Advanced Ovarian Cancer Displays Functional Intratumor Heterogeneity That Correlates to Ex Vivo Drug Sensitivity

IntroductionEpithelial ovarian cancer is recognized to be heterogeneous but is currently treated with a single treatment strategy. Successful patient stratification of emerging chemotherapy agents is dependent upon the availability of reliable biomarkers indicative of the entire tumor.AimThe aim of this study was to evaluate intertumor and intratumor heterogeneity within a series of epithelial ovarian cancer using homologous recombination (HR) DNA repair status.MethodsPrimary cultures generated from ascites and solid tumor from multiple intra-abdominal sites were characterized by their morphology and expression of protein markers. Results were compared with Formalin fixed paraffin embedded tissue pathology.Homologous recombination function was determined by quantification of nuclear Rad51 foci. Growth inhibition (sulforhodamine B) assays were used to calculate the GI50 for cisplatin and rucaparib.ResultsAscites with matched solid tumor were cultured from 25 patients.Concordance in functional HR status between ascites and solid tumor subcultures was seen in only 13 (52%) of 25 patients. Heterogeneity in HR status was seen even in patients with homogeneous histological subtype. Homologous recombination defective cultures were significantly more sensitive to cisplatin and rucaparib.Additionally, intertumor and intratumor heterogeneity was seen between the expression of epithelial and ovarian markers (EpCAM, cytokeratin, CA125, MOC-31, and vimentin). There was no relationship between heterogeneity of HR functional status and antigen expression.ConclusionsIntertumor and intratumor functional HR heterogeneity exists that cannot be detected using histological classification. This has implications for biomarker-directed treatment.

Download Full-text

Cancer-testis antigen expression is shared between epithelial ovarian cancer tumors

Gynecologic Oncology ◽

10.1016/j.ygyno.2014.03.253 ◽

2014 ◽

Vol 133 ◽

pp. 95

Author(s):

A.E. Garcia-Soto ◽

J.A. Lucci ◽

E. Podack ◽

T. Schreiber ◽

E.D. Schroeder

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Antigen Expression ◽

Cancer Testis Antigen ◽

Cancer Testis

Download Full-text

Abstract 659: Evaluation of homologous recombination repair related gene mutation on survival and drug response in Chinese epithelial ovarian cancer patients

10.1158/1538-7445.am2021-659 ◽

2021 ◽

Author(s):

Lei Li ◽

Kang Shao ◽

Jianwei Zhang ◽

Meng Liu ◽

Kui Wu ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Epithelial Ovarian Cancer ◽

Cancer Patients ◽

Gene Mutation ◽

Drug Response ◽

Homologous Recombination Repair ◽

Related Gene ◽

Recombination Repair

Download Full-text

Oral Topotecan as Single-Agent Second-Line Chemotherapy in Patients With Advanced Ovarian Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.19.3967 ◽

2001 ◽

Vol 19 (19) ◽

pp. 3967-3975 ◽

Cited By ~ 36

Author(s):

D. L. Clarke-Pearson ◽

L. Van Le ◽

T. Iveson ◽

C. W. Whitney ◽

P. Hanjani ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Median Time ◽

Single Agent ◽

Advanced Ovarian Cancer ◽

Prolonged Treatment ◽

Second Line ◽

Gynecology And Obstetrics ◽

Platinum Based Chemotherapy ◽

Oral Topotecan

PURPOSE: To evaluate oral topotecan as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. PATIENTS AND METHODS: Patients (N = 116) received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Eligibility criteria included histologic diagnosis of International Federation of Gynecology and Obstetrics stage III or IV epithelial ovarian cancer, bidimensionally measurable disease, prior platinum-containing chemotherapy, age ≥ 18 years, performance status ≤ 2, and life expectancy ≥ 12 weeks. RESULTS: Overall response rate was 21.6% (25 of 116 patients). Median duration of response was 25.0 weeks; median time to response was 8.4 weeks. Median time to progression was 14.1 weeks; median survival was 62.2 weeks. Grade 4 neutropenia was experienced by 50.4% of patients in 13.4% of courses administered. Grade 4 thrombocytopenia was experienced by 22.1% of patients in 5.1% of courses. Grade 3 or 4 anemia was experienced by 29.2% of patients in 8.5% of courses. Most frequent nonhematologic toxicities were predominantly (> 90%) grade 1 or 2 and included nausea, alopecia, diarrhea, and vomiting. CONCLUSION: Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan. Oral topotecan is an active, tolerable, and convenient formulation of an established agent for the second-line treatment of advanced epithelial ovarian cancer and may also facilitate exploring prolonged treatment schedules.

Download Full-text

Cancer-testis antigen expression is shared between epithelial ovarian cancer tumors

Gynecologic Oncology ◽

10.1016/j.ygyno.2017.03.512 ◽

2017 ◽

Vol 145 (3) ◽

pp. 413-419 ◽

Cited By ~ 9

Author(s):

Arlene E. Garcia-Soto ◽

Taylor Schreiber ◽

Natasa Strbo ◽

Parvin Ganjei-Azar ◽

Feng Miao ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Antigen Expression ◽

Cancer Testis Antigen ◽

Cancer Testis

Download Full-text

Poly (ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer

Future Oncology ◽

10.2217/fon-2021-0059 ◽

2021 ◽

Author(s):

Olivia Le Saux ◽

Hélène Vanacker ◽

Fatma Guermazi ◽

Mélodie Carbonnaux ◽

Clémence Roméo ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Advanced Ovarian Cancer ◽

Cost Effective ◽

Preclinical Study ◽

The Body ◽

Synergistic Activity ◽

High Grade ◽

First Line ◽

Homologous Recombination Deficiency

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

Download Full-text

Laboratory cross-comparison of homologous recombination repair mutation analysis in tumor in a multicenter epithelial ovarian cancer series: The BORNEO GEICO 60-0 study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e17550 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e17550-e17550

Author(s):

Ignacio Romero ◽

Ana Oaknin ◽

Zaida Garcia-Casado ◽

Raul Marquez ◽

Alfonso Yubero Esteban ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Epithelial Ovarian Cancer ◽

Mutational Analysis ◽

Figo Stage ◽

Parp Inhibitors ◽

Homologous Recombination Repair ◽

Recombination Repair ◽

Class 1 ◽

Uncertain Significance

e17550 Background: In epithelial ovarian cancer (EOC), the identification of mutations in homologous recombination repair (HRR) genes on tumor is prognostic, predictive of response to PARP inhibitors, and a tool to identify individuals at genetic cancer risk. The aim of this study is to compare the concordance between two laboratories in identifying and classifying genetic variants in HRR genes. Methods: In a multicentre ambispective series of unselected, non mucinous EOC of all stages formalin-fixed and paraffin embedded tumors were collected. These samples underwent the same mutational analysis of 15 HRR genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L) in two different Laboratories (Lab1, Lab2) that used their own validated multi-gene NGS panels. Variant allele frequency (VAF) threshold was 5% for single nucleotide polymorphism and 10% for indels. Large rearrangements were not analyzed. Variants were classified into three categories based on ACMG criteria: non-mutated (class 1-2), Variants of Uncertain Significance (VUS: class 3) and likely pathogenic/pathogenic (class 4-5). Results: A total of 81 cases were sent for the analysis. One had low DNA quality and therefore 80 cases were finally studied (85% high grade serous and 74% FIGO stage III-IV). Results reported by Lab1 and Lab2 (lab1/Lab2) were the following: 21/19 (26%/24%) cases had BRCA1/2 mutations, 7/8 (8.7%/10%) mutations on other HRR genes including two in ATM and RAD51D, one in CHEK1, CHEK2, and FANCL and one RAD51C reported in Lab2 only while the rest were either VUS 23/27 (29%/34%) or non-mutated 29/26 (36%/33%). Concordance between laboratories in classifying patients was 93.75% (kappa coefficient 0.86). Discrepancies (DC) on variants were classified into arbitrary categories, namely 0= complete concordance, category 1 meaning DC in detection assumed to be due to tumor heterogeneity (VAF nearby the threshold) or technique (1A), or caused by laboratories performance and avoidable (1B) and the category 2 identified DC in interpretation without clinical relevance (2A) or clinically relevant (2B), the results of total number of variants are shown in table. Overall, regarding clinically relevant DC in HRR genes, 9 DC in variants were observed including six 2B, two 1A and one 1B and they affect 5 (6.3%) patients since some were overlapping. Conclusions: In our EOC series the concordance of two Laboratories in the identification of clinically relevant HRR mutations on tumor is high but discrepancies in interpretation remain a challenge that needs further harmonization.[Table: see text]

Download Full-text