Bio

Bio


Dr. Diana P. English is a Gynecologic Oncologist at Stanford Hospital and Clinics. Dr. English received her medical school training at The University of the West Indies, Mona Campus, Jamaica where she graduated with honors. After graduating from medical school in 2005, she then worked as an intern followed by working as a medical officer in Jamaica for 2 years before starting residency in Obstetrics and Gynecology at University of Miami/Jackson Memorial Hospital in Florida. After completing residency, she began fellowship training in Gynecologic Oncology at Yale University in 2012. Following her fellowship, Dr. English joined the Gynecologic Oncology team at Stanford Hospital and Clinics.
Dr. English has shown herself to be a dedicated researcher and has several original research papers related to targeted therapeutic approaches to uterine serous cancer, health disparity research and research on novel treatment approaches to ovarian cancer. Her publications have been in several high impact journals.

She also has a strong interest in palliative medicine/supportive care for patients with chronic medical conditions and is pursuing a fellowship in palliative medicine. Dr. English has been involved in international service particularly medical mission trips to developing countries.

Her main interests include

•Cancer prevention strategies
•Uterine cancer
•Cervical cancer
•Ovarian cancer
•Health disparities in gynecologic oncology



Outside of work, Dr. English maintains an avid interest in playing and watching sport and reading poetry when the time allows.

Clinical Focus


  • Gynecologic Oncology
  • Palliative Medicine
  • Fellow

Academic Appointments


Professional Education


  • Board Certification, American Board of Obstetrics and Gynecology, Obstetrics and Gynecology (2016)

Research & Scholarship

Clinical Trials


  • Health and Recovery Program in Increasing Physical Activity Level in Stage IA-IIIA Endometrial Cancer Survivors Recruiting

    This randomized phase II trial studies how well a health and recovery program works in increasing physical activity level in stage IA-IIIA endometrial cancer survivors. Health and recovery program which includes exercise counseling, Fitbit tracker, and phone or email/text communication may increase the level of physical activity in endometrial cancer survivors and promote and maintain behavior change at a lower cost.

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  • Study of DPX-Survivac Therapy in Patients With Recurrent Ovarian Cancer Recruiting

    T cell activating therapy DPX-Survivac, low dose oral cyclophosphamide, and IDO1 inhibitor epacadostat will be tested together for the first time in patients with recurrent ovarian, fallopian tube, or peritoneal cancer to determine the safety and potential immune-modulating activity of the combination of these agents.

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  • Safety and Efficacy of CRS-207 With Epacadostat in Platinum Resistant Ovarian, Fallopian or Peritoneal Cancer Not Recruiting

    This 2-part, Phase 1/2 study will test investigational cancer drugs known as CRS-207, epacadostat (IDO), and pembrolizumab (pembro). The purpose of this study is to find out how safe it is to give the investigational drugs to women with platinum-resistant ovarian, fallopian tube, or peritoneal cancer and if it helps patients with these types of cancer live longer or can help shrink or slow the growth of cancer.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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Publications

All Publications


  • Sentinel lymph node biopsies in endometrial cancer - practice patterns among Gynecologic Oncologists in the United States. Journal of minimally invasive gynecology Renz, M., Diver, E., English, D., Kidd, E., Dorigo, O., Karam, A. 2019

    Abstract

    To evaluate practice patterns among gynecologic oncologists with regards to sentinel lymph node injection and biopsy in endometrial cancer.Observational study with no control group.Active members of the Society of Gynecologic Oncology.After IRB approval, we performed an online survey amongst active members of the Society of Gynecologic Oncology. Members were contacted via email and their answers anonymously captured. Study data were collected using REDCap.318 of 1216 listed members completed the online survey, The majority of respondents (82.7%) perform sentinel lymph node sampling for endometrial cancer staging. Most technical aspects of sentinel lymph node sampling were consistently applied by the vast majority of respondents, including the choice of indocyanine green (ICG) as lymphatic tracer (97.3%) and its injection into the cervix (100%). Other technical aspects of sentinel lymph node sampling, such as the depth of injection, varied amongst respondents. While 50.9% of the respondents perform an intraoperative assessment of the uterus by frozen section, only 17.9% assess sentinel lymph nodes by frozen section and/or touch prep. Some of the respondents' approaches are based on limited data, including (i) the use of sentinel lymph node injection and biopsy for high-risk histologies (performed by 69 - 75% of the respondents dependent upon the histology), (ii) omitting side-specific completion lymphadenectomy in the absence of sentinel node mapping (in up to 57.8%) or (iii) when lymph node metastases are present (in 39.9%).In summary, despite the growing use of sentinel lymph node injection and biopsy in endometrial cancer, practice patterns vary considerably among providers sampled by this survey. Some of the decisions are based on limited evidence and, in some instances, deviate from current published guidelines.

    View details for PubMedID 30980995

  • National patterns of care and cancer-specific outcomes of adjuvant treatment in patients with serous and clear cell endometrial carcinoma. Gynecologic oncology Xiang, M., English, D. P., Kidd, E. A. 2018

    Abstract

    OBJECTIVES: To investigate outcomes of adjuvant therapy for serous and clear cell endometrial carcinoma, as prior studies are limited by sample size and/or patient heterogeneity. National guidelines permit substantial variations in treatment, suggesting the need for additional data.METHODS: Patients with FIGO stages I-III serous or clear cell uterine carcinoma who underwent at least total hysterectomy were identified in SEER-Medicare. Adjuvant external beam radiation, brachytherapy, and chemotherapy were determined using SEER fields and Medicare claims. The primary outcome was death from endometrial cancer (cancer-specific mortality [CSM]) evaluated using Gray's test (univariable analysis, UVA) and Fine-Gray regression (multivariable analysis, MVA).RESULTS: A total of 1789 patients (1437 serous, 352 clear cell) were identified. In stages I-II patients (n = 1188), brachytherapy was significant for survival in UVA (P = 0.03) and MVA (P = 0.02). Additionally, in the subset with serous histology (n = 947), chemotherapy was also significant in UVA (P = 0.002) and approached significance in MVA (P = 0.05). The 4-year CSM for stages I-II serous cancers was 25% without brachytherapy or chemotherapy, 15% with one, and 9% with both (P ≤ 0.05 for all pairwise comparisons). In stage III patients (n = 601), chemotherapy was significant in UVA (P = 0.002) and MVA (P = 0.006). Most (81%) patients underwent lymph node dissection, which predicted lower CSM in stage III (P = 0.001) but not stages I-II patients.CONCLUSIONS: Our results suggest brachytherapy benefits stages I-II serous/clear cell cancers, chemotherapy benefits stage III serous/clear cell cancers, and both chemotherapy and brachytherapy benefit stages I-II serous cancers.

    View details for PubMedID 30551884

  • Palliative Total Pelvic Exenteration for Gynecologic Cancers: A Cross-sectional Study of Society of Gynecologic Oncology Members. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society MacLaughlan David, S., Marjon, N., English, D., Purington, N., Han, S. S., Dizon, D. S. 2018; 28 (9): 1796–1804

    Abstract

    OBJECTIVE: The aim of this study was to evaluate contemporary practices and opinions among gynecologic oncologists regarding the use of total pelvic exenteration (TPE) for palliative intent.METHODS: This cross-sectional study of the membership of the Society of Gynecologic Oncology utilized an electronic survey to assess the opinions and practice patterns of gynecologic oncologists regarding TPEs. The primary outcome was willingness to consider a TPE for palliative intent, and demographic and practice characteristics were collected for correlation. Qualitative data were also collected. Descriptive statistics are presented, and chi tests, Fisher exact tests, and logistic regression analyses were used.RESULTS: We included 315 surveys for analysis, for a completed response rate of 23.5%. Approximately half (52.4%, n = 165) of respondents indicated willingness to consider palliative TPE. When controlled for all variables, gynecologic oncologists who were more than 10 years out of fellowship were less likely to perform a palliative exenteration (odds ratio, 0.55; 95% confidence interval, 0.30-0.98), whereas those who reported experience with minimally invasive exenteration were more likely to offer it for palliation (odds ratio, 2.20; 95% confidence interval, 1.07-4.73). Fifty-three respondents (16.8%) provided qualitative data. The themes that emerged as considerations for TPE as palliation were (1) symptoms and quality of life, (2) surgical and perioperative morbidity, (3) anticipated overall survival, (4) counseling and informed consent, (5) functional status and comorbidities, (6) likelihood of residual disease, and (7) alternative procedures available for palliation.CONCLUSION: Half of gynecologic oncologists seem to be willing to offer a palliative TPE, although more-experienced gynecologic oncologists are more likely to reserve the procedure for curative intent.

    View details for DOI 10.1097/IGC.0000000000001371

    View details for PubMedID 30371565

  • Racial disparities in outcomes for high-grade uterine cancer: A California cancer registry study. Cancer medicine Baskovic, M., Lichtensztajn, D. Y., Nguyen, T., Karam, A., English, D. P. 2018

    Abstract

    BACKGROUND: Endometrial cancer (EC) is the most common gynecologic malignancy. We examined factors affecting overall prognosis and survival among different racial groups diagnosed with high-grade EC.METHODS: We utilized the California Cancer Registry database (CCR) to identify women with high-grade II EC from 1998 to 2009. Using the Kaplan-Meier method, we described disease-specific survival. Survival by stage, race, and time to treatment category was compared using the log-rank test. The associations of race with disease-specific survival were modeled using Cox proportional hazards regression. Covariates were selected a priori.RESULTS: A total of 10647 patients met study eligibility criteria. The majority of patients in this cohort of high-grade EC were non-Hispanic (NH) white (64.1%), followed by Hispanic (15.7%), Asian (10.4%), and NH black (9.8%). NH black women had higher incidence of certain aggressive histologic subtypes in comparison with NH whites, including serous carcinomas and carcinosarcoma. Non-Hispanic black patients had a worse 5-year disease-specific survival (DSS) when compared to other racial groups. The five-year DSS for NH black women was 54% (51%-57%), compared to NH white women 66% (65%-67%), Hispanic 67% (64%-69%), and Asians 69% (67%-72%) (P<0.0001). This clear survival disadvantage of NH black women persisted when controlling for other factors.CONCLUSIONS: Non-Hispanic black women have a higher incidence of more aggressive histologic subtypes even among a cohort of women high-grade EC and have a disproportionately worse disease-specific survival after controlling for factors such as age, histologic subtype, stage, time to treatment, and type of treatment.

    View details for DOI 10.1002/cam4.1742

    View details for PubMedID 30123978

  • Case of Metastatic Extramammary Paget Disease of the Vulva Treated Successfully With Trastuzumab Emtansine JCO PRECISION ONCOLOGY Hsieh, G. L., English, D. P., Tu, P., Folkins, A. K., Karam, A. K. 2018; 2
  • Platinum desensitization in patients with carboplatin hypersensitivity: A single-institution retrospective study GYNECOLOGIC ONCOLOGY Altwerger, G., Gressel, G. M., English, D. P., Nelson, W. K., Carusillo, N., Silasi, D., Azodi, M., Santin, A., Schwartz, P. E., Ratner, E. S. 2017; 144 (1): 77–82

    Abstract

    The carboplatin desensitization (CD) protocol presented here allows patients with either a positive skin test or a prior hypersensitivity reaction (HSR) to safely, rapidly and effectively continue with carboplatin infusions. Newly described factors can identify patients at risk for developing adverse events during CD.A retrospective review was performed on patients with gynecologic cancer who underwent CD between 2005 and 2014. The CD protocol uses a four-step dilution process over 3.5h.129 patients underwent CD and completed a total of 788cycles. The desensitization protocol prevented HSRs in 96% (753 out of 788) of these cycles. Patients achieved an average of 6.1cycles (SD±4.55, range 0-23) with CD. The CD protocol allowed 73% (94 of 129) of the patients to undergo carboplatin infusion without reaction. Patients with moderate to life-threatening HSRs (grade 2 through 4) were 10.5years younger at initial CD than patients with grades 0 or 1 HSRs (52.3 vs. 63, P = 0.0307). One patient death occurred during her thirteenth desensitization cycle. The HSR in this case was complicated by pre-exisiting pulmonary hypertension.This is the largest study of its kind showing a safe, effective and rapid (3.5h) CD protocol. The majority of patients with a history of either carboplatin hypersensitivity reaction or a positive skin test completed the CD protocol without HSRs. Age was identified as a risk factor for HSR severity during CD. Age can be employed along with pre-load dependent cardiac conditions as a way to help risk stratify patients undergoing CD.

    View details for DOI 10.1016/j.ygyno.2016.09.027

    View details for Web of Science ID 000392367000015

    View details for PubMedID 27789084

  • Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhao, S., Bellone, S., Lopez, S., Thakral, D., Schwab, C., English, D. P., Black, J., Cocco, E., Choi, J., Zammataro, L., Predolini, F., Bonazzoli, E., Bi, M., Buza, N., Hui, P., Wong, S., Abu-Khalaf, M., Ravaggi, A., Bignotti, E., Bandiera, E., Romani, C., Todeschini, P., Tassi, R., Zanotti, L., Odicino, F., Pecorelli, S., Donzelli, C., Ardighieri, L., Facchetti, F., Falchetti, M., Silasi, D., Ratner, E., Azodi, M., Schwartz, P. E., Mane, S., Angioli, R., Terranova, C., Quick, C., Edraki, B., Bilguvar, K., Lee, M., Choi, M., Stiegler, A. L., Boggon, T. J., Schlessinger, J., Lifton, R. P., Santin, A. D. 2016; 113 (43): 12238–43

    Abstract

    Carcinosarcomas (CSs) of the uterus and ovary are highly aggressive neoplasms containing both carcinomatous and sarcomatous elements. We analyzed the mutational landscape of 68 uterine and ovarian CSs by whole-exome sequencing. We also performed multiregion whole-exome sequencing comprising two carcinoma and sarcoma samples from six tumors to resolve their evolutionary histories. The results demonstrated that carcinomatous and sarcomatous elements derive from a common precursor having mutations typical of carcinomas. In addition to mutations in cancer genes previously identified in uterine and ovarian carcinomas such as TP53, PIK3CA, PPP2R1A, KRAS, PTEN, CHD4, and BCOR, we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes. We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex) and frequent amplification of chromosome segments containing the genes PIK3CA, TERT, and MYC Stable transgenic expression of H2A and H2B in a uterine serous carcinoma cell line demonstrated that mutant, but not wild-type, histones increased expression of markers of epithelial-mesenchymal transition (EMT) as well as tumor migratory and invasive properties, suggesting a role in sarcomatous transformation. Comparison of the phylogenetic relationships of carcinomatous and sarcomatous elements of the same tumors demonstrated separate lineages leading to these two components. These findings define the genetic landscape of CSs and suggest therapeutic targets for these highly aggressive neoplasms.

    View details for DOI 10.1073/pnas.1614120113

    View details for Web of Science ID 000386087100072

    View details for PubMedID 27791010

    View details for PubMedCentralID PMC5087050

  • Molecular diagnosis and molecular profiling to detect treatment-resistant ovarian cancer. Expert review of molecular diagnostics English, D. P., Menderes, G., Black, J., Schwab, C. L., Santin, A. D. 2016; 16 (7): 769-782

    Abstract

    Epithelial ovarian cancer remains the gynecologic tumor with the highest rate of recurrence after initial optimal cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, with the development of recurrent ovarian cancer often comes the discovery of chemo-resistant disease. The absence of improvement in long term survival, notwithstanding the use of newer agents as is seen in other cancers, emphasizes the need for improved understanding of the processes that lead to chemo-resistant disease.This review will cover the following topics: 1. Molecular and cellular mechanisms in platinum and paclitaxel resistance 2. Other molecular mediators of chemo-resistance 3. Expression of stem cell markers in ovarian cancer and relationship to chemo-resistance 4. MicroRNA and long non-coding RNA expression in chemo-resistant ovarian cancer 5. Determination of chromosomal aberrations as markers of chemo-resistance 6. Molecular profiling in chemo-resistant disease. A standard MEDLINE search was performed using the key words; ovarian cancer, chemo-resistant disease, molecular profiling, cancer stem cells and chemotherapy. Expert Commentary: Over the next few years the challenge remains to precisely determine the mechanisms responsible for the onset and maintenance of chemo-resistance and to effectively target these mechanisms.

    View details for DOI 10.1080/14737159.2016.1188692

    View details for PubMedID 27169329

  • An update on the current pharmacotherapy for endometrial cancer EXPERT OPINION ON PHARMACOTHERAPY de Haydu, C., Black, J. D., Schwab, C. L., English, D. P., Santin, A. D. 2016; 17 (4): 489-499

    Abstract

    Endometrial cancer (EC) is the most common gynecologic malignancy in the developed world and is increasing in incidence. While the mainstay of treatment for EC is surgery followed by chemotherapy and/or radiation therapy, the available pharmacotherapies are rapidly and constantly evolving. Understanding these new therapies is an important part of the research and clinical care of women with EC. A review of available literature from MEDLINE (1879-2015) was conducted for the historic treatments and current therapies available for endometrial tumors.This article reviews the current conventional therapies and discusses novel therapeutic agents, some of which are available to clinicians while others are currently being investigated in the preclinical setting.Genomic and immunohistochemical characterization of endometrial cancer may soon be the best approach for the identification of aggressive forms of tumor. Targeted therapies will soon be standard in the management of endometrial cancer.

    View details for DOI 10.1517/14656566.2016.1127351

    View details for Web of Science ID 000370758500002

    View details for PubMedID 26629895

  • Challenging Case of Postmenopausal Bleeding and Complete Urogenital Duplication. The American journal of case reports Grechukhina, O., English, D. P., Miller, D., Ratner, E. 2016; 17: 331-336

    Abstract

    Müllerian duct anomalies represent a wide spectrum of congenital abnormalities ranging from simple uterine anomalies to more complex multisystem derangements. Complete duplication of uterus, cervix, and vagina may be associated with urologic and caudal gastrointestinal malformations.We present a case report detailing the management of a morbidly obese patient with postmenopausal bleeding and thickened endometrial stripe who had a very rare condition of pelvic organ duplication, including 2 hemiuteri, 2 vaginas, 2 hemibladders, and 2 each of ovaries, fallopian tubes, kidneys, and ureters. Laparoscopic hysterectomy was complicated by difficulties understanding urinary system anatomy requiring intraoperative urology consultation and imaging.Management of patients with urogenital duplication and abnormal uterine bleeding requires a thorough understanding of possible associated malformations. Thorough preoperative evaluation, careful surgical exploration, and multidisciplinary approach may be necessary to avoid urologic injury in such patients.

    View details for PubMedID 27180733

    View details for PubMedCentralID PMC4913742

  • Solitomab, an EpCAM/CD3 bispecific antibody construct (BiTE), is highly active against primary uterine serous papillary carcinoma cell lines in vitro AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Bellone, S., Black, J., English, D. P., Schwab, C. L., Lopez, S., Cocco, E., Bonazzoli, E., Predolini, F., Ferrari, F., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Santin, A. D. 2016; 214 (1): 99.e1–8

    Abstract

    Uterine serous carcinoma is an aggressive form of endometrial cancer that carries an extremely poor prognosis. Solitomab is a novel bispecific single-chain antibody construct that targets epithelial cell adhesion molecule on tumor cells and also contains a CD3 binding region. We evaluated the expression levels of epithelial cell adhesion molecule and the in vitro activity of solitomab against primary uterine serous carcinoma cell lines in vitro and ex-vivo in the ascites of patients with uterine serous carcinoma.The purpose of this study was to determine the frequency of expression of epithelial cell adhesion molecule on uterine serous carcinoma cell lines and the ability of solitomab to modulate immune responses (T-cell proliferation, activation, cytokine production, and tumor killing) to tumor cells when it is combined with lymphocytes and epithelial cell adhesion molecule-positive cell lines or epithelial cell adhesion molecule-positive ascitic fluid in vitro.Epithelial cell adhesion molecule expression was evaluated by flow cytometry in a total of 14 primary uterine serous carcinoma cell lines. Sensitivity to solitomab-dependent cellular-cytotoxicity was tested against a panel of primary uterine serous carcinoma cell lines that express different levels of epithelial cell adhesion molecule in standard 4-hour chromium release assays. The proliferative activity, activation, cytokine secretion (ie, type I vs type II), and cytotoxicity of solitomab in autologous tumor-associated T cells in the ascitic fluid of patients with uterine serous carcinoma was also evaluated by carboxyfluorescein succinimidyl ester and flow-cytometry assays. Differences in epithelial cell adhesion molecule expression, solitomab-dependent cellular-cytotoxicity levels were analyzed with the use of an unpaired t test. T-cell activation marker increase and cytokine release were analyzed by a paired t test.Surface expression of epithelial cell adhesion molecule was found in 85.7% (12 of 14) of the uterine serous carcinoma cell lines that were tested by flow cytometry. Epithelial cell adhesion molecule-positive cell lines were found resistant to natural killer cells or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean killing ± standard of the mean, 2.7% ± 3.1% after incubation of epithelial cell adhesion molecule-positive cell lines with control bispecific antibody construct). In contrast, after incubation with solitomab, epithelial cell adhesion molecule-positive uterine serous carcinoma cells became highly sensitive to T-cell cytotoxicity (mean killing, 25.7% ± 4.5%; P < .0001) by peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with epithelial cell adhesion molecule that expressed malignant cells in ascites with solitomab resulted in a significant increase in T-cell proliferation in both CD4+ and CD8+ T cells, increase in T-cell activation markers (ie, CD25 and HLA-DR), and a reduction in number of viable uterine serous carcinoma cells in ascites (P < .001).Solitomab induces robust immunologic responses in vitro that result in increased T-cell activation, proliferation, production of cytokines, and direct killing of tumor cells. These findings suggest that solitomab may represent a novel, potentially effective agent for the treatment of recurrent/metastatic and/or chemo-resistant uterine serous carcinoma-overexpressing epithelial cell adhesion molecule.

    View details for DOI 10.1016/j.ajog.2015.08.011

    View details for Web of Science ID 000367093000015

    View details for PubMedID 26272866

    View details for PubMedCentralID PMC4698047

  • Chlamydia Peritonitis and Ascites Mimicking Ovarian Cancer. Case reports in obstetrics and gynecology Gojayev, A., English, D. P., Macer, M., Azodi, M. 2016; 2016: 8547173

    Abstract

    Background. Pelvic inflammatory disease (PID) rarely results in diffuse ascites. Severe adhesive disease secondary to PID may lead to the formation of inclusion cysts and even pelvic peritoneal nodularity due to postinflammatory scarring and cause an elevation of serum CA-125 levels. The constellation of these findings may mimic an ovarian neoplasm. Case. We report a case of a 22-year-old female who presented with multiple pelvic cysts and diffuse ascites due to Chlamydia trachomatis infection. The initial gynecologic exam did not reveal obvious evidence of PID; however, a positive Chlamydia trachomatis test, pathologic findings, and the exclusion of other etiologies facilitated the diagnosis. Conclusion. Chlamydia trachomatis and other infectious agents should be considered in the differential diagnosis of a young sexually active female with abdominal pain, ascites, and pelvic cystic masses. Thorough workup in such a population may reduce the number of more invasive procedures as well as unnecessary repeat surgical procedures.

    View details for PubMedID 27747116

  • 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 Lopez, S., Cocco, E., Black, J., Bellone, S., Bonazzoli, E., Predolini, F., Ferrari, F., Schwab, C. L., English, D. P., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Terranova, C., Angioli, R., Santin, A. D. 2015; 14 (11): 2519–26

    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.

    View details for DOI 10.1158/1535-7163.MCT-15-0383

    View details for Web of Science ID 000364592000011

    View details for PubMedID 26333383

    View details for PubMedCentralID PMC4636465

  • Neratinib shows efficacy in the treatment of HER2 amplified carcinosarcoma in vitro and in vivo GYNECOLOGIC ONCOLOGY Schwab, C. L., English, D. P., Black, J., Bellone, S., Lopez, S., Cocco, E., Bonazzoli, E., Bussi, B., Predolini, F., Ferrari, F., Ratner, E., Silasi, D., Azodi, M., Rutherford, T., Schwartz, P. E., Santin, A. D. 2015; 139 (1): 112–17

    Abstract

    Carcinosarcoma is a deadly gynecologic malignancy with few effective treatment options. The study of new therapies is difficult because of its rarity. The objective of this study was to determine the efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma.The efficacy of neratinib in the treatment of HER2 amplified carcinosarcoma was determined in vitro using seven primary carcinosarcoma cell lines with differential expression of HER2/neu. Data regarding IC50, cell cycle distribution, and cell signaling changes were assessed by flow cytometry. The efficacy of neratinib was determined in treating mice harboring HER2 amplified carcinosarcoma xenografts.Two of seven (28.5%) carcinosarcoma cell lines were HER2/neu amplified. HER2/neu amplified cell lines SARARK6 and SARARK9 were significantly more sensitive to neratinib than the five non-HER2/neu amplified carcinosarcoma cell lines (mean±SEM IC50:0.014μM±0.004vs.0.164μM±0.019 p=0.0003). Neratinib treatment caused a significant build up in G0/G1 phase of the cell cycle, arrest auto phosphorylation of HER2/neu and activation of S6. Neratinib inhibited tumor growth (p=0.012) and prolonged survival in mice harboring HER2 amplified carcinosarcoma xenografts (p=0.0039).Neratinib inhibits HER2 amplified carcinosarcoma proliferation, signaling, cell cycle progression and tumor growth in vitro. Neratinib inhibits HER2/neu amplified xenograft growth and improves overall survival. Clinical trials are warranted.

    View details for DOI 10.1016/j.ygyno.2015.08.002

    View details for Web of Science ID 000362928800018

    View details for PubMedID 26260909

    View details for PubMedCentralID PMC4587290

  • PIK3CA oncogenic mutations represent a major mechanism of resistance to trastuzumab in HER2/neu overexpressing uterine serous carcinomas BRITISH JOURNAL OF CANCER Black, J. D., Lopez, S., Cocco, E., Bellone, S., Altwerger, G., Schwab, C. L., English, D. P., Bonazzoli, E., Predolini, F., Ferrari, F., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Santin, A. D. 2015; 113 (7): 1020–26

    Abstract

    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.

    View details for DOI 10.1038/bjc.2015.306

    View details for Web of Science ID 000362039500005

    View details for PubMedID 26325104

    View details for PubMedCentralID PMC4651122

  • SYD985, a novel HER2-targeting antibody-drug conjugate, shows strong antitumor activity in primary USC cell lines with low (1+) and moderate (2+) HER2/Neu expression Black, J. D., Lopez, S., Cocco, E., Bellone, S., Bonazzoli, E., Schwab, C., English, D., Goedings, P., Beusker, P., van der Lee, M., Timmers, M., Dokter, W., Rutherfor, T., Schwartz, P., Santin, A. AMER ASSOC CANCER RESEARCH. 2015
  • Polymerase epsilon (POLE) ultra-mutated tumors induce robust tumor-specific CD4+T cell responses in endometrial cancer patients GYNECOLOGIC ONCOLOGY Bellone, S., Centritto, F., Black, J., Schwab, C., English, D., Cocco, E., Lopez, S., Bonazzoli, E., Predolini, F., Ferrari, F., Silasi, D., Ratner, E., Azodi, M., Schwartz, P. E., Santin, A. D. 2015; 138 (1): 11-17

    Abstract

    Around 7-10% of endometrial carcinomas are characterized by polymerase-ε-(POLE) exonuclease-domain-mutations, an ultra-mutated-phenotype and a favorable prognosis. It is currently unknown whether POLE ultra-mutated-tumors are more immunogenic when compared to the other groups of endometrial cancers.We used autologous-dendritic-cells (DC) pulsed with whole-tumor-extracts to assess the level of CD8+ and CD4+ T-cell-activation induced by POLE-ultramutated (+) and POLE wild-type (-) endometrial cancer cells in vitro. T-lymphocyte-proliferations were evaluated using CFSE and/or ([3H])thymidine-incorporation-assays while the ability to specifically kill autologous-tumor-cells by cytotoxic-T-lymphocyte (CTL) was tested in standard 4-h-(51)Cr-cytotoxicity-assays. In order to correlate cytotoxic activity and proliferation by CD4+ and CD8+ T-lymphocytes, respectively, with a particular lymphoid subset, two-color-flow-cytometric analysis of intracellular-cytokine-expression (IFN-γ vs IL-4) at the single cell level was also performed.DC-pulsed with tumor extracts were able to induce CTL-responses against autologous-tumor-cells in both POLE (+) and POLE (-) cancer patients (P=0.305). These CD8+ T-cell-populations were cytotoxic against tumor-cells but they did not lyse PHA-stimulated-autologous-lymphocytes or autologous-EBV-transformed-lymphoblastoid-control-cell-lines. In contrast, only POLE (+) tumor-lysate-pulsed-DC were able to induce significant proliferation and high IFN-γ expression (i.e., Th1-cytokine-bias) in autologous in vitro DC-stimulated CD4+ T-cells as well as naïve CD4+ and CD8+ T-cells from patients-peripheral-blood (P<0.05).POLE ultra-mutated-tumors are significantly more immunogenic when compared to POLE (-) tumors, in particular to the helper arm of the immune system. These data lend support to the hypothesis that the better prognosis of patients with POLE (+) tumors may at least in part be linked to their enhanced immunogenicity.

    View details for DOI 10.1016/j.ygyno.2015.04.027

    View details for Web of Science ID 000356841100002

    View details for PubMedID 25931171

    View details for PubMedCentralID PMC4469551

  • 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 Zhu, L., Lopez, S., Bellone, S., Black, J., Cocco, E., Zigras, T., Predolini, F., Bonazzoli, E., Bussi, B., Stuhmer, Z., Schwab, C. L., English, D. P., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Rutherford, T. J., Santin, A. D. 2015; 36 (7): 5505–13

    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.

    View details for DOI 10.1007/s13277-015-3218-4

    View details for Web of Science ID 000359569000077

    View details for PubMedID 25669172

    View details for PubMedCentralID PMC5573583

  • Controlled removal of a large uterus within a bowel bag and morcellation in the bowel bag from the vagina GYNECOLOGIC ONCOLOGY English, D., Menderes, G., Azodi, M. 2015; 137 (3): 589-590

    View details for DOI 10.1016/j.ygyno.2015.03.014

    View details for Web of Science ID 000355779000035

    View details for PubMedID 25797081

  • SYD985, a novel HER2-targeting antibody-drug conjugate in preclinical models for USC, both in vitro and in vivo. Black, J., Lopez, S., Cocco, E., Bellone, S., Bonazzoli, E., Schwab, C., English, D., Goedings, P. J., Beusker, P., van der Lee, M., Timmers, M., Dokter, W., Schwartz, P. E., Santin, A. AMER SOC CLINICAL ONCOLOGY. 2015
  • Clostridium Perfringens Enterotoxin (CPE) and CPE-Binding Domain (c-CPE) for the Detection and Treatment of Gynecologic Cancers TOXINS Black, J. D., Lopez, S., Cocco, E., Schwab, C. L., English, D. P., Santin, A. D. 2015; 7 (4): 1116-1125

    Abstract

    Clostridium perfringens enterotoxin (CPE) is a three-domain polypeptide, which binds to Claudin-3 and Claudin-4 with high affinity. Because these receptors are highly differentially expressed in many human tumors, claudin-3 and claudin-4 may provide an efficient molecular tool to specifically identify and target biologically aggressive human cancer cells for CPE-specific binding and cytolysis. In this review we will discuss these surface proteins as targets for the detection and treatment of chemotherapy-resistant gynecologic malignancies overexpressing claudin-3 and -4 using CPE-based theranostic agents. We will also discuss the use of fluorescent c-CPE peptide in the operative setting for real time detection of micro-metastatic tumors during surgery and review the potential role of CPE in other medical applications.

    View details for DOI 10.3390/toxins7041116

    View details for Web of Science ID 000353963700008

    View details for PubMedID 25835384

    View details for PubMedCentralID PMC4417958

  • Mutations in the PIK3 Pathway as a Major Determinant of Trastuzumab Resistance in Uterine Serous Carcinoma Black, J., Lopez, S., Schwab, C., English, D., Santin, A. SAGE PUBLICATIONS INC. 2015: 77A
  • Mucinous Ovarian Carcinomas: An Institutional Experience English, D., De Haydu, C., Altwerger, G., Silasi, D., Azodi, M., Santin, A., Rutherford, T., Schwartz, P., Ratner, E. SAGE PUBLICATIONS INC. 2015: 122A
  • Combined Modality Therapy for Advanced Endometrial Cancer English, D. P., Pasternak, M., Seagle, B., Young, M., Damast, S., Silasi, D., Azodi, M., Santin, A., Rutherford, T., Schwartz, P., Ratner, E. SAGE PUBLICATIONS INC. 2015: 122A–123A
  • Evaluation of the Diagnostic Accuracy of Cervical Biopsy and the Determination of Margin Status and Associated Risk Factors for Recurrent Cervical Dysplasia After LEEP or Conization. English, D. P., Pasternak, M., Chatterjee, S., Silasi, D., Azodi, M., Santin, A., Rutherford, T., Schwartz, P., Ratner, E. SAGE PUBLICATIONS INC. 2015: 309A
  • Solitomab, an Epithelial Cell Adhesion Molecule/CD3 Bispecific Antibody (BiTE), Is Highly Active Against Primary Chemotherapy-Resistant Ovarian Cancer Cell Lines In Vitro and Fresh Tumor Cells Ex Vivo CANCER English, D. P., Bellone, S., Schwab, C. L., Roque, D. M., Lopez, S., Bortolomai, I., Cocco, E., Bonazzoli, E., Chatterjee, S., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Rutherford, T. J., Santin, A. D. 2015; 121 (3): 403-412

    Abstract

    Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites.EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines and in 42 fresh ovarian tumor cell cultures in ascites from patients with mainly advanced or recurrent, chemotherapy-resistant disease. The potential activity of solitomab against EpCAM-positive tumor cells was evaluated by flow cytometry, proliferation, and 4-hour chromium-release, cell-mediated cytotoxicity assays.EpCAM expression was detected by flow cytometry in approximately 80% of the fresh ovarian tumors and primary ovarian tumor cell lines tested. EpCAM-positive, chemotherapy-resistant cell lines were identified as resistant to natural killer cell-mediated or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean±standard error of the mean, 3.6%±0.7% of cells killed after incubation of EpCAM-positive cell lines with control bispecific antibody). In contrast, after incubation with solitomab, EpCAM-positive, chemotherapy-resistant cells became highly sensitive to T-cell cytotoxicity (mean±standard error of the mean, 28.2%±2.05% of cells killed; P<.0001) after exposure to peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with EpCAM-expressing malignant cells in ascites with solitomab resulted in a significant increase in T-cell activation markers and a reduction in the number of viable ovarian tumor cells in ascites (P<.001).Solitomab may represent a novel, potentially effective agent for the treatment of chemotherapy-resistant ovarian cancers that overexpress EpCAM.

    View details for DOI 10.1002/cncr.29062

    View details for Web of Science ID 000349394900014

    View details for PubMedID 25251053

    View details for PubMedCentralID PMC4304922

  • Basic Science Ovarian Cancer Solitomab, an EpCAM/CD3 bispecific antibody (BITE), is highly active against primary chemotherapy resistant ovarian cancer cell lines in vitro and fresh tumor cells ex vivo English, D. P., Bellone, S., Schwab, C. L., Roque, D. M., Chatterjee, S., Ratner, E., Schwartz, P. E., Rutherford, T. J., Santin, A. D. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2015: 401
  • Afatinib, an irreversible ErbB family blocker, demonstrates remarkable activity against HER2 amplified uterine serous endometrial cancer in vitro and in vivo Schwab, C. L., Roque, D. M., English, D. P., Bellone, S., Lopez, S., Cocco, E., Nicoletti, R., Bortolomai, I., Bonazzoli, E., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Rutherford, T. J., Santin, A. D. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2015: 397–98
  • Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo GYNECOLOGIC ONCOLOGY Lopez, S., Schwab, C. L., Cocco, E., Bellone, S., Bonazzoli, E., English, D. P., Schwartz, P. E., Rutherford, T., Angioli, R., Santin, A. D. 2014; 135 (2): 312–17

    Abstract

    To evaluate the efficacy of taselisib, a selective inhibitor of PIK3CA, against primary uterine serous carcinomas (USC) harboring PIK3CA mutations and HER2/neu gene amplification.Sensitivity to taselisib was evaluated by flow-cytometry viability assays in vitro against nine primary USC cell lines. Cell cycle distribution and downstream signaling were assessed by measuring the DNA content of cells and by phosphorylation of the S6 protein by flow-cytometry. Preclinical efficacy of taselisib was also evaluated in vivo in a mouse model.Four USC cell lines harbored HER2/neu gene amplification by FISH and two of them harbored oncogenic PIK3CA mutations. Taselisib caused a strong differential growth inhibition in both HER2/neu FISH positive and HER2/neu FISH positive/PIK3CA mutated USC cell lines when compared to lines that were FISH negative and PIK3CA wild type (taselisib IC50 mean±SEM=0.042±0.006μM in FISH+ versus 0.38±0.06μM in FISH-tumors, P<0.0001). Taselisib growth-inhibition was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and dose-dependent decline in the phosphorylation of S6. Taselisib was highly active at reducing tumor growth in vivo in USC mouse xenografts harboring PIK3CA mutation and overexpressing HER2/neu (P=0.007). Mice treated with taselisib had significantly longer survival when compared to control mice (P<0.0001).Taselisib represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification.

    View details for DOI 10.1016/j.ygyno.2014.08.024

    View details for Web of Science ID 000345605200024

    View details for PubMedID 25172762

    View details for PubMedCentralID PMC4270135

  • T-DM1, a novel antibody-drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo CANCER MEDICINE English, D. P., Bellone, S., Schwab, C. L., Bortolomai, I., Bonazzoli, E., Cocco, E., Buza, N., Hui, P., Lopez, S., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Rutherford, T. J., Santin, A. D. 2014; 3 (5): 1256-1265

    Abstract

    Amplification of c-erbB2 has been reported in over 30% of uterine serous carcinoma (USC) and found to confer poor survival because of high proliferation and increased resistance to therapy. In this study, we evaluated for the first time Trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate, against multiple epidermal growth factor receptor-2 (HER2)-positive USC cells in vitro followed by developing a supportive in vivo model. Fifteen primary USC cell lines were assessed by immunohistochemistry (IHC) and flow cytometry for HER2 protein expression. C-erbB2 gene amplification was evaluated using fluorescent in situ hybridization. Sensitivity to T-DM1 and trastuzumab (T)-induced antibody-dependent cell-mediated cytotoxicity was evaluated in 5-h chromium release assays. T-DM1 and T cytostatic and apoptotic activities were evaluated using flow-cytometry-based proliferation assays. In vivo activity of T-DM1 versus T in USC xenografts in SCID mice was also evaluated. High levels of HER2 protein overexpression and HER2 gene amplification were detected in 33% of USC cell lines. T-DM1 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis (P = 0.004) of USC showing HER2 overexpression. Importantly, T-DM1 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing HER2 (P = 0.04) and mice treated with TDM-1 had significantly longer survival when compared to T-treated mice and control mice (P ≤ 0.0001). T-DM1 shows promising antitumor effect in HER2-positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T. T-DM1 may represent a novel treatment option for HER2-positive USC patients with disease refractory to trastuzumab and traditional chemotherapy.

    View details for DOI 10.1002/cam4.274

    View details for Web of Science ID 000348223900014

    View details for PubMedID 24890382

    View details for PubMedCentralID PMC4302675

  • Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo GYNECOLOGIC ONCOLOGY Schwab, C. L., English, D. P., Roque, D. M., Bellone, S., Lopez, S., Cocco, E., Nicoletti, R., Rutherford, T. J., Schwartz, P. E., Santin, A. D. 2014; 135 (1): 142–48

    Abstract

    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.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.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 IC50: 0.011μM ± 0.0008 vs. 0.312μM ± 0.0456 p<0.0001). Neratinib caused arrest in the G0/G1 phase of the cell cycle and resulted in decreased autophosphorylation of HER2 and activation of S6. Neratinib treated mice harboring xenografts of HER2/neu amplified USC showed delayed tumor growth and improved overall survival compared to vehicle (p=0.0019).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.

    View details for DOI 10.1016/j.ygyno.2014.08.006

    View details for Web of Science ID 000343955900025

    View details for PubMedID 25124161

  • Afatinib, an irreversible ErbB family inhibitor, demonstrates activity against HER2 mutated cervical cancer in vitro Lopez, S., Cocco, E., Stefania, B., Bortolomai, I., Bonazzoli, E., Nicoletti, R., Schwab, C., English, D. P., Terranova, C., Angioli, R., Santin, A. D. AMER ASSOC CANCER RESEARCH. 2014
  • Taxanes: their impact on gynecologic malignancy ANTI-CANCER DRUGS Schwab, C. L., English, D. P., Roque, D. M., Santin, A. D. 2014; 25 (5): 522-535

    Abstract

    The use of taxanes in the treatment of gynecologic malignancies has expanded tremendously over the past 30 years. Both paclitaxel and docetaxel have unique microtubule stabilizing, antiangiogenic and radiation sensitizing properties that endow them with remarkable activity as chemotherapeutic agents. As research into the appropriate dose, timing, treatment interval, and response rates have been studied, they have emerged as one of the most active agents available in the treatment of gynecologic cancer. The body of research on taxanes continues to expand especially with regard to the use of taxanes in alternative formulations and in combination with newer treatments or routes of treatment. This review focuses on the development of taxanes as an effective therapy in the treatment of gynecologic cancers and data currently available in the literature regarding their efficacy. Future directions of taxane-based chemotherapy with regards to ovarian, uterine, and cervical cancers are also addressed. There is little doubt that taxane-based chemotherapy will remain an integral part of the treatment of gynecologic cancer for the foreseeable future.

    View details for DOI 10.1097/CAD.0000000000000057

    View details for Web of Science ID 000334591200007

    View details for PubMedID 24300913

    View details for PubMedCentralID PMC3980024

  • Evaluation of the diagnostic accuracy of cervical biopsy and determination of associated risk factors for positive margin status in recurrent cervical dysplasia after leep or conization. English, D., Pasternak, M., Warmington, J., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Santin, A., Rutherford, T. J. AMER SOC CLINICAL ONCOLOGY. 2014
  • Afatinib, an Irreversible ErbB Family Blocker, Demonstrates Remarkable Activity Against HER2 Amplified Uterine Serous Endometrial Cancer In Vitro Schwab, C. L., Roque, D. M., English, D. P., Bellone, S., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Rutherford, T. J., Santin, A. D. SAGE PUBLICATIONS INC. 2014: 214A–215A
  • Weekly Ixabepilone +/- Bevacizumab in the Treatment of Platinum/Taxane-Resistant Endometrial & Ovarian Cancers Roque, D. M., Schwab, C. L., English, D. P., Ratner, E. S., Silasi, D., Azodi, M., Rutherford, T., Schwartz, P. E., Santin, A. D. SAGE PUBLICATIONS INC. 2014: 120A
  • Treatment of Uterine Carcinosarcoma with Cisplatin/Ifosfamide, Paclitaxel/Ifosfamide, or Carboplatin/Paclitaxel Roque, D. M., Varughese, J., English, D. P., Gressel, G. M., Lundsberg, L., Ratner, E. S., Rutherford, T. J., Schwartz, P. E. SAGE PUBLICATIONS INC. 2014: 211A–212A
  • Past, present and future targets for immunotherapy in ovarian cancer IMMUNOTHERAPY Schwab, C. L., English, D. P., Roque, D. M., Pasternak, M., Santin, A. D. 2014; 6 (12): 1279-1293

    Abstract

    Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions.

    View details for DOI 10.2217/imt.14.90

    View details for Web of Science ID 000346639000005

    View details for PubMedID 25524384

    View details for PubMedCentralID PMC4312614

  • Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer WOMENS HEALTH Black, J. D., English, D. P., Roque, D. M., Santin, A. D. 2014; 10 (1): 45–57

    Abstract

    Uterine serous carcinoma (USC) is a highly aggressive variant of endometrial cancer. Although it only represents less than 10% of all cases, it accounts for a disproportionate number of deaths from endometrial cancer. Comprehensive surgical staging followed by carboplatin and paclitaxel chemotherapy represents the mainstay of USC therapy. Vaginal cuff brachytherapy is also of potential benefit in USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. These results emphasize the relevance of these novel therapeutic targets for biologic therapy of chemotherapy-resistant recurrent USC.

    View details for DOI 10.2217/WHE.13.72

    View details for Web of Science ID 000213218300011

    View details for PubMedID 24328598

    View details for PubMedCentralID PMC3984476

  • HER2/neu gene amplification determines the sensitivity of uterine serous carcinoma cell lines to AZD8055, a novel dual mTORC1/2 inhibitor GYNECOLOGIC ONCOLOGY English, D. P., Roque, D. M., Carrara, L., Lopez, S., Bellone, S., Cocco, E., Bortolomai, I., Schwartz, P. E., Rutherford, T., Santin, A. D. 2013; 131 (3): 753-758

    Abstract

    To evaluate c-erbB2 gene amplification in a series of primary uterine serous carcinoma (USC) cell lines. To assess the efficacy of AZD8055, a novel dual mTORC1/2 inhibitor against primary HER2/neu amplified vs HER2/neu not amplified USC cell lines.Twenty-two primary USC cell lines were evaluated for c-erbB2 oncogene amplification by FISH assays. In vitro sensitivity to AZD8055 was evaluated by flow-cytometry-based viability and proliferation assays. Cell cycle profile and downstream cellular responses to AZD8055 were assessed by measuring the DNA content of cells and by phosphorylation of the S6 protein by flow-cytometry.Nine of 22 (40.9%) USC cell lines demonstrated c-erbB2 gene amplification by FISH. AZD8055 caused a strong differential growth inhibition in USC cell lines, with high HER-2/neu-expressors demonstrating significantly higher sensitivity when compared to low HER-2/neu-expressors (AZD-8055 IC50 mean±SEM=0.27±0.05μM in c-erbB2 amplified versus 1.67±0.68μM in c-erbB2 not amplified tumors, P=0.03). AZD8055 growth-inhibition was associated with a significant and dose-dependent increase in the percentage of cells blocked in the G0/G1 cell cycle phase and a dose-dependent decline in pS6 levels in both c-erbB2 amplified vs c-erbB2 not amplified USC cell lines.AZD8055 may represent a novel targeted therapeutic agent in patients harboring advanced/recurrent/refractory USC. c-erbB2 gene amplification may represent a biomarker to identify USC patients who may benefit most from the use of AZD8055.

    View details for DOI 10.1016/j.ygyno.2013.08.033

    View details for Web of Science ID 000327923400046

    View details for PubMedID 24012800

  • Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice MODERN PATHOLOGY Buza, N., English, D. P., Santin, A. D., Hui, P. 2013; 26 (12): 1605-1612

    Abstract

    HER2 overexpression and/or amplification have been reported in endometrial serous carcinoma, suggesting that HER2 may be a promising therapeutic target. However, there is considerable variation in the reported rates of HER2 overexpression and amplification, likely--at least in part--resulting from variability in the testing methods, interpretation, and scoring criteria used. Unlike in breast and gastric cancer, currently there are no established guidelines for HER2 testing in endometrial carcinoma. A total of 108 endometrial carcinoma cases--85 pure serous carcinomas and 23 mixed endometrial carcinomas with serous component--were identified over a 4-year period. All H&E and HER2 immunohistochemical slides were reviewed and HER2 FISH results (available on 52 cases) were retrieved from pathology reports. HER2 immunohistochemical scores were assigned according to the FDA criteria and the current breast ASCO/CAP scoring criteria. Clinical information was retrieved from the patients' medical records. Thirty-eight cases (35%) showed HER2 overexpression and/or gene amplification, 20 of which (53%) had significant heterogeneity of protein expression by immunohistochemistry. Lack of apical membrane staining resulting in a lateral/basolateral staining pattern was observed in the majority of HER2-positive tumors. Five of the HER2-positive cases (13%) demonstrated discrepant immunohistochemical scores when using the FDA versus ASCO/CAP scoring system. The overall concordance rate between HER2 immunohistochemistry and FISH was 75% (39/52) when using the FDA criteria, compared with 81% (42/52) by the ASCO/CAP scoring system. In conclusion, in this largest comprehensive study, 35% of endometrial serous carcinoma harbors HER2 protein overexpression and/or gene amplification, over half of which demonstrate significant heterogeneity of protein expression. The current breast ASCO/CAP scoring criteria provide the highest concordance between immunohistochemistry and FISH. Assessment of HER2 immunohistochemistry on multiple tumor sections or sections with large tumor areas is recommended, due to the significant heterogeneity of HER2 protein expression.

    View details for DOI 10.1038/modpathol.2013.113

    View details for Web of Science ID 000328012700008

    View details for PubMedID 23765245

  • Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY English, D. P., Bellone, S., Cocco, E., Bortolomai, I., Pecorelli, S., Lopez, S., Silasi, D., Schwartz, P. E., Rutherford, T., Santin, A. D. 2013; 209 (5)

    Abstract

    To evaluate PIK3CA mutational status and c-erbB2 gene amplification in a series of primary uterine serous carcinomas (USC) cell lines. To assess the efficacy of GDC-0980, a potent inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2), against primary USC harboring HER2/neu gene amplification and/or PIK3CA mutations.Twenty-two primary USC cell lines were evaluated for c-erbB2 oncogene amplification by fluorescence in situ hybridization (FISH) assays and for PIK3CA gene mutations by direct DNA sequencing of exons 9 and 20. In vitro sensitivity to GDC-0980 was evaluated by flow-cytometry-based viability and proliferation assays. Downstream cellular responses to GDC-0980 were assessed by measuring phosphorylation of the 4-EBP1 protein by flow-cytometry.Five of 22 (22.7%) USC cell lines contained oncogenic PIK3CA mutations although 9 (40.9%) harbored c-erbB2 gene amplification by FISH. GDC-0980 caused a strong differential growth inhibition in FISH+ USC when compared with FISH- (GDC-0980 IC50 mean ± SEM = 0.29 ± 0.05 μM in FISH+ vs 1.09 ± 0.20 μM in FISH- tumors, P = .02). FISH+ USC harboring PIK3CA mutations were significantly more sensitive to GDC-0980 exposure when compared with USC cell lines harboring wild-type PIK3CA (P = .03). GDC-0980 growth-inhibition was associated with a significant and dose-dependent decline in phosphorylated 4-EBP1 levels.Oncogenic PIK3CA mutations and c-erbB2 gene amplification may represent biomarkers to identify patients harboring USC who may benefit most from the use of GDC-0980.

    View details for DOI 10.1016/j.ajog.2013.07.020

    View details for Web of Science ID 000326243700024

    View details for PubMedID 23891627

  • Tubulin--III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones CANCER Roque, D. M., Bellone, S., English, D. P., Buza, N., Cocco, E., Gasparrini, S., Bortolomai, I., Ratner, E., Silasi, D., Azodi, M., Rutherford, T. J., Schwartz, P. E., Santin, A. D. 2013; 119 (14): 2582–92

    Abstract

    Uterine serous carcinoma (USC) is a subtype of endometrial cancer associated with chemoresistance and poor outcome. Overexpression of tubulin-β-III and p-glycoprotein has been linked to paclitaxel resistance in many cancers but has been undercharacterized among USCs. Epothilones have demonstrated activity in certain paclitaxel-resistant malignancies. In this study, relationships are clarified, in USCs relative to ovarian serous carcinomas (OSCs), between tubulin-β-III and p-glycoprotein expression, clinical outcome, and in vitro chemoresponsiveness to epothilone B, ixabepilone, and paclitaxel.Tubulin-β-III and p-glycoprotein were quantified by real-time polymerase chain reaction in 48 fresh-frozen tissue samples and 13 cell lines. Copy number was correlated with immunohistochemistry and overall survival. Median inhibitory concentration (IC50 ) was determined using viability and metabolic assays. Impact of tubulin-β-III knockdown on IC50 was assessed with small interfering RNAs.USC overexpressed tubulin-β-III but not p-glycoprotein relative to OSC in both fresh-frozen tissues (552.9 ± 106.7 versus 202.0 ± 43.99, P = .01) and cell lines (1701.0 ± 376.4 versus 645.1 ± 157.9, P = .02). Tubulin-β-III immunohistochemistry reflected quantitative real-time polymerase chain reaction copy number and overexpression stratified patients by overall survival (copy number ≤ 400: 615 days; copy number > 400: 165 days, P = .049); p-glycoprotein did not predict clinical outcome. USCs remained exquisitely sensitive to patupilone in vitro despite tubulin-β-III overexpression (IC50,USC 0.245 ± 0.11 nM versus IC50,OSC 1.01 ± 0.13 nM, P = .006).Tubulin-β-III overexpression in USCs discriminates poor prognosis, serves as a marker for sensitivity to epothilones, and may contribute to paclitaxel resistance. Immunohistochemistry reliably identifies tumors with overexpression of tubulin-β-III, and a subset of individuals likely to respond to patupilone and ixabepilone. Epothilones warrant clinical investigation for treatment of USCs.

    View details for DOI 10.1002/cncr.28017

    View details for Web of Science ID 000325864500012

    View details for PubMedID 23585021

    View details for PubMedCentralID PMC3700638

  • Claudins Overexpression in Ovarian Cancer: Potential Targets for Clostridium Perfringens Enterotoxin (CPE) Based Diagnosis and Therapy INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES English, D. P., Santin, A. D. 2013; 14 (5): 10412-10437

    Abstract

    Claudins are a family of tight junction proteins regulating paracellular permeability and cell polarity with different patterns of expression in benign and malignant human tissues. There are approximately 27 members of the claudin family identified to date with varying cell and tissue-specific expression. Claudins-3, -4 and -7 represent the most highly differentially expressed claudins in ovarian cancer. While their exact role in ovarian tumors is still being elucidated, these proteins are thought to be critical for ovarian cancer cell invasion/dissemination and resistance to chemotherapy. Claudin-3 and claudin-4 are the natural receptors for the Clostridium perfringens enterotoxin (CPE), a potent cytolytic toxin. These surface proteins may therefore represent attractive targets for the detection and treatment of chemotherapy-resistant ovarian cancer and other aggressive solid tumors overexpressing claudin-3 and -4 using CPE-based theranostic agents.

    View details for DOI 10.3390/ijms140510412

    View details for Web of Science ID 000319441500098

    View details for PubMedID 23685873

    View details for PubMedCentralID PMC3676847

  • T-DM1, a Novel Antibody-Drug Conjugate, Is Highly Effective Against Primary Uterine Serous Carcinoma Cell Lines Overexpressing HER2. English, D. P., Bellone, S., Varughese, J., Ratner, E., Silasi, D., Azodi, M., Schwartz, P. E., Rutherford, T. J., Pecorelli, S., Santin, A. D. SAGE PUBLICATIONS INC. 2013: 339A
  • Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhao, S., Choi, M., Overton, J. D., Bellone, S., Roque, D. M., Cocco, E., Guzzo, F., English, D. P., Varughese, J., Gasparrini, S., Bortolomai, I., Buza, N., Hui, P., Abu-Khalaf, M., Ravaggi, A., Bignotti, E., Bandiera, E., Romani, C., Todeschini, P., Tassi, R., Zanotti, L., Carrara, L., Pecorelli, S., Silasi, D., Ratner, E., Azodi, M., Schwartz, P. E., Rutherford, T. J., Stiegler, A. L., Mane, S., Boggon, T. J., Schlessinger, J., Lifton, R. P., Santin, A. D. 2013; 110 (8): 2916–21

    Abstract

    Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. We analyzed the mutational landscape of USC by whole-exome sequencing of 57 cancers, most of which were matched to normal DNA from the same patients. The distribution of the number of protein-altering somatic mutations revealed that 52 USC tumors had fewer than 100 (median 36), whereas 5 had more than 3,000 somatic mutations. The mutations in these latter tumors showed hallmarks of defects in DNA mismatch repair. Among the remainder, we found a significantly increased burden of mutation in 14 genes. In addition to well-known cancer genes (i.e., TP53, PIK3CA, PPP2R1A, KRAS, FBXW7), there were frequent mutations in CHD4/Mi2b, a member of the NuRD-chromatin-remodeling complex, and TAF1, an element of the core TFIID transcriptional machinery. Additionally, somatic copy-number variation was found to play an important role in USC, with 13 copy-number gains and 12 copy-number losses that occurred more often than expected by chance. In addition to loss of TP53, we found frequent deletion of a small segment of chromosome 19 containing MBD3, also a member of the NuRD-chromatin-modification complex, and frequent amplification of chromosome segments containing PIK3CA, ERBB2 (an upstream activator of PIK3CA), and CCNE1 (a target of FBXW7-mediated ubiquitination). These findings identify frequent mutation of DNA damage, chromatin remodeling, cell cycle, and cell proliferation pathways in USC and suggest potential targets for treatment of this lethal variant of endometrial cancer.

    View details for DOI 10.1073/pnas.1222577110

    View details for Web of Science ID 000315954400066

    View details for PubMedID 23359684

    View details for PubMedCentralID PMC3581983

  • Class III beta-tubulin overexpression in gynecologic tumors: implications for the choice of microtubule targeted agents? EXPERT REVIEW OF ANTICANCER THERAPY English, D. P., Roque, D. M., Santin, A. D. 2013; 13 (1): 63-74

    Abstract

    The tubulins are significant players in maintaining microtubule dynamics and have important signaling and apoptotic functions. Alterations in microtubules as a result of changes in tubulin isotype content or polymerization affect the sensitivity of cell lines to tubulin-binding agents (e.g., taxol) in vitro. Epothilones, such as patupilone and ixabepilone, contain a 16-membered macrolide ring and act as competitive inhibitors of taxol. Class III β-tubulin overexpression has been linked to resistance to paclitaxel and correlated with poor survival in ovarian, breast, gastric, non-small-cell lung cancer and unknown primary tumors. Recent data suggest that class III β-tubulin may not only serve as a marker for sensitivity to epothilones, but also as a mediator of a bioaggressive tumor phenotype through activation of multiple cell survival pathways active under stress conditions.

    View details for DOI 10.1586/ERA.12.158

    View details for Web of Science ID 000314927700014

    View details for PubMedID 23259428

  • HER2 Expression Beyond Breast Cancer: Therapeutic Implications for Gynecologic Malignancies MOLECULAR DIAGNOSIS & THERAPY English, D. P., Roque, D. M., Santin, A. D. 2013; 17 (2): 85-99

    Abstract

    HER2 or ErbB2 is a member of the epidermal growth factor family and is overexpressed in subsets of breast, ovarian, gastric, colorectal, pancreatic, and endometrial cancers. HER2 regulates signaling through several pathways (Ras/Raf/mitogen-activated protein kinase and phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin pathways) associated with cell survival and proliferation. HER2-overexpressed and/or gene-amplified tumors are generally regarded as biologically aggressive neoplasms. In breast, cervical, endometrial, and ovarian cancer, there have been several studies linking the amplification of the c-erbB2 gene with chemoresistance and overall poor survival. Tyrosine kinase inhibitors and immunotherapy with monoclonal antibodies targeting HER2 hold promise for patients harboring these aggressive neoplasms. Trastuzumab combined with cytotoxic chemotherapy agents or conjugated with radioactive isotopes is currently being investigated in clinical trials of several tumor types.

    View details for DOI 10.1007/s40291-013-0024-9

    View details for Web of Science ID 000318043900003

    View details for PubMedID 23529353

    View details for PubMedCentralID PMC3660991

  • Uterine Cyst as a Cause of Chronic Pelvic Pain A Case Report JOURNAL OF REPRODUCTIVE MEDICINE English, D. P., Verma, U., Pearson, J. 2012; 57 (9-10): 446–48

    Abstract

    Cystic adenomyosis is a rare form of adenomyosis. Presently, these cysts are generally considered to be of a benign nature and result from cyclical response to menstrual dynamics.A 31-year-old, African-American female presented for a second opinion with a chief complaint of pelvic pain. She had recently undergone an exploratory laparoscopy with findings suggestive of endometriosis. She was never pregnant and had been taking oral contraceptive pills for over 3 months with little relief This patient had no history of uterine surgery. Pelvic ultrasound performed after her surgery revealed a cystic structure, homogeneously echogenic in the anterior corpus of the uterus, measuring 2.7 x 2.4 x 3.5 cm. This structure appeared consistent with an adenomyotic cyst. The patient's symptoms improved after the transvaginal aspiration, and she no longer required narcotics.Of all the possibilities considered, this cyst most closely resembled an adenomyotic cyst in its clinical presentation, location within the myometrium and gross appearance of the chocolate cyst fluid. Imaging is key in distinguishing this process from other congenital and acquired gynecologic entities. Awareness of this condition is important for timely and accurate diagnosis followed by appropriate intervention.

    View details for Web of Science ID 000309639600015

    View details for PubMedID 23091995