Impact of Different BRCA1/2 Gene Variants on Response to Therapy and Prognosis of Ovarian Cancer

Impatto Delle Diverse Varianti Dei Geni BRCA1/2 su Risposta Alla Terapia e Prognosi Del Carcinoma Ovarico

Identify any significant differences in terms of drug response and survival between the different possible alterations in the BRCA1/2 genes, in order to stratify ovarian cancer patients with a view to increasingly personalised and thus effective therapy.

Study Overview

• Status: Recruiting
• Conditions: Ovarian Cancer
• Intervention / Treatment: Diagnostic test: Patients must have been diagnosed with ovarian cancer and be BRCA positive; Diagnostic test: BRCA1 and BRCA2 positive, and be affected by Ovarian Cancer

Detailed Description

Ovarian carcinoma (OC) is the leading cause of death among gynaecological neoplasms. It is, in fact, a neoplasm that is not very frequent but highly lethal: in Emilia-Romagna, the incidence is about 17 cases per 100,000 inhabitants and the mortality rate is around 15 cases per 100,000, with a very high mortality/incidence ratio (0.83). The high mortality rate is mainly due to the fact that, due to the non-specific and late symptoms, 75-80% of patients arrive at the diagnosis at an advanced stage of the disease (III-IV), characterised by a 5-year survival of less than 25%.

The primary therapeutic approach for this tumour is a combination of debulking surgery and platinum-based chemotherapy generally associated with taxanes, while as far as maintenance therapies are concerned, PARP inhibitors (PARPi), drugs capable of blocking a DNA repair mechanism alternative to that of homologous recombination, have been gaining in importance in recent years. They have proved particularly effective in tumours that present alterations in the BRCA1 and BRCA2 genes, which are key players in homologous recombination. For this reason, the detection of mutations in the BRCA1 and BRCA2 genes is predictive of the efficacy of PARPi maintenance therapy and, consequently, as of 2015, the BRCA test has been indicated in all women newly diagnosed with ovarian cancer (excluding borderline and mucinous forms), possibly from tumour tissue, given the evidence that in addition to constitutional (inherited) variants, somatic variants (acquired and tumour-confined), present in about 9%, are also associated with a PARPi benefit.

Recent data, however, have challenged the assumption that functionally significant variants for which a predisposing role has been demonstrated for hereditary breast and ovarian cancers are necessarily predictive of drug response. Furthermore, the fact that somatic mutations are present in only a limited fraction of the DNA copies analysed in a tumour suggests that there may be residual BRCA activity that compromises effective PARPi activity.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Daniela Turchetti, MD; Phone Number: +390512143694; Email: daniela.turchetti@unibo.it

Study Locations

• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola
    • Contact: Daniela Turchetti, MD; Phone Number: +390512143694; Email: daniela.turchetti@unibo.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

From 2012 to the end of 2021, 869 patients underwent BRCA testing at the UOC of Medical Genetics of the IRCCS AOU of Bologna Policlinico S.Orsola 869 patients with CO, almost all of whom have given informed consent to the acquisition of clinical documentation relating to their case and to the use of their data for scientific purposes and about half of them were taken on for a period of at least 1 year at the Medical Oncology - Zamagni and/or the Gynaecological Oncology - De Iaco. The investigators estimated a sample of about 300 patients.

Description

Inclusion Criteria:

• ovarian cancer diagnosis by 31/12/2021;
• BRCA test at the UOC of Medical Genetics of the IRCCS AOU of Bologna Policlinico S.Orsola by 31/12/2021;
• follow-up and/or treatment at Medical Oncology and/or Gynaecological Oncology of the IRCCS Azienda Ospedaliero-Universitaria (AOU) of Bologna for a period of time of at least 1 year and by 31/12/2021 and for a minimum period of 6 months

Exclusion Criteria:

• ovarian carcinoma of 'mucinous' or 'borderline' histotype.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in BRCA1/2 status for predictive response to chemotherapy	The primary objective of the study is to clarify whether differences in the status of BRCA1/2 (presence/absence of germline and/or somatic) may be predictive in the response to chemotherapy and survival of patients with ovarian cancer.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences in response to chemotherapy based on BRCA variant	The secondary objective is to determine whether among the variant carriers germline and/or somatic pathogenesis of BRCA1/2 differences exist in terms of response to chemotherapy and survival based on the specific variant found.	12 months

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Investigators: Principal Investigator: Daniela Turchetti, MD, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant'Orsola

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2022
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: November 28, 2024
• First Submitted That Met QC Criteria: January 9, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 9, 2025
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: BRCA2; BRCA1; PARP
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Genital Diseases, Female; Endocrine Gland Neoplasms; Neoplasms, Glandular and Epithelial; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Carcinoma; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms
• Other Study ID Numbers: IMBARCO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No