Publications

Director, Stanford Gynecologic Oncology Fellowship (2016 - Present) Director, Stanford Clinical Research Group for Gynecologic Cancer Trials (2014 - Present) Director, Stanford Gynecologic Oncology Clinical Care Program (2013 - Present) Director, Mary Lake Polan Gynecologic Oncology Research Laboratory (2013 - Present) Director, Stanford Obstetrics and Gynecology, Division of Gynecologic Oncology (2013 - Present)

Publications

  • Macrophage-derived CCL23 upregulates expression of T-cell exhaustion markers in ovarian cancer. British journal of cancer Kamat, K., Krishnan, V., Dorigo, O. 2022

    Abstract

    BACKGROUND: Macrophages are an important component of the tumour immune microenvironment (TME) and can promote tumour growth and metastasis. Macrophage-secreted chemokine-ligand-23 (CCL23) induces ovarian cancer cell migration via chemokine-receptor 1 (CCR1). However, the effect of CCL23 on other immune cells in the TME is unknown.METHODS: CCL23 levels were measured by ELISA. The expression of surface markers in exhaustion assays was quantified by flow cytometry. Signalling pathways were identified by phosphokinase array and validated by western blot.RESULTS: Ascites from patients with high-grade serous ovarian cancer (HGSC) contain high levels of CCL23. Similarly, significantly higher CCL23 levels were found in plasma from HGSC patients compared to healthy individuals. RNA-seq analysis of ovarian cancer tissues from TCGA showed that expression of CCL23 correlated with the presence of macrophages. In tissues with high levels of CCL23 and macrophage content, the fraction of CD8+T cells expressing exhaustion markers CTLA-4 and PD-1 were significantly higher compared to low-level CCL23 tissues. In vitro, CCL23 induced upregulation of immune checkpoint proteins on CD8+T cells, including CTLA-4, TIGIT, TIM-3 and LAG-3 via phosphorylation of GSK3beta in CD8+T cells.CONCLUSIONS: Our data suggest that CCL23 produced by macrophages contributes to the immune-suppressive TME in ovarian cancer by inducing an exhausted T-cell phenotype.

    View details for DOI 10.1038/s41416-022-01887-3

    View details for PubMedID 35750747

  • Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1. Communications biology Krishnan, V., Tallapragada, S., Schaar, B., Kamat, K., Chanana, A. M., Zhang, Y., Patel, S., Parkash, V., Rinker-Schaeffer, C., Folkins, A. K., Rankin, E. B., Dorigo, O. 2020; 3 (1): 524

    Abstract

    The omentum is the most common site of ovarian cancer metastasis. Immune cell clusters called milky spots are found throughout the omentum. It is however unknown if these immune cells contribute to ovarian cancer metastasis. Here we report that omental macrophages promote the migration and colonization of ovarian cancer cells to the omentum through the secretion of chemokine ligands that interact with chemokine receptor 1 (CCR1). We found that depletion of macrophages reduces ovarian cancer colonization of the omentum. RNA-sequencing of macrophages isolated from mouse omentum and mesenteric adipose tissue revealed a specific enrichment of chemokine ligandCCL6 in omental macrophages. CCL6 and the human homolog CCL23 were both necessary and sufficient to promote ovarian cancer migration by activating ERK1/2 and PI3K pathways. Importantly, inhibition of CCR1 reduced ovarian cancer colonization. These findings demonstrate a critical mechanism of omental macrophage induced colonization by ovarian cancer cells via CCR1 signaling.

    View details for DOI 10.1038/s42003-020-01246-z

    View details for PubMedID 32963283

  • Aberrant nuclear β-catenin distribution does not prognosticate recurrences of endometrioid endometrial cancers - A retrospective single-institutional study. Gynecologic oncology Beshar, I., Moon, A. S., Darji, H., Liu, C., Jennings, M. T., Dorigo, O., Litkouhi, B., Diver, E. J., Karam, A. K., Howitt, B. E., Renz, M. 2023; 179: 85-90

    Abstract

    Aberrant β-catenin distribution has been theorized as a predictive biomarker for recurrence in early stage, low grade endometrioid endometrial cancer.This retrospective single-institution cohort study reviewed 410 patients with endometrial cancer from May 2018 to May 2022. Only endometrioid histology was included. Demographic and clinicopathological data were collected from the medical records. Univariate and multivariate logistic regressions, and sensitivity analyses for early stage, low grade and no specific molecular profile (NSMP) tumors were performed.297 patients were included for analysis. Most patients were over 60 years old, White, and with a BMI >30 and early stage low grade disease. Aberrant β-catenin distribution was found in 135 patients (45.5%) and wild type membranous β-catenin distribution in 162 (54.5%). While TP53 mutation correlated with endometrial cancer recurrence in this cohort (OR = 4.78), aberrant β-catenin distribution did not correlate in the overall population (OR = 0.75), the early stage low grade cancers (OR = 0.84), or the NSMP group (OR = 1.41) on univariate or multivariate analysis. No correlation between β-catenin distribution and local (OR = 0.61) or distant recurrences (OR = 0.90) was detected.Aberrant β-catenin distribution did not significantly correlate with recurrence in endometrioid endometrial cancer, nor in the early stage, low grade and NSMP sub-cohorts.

    View details for DOI 10.1016/j.ygyno.2023.10.025

    View details for PubMedID 37944330

  • Does lymph node assessment change the prognostic significance of substantial LVSI and p53 status in endometrial endometrioid carcinoma? Gynecologic oncology Hui, C., Mendoza, M. G., von Eyben, R., Dorigo, O., Litkouhi, B., Renz, M., Karam, A., Hammer, P. M., Howitt, B. E., Kidd, E. 2023; 177: 150-156

    Abstract

    The PORTEC-2 update suggested that substantial lymphovascular space invasion (LVSI) and abnormal p53 expression (p53abnl) predict for poorer outcomes and that these patients should be treated with external beam radiation therapy (EBRT). We aim to determine if patients with these risk factors who undergo a lymph node (LN) assessment show similar outcomes.We retrospectively reviewed 126 patients with FIGO 2009 stage IA grade 3, stage IB grade 1-2, and stage IIIC (positive LN but no other stage II/III risk factors) endometrioid endometrial cancer who underwent LN assessment. Local (LR), regional recurrences (RR), and distant metastases were analyzed using competing risk methods, and overall survival (OS) was analyzed using Kaplan-Meier.Median follow-up time was 37.2 months. OS was significantly different between patients with and without p53abnl expression (16.7% versus 3.1% deceased), and between patients with and without LVSI (11.1% versus 1.5% deceased; p < 0.01 for both). The 2-year cumulative incidence of LR for patients with p53abnl versus wild type p53 and LVSI versus no LVSI was 11.1% (95% CI 0-25.6) versus 2.2% (95% CI 0-5.25; p = 0.04), and 11.4% (95% CI 2.0-20.9) versus 0%, respectively (p < 0.01). The 2-year cumulative RR in patients with LVSI versus no LVSI was 6.9% (95% CI 0-14.4) versus 0% (p = 0.05). No patients who completed pelvic RT experienced an in-field recurrence.Despite LN assessment, patients with high-intermediate risk early-stage or stage IIIC (with positive lymph nodes only but no other stage II or III risk factors) endometrial cancer with p53abnl expression and/or LVSI have worse outcomes. These patients may derive benefit from intensification with EBRT to improve local and pelvic control.

    View details for DOI 10.1016/j.ygyno.2023.09.001

    View details for PubMedID 37696217

  • Adjuvant radiation therapy in early-stage endometrial cancer with abnormal beta-catenin expression is associated with improved local control. Gynecologic oncology Hui, C., Mendoza, M. G., Snyder, J., Dorigo, O., Litkouhi, B., Renz, M., Karam, A., Devereaux, K., Howitt, B. E., Kidd, E. A. 2023; 174: 42-48

    Abstract

    Emerging data suggests that abnormal (nuclear) β-catenin expression in some settings is associated with poorer outcomes. Our study aimed to verify the significance of abnormal β-catenin expression in early-stage endometrial cancer patients and determine if adjuvant radiation therapy (RT) improves local control.We identified 213 patients with FIGO 2018 stage I-II endometrioid endometrial cancer who underwent surgery from 2009 to 2021 with β-catenin expression assessed. Vaginal, regional, and distant recurrences were analyzed using competing risk methods, and overall survival was analyzed using Kaplan-Meier.Median follow up was 53.2 months; 6.9% experienced vaginal, 8.2% regional, and 7.4% distant recurrence. For the entire cohort, abnormal β-catenin expression was significantly associated with vaginal recurrence and remained significant on multivariate analysis (p = 0.03). There were 114 patients in the no specific molecular profile (NSMP) subgroup, and abnormal β-catenin expression was present in 46.5%. In the NSMP subgroup, abnormal β-catenin expression was associated with increased rates of vaginal recurrence (p = 0.06). Abnormal β-catenin expression in the NSMP subgroup was significant on multivariate analysis for vaginal recurrence (p = 0.04). RT significantly decreased vaginal recurrences in the entire cohort in patients with abnormal β-catenin expression (0%) versus wild type expression (17.5%; p = 0.03). In the NSMP subgroup 0% of patients who received RT versus 20.9% of patients who did not receive RT experienced a vaginal recurrence (p = 0.03).Use of adjuvant RT for stage I-II NSMP endometrial cancer with abnormal β-catenin expression improved local control. RT should be considered in these patients to decrease risk of vaginal recurrences.

    View details for DOI 10.1016/j.ygyno.2023.04.018

    View details for PubMedID 37149904

  • Maveropepimut-S, a DPX-based immune-educating therapy, shows promising and durable clinical benefit in patients with recurrent ovarian cancer, a phase 2 trial. Clinical cancer research : an official journal of the American Association for Cancer Research Dorigo, O., Oza, A. M., Pejovic, T., Ghatage, P., Ghamande, S., Provencher, D., MacDonald, L. D., Torrey, H., Kaliaperumal, V., Ebrahimizadeh, W., Hirsch, H. A., Bramhecha, Y., Villella, J., Fiset, S. 2023

    Abstract

    Patients with platinum resistant ovarian cancer (OvCa) respond poorly to existing therapies. Hence there is a need for more effective treatments.The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase 2 study to evaluate the safety and effectiveness of maveropepimut-S (MVP-S) with cyclophosphamide (CPA) in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL MVP-S 3 weeks apart, followed by one 0.1 mL doses, every 8 weeks up to progression. Oral CPA, 50 mg twice daily, was administered in repeating weekly on and off cycles.Twenty-two patients were enrolled. Median age was 58 years (38-78 years). Among the evaluable population, ORR was 21% (90% CI, 7.5%-41.9%), with a DCR of 63% (90% CI, 41.8%-81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum-sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four stable disease patients maintained clinical benefit up to 25 months. Most treatment related adverse events (TRAEs) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T cell responses were observed in treated patients with clinical benefit.MVP-S with intermittent low-dose CPA is well-tolerated, with clinical benefit for patients with recurrent OvCa. Observed responses are irrespective of the platinum status.

    View details for DOI 10.1158/1078-0432.CCR-22-2595

    View details for PubMedID 37126016

  • Monocytes - A Promising New TRAIL in Ovarian Cancer Cell Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research Chow, S., Dorigo, O. 2022

    Abstract

    Adoptive cell transfer of interferon (IFN)-activated monocytes administered intraperitoneally to patients with platinum-resistant ovarian cancer demonstrated anti-tumor effects and acceptable tolerability. The exposure of monocytes to IFNalpha and IFNgamma upregulated TRAIL, which triggered caspase 8 and direct cell-to-cell contact-dependent apoptosis of ovarian cancer cells.

    View details for DOI 10.1158/1078-0432.CCR-22-2877

    View details for PubMedID 36383129

  • ASO Visual Abstract: Impact of BRCA Mutation Status on Tumor Dissemination Pattern, Surgical Outcome, and Patient Survival in Primary and Recurrent High-Grade Serous Ovarian Cancer (HGSOC). A Multicenter, Retrospective Study of the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS) Consortium. Annals of surgical oncology Glajzer, J., Castillo-Tong, D. C., Richter, R., Vergote, I., Kulbe, H., Vanderstichele, A., Ruscito, I., Trillsch, F., Mustea, A., Kreuzinger, C., Gourley, C., Gabra, H., Taube, E. T., Dorigo, O., Horst, D., Keunecke, C., Baum, J., Angelotti, T., Sehouli, J., Braicu, E. I. 2022

    View details for DOI 10.1245/s10434-022-12681-z

    View details for PubMedID 36335272

  • Impact of BRCA Mutation Status on Tumor Dissemination Pattern, Surgical Outcome and Patient Survival in Primary and Recurrent High-Grade Serous Ovarian Cancer: A Multicenter Retrospective Study by the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS)Consortium. Annals of surgical oncology Glajzer, J., Castillo-Tong, D. C., Richter, R., Vergote, I., Kulbe, H., Vanderstichele, A., Ruscito, I., Trillsch, F., Mustea, A., Kreuzinger, C., Gourley, C., Gabra, H., Taube, E. T., Dorigo, O., Horst, D., Keunecke, C., Baum, J., Angelotti, T., Sehouli, J., Braicu, E. I. 2022

    Abstract

    BACKGROUND: This study seeks to evaluate the impact of breast cancer (BRCA) gene status on tumor dissemination pattern, surgical outcome and survival in a multicenter cohort of paired primary ovarian cancer (pOC) and recurrent ovarian cancer (rOC).PATIENTS AND METHODS: Medical records and follow-up data from 190 patients were gathered retrospectively. All patients had surgery at pOC and at least one further rOC surgery at four European high-volume centers. Patients were divided into one cohort with confirmed mutation for BRCA1 and/or BRCA2 (BRCAmut) and a second cohort with BRCA wild type or unknown (BRCAwt). Patterns of tumor presentation, surgical outcome and survival data were analyzed between the two groups.RESULTS: Patients with BRCAmut disease were on average 4 years younger and had significantly more tumor involvement upon diagnosis. Patients with BRCAmut disease showed higher debulking rates at all stages. Multivariate analysis showed that only patient age had significant predictive value for complete tumor resection in pOC. At rOC, however, only BRCAmut status significantly correlated with optimal debulking. Patients with BRCAmut disease showed significantly prolonged overall survival (OS) by 24.3 months. Progression-free survival (PFS) was prolonged in the BRCAmut group at all stages as well, reaching statistical significance during recurrence.CONCLUSIONS: Patients with BRCAmut disease showed a more aggressive course of disease with earlier onset and more extensive tumor dissemination at pOC. However, surgical outcome and OS were significantly better in patients with BRCAmut disease compared with patients with BRCAwt disease. We therefore propose to consider BRCAmut status in regard to patient selection for cytoreductive surgery, especially in rOC.

    View details for DOI 10.1245/s10434-022-12459-3

    View details for PubMedID 36085390

  • Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup. The Lancet. Oncology Vergote, I., Gonzalez-Martin, A., Lorusso, D., Gourley, C., Mirza, M. R., Kurtz, J., Okamoto, A., Moore, K., Kridelka, F., McNeish, I., Reuss, A., Votan, B., du Bois, A., Mahner, S., Ray-Coquard, I., Kohn, E. C., Berek, J. S., Tan, D. S., Colombo, N., Zang, R., Concin, N., O'Donnell, D., Rauh-Hain, A., Herrington, C. S., Marth, C., Poveda, A., Fujiwara, K., Stuart, G. C., Oza, A. M., Bookman, M. A., participants of the 6th Gynecologic Cancer InterGroup (GCIG) Ovarian Cancer Consensus Conference on Clinical Research, Mahner, S., Reuss, A., du Bois, A., Grimm, C., Marth, C., Berger, R., Concin, N., Chang, T., Ochiai, K., Gebski, V., Davis, A., Beale, P., Vergote, I., Kridelka, F., Denys, H., Vandecaveye, V., Cancido Dos Reis, F. J., Del Pilar Estevez Diz, M., Stuart, G., MacKay, H., Carey, M., Cibula, D., Dundr Path, P., Dorigo, O., Berek, J., O'Donnell, D., Saadeh, A., Boere, I., Lok, C., Coronado, P., Ottevanger, N., Tan, D. S., Ng, J., Gonzalez Martin, A., Oaknin, A., Poveda, A., Perez Fidalgo, A., Rauh-Hain, A., Lu, K., Lopez-Zavala, C., Gomez-Garcia, E. M., Ray-Coquard, I., Paoletti, X., Kurtz, J., Joly, F., Votan, B., Bookman, M., Moore, K., Arend, R., Fujiwara, K., Fujiwara, H., Hasegawa, K., Bruchim, I., Tsoref, D., Oda, K., Okamoto, A., Enomoto, T., Michel, D., Kim, H., Lee, J., Mukhopadhyay, A., Katsaros, D., Colombo, N., Pignata, S., Lorusso, D., Scambia, G., Kohn, E., Lee, J., McNeish, I., Nicum, S., Farrelly, L., Sehouli, J., Keller, M., Braicu, E., Bjorge, L., Mirza, M. R., Auranen, A., Welch, S., Oza, A. M., Heinzelmann, V., Gourley, C., Roxburgh, P., Herrington, C. S., Glasspool, R., Zang, R., Zhu, J. 2022; 23 (8): e374-e384

    Abstract

    The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

    View details for DOI 10.1016/S1470-2045(22)00139-5

    View details for PubMedID 35901833