Talayeh Ghezelayagh

All Publications

• Early experience and assessment of real-world toxicities with mirvetuximab soravtansine in a heavily pretreated patient cohort with ovarian cancer. Gynecologic oncology reports Lang, S. M., Vingopoulos, F., Beshar, I., Somasegar, S., Adams, E. V., Sasse, S. A., Ghezelayagh, T., McClung, E. C., Karam, A., Dorigo, O., Mruthyunjaya, P., Litkouhi, B. 2025; 59: 101738

  Abstract

  Mirvetuximab soravtansine (MIRV) recently emerged as a promising therapeutic option for patients with platinum resistant ovarian cancer (PROC). In trials leading up to its approval, several ocular and other toxicities were identified. We report our experience with MIRV in a less-selected "real-world" population.A retrospective review of patients with folate-receptor alpha positive, recurrent PROC treated with MIRV between December 2022-April 2024 was performed. Demographic, treatment, and toxicity data were abstracted from the medical record. The primary outcomes of interest were the incidence and nature of MIRV-related toxicities, as well as the clinical response to treatment.25 patients were analyzed, and 44 % had >3 previous lines of treatment. The median duration of MIRV treatment 4.7 months, and 36 % of patients received more than 6 months of MIRV. Ocular events were common and occurred early, resulting in grade 1, 2, and 3 toxicity (28 %, 20 %, and 16 % respectively). As a result, 36 % of patients had an increased frequency of ophthalmologic care, 48 % required a medication change, and 32 % had dose reduction, but none required MIRV discontinuation. Pneumonitis occurred in 24 % of patients, was the leading cause of treatment discontinuation and may be associated with significant underlying cardiopulmonary comorbidities and pulmonary disease burden.Our real-world experience with MIRV mirrors previously published data and suggests a benefit may also be seen in a more heavily pretreated population. Toxicities were similar to those previously reported, although our increased incidence of pneumonitis suggests care when treating patients with significant underlying cardiopulmonary comorbidities.

  View details for DOI 10.1016/j.gore.2025.101738

  View details for PubMedID 40270982

  View details for PubMedCentralID PMC12013391

• Robotic-assisted laparoscopic technique for splenectomy and pericolonic tumor removal in a patient with recurrent ovarian cancer Rios-Doria, E., Ghezelayagh, T., Mcnevin, K., Park, J., Gray, H. BMJ PUBLISHING GROUP. 2023: A266

  View details for DOI 10.1136/ijgc-2023-IGCS.509

  View details for Web of Science ID 001262421600337

• Increased TP53 somatic evolution in peritoneal washes of individuals with BRCA1 mutations GYNECOLOGIC ONCOLOGY Tee, X., Hazard, E., Latorre-Esteves, E., Kohrn, B. F., Ghezelayagh, T. S., Fredrickson, J., Coombes, C., Radke, M. R., Manhardt, E., Katz, R., Soong, T., Swisher, E. M., Norquist, B. M., Risques, R. 2024; 190: 18-27

  Abstract

  Individuals with germline BRCA1 and BRCA2 pathogenic variants (BRCA carriers) are at high risk of developing high grade serous ovarian carcinoma (HGSC). HGSC is predominantly driven by TP53 mutations, but mutations in this gene are also commonly found in non-cancerous tissue as a feature of normal human aging. We hypothesized that HGSC predisposition in BRCA carriers may be related to increased TP53 somatic evolution, which could be detectable by ultra-deep sequencing of TP53 mutations in gynecological liquid biopsies.Duplex sequencing was used to identify TP53 mutations with high sensitivity in peritoneal washes and cervical liquid-based cytology (LBC) collected at surgery from 60 individuals including BRCA1 and BRCA2 carriers, and non-carriers. TP53 mutation pathogenicity was compared across groups and with TP53 cancer mutations.TP53 mutations were more abundant in cervical LBC than in peritoneal washes but increased with age in both sample types. In peritoneal washes, but not in cervical LBC, pathogenic TP53 mutation burden was increased in BRCA1 carriers compared to non-carriers, independently of age. Five individuals shared identical pathogenic TP53 mutations in peritoneal washes and cervical LBC, but not in blood.Ultra-deep sequencing of TP53 mutations in peritoneal washes collected at surgery reveals increased burden of pathogenic TP53 mutations in BRCA1 carriers. This excess of pathogenic TP53 mutations might be linked to the elevated risk of HGSC in these individuals. In some patients, concordant TP53 mutations were found in peritoneal washes and cervical LBCs, but the cell of origin remains unknown and deserves further investigation.

  View details for DOI 10.1016/j.ygyno.2024.07.690

  View details for Web of Science ID 001295208500001

  View details for PubMedID 39128337

  View details for PubMedCentralID PMC11560739

• Prevention of Ovarian Cancer: Where are We Now and Where are We Going? Current oncology reports Rodriguez, I. V., Ghezelayagh, T., Pennington, K. P., Norquist, B. M. 2024

  Abstract

  To describe current and future strategies to reduce the burden of ovarian cancer through prevention.Current strategies in genetic testing are missing a substantial number of individuals at risk, representing a missed opportunity for ovarian cancer prevention. Past efforts at screening and early detection have thus far failed to improve ovarian cancer mortality, and novel techniques are needed. Surgical prevention is highly effective, but surgical menopause from oophorectomy has significant side effects. Novel surgical strategies aimed at reducing risk while minimizing these harms are currently being studied. To maximize ovarian cancer prevention, a multi-pronged approach is needed. We propose that more inclusive and accurate genetic testing to identify more individuals at risk, novel molecular screening and early detection, surgical prevention that maximizes quality of life while reducing risk, and broader adoption of targeted and opportunistic salpingectomy will together reduce the burden of ovarian cancer.

  View details for DOI 10.1007/s11912-024-01587-6

  View details for PubMedID 39115678

  View details for PubMedCentralID 4845939

• TP53 somatic evolution in cervical liquid-based cytology and blood from individuals with and without ovarian cancer and BRCA1 or BRCA2 germline mutations. Oncogene Ghezelayagh, T. S., Kohrn, B. F., Fredrickson, J., Krimmel-Morrison, J. D., Latorre-Esteves, E., Tee, X. R., Radke, M. R., Manhardt, E., Norquist, B. M., Katz, R., Swisher, E. M., Risques, R. A. 2024

  Abstract

  Somatic TP53 mutations are prevalent in normal tissue but little is known about their association with cancer risk. Cervical liquid-based cytology (LBC), commonly known as Pap test, provides an accessible gynecological sample to test the value of TP53 somatic mutations as a biomarker for high-grade serous ovarian cancer (HGSC), a cancer type mostly driven by TP53 mutations. We used ultra-deep duplex sequencing to analyze TP53 mutations in LBC and blood samples from 70 individuals (30 with and 40 without HGSC) undergoing gynecologic surgery, 30 carrying BRCA1 or BRCA2 germline pathogenic variants (BRCApv). Only 30% of the tumor mutations were found in LBC samples. However, TP53 pathogenic mutations were identified in nearly all LBC and blood samples, with only 5.4% of mutations in LBC (20/368) also found in the corresponding blood sample. TP53 mutations were more abundant in LBC than in blood and increased with age in both sample types. BRCApv carriers with HGSC had more TP53 clonal expansions in LBC than BRCApv carriers without cancer. Our results show that, while not useful for direct cancer detection, LBC samples capture TP53 mutation burden in the gynecological tract, presenting potential value for cancer risk assessment in individuals at higher hereditary risk for ovarian cancer.

  View details for DOI 10.1038/s41388-024-03089-y

  View details for PubMedID 38918516

  View details for PubMedCentralID 9763223

• Incorporation of a social needs screening tool with subsequent social work support in a large-volume gynecologic oncology clinic Ghezelayagh, T., Bang, D., Busch, T., Doll, K., Urban, R. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2023: S13-S14

  View details for DOI 10.1016/j.ygyno.2023.05.037

  View details for Web of Science ID 001057877600021

• Timing and duration of bevacizumab treatment and survival in patients with recurrent ovarian, fallopian tube, and peritoneal cancer: a multi-institution study EUROPEAN JOURNAL OF GYNAECOLOGICAL ONCOLOGY Ghezelayagh, T. S., Wu, E. S., Barber, E. L., Dao, M. D., Zsiros, E., Urban, R. R., Gray, H. J., Goff, B. A., Shah, C. A., Neubauer, N. L., Dai, J. Y., Tanyi, J. L., Liao, J. B. 2023; 44 (1): 17-25

  Abstract

  Bevacizumab has demonstrated significant benefit in recurrent ovarian, fallopian tube and peritoneal cancer (OC), but its optimal position within the sequence of systemic therapies remains controversial. Since rebound progression after bevacizumab has been observed in other cancers, and because bevacizumab is incorporated in several regimens used in the recurrent setting, the duration of treatment may impact survival. We sought to identify whether earlier bevacizumab exposure is associated with prolonged bevacizumab therapy and survival by conducting a multi-institution retrospective study of recurrent OC patients treated with bevacizumab from 2004-2014. Multivariate logistic regression identified factors associated with receiving more than six bevacizumab cycles. Overall survival by duration and ordinal sequence of bevacizumab therapy were evaluated using logrank testing and Cox regression. In total, 318 patients were identified. 89.1% had stage III or IV disease; 36% had primary platinum resistance; 40.5% received two or fewer prior chemotherapy regimens. Multivariate logistic regression demonstrated that primary platinum sensitivity (Odds Ratio (OR) 2.34, p = 0.001) or initiating bevacizumab at the first or second recurrence (OR 2.73, p < 0.001) were independently associated with receiving more than six cycles of bevacizumab. Receiving more cycles of bevacizumab was associated with improved overall survival whether measured from time of diagnosis (logrank p < 0.001), bevacizumab initiation (logrank p < 0.001), or bevacizumab discontinuation (logrank p = 0.017). Waiting one additional recurrence to initiate bevacizumab resulted in a 27% increased hazard of death (Hazard Ratio (HR) 1.27, p < 0.001) by multivariate analysis. In conclusion, patients with primary platinum sensitive disease who received fewer prior lines of chemotherapy were able to receive more cycles of bevacizumab, which was associated with improved overall survival. Survival worsened when bevacizumab was initiated later in the ordinal sequence of therapies.

  View details for DOI 10.22514/ejgo.2023.002

  View details for Web of Science ID 000938765900002

  View details for PubMedID 36874058

  View details for PubMedCentralID PMC9980410

• Uterine Lavage Identifies Cancer Mutations and Increased<i> TP53</i> Somatic Mutation Burden in Individuals with Ovarian Cancer CANCER RESEARCH COMMUNICATIONS Ghezelayagh, T. S., Kohrn, B. F., Fredrickson, J., Manhardt, E., Radke, M. R., Katz, R., Gray, H. J., Urban, R. R., Pennington, K. P., Liao, J. B., Doll, K. M., Simons, E. J., Burzawa, J. K., Goff, B. A., Speiser, P., Swisher, E. M., Norquist, B. M., Risques, R. 2022; 2 (10): 1282-1292

  Abstract

  Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with OC (6 non-serous and 14 high grade serous-like (serous)). Ultra-deep duplex sequencing (~3000x) with a panel of common OC genes identified the tumor mutation in 33% of non-serous (all early stage) and in 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without OC, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with OC, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential OC risk factor.

  View details for DOI 10.1158/2767-9764.CRC-22-0314

  View details for Web of Science ID 001033741900001

  View details for PubMedID 36311816

  View details for PubMedCentralID PMC9615025

• Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women GENOME MEDICINE Bartlett, T. E., Evans, I., Jones, A., Barrett, J. E., Haran, S., Reisel, D., Papaikonomou, K., Jones, L., Herzog, C., Pashayan, N., Simoes, B. M., Clarke, R. B., Evans, D., Ghezelayagh, T. S., Ponandai-Srinivasan, S., Boggavarapu, N. R., Lalitkumar, P. G., Howell, S. J., Risques, R., Radestad, A., Dubeau, L., Gemzell-Danielsson, K., Widschwendter, M. 2022; 14 (1): 64

  Abstract

  Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation.In healthy premenopausal women with and without a BRCA mutation we studied (i) estrogen and progesterone levels in saliva over an entire menstrual cycle (n = 20); (ii) cancer-free normal breast-tissue from a control population who had no family or personal history of breast cancer and equivalently from BRCA1/2 mutation carriers (n = 28); triple negative breast cancer (TNBC) biopsies and healthy breast tissue taken from sites surrounding the TNBC in the same individuals (n = 14); and biopsies of ER+ve/PR+ve stage T1-T2 cancers and healthy breast tissue taken from sites surrounding the cancer in the same individuals (n = 31); and (iii) DNA methylation and DNA mutations in normal breast tissue (before and after treatment) from clinical trials that assessed the potential preventative effects of vitamins and antiprogestins (mifepristone and ulipristal acetate; n = 44).Daily levels of progesterone were higher throughout the menstrual cycle of BRCA1/2 mutation carriers, raising the prospect of targeting progesterone signalling as a means of cancer risk reduction in this population. Furthermore, breast field cancerization DNA methylation signatures reflective of (i) the mitotic age of normal breast epithelium and (ii) the proportion of luminal progenitor cells were increased in breast cancers, indicating that luminal progenitor cells with elevated replicative age are more prone to malignant transformation. The progesterone receptor antagonist mifepristone reduced both the mitotic age and the proportion of luminal progenitor cells in normal breast tissue of all control women and in 64% of BRCA1/2 mutation carriers. These findings were validated by an alternate progesterone receptor antagonist, ulipristal acetate, which yielded similar results. Importantly, mifepristone reduced both the TP53 mutation frequency as well as the number of TP53 mutations in mitotic-age-responders.These data support the potential usage of antiprogestins for primary prevention of poor-prognostic breast cancers.Clinical trial 1 Mifepristone treatment prior to insertion of a levonorgestrel releasing intrauterine system for improved bleeding control - a randomized controlled trial, clinicaltrialsregister.eu, 2009-009014-40 ; registered on 20 July 2009. Clinical trial 2 The effect of a progesterone receptor modulator on breast tissue in women with BRCA1 and 2 mutations, clinicaltrials.gov, NCT01898312 ; registered on 07 May 2013. Clinical trial 3 A pilot prevention study of the effects of the anti- progestin Ulipristal Acetate (UA) on surrogate markers of breast cancer risk, clinicaltrialsregister.eu, 2015-001587-19 ; registered on 15 July 2015.

  View details for DOI 10.1186/s13073-022-01063-5

  View details for Web of Science ID 000811196900001

  View details for PubMedID 35701800

  View details for PubMedCentralID PMC9199133

• Evaluation of <i>TP53</i> mutations in Pap test and blood DNA as novel biomarkers of ovarian cancer risk. Ghezelayagh, T., Fredrickson, J., Krimmel-Morrison, J. D., Kohrn, B., Radke, M. R., Manhardt, E., Norquist, B. S., Swisher, E. M., Risques, R. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000680263501130

• Characterizing <i>TP53</i> mutations in ovarian carcinomas with and without concurrent <i>BRCA1</i> or <i>BRCA2</i> mutations GYNECOLOGIC ONCOLOGY Ghezelayagh, T. S., Pennington, K. P., Norquist, B. M., Khasnavis, N., Radke, M. R., Kilgore, M. R., Garcia, R. L., Lee, M., Katz, R., Leslie, K. K., Risques, R., Swisher, E. M. 2021; 160 (3): 786-792

  Abstract

  Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes.We performed next generation sequencing on 393 cases of OC prospectively followed for survival. TP53 mutations were classified according to three schemes termed Structural, Functional, and Hotspot. Mutation distribution was compared between cases with and without BRCA mutations. In a subset of 281 cases of high grade serous carcinoma (HGSC), overall survival was compared using Kaplan-Meier curves, logrank testing, and multivariate Cox regression analysis, both stratified and adjusted for BRCA mutation status. Multivariate logistic regression was used to analyze the effects of TP53 mutation type on platinum resistance.TP53 mutations were identified in 76.8% of the total cohort (n = 302/393) and 87.9% of HGSC (n = 247/281). Cases with BRCA mutations demonstrated significantly higher TP53 mutation frequency overall (n = 84/91, 92.3% vs. n = 218/302, 72.2%, p < 0.001). TP53 mutations were not associated with overall survival, even when stratified by BRCA mutation. TP53 mutations were associated with platinum sensitivity, even after adjusting for BRCA mutation status (OR 0.41, p = 0.048). The choice of TP53 mutation classification scheme was not found to alter any significant outcome.BRCA mutations significantly co-occur with TP53 mutations. After adjusting for BRCA mutations, TP53 mutations are associated with platinum sensitivity, and this effect is not dependent on TP53 mutation type.

  View details for DOI 10.1016/j.ygyno.2020.12.007

  View details for Web of Science ID 000620805400022

  View details for PubMedID 33375991

  View details for PubMedCentralID PMC8491988

• Perceptions of risk and reward in <i>BRCA1</i> and <i>BRCA2</i> mutation carriers choosing salpingectomy for ovarian cancer prevention FAMILIAL CANCER Ghezelayagh, T. S., Stewart, L. E., Norquist, B. M., Bowen, D. J., Yu, V., Agnew, K. J., Pennington, K. P., Swisher, E. M. 2020; 19 (2): 143-151

  Abstract

  Salpingectomy with interval oophorectomy has gained traction as an ovarian cancer prevention strategy, but is not currently recommended for high risk women. Nevertheless, some choose this approach. We aimed to understand risk perception and plans for oophorectomy in BRCA1 and BRCA2 (BRCA) mutation carriers choosing salpingectomy for ovarian cancer prevention. This was a longitudinal survey study of BRCA mutation carriers who underwent bilateral salpingectomy to reduce ovarian cancer risk. An initial written questionnaire and telephone interview was followed by annual phone interviews. 22 women with BRCA mutations were enrolled. Median follow-up was three years. The median age at salpingectomy was 39.5 years (range 27-49). Perceived lifetime ovarian cancer risk decreased by half after salpingectomy (median risk reduction 25%, range 0-40%). At final follow-up, five (22.7%) had undergone oophorectomy and five women (22.7%) were not planning to undergo completion oophorectomy. BRCA mutation carriers who had salpingectomy after the recommended age of prophylactic surgery (vs. before the recommended age) were less likely to plan for future oophorectomy (28.6% vs. 66.7%, p = 0.037). All women were satisfied with their decision to undergo salpingectomy with eighteen (81.8%) expressing decreased cancer-related worry. There were no diagnoses of ovarian cancer during our study period. In conclusion, most BRCA mutation carriers undergoing risk-reducing salpingectomy are satisfied with their decision and have lower risk perception after salpingectomy, though some older mutation carriers did not plan on future oophorectomy. Salpingectomy with delayed oophorectomy in BRCA mutation carriers remains investigational and should preferably be performed within a clinical trial to prevent introduction of an innovation before safety has been proven.

  View details for DOI 10.1007/s10689-020-00166-5

  View details for Web of Science ID 000516475800001

  View details for PubMedID 32096072

• Comparing Mortality of Vaginal Sarcoma, Squamous Cell Carcinoma, and Adenocarcinoma in the Surveillance, Epidemiology, and End Results Database OBSTETRICS AND GYNECOLOGY Ghezelayagh, T., Rauh-Hain, J., Growdon, W. B. 2015; 125 (6): 1353-1361

  Abstract

  To evaluate the mortality outcomes of vaginal sarcomas in a large cohort compared with vaginal squamous cell and adenocarcinomas.Women with primary invasive vaginal sarcomas, squamous cell carcinomas, and adenocarcinomas diagnosed between 1988 and 2010 were identified within the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Parametric and nonparametric methods were used to compare the demographic and clinical characteristics of women among the three tumor types as well as between sarcoma histologic subtypes. Overall and cancer-specific mortality outcomes were examined using Kaplan-Meier and multivariable Cox proportional hazards models.The final cohort consisted of 3,121 patients with vaginal squamous cell carcinoma, 720 patients with adenocarcinoma, and 221 patients with sarcoma. Compared with women with squamous cell carcinoma and adenocarcinoma, patients diagnosed with vaginal sarcomas tended to be younger, have larger tumors with less regional extension and lymph node positivity, and be treated primarily with surgery without radiation. In unadjusted analysis, 5-year mortality rates border 30% for all three histologies. After adjusting for other prognostic factors including use of radiation and surgery, patients with vaginal sarcomas had a 69% greater risk of cancer-related mortality compared with patients with squamous cell carcinoma (hazard ratio 1.69, 95% confidence interval 1.26-2.26). Although sarcoma histology failed to associate with mortality risk, age, tumor extension and metastasis, and surgery were poor prognostic factors.Primary vaginal sarcomas are aggressive neoplasms with different presenting characteristics and increased adjusted risk of mortality compared with squamous cell and adenocarcinoma subtypes.III.

  View details for DOI 10.1097/AOG.0000000000000861

  View details for Web of Science ID 000369637100014

  View details for PubMedID 26000506