Circulating Tumor DNA and BRCA Reversion Mutation in Advanced or Recurrent Ovarian Cancer Patients With Germline Mutation.

NCT05458973UNKNOWNOBSERVATIONAL

Summary

Increasing number of ovarian cancer patients are receiving PARP inhibitor as maintenance or salvage therapy. Predictive factors to PARP inhibitor other than BRCA mutation or HRD status as well as specific resistance mechanism are unknown. Thus, the objective of this study was to prospectively collect serial blood samples in ovarian cancer patients with germline BRCA mutation who receive PARP inhibitor. We investigated circulating tumor DNA (ctDNA) before patients are started on PARP inhibitor and every 3 months thereafter until progression on PARP inhibitor. Through assessment of the changes in ctDNA mutational landscape, we aimed to investigate resistance mechanism to PARP inhibitor including BRCA reversion mutation.

Key Facts

Lead Sponsor

Yonsei University

Enrollment

100

Start Date

2017-10-31

Completion Date

2024-10-01

Study Type

OBSERVATIONAL

Official Title

Circulating Tumor DNA and BRCA Reversion Mutation in Advanced or Recurrent Ovarian Cancer Patients With Germline Mutation.

Conditions

Ovarian Cancer

Eligibility

Age Range

19 Years – 85 Years

Sex

FEMALE

Inclusion Criteria:

1. Pathological diagnosis of epithelial ovarian cancer,
2. Presence of germline or somatic BRCA mutation,
3. Patients receiving chemotherapy after primary debulking surgery or interval debulking surgery or patients who are planned to receive chemotherapy after recurrence on first line treatment,
4. Patients with platinum sensitive recurrence (recurrence after 6 months or longer after 1st line treatment) who are planned to receive PARP inhibitor following response to 2nd line chemotherapy.
5. Patients who recurred after 3rd or more lines of chemotherapy and are planned to receive PARP inhibitor.

Exclusion Criteria:

1. Patients who refuse to participate,
2. Patients having difficulty understanding the protocol due to language barrier

Outcome Measures

Primary Outcomes

identify resistance mechanism after PARPi

Investigators will utilize baseline and post-progression samples to identify PARP resistance mechanism for each patient. For patients without baseline blood sample prior to PARP inhibitor usage, tumor Next Generation Sequencing results will be utilized. After identification of newly acquired mutations after PARP inhibitor use, these genes then will be classified into resistance mechanism category. Patients will undergo standard clinical surveillance, which will be based on serum CA125 and radiological assessment every 3 months interval; whole blood for ctDNA will also be collected at every 3 months interval. Upon progression based on clinical surveillance (which usually ranges from 6 months to 2 years), the corresponding whole blood-based ctDNA sample can be used as post-progression sample. The post-progression sample can then be compared with the baseline sample to inform PARP resistance mechanism.

Time frame: every 3 months interval until progression based on clinical surveillance (which usually ranges from 6 months to 2 years)

Secondary Outcomes

Identify pre-existing genomic profiles that may predict response to PARPi

Investigators will utilize baseline blood samples to identify pre-existing genomic profiles that may predict response to PARPi. Post progression blood samples will be used to identify post-specific mechanisms that may predict response to subsequent therapy.

Time frame: every 3 months interval until progression based on clinical surveillance (which usually ranges from 6 months to 2 years)

Identify post-progression resistance mechanisms that may predict response to subsequent therapy

Investigators will utilize baseline blood samples to identify pre-existing genomic profiles that may predict response to PARPi. Post progression blood samples will be used to identify post-specific mechanisms that may predict response to subsequent therapy. Time frame for measurement of secondary outcome will be the same as the time frame for primary outcome. Clinical profiles such as progression-free survival with respect to PARPi, progression-free survival to post-progression subsequent therapy, and overall survival will be utilized.

Time frame: every 3 months interval until progression based on clinical surveillance (which usually ranges from 6 months to 2 years)

Locations

Yonsei University Health System, Severance Hospital, Seoul, South Korea

Linked Papers

Investigation of PARP Inhibitor Resistance Based on Serially Collected Circulating Tumor DNA in Patients With BRCA -Mutated Ovarian Cancer

Abstract Purpose: Patient-specific molecular alterations leading to PARP inhibitor (PARPi) resistance are relatively unexplored. In this study, we analyzed serially collected circulating tumor DNA (ctDNA) from patients with BRCA1/2 mutations who received PARPis to investigate the resistance mechanisms and their significance in postprogression treatment response and survival. Experimental Design: Patients were prospectively enrolled between January 2018 and December 2021 (NCT05458973). Whole-blood samples were obtained before PARPi administration and serially every 3 months until progression. ctDNA was extracted from the samples and sequenced with a 531-gene panel; gene sets for each resistance mechanism were curated. Results: Fifty-four patients were included in this analysis. Mutation profiles of genes in pre-PARPi samples indicating a high tumor mutational burden and alterations in genes associated with replication fork stabilization and drug efflux were associated with poor progression-free survival on PARPis. BRCA hypomorphism and reversion were found in 1 and 3 patients, respectively. Among 29 patients with matched samples, mutational heterogeneity increased postprogression on PARPis, showing at least one postspecific mutation in 89.7% of the patients. These mutations indicate non-exclusive acquired resistance mechanisms—homologous recombination repair restoration (28%), replication fork stability (34%), upregulated survival pathway (41%), target loss (10%), and drug efflux (3%). We observed poor progression-free survival with subsequent chemotherapy in patients with homologous recombination repair restoration (P = 0.003) and those with the simultaneous involvement of two or more resistance mechanisms (P = 0.040). Conclusions: Analysis of serial ctDNAs highlighted multiple acquired resistance mechanisms, providing valuable insights for improving postprogression treatment and survival.

Linked Investigators

Jieun Seo

Jong Rak Choi

Jung-Yun Lee

Saeam Shin

Sang Wun Kim

I am interested in gynecologic cancer minimally invasive surgery such as single-port endometrial cancer surgical staging with sentinel lymph node mapping and da Vinci SP robot surgery, and chemotherapy, targeted therapy, and immunotherapy. I have been performing multiple clinical trials in gynecologic oncology field.

Seung-Tae Lee

Sunghoon Kim

Yeeun Shim

Yong Jae Lee

Yoo-Na Kim

Zisun Choi