) had a recurrence. In contrast, 19 of 77 (24.7%) patients had advanced stage (stage III or IV) disease and 17 (89.5%) patients had recurrence (p

  • Uterine Serous Carcinoma molecular features clinical management and new and future therapies
    Gynecologic Oncology, 2021
    Co-Authors: Elizabeth K Lee, Alessandro D. Santin, Amanda N. Fader, Joyce F Liu
    Abstract:

    Uterine Serous Carcinoma (USC) is an aggressive subtype of endometrial cancer. Multimodality treatment with surgery, radiotherapy, and chemotherapy is commonly used, given its propensity for extraUterine spread, distant recurrences, and poor prognosis. However, the use of molecularly-based therapy is expanding. Here, we review key molecular features of USC, discuss current management, and assess the landscape of novel therapies and combinations.

  • human epidermal growth factor 2 her2 in early stage Uterine Serous Carcinoma a multi institutional cohort study
    Gynecologic Oncology, 2020
    Co-Authors: Britt K Erickson, Alessandro D. Santin, Omar Najjar, Maryam Shahi, Molly Klein, Michelle M Dolan, Joan Tymonrosario, Shari Damast, Adriana Blakaj, Ashley Ciminomathews
    Abstract:

    Abstract Background Human epidermal growth factor receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in advanced stage and recurrent Uterine Serous Carcinoma (USC). The significance of tumoral HER2 expression in early-stage disease has not been established. Methods This multi-center cohort study included women with stage I USC treated from 2000 to 2019. Demographic, treatment, recurrence, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0–3+. Equivocal IHC results (2+) were further tested with fluorescence in-situ hybridization (FISH). HER2 positivity was defined as 3+ IHC or FISH positive. Results One hundred sixty-nine patients with stage I USC were tested for HER2; 26% were HER2-positive. There were no significant differences in age, race, stage, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. Presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p = .003). After a median follow-up of 50 months, there were 43 (25.4%) recurrences. There were significantly more recurrences in the HER2-positive cohort (50.0% vs 16.8%, p  Conclusions Given its significant association with worse recurrence and survival outcomes, HER2 positivity appears to be a prognostic biomarker in women with stage I Uterine Serous Carcinoma. These data provide support for clinical trials with anti-HER2-directed therapy in early-stage disease.

  • stage iii Uterine Serous Carcinoma modern trends in multimodality treatment
    Journal of Gynecologic Oncology, 2020
    Co-Authors: Melissa R Young, Alessandro D. Santin, Peter E. Schwartz, Gloria S Huang, Babak Litkouhi, Shari Damast
    Abstract:

    Objective To examine outcomes in a modern treatment era for stage III Uterine Serous Carcinoma (USC). Methods Fifty women were retrospectively identified as 2009 International Federation of Gynecology and Obstetrics stage III USC patients who received radiotherapy (RT) at our institution between 1/2003-5/2018. The patients were divided into 2 cohorts: 20 in the early era (2003-2010) and 30 in the modern era (2011-2018). Patient characteristics were compared using χ² tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards. Results The modern era differed from the early era in the increased use of volume-directed external beam RT (EBRT) as opposed to vaginal brachytherapy (VB) alone (33.3% vs 5.0%, p=0.048), minimally invasive surgery (56.7% vs. 25%, p=0.027), sentinel node sampling (26.7% vs. 0%, p=0.012), computed tomography imaging in the perioperative period (63.3% vs. 30%, p=0.044), and human epidermal growth factor receptor 2/neu testing (96.7% vs. 55%, p=0.001). Median follow-up for early and modern eras was 37.27 and 33.23 months, respectively. The early vs. modern 3-year RFS was 33% and 64% (p=0.039), respectively, while the 3-year OS was 55% and 90% (p=0.034). Regional nodal recurrence more common among the patients who received VB only (p=0.048). Conclusion Modern era treatment was associated with improved RFS and OS in patients with stage III USC. Regional nodal recurrences were significantly reduced in patients who received EBRT.

  • selection of her2 neu negative tumor cells as a mechanism of resistance to trastuzumab in Uterine Serous Carcinoma
    Gynecologic oncology reports, 2020
    Co-Authors: Silvia Pelligra, Natalia Buza, Stefania Bellone, Peter E. Schwartz, Pei Hui, Elena Ratner, Burak Zeybek, Giovanni Scambia, Alessandro D. Santin
    Abstract:

    Abstract Background Uterine Serous Carcinoma (USC) is an aggressive variant of endometrial cancer overexpressing HER2/neu in about 30% of cases. Trastuzumab, a humanized monoclonal antibody targeting Her2/Neu, in combination with carboplatin/paclitaxel, is considered the preferred regimen for the treatment of advanced or recurrent HER2/Neu+ USC per NCCN guidelines. Case We describe two USC patients with overexpression of HER2/neu at 2+/3+ level by immunohistochemistry and c-erbB2 gene amplification by fluorescence in situ hybridization (FISH) assay that, after an initial clinical response to trastuzumab, developed resistance/progression. Post-treatment biopsy (collected at the time of clinical progression on trastuzumab) demonstrated loss of HER2/neu overexpression in the recurrent/progressing tumor cells in both patients. Conclusion Selection of HER2/NEU negative tumor cells may represent a major mechanism of resistance to trastuzumab in USC patients.

Stefania Bellone - One of the best experts on this subject based on the ideXlab platform.

  • in vitro and in vivo activity of dhes0815a an antibody drug conjugate targeting her2 neu in Uterine Serous Carcinoma
    Gynecologic Oncology, 2021
    Co-Authors: Joan Tymonrosario, Stefania Bellone, Elena Bonazzoli, Burak Zeybek, Luca Zammataro, Adele Guglielmi, Nupur Nagarkatti, Justin Harold, Dennis Mauricio, Mitchell Clark
    Abstract:

    Objectives: Uterine Serous Carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2-amplified USC tumors at a distinct epitope from that bound by trastuzumab, pertuzumab, and T-DM1 (trastuzumab emtansine) after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A as a single agent against primary USC cell lines and xenografts. Methods: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability in USC primary cell lines after exposure to DHES0815A, the non-targeted ADC, the unconjugated antibody MHES0488A, and T-DM1 were evaluated using flow cytometry-based-assays. in vivo activity of these respective agents was tested against HER2/neu overexpressing USC (ARK2) xenografts. Results: High HER2/neu protein expression by IHC and C-erbB2 gene amplification by FISH was seen in 25% (3/12) of the primary USC cell lines. Primary tumor cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p Conclusions: DHES0815A as a single agent is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel and less toxic treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.

  • abstract 911 in vitro and in vivo activity of dhes0815a an antibody drug conjugate targeting her2 neu in Uterine Serous Carcinoma
    Cancer Research, 2021
    Co-Authors: Joan Tymonrosario, Stefania Bellone, Elena Bonazzoli, Paola Manara, Luca Zammataro, Silvia Pelligra, Arancha Manzano, Adele Guglielmi, Barbara Gnutti, Burak Zeybek
    Abstract:

    Objective: Uterine Serous Carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts. Methods: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts. Results: High HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p Conclusions: DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy. Citation Format: Joan Tymon R. Tymon-Rosario, Elena Bonazzoli, Stefania Bellone, Arancha Manzano, Paola Manara, Luca Zammataro, Silvia Pelligra, Adele Guglielmi, Barbara Gnutti, Burak Zeybek, Justin Harold, Dennis Mauricio, Elena Ratner, Peter Schwartz, Alessandro D. Santin. In vitro and in vivo activity of DHES0815A, an antibody-drug conjugate targeting HER2/neu in Uterine Serous Carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 911.

  • selection of her2 neu negative tumor cells as a mechanism of resistance to trastuzumab in Uterine Serous Carcinoma
    Gynecologic oncology reports, 2020
    Co-Authors: Silvia Pelligra, Natalia Buza, Stefania Bellone, Peter E. Schwartz, Pei Hui, Elena Ratner, Burak Zeybek, Giovanni Scambia, Alessandro D. Santin
    Abstract:

    Abstract Background Uterine Serous Carcinoma (USC) is an aggressive variant of endometrial cancer overexpressing HER2/neu in about 30% of cases. Trastuzumab, a humanized monoclonal antibody targeting Her2/Neu, in combination with carboplatin/paclitaxel, is considered the preferred regimen for the treatment of advanced or recurrent HER2/Neu+ USC per NCCN guidelines. Case We describe two USC patients with overexpression of HER2/neu at 2+/3+ level by immunohistochemistry and c-erbB2 gene amplification by fluorescence in situ hybridization (FISH) assay that, after an initial clinical response to trastuzumab, developed resistance/progression. Post-treatment biopsy (collected at the time of clinical progression on trastuzumab) demonstrated loss of HER2/neu overexpression in the recurrent/progressing tumor cells in both patients. Conclusion Selection of HER2/NEU negative tumor cells may represent a major mechanism of resistance to trastuzumab in USC patients.

  • in vitro and in vivo activity of sacituzumab govitecan an antibody drug conjugate targeting trophoblast cell surface antigen 2 trop 2 in Uterine Serous Carcinoma
    Gynecologic Oncology, 2020
    Co-Authors: Chanhee Han, Stefania Bellone, Joan Tymonrosario, Burak Zeybek, Emanuele Perrone, Gulden Menderes, Gary Altwerger, Jacqueline Feinberg, Kaitlin Haines
    Abstract:

    Abstract Objective Uterine Serous Carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast cell-surface antigen 2 (Trop-2), a transmembrane-calcium-signal-transducer, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to evaluate the expression of Trop-2 in USC and the preclinical activity of SG against primary USC cell-lines and xenografts. Methods We used immunohistochemistry (IHC) and flow-cytometry-based assays to evaluate Trop-2 expression and cell-viability in USC tissue and primary tumor-cell-lines after exposure to SG, non-targeting control ADC, and naked antibody hRS7-IgG. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell-lines was evaluated in vitro using 4-hr-Chromium-release-assays. In vivo activity of SG was tested against Trop-2+ USC xenografts by intravenous administration of SG, control ADC, and hRS7. Results Trop-2 expression by IHC was detected in 95.1% of USC samples (99/104). Primary tumor cell-lines overexpressing Trop-2 were significantly more sensitive to SG when compared to control ADC (p Conclusions SG is remarkably active against USC overexpressing Trop-2 in vitro and in vivo. Our results combined with SG clinical responses recently reported against multiple chemotherapy resistant human tumors further support clinical development of SG in USC patients with advanced/recurrent disease.

  • abstract 4819 sacituzumab govitecan immu 132 in Uterine Serous Carcinoma
    Cancer Research, 2019
    Co-Authors: Salvatore Lopez, Stefania Bellone, Elena Bonazzoli, Chanhee Han, Burak Zeybek, Anna Bianchi, Paola Manara, Aranzazu Manzano, Emanuele Perrone, Luca Zammataro
    Abstract:

    Objective: Uterine Serous Carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (IMMU-132) is a novel antibody-drug conjugate (ADC) targeting trophoblast antigen 2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors including USC, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to preclinically evaluate the efficacy of IMMU-132 against primary USC cell lines and xenografts. Methods: Trop-2 expression in primary tumor cell lines and USC cell viability after exposure to IMMU-132 ADC (hRS7-CL2A-SN-38), non-targeting control ADC (h679-CL2A-SN-38), and naked antibody hRS7 IgG were evaluated using RT-PCR and flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell lines was evaluated in vitro using 4 hr Chromium release assays. Finally, in vivo activity of Sacituzumab govitecan was tested against Trop-2+ USC xenografts by 3 twice-a-week retro-orbital injection of 500 μg of IMMU-132, control-ADC, and hRS7 naked-IgG. Results: Overexpression of Trop-2 was detected in 67% (8 out of 12) of primary USC cell lines. Primary tumors overexpressing Trop-2 were significantly more sensitive (ie, lower IC50) to IMMU-132 (hRS7-CL2A-SN-38) when compared to control ADC (h679-CL2A-SN-38). Both sacituzumab govitecan (IMMU-132) and the naked antibody hRS7 induced high level of ADCC against Trop2+ USC cell lines while no cytotoxicity was detected against Trop-2 negative tumors. In vivo experiments comparing IMMU-132 activity to control ADC and hRS7 showed a dramatically improved tumor suppression and increased survival in IMMU-132 treated mice when compared to controls (P = 0.0001 and P = 0.0002, respectively). Conclusion: IMMU-132 demonstrated remarkable antitumor activity against biologically aggressive USC overexpressing Trop-2. Our preclinical results combined with the dramatic clinical response recently reported in an USC patient treated with IMMU-132 (https://doi.org/10.1016/j.gore.2018.05.009) strongly supports further clinical development of sacituzumab govitecan in USC patients with advanced/recurrent disease. (ie, clinical trial IND 140394). Furthermore, due to a cleavable linker that can cause bystander effect, sacituzumab govitecan could be also effective in tumors with heterogenous TROP-2 expression. Citation Format: Salvatore Lopez, Chanhee Han, Burak Zeybek, Elena Bonazzoli, Anna Bianchi, Paola Manara, Stefania Bellone, Aranzazu Manzano, Emanuele Perrone, Luca Zammataro, Gary Altwerger, Alessandro D. Santin. Sacituzumab Govitecan (IMMU-132) in Uterine Serous Carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4819.

Natalia Buza - One of the best experts on this subject based on the ideXlab platform.

  • minimal Uterine Serous Carcinoma and endometrial polyp a close clinicopathological relationship
    Human Pathology, 2021
    Co-Authors: Hisham Assem, Alessandro D. Santin, Natalia Buza, Elena Ratner, Douglas Rottmann, Alexander Finkelstein, Minhua Wang, Pei Hui
    Abstract:

    Summary Frequently involving an endometrial polyp, minimal Uterine Serous Carcinoma (MUSC) represents the earliest recognizable forms of endometrial Serous Carcinoma. The aim of this study was to provide a comprehensive morphological and clinical outcome assessment of MUSC involving endometrial polyp. A total of 77 fully staged MUSCs involving endometrial polyp were identified, including 53 MUSCs confined to polyp and 24 nonpolyp confined tumors. ExtraUterine disease was found in 17% (9/53) of polyp-confined MUSCs compared to 41.7% (10/24) of nonpolyp confined tumors (p = 0.02). Lymphovascular invasion was observed in 3.8% (2/53) of polyp-confined cases compared to 25% (6/24) of nonpolyp confined cases (p = 0.047). Lymph node metastasis was observed in 11.3% (6/53) of polyp-confined cases, compared to 29.2% (7/24) of nonpolyp confined cases (p = 0.058). Positive pelvic washing cytology was seen in 18.9% (10/53) of polyp-confined versus 37.5% (9/24) of nonpolyp confined tumors (p = 0.078). Overall, 58 of 77 (75.3%) patients had low tumor stage (57 stage I cases and 1 stage II case) and only two patients (3.5%) had a recurrence. In contrast, 19 of 77 (24.7%) patients had advanced stage (stage III or IV) disease and 17 (89.5%) patients had recurrence (p

  • human epidermal growth factor 2 her2 in early stage Uterine Serous Carcinoma a multi institutional cohort
    Journal of Clinical Oncology, 2020
    Co-Authors: Britt K Erickson, Natalia Buza, Omar Najjar, Maryam Shahi, Molly Klein, Michelle M Dolan, Ashley Ciminomathews, Anthony Grandelis, Paris Delaney, Joan Tymonrosario
    Abstract:

    6084Background: Uterine Serous Carcinoma (USC) is a rare and aggressive malignancy, accounting for 40% of all endometrial cancer deaths. Human Epidermal Growth Factor Receptor 2 (HER2) has emerged ...

  • selection of her2 neu negative tumor cells as a mechanism of resistance to trastuzumab in Uterine Serous Carcinoma
    Gynecologic oncology reports, 2020
    Co-Authors: Silvia Pelligra, Natalia Buza, Stefania Bellone, Peter E. Schwartz, Pei Hui, Elena Ratner, Burak Zeybek, Giovanni Scambia, Alessandro D. Santin
    Abstract:

    Abstract Background Uterine Serous Carcinoma (USC) is an aggressive variant of endometrial cancer overexpressing HER2/neu in about 30% of cases. Trastuzumab, a humanized monoclonal antibody targeting Her2/Neu, in combination with carboplatin/paclitaxel, is considered the preferred regimen for the treatment of advanced or recurrent HER2/Neu+ USC per NCCN guidelines. Case We describe two USC patients with overexpression of HER2/neu at 2+/3+ level by immunohistochemistry and c-erbB2 gene amplification by fluorescence in situ hybridization (FISH) assay that, after an initial clinical response to trastuzumab, developed resistance/progression. Post-treatment biopsy (collected at the time of clinical progression on trastuzumab) demonstrated loss of HER2/neu overexpression in the recurrent/progressing tumor cells in both patients. Conclusion Selection of HER2/NEU negative tumor cells may represent a major mechanism of resistance to trastuzumab in USC patients.

  • randomized phase ii trial of carboplatin paclitaxel versus carboplatin paclitaxel trastuzumab in Uterine Serous Carcinomas that overexpress human epidermal growth factor receptor 2 neu
    Journal of Clinical Oncology, 2018
    Co-Authors: Amanda N Fader, Natalia Buza, Pei Hui, Dana M Roque, Eric R Siegel, Osama Abdelghany, Setsuko K Chambers, Angeles Alvarez Secord, Laura J Havrilesky, David M Omalley
    Abstract:

    PurposeUterine Serous Carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of Uterine Serous Carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent Uterine Serous Carcinoma who overexpress HER2/neu.MethodsEligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests.ResultsFrom August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival–related events occurred a...

  • syd985 a novel duocarmycin based her2 targeting antibody drug conjugate shows antitumor activity in Uterine Serous Carcinoma with her2 neu expression
    Molecular Cancer Therapeutics, 2017
    Co-Authors: Gulden Menderes, Stefania Bellone, Jonathan Black, Federica Predolini, Elena Bonazzoli, Luca Zammataro, Gary Altwerger, Francesca Pettinella, Alice Masserdotti, Natalia Buza
    Abstract:

    Uterine Serous Carcinoma (USC) is an aggressive form of endometrial cancer. Up to 35% of USC may overexpress the HER2/neu oncogene at strong (i.e., 3+) levels by IHC while an additional 40% to 50% express HER2/neu at moderate (2+) or low (1+) levels. We investigated the efficacy of SYD985, (Synthon Biopharmaceuticals), a novel HER2-targeting antibody-drug conjugate (ADC) composed of the mAb trastuzumab linked to a highly potent DNA-alkylating agent (i.e., duocarmycin) in USC. We also compared the antitumor activity of SYD985 in head-to-head experiments to trastuzumab emtansine (T-DM1), a FDA-approved ADC, against multiple primary USC cell lines expressing different levels of HER2/neu in in vitro and in vivo experiments. Using antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing assays as well as propidium iodide-based flow cytometry assays and multiple in vivo USC mouse xenograft models, we demonstrate for the first time that SYD985 is a novel ADC with activity against USC with strong (3+) as well as low to moderate (i.e., 1+/2+) HER2/neu expression. SYD985 is 10- to 70-fold more potent than T-DM1 in comparative experiments and, unlike T-DM1, it is active against USC demonstrating moderate/low or heterogeneous HER2/neu expression. Clinical studies with SYD985 in patients harboring chemotherapy-resistant USC with low, moderate, and high HER2 expression are warranted. Mol Cancer Ther; 15(8); 1900-9. ©2016 AACR.

Peter E. Schwartz - One of the best experts on this subject based on the ideXlab platform.

  • stage iii Uterine Serous Carcinoma modern trends in multimodality treatment
    Journal of Gynecologic Oncology, 2020
    Co-Authors: Melissa R Young, Alessandro D. Santin, Peter E. Schwartz, Gloria S Huang, Babak Litkouhi, Shari Damast
    Abstract:

    Objective To examine outcomes in a modern treatment era for stage III Uterine Serous Carcinoma (USC). Methods Fifty women were retrospectively identified as 2009 International Federation of Gynecology and Obstetrics stage III USC patients who received radiotherapy (RT) at our institution between 1/2003-5/2018. The patients were divided into 2 cohorts: 20 in the early era (2003-2010) and 30 in the modern era (2011-2018). Patient characteristics were compared using χ² tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards. Results The modern era differed from the early era in the increased use of volume-directed external beam RT (EBRT) as opposed to vaginal brachytherapy (VB) alone (33.3% vs 5.0%, p=0.048), minimally invasive surgery (56.7% vs. 25%, p=0.027), sentinel node sampling (26.7% vs. 0%, p=0.012), computed tomography imaging in the perioperative period (63.3% vs. 30%, p=0.044), and human epidermal growth factor receptor 2/neu testing (96.7% vs. 55%, p=0.001). Median follow-up for early and modern eras was 37.27 and 33.23 months, respectively. The early vs. modern 3-year RFS was 33% and 64% (p=0.039), respectively, while the 3-year OS was 55% and 90% (p=0.034). Regional nodal recurrence more common among the patients who received VB only (p=0.048). Conclusion Modern era treatment was associated with improved RFS and OS in patients with stage III USC. Regional nodal recurrences were significantly reduced in patients who received EBRT.

  • selection of her2 neu negative tumor cells as a mechanism of resistance to trastuzumab in Uterine Serous Carcinoma
    Gynecologic oncology reports, 2020
    Co-Authors: Silvia Pelligra, Natalia Buza, Stefania Bellone, Peter E. Schwartz, Pei Hui, Elena Ratner, Burak Zeybek, Giovanni Scambia, Alessandro D. Santin
    Abstract:

    Abstract Background Uterine Serous Carcinoma (USC) is an aggressive variant of endometrial cancer overexpressing HER2/neu in about 30% of cases. Trastuzumab, a humanized monoclonal antibody targeting Her2/Neu, in combination with carboplatin/paclitaxel, is considered the preferred regimen for the treatment of advanced or recurrent HER2/Neu+ USC per NCCN guidelines. Case We describe two USC patients with overexpression of HER2/neu at 2+/3+ level by immunohistochemistry and c-erbB2 gene amplification by fluorescence in situ hybridization (FISH) assay that, after an initial clinical response to trastuzumab, developed resistance/progression. Post-treatment biopsy (collected at the time of clinical progression on trastuzumab) demonstrated loss of HER2/neu overexpression in the recurrent/progressing tumor cells in both patients. Conclusion Selection of HER2/NEU negative tumor cells may represent a major mechanism of resistance to trastuzumab in USC patients.

  • mechanisms of resistance to her2 targeted therapies in her2 amplified Uterine Serous Carcinoma and strategies to overcome it
    Discovery Medicine, 2018
    Co-Authors: Gulden Menderes, Peter E. Schwartz, Salvatore Lopez, Chanhee Han, Gary Altwerger, Stepan Gysler, Joyce Varughese, Alessandro D. Santin
    Abstract:

    Uterine Serous Carcinoma (USC) is an aggressive subtype of endometrial cancer that accounts for up to 40% of all endometrial cancer-related deaths. Recent whole-exome sequencing studies have revealed HER2/neu amplification in 27-44% of USC patients, supporting HER2 as an attractive pathway for target therapies based on monoclonal antibodies or tyrosine kinase inhibitors. Preclinical studies and a recently published prospective randomized trial with trastuzumab in combination with chemotherapy demonstrated promising results with anti-HER2-targeted therapies in advanced and recurrent USC patients. In contrast, single-agent trastuzumab or tyrosine kinase inhibitors (i.e., lapatinib) were unable to demonstrate significant clinical activity and/or durable tumor growth inhibition. Combinatorial therapies may represent novel, highly effective therapeutic strategies to overcome inborn or acquired resistance to HER2/neu-targeted therapies in HER2-amplified USC patients. This study presents a comprehensive review of the mechanisms of USC resistance to HER2-targeted therapies and potential strategies to overcome it.

  • sacituzumab govitecan immu 132 in treatment resistant Uterine Serous Carcinoma a case report
    Gynecologic oncology reports, 2018
    Co-Authors: Chanhee Han, Stefania Bellone, Peter E. Schwartz, Serengulam V. Govindan, Robert M. Sharkey, David M. Goldenberg, Alessandro D. Santin
    Abstract:

    Abstract Background Uterine Serous Carcinoma (USC) is a biologically aggressive variant of Uterine cancer. Effective treatment options for recurrent, chemotherapy-resistant USC are extremely limited. Case We describe a 74-year-old woman with recurrent and widespread treatment-resistant disease, who experienced a dramatic response to sacituzumab govitecan, a novel antibody-drug conjugate (ADC) targeting human trophoblast-cell-surface antigen (TROP-2), after failing multiple chemotherapy and immunotherapy. The impressive clinical response (66% reduction of target lesions by RECIST 1.1 with a duration response of over 10 months) was confirmed with serial CT scans in the absence of significant adverse events. Conclusion Sacituzumab govitecan may present a new treatment option for recurrent USC patients harboring Trop-2+ tumors resistant to chemotherapy. Clinical trials with sacituzumab govitecan are warranted.

  • Sacituzumab Govitecan (IMMU-132) in treatment-resistant Uterine Serous Carcinoma: A case report
    'Elsevier BV', 2018
    Co-Authors: Chanhee Han, Stefania Bellone, Peter E. Schwartz, Serengulam V. Govindan, Robert M. Sharkey, David M. Goldenberg, Alessandro D. Santin
    Abstract:

    Background: Uterine Serous Carcinoma (USC) is a biologically aggressive variant of Uterine cancer. Effective treatment options for recurrent, chemotherapy-resistant USC are extremely limited. Case: We describe a 74-year-old woman with recurrent and widespread treatment-resistant disease, who experienced a dramatic response to sacituzumab govitecan, a novel antibody-drug conjugate (ADC) targeting human trophoblast-cell-surface antigen (TROP-2), after failing multiple chemotherapy and immunotherapy. The impressive clinical response (66% reduction of target lesions by RECIST 1.1 with a duration response of over 10 months) was confirmed with serial CT scans in the absence of significant adverse events. Conclusion: Sacituzumab govitecan may present a new treatment option for recurrent USC patients harboring Trop-2+ tumors resistant to chemotherapy. Clinical trials with sacituzumab govitecan are warranted. Keywords: Sacituzumab govitecan, IMMU-132, Uterine Serous Carcinoma, Recurrent, Treatment-resistan

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  • abstract 4819 sacituzumab govitecan immu 132 in Uterine Serous Carcinoma
    Cancer Research, 2019
    Co-Authors: Salvatore Lopez, Stefania Bellone, Elena Bonazzoli, Chanhee Han, Burak Zeybek, Anna Bianchi, Paola Manara, Aranzazu Manzano, Emanuele Perrone, Luca Zammataro
    Abstract:

    Objective: Uterine Serous Carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (IMMU-132) is a novel antibody-drug conjugate (ADC) targeting trophoblast antigen 2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors including USC, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to preclinically evaluate the efficacy of IMMU-132 against primary USC cell lines and xenografts. Methods: Trop-2 expression in primary tumor cell lines and USC cell viability after exposure to IMMU-132 ADC (hRS7-CL2A-SN-38), non-targeting control ADC (h679-CL2A-SN-38), and naked antibody hRS7 IgG were evaluated using RT-PCR and flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell lines was evaluated in vitro using 4 hr Chromium release assays. Finally, in vivo activity of Sacituzumab govitecan was tested against Trop-2+ USC xenografts by 3 twice-a-week retro-orbital injection of 500 μg of IMMU-132, control-ADC, and hRS7 naked-IgG. Results: Overexpression of Trop-2 was detected in 67% (8 out of 12) of primary USC cell lines. Primary tumors overexpressing Trop-2 were significantly more sensitive (ie, lower IC50) to IMMU-132 (hRS7-CL2A-SN-38) when compared to control ADC (h679-CL2A-SN-38). Both sacituzumab govitecan (IMMU-132) and the naked antibody hRS7 induced high level of ADCC against Trop2+ USC cell lines while no cytotoxicity was detected against Trop-2 negative tumors. In vivo experiments comparing IMMU-132 activity to control ADC and hRS7 showed a dramatically improved tumor suppression and increased survival in IMMU-132 treated mice when compared to controls (P = 0.0001 and P = 0.0002, respectively). Conclusion: IMMU-132 demonstrated remarkable antitumor activity against biologically aggressive USC overexpressing Trop-2. Our preclinical results combined with the dramatic clinical response recently reported in an USC patient treated with IMMU-132 (https://doi.org/10.1016/j.gore.2018.05.009) strongly supports further clinical development of sacituzumab govitecan in USC patients with advanced/recurrent disease. (ie, clinical trial IND 140394). Furthermore, due to a cleavable linker that can cause bystander effect, sacituzumab govitecan could be also effective in tumors with heterogenous TROP-2 expression. Citation Format: Salvatore Lopez, Chanhee Han, Burak Zeybek, Elena Bonazzoli, Anna Bianchi, Paola Manara, Stefania Bellone, Aranzazu Manzano, Emanuele Perrone, Luca Zammataro, Gary Altwerger, Alessandro D. Santin. Sacituzumab Govitecan (IMMU-132) in Uterine Serous Carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4819.

  • mechanisms of resistance to her2 targeted therapies in her2 amplified Uterine Serous Carcinoma and strategies to overcome it
    Discovery Medicine, 2018
    Co-Authors: Gulden Menderes, Peter E. Schwartz, Salvatore Lopez, Chanhee Han, Gary Altwerger, Stepan Gysler, Joyce Varughese, Alessandro D. Santin
    Abstract:

    Uterine Serous Carcinoma (USC) is an aggressive subtype of endometrial cancer that accounts for up to 40% of all endometrial cancer-related deaths. Recent whole-exome sequencing studies have revealed HER2/neu amplification in 27-44% of USC patients, supporting HER2 as an attractive pathway for target therapies based on monoclonal antibodies or tyrosine kinase inhibitors. Preclinical studies and a recently published prospective randomized trial with trastuzumab in combination with chemotherapy demonstrated promising results with anti-HER2-targeted therapies in advanced and recurrent USC patients. In contrast, single-agent trastuzumab or tyrosine kinase inhibitors (i.e., lapatinib) were unable to demonstrate significant clinical activity and/or durable tumor growth inhibition. Combinatorial therapies may represent novel, highly effective therapeutic strategies to overcome inborn or acquired resistance to HER2/neu-targeted therapies in HER2-amplified USC patients. This study presents a comprehensive review of the mechanisms of USC resistance to HER2-targeted therapies and potential strategies to overcome it.

  • dual her2 pik3ca targeting overcomes single agent acquired resistance in her2 amplified Uterine Serous Carcinoma cell lines in vitro and in vivo
    Molecular Cancer Therapeutics, 2015
    Co-Authors: Salvatore Lopez, Stefania Bellone, Emiliano Cocco, Carlton L. Schwab, Diana P. English, Jonathan Black, Federica Predolini, Elena Bonazzoli, Francesca Ferrari, Elena Ratner
    Abstract:

    HER2/neu gene amplification and PIK3CA driver mutations are common in Uterine Serous Carcinoma (USC) and may represent ideal therapeutic targets against this aggressive variant of endometrial cancer. We examined the sensitivity to neratinib, taselisib, and the combination of the two compounds in in vitro and in vivo experiments using PIK3CA-mutated and PIK3CA wild-type HER2/neu-amplified USC cell lines. Cell viability and cell-cycle distribution were assessed using flow-cytometry assays. Downstream signaling was assessed by immunoblotting. Preclinical efficacy of single versus dual inhibition was evaluated in vivo using two USC xenografts. We found both single-agent neratinib and taselisib to be active but only transiently effective in controlling the in vivo growth of USC xenografts harboring HER2/neu gene amplification with or without oncogenic PIK3CA mutations. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in both USC xenografts when compared with single-agent therapy. Combined targeting of HER2 and PIK3CA was associated with a significant and dose-dependent increase in the percentage of cells in the G0-G1 phase of the cell cycle and a dose-dependent decline in the phosphorylation of S6. Importantly, dual inhibition therapy initiated after tumor progression in single-agent-treated mice was still remarkably effective at inducing tumor regression in both large PIK3CA and pan-ErbB inhibitor-resistant USC xenografts. Dual HER2/PIK3CA blockade may represent a novel therapeutic option for USC patients harboring tumors with HER2/neu gene amplification and mutated or wild-type PIK3CA resistant to chemotherapy.

  • dacomitinib pf 00299804 a second generation irreversible pan erbb receptor tyrosine kinase inhibitor demonstrates remarkable activity against her2 amplified Uterine Serous endometrial cancer in vitro
    Tumor Biology, 2015
    Co-Authors: Liancheng Zhu, Stefania Bellone, Emiliano Cocco, Salvatore Lopez, Jonathan Black, Tiffany Zigras, Federica Predolini, Elena Bonazzoli, Beatrice Bussi
    Abstract:

    Uterine Serous Carcinoma (USC) is an aggressive subtype of endometrial cancer that carries an extremely poor prognosis. Up to 35 % of USC may overexpress the epidermal growth factor receptor-2 (HER2/neu) at strong (i.e., 3+) level by immunohistochemistry (IHC) or harbor HER2/neu gene amplification by fluorescence in situ hybridization (FISH). In this study, we assessed the sensitivity of a panel of USC cell lines with and without HER2/neu gene amplification to dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor tyrosine kinase inhibitor. Eight primary cell lines (i.e., four harboring HER2/neu gene amplification by FISH and four FISH- cell lines), all demonstrating similar in vitro growth rates, were evaluated in viability/proliferation assays. The effect of dacomitinib on cell growth, cell cycle distribution, and signaling was determined using flow cytometry-based assays. Dacomitinib caused a significantly stronger growth inhibition in HER2/neu FISH+ USC cell lines when compared to FISH- USC (dacomitinib half maximal inhibitory concentration (IC50) mean ± SEM = 0.02803 ± 0.003355 μM in FISH+ versus 1.498 ± 0.2209 μM in FISH- tumors, P < 0.0001). Dacomitinib growth inhibition was associated with a significant and dose-dependent decline in phosphorylated HER2/neu and S6 transcription factor and a dose-dependent and time-dependent cell cycle arrest in G0/G1 in FISH+ USC. Dacomitinib is remarkably effective against chemotherapy-resistant HER2/neu gene-amplified USC. Clinical studies with dacomitinib in HER2/neu FISH+ USC patients resistant to standard salvage chemotherapy are warranted.

  • neratinib shows efficacy in the treatment of her2 neu amplified Uterine Serous Carcinoma in vitro and in vivo
    Gynecologic Oncology, 2014
    Co-Authors: Carlton L. Schwab, Stefania Bellone, Peter E. Schwartz, Dana M Roque, Emiliano Cocco, Diana P. English, Salvatore Lopez, Roberta Nicoletti, Thomas J. Rutherford, Alessandro D. Santin
    Abstract:

    Abstract Objectives Uterine Serous Carcinoma (USC) represents an aggressive variant of endometrial cancer and accounts for a large proportion of deaths annually. HER2/neu amplification is associated with USC in approximately 30–35% of cases. The objective of this study was to determine the sensitivity of a panel of primary USC cell lines to the small tyrosine kinase inhibitor neratinib, an ErbB1 and HER2 inhibitor, both in vitro and in vivo . Methods HER2/neu amplification was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in 24 USC cell lines. Flow cytometry was used to determine the effects of neratinib on cell viability, cell cycle distribution and signaling in vitro . Mice harboring HER2/neu amplified xenografts were treated with neratinib to assess the efficacy of the drug in vivo . Results HER2/neu amplification was noted in 8/24 primary cell lines. Data regarding the efficacy of neratinib was determined using 4 HER2 amplified cell lines and 4 non-amplified cell lines with similar growth rates. Data revealed that cell lines with HER2/neu amplification were exquisitely more sensitive to neratinib compared to non-amplified cell lines (mean±SEM IC 50 : 0.011μM±0.0008 vs. 0.312μM±0.0456 p p =0.0019). Conclusions Neratinib may be a potential treatment option for patients harboring HER2/neu amplified USC. Clinical trials for this subset of endometrial cancer patients are warranted.

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