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

O’Donnell, Rachel; Kaufmann, Angelika; Woodhouse, Laura; McCormick, Aiste; Cross, Paul; Edmondson, Richard J.; Curtin, Nicola J.

doi:10.1097/igc.0000000000000745

Cited by 10 publications

(10 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The main obstacles hindering a more effective cancer management are late stage diagnosis, inadequate chemotherapy and lack of reliable methods to predict treatment response. As many HGSOCs are homologous recombination-defective, several groups have tried to develop predictive tools based on the detection of HR genes mutations, such as BRCA1 and BRCA2, and the distinct genomic signatures associated with defective HR (16). Although being relatively sensitive in detecting HRD, genetic testing has, however, its limitations.…”

Section: Discussionmentioning

confidence: 99%

“…BRCA sequencing and HRD genetic tests are usually performed on a single sample per patient (20,40,41). However, at the time of diagnosis, HGSOC typically affects several abdominal tissues or organs and, while probably deriving from the same primary tumor, each cancer possesses significant clonal, spatial and temporal heterogeneity, and can develop its independent properties and characteristics (16,42,43). DNA repair capacity can be one of these properties.…”

Section: Independent Tumors From a Single Patient Can Display Differementioning

confidence: 99%

“…13 Attributed to activity of the AID/APOBEC family of cytidine deaminases. 16 Found mostly in liver cancer, aetiology unknown. 19 Found exclusively in pilocytic astrocytoma, aetiology unknown.…”

Section: Lack Of Mutations In Brca1 and Brca2 Genes Does Not Exclude mentioning

confidence: 99%

“…In these studies, patients with either germline or somatic BRCA1/2 mutations responded better to the PARPi olaparib, niraparib and rucaparib than patients with wild-type BRCA. However, it was also found that clinical response to PARPi was not simply restricted to BRCA1/2-mutated tumors, but generally extended to patients with HR-deficient cancers (16).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Functional Homologous Recombination Assay Predicts Primary Chemotherapy Response and Long-Term Survival in Ovarian Cancer Patients

Tumiati

Hietanen

Hynninen

et al. 2018

Clinical Cancer Research

View full text Add to dashboard Cite

Homologous recombination deficiency (HRD) correlates with platinum sensitivity in patients with ovarian cancer, which clinically is the most useful predictor of sensitivity to PARPi. To date, there are no reliable diagnostic tools to anticipate response to platinum-based chemotherapy, thus we aimed to develop an functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments. We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples ( = 32). Samples clustered in 3 categories: HR-deficient, HR-low, and HR-proficient. We analyzed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters. In parallel, we performed DNA-sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening. Low HR scores predicted primary platinum sensitivity with high statistical significance ( = 0.0103), associated with longer PFI (HR-deficient vs. HR-proficient: 531 vs. 53 days), and significantly correlated with improved OS (HR score <35 vs. ≥35, hazard ratio = 0.08, = 0.0116). At the genomic level, we identified a few unclear mutations in HR genes and the mutational signature associated with HRD, but, overall, genetic screening failed to predict functional HRD. We developed an assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of patients with ovarian cancer..

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Independent Tumors From a Single Patient Can Display Differementioning

confidence: 99%

Section: Lack Of Mutations In Brca1 and Brca2 Genes Does Not Exclude mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Functional Homologous Recombination Assay Predicts Primary Chemotherapy Response and Long-Term Survival in Ovarian Cancer Patients

Tumiati

Hietanen

Hynninen

et al. 2018

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…The genetic heterogeneity of HGSC has been described previously [12][13][14]. In 66% of cases, HGSC occurs bilaterally and often synchronously, affecting both ovaries; whether they are independent primary tumors from multifocal oncogenesis, arising spontaneously from a similar genetic background, clonally related due to tumorigenesis initiating from one ovary and then metastasizing to the contralateral ovary, or two metastases, has also been evaluated [15].…”

Section: Discussionmentioning

confidence: 99%

Intratumoral Genomic Heterogeneity May Hinder Precision Medicine Strategies in Patients with Serous Ovarian Carcinoma

et al. 2020

View full text Add to dashboard Cite

Precision medicine, which includes comprehensive genome sequencing, is a potential therapeutic option for treating high-grade serous carcinoma (HGSC). However, HGSC is a heterogeneous tumor at the architectural, cellular, and molecular levels. Intratumoral molecular heterogeneity currently limits the precision of medical strategies based on the gene mutation status. This study was carried out to analyze the presence of 160 cancer-related genetic alterations in three tissue regions with different pathological features in a patient with HGSC. The patient exhibited histological heterogeneous features with different degrees of large atypical cells and desmoplastic reactions. TP53 mutation, ERBB2 and KRAS amplification, and WT1, CDH1, and KDM6A loss were detected as actionable gene alterations. Interestingly, the ERBB2 and KRAS amplification status gradually changed according to the region examined. The difference was consistent with the differences in pathological features. Our results demonstrate the need for sampling of the appropriate tissue region showing progression of pathological features for molecular analysis to solve issues related to tumor heterogeneity prior to developing precision oncology strategies.

show abstract

Approaches for Identifying Novel Targets in Precision Medicine: Lessons from DNA Repair

Williams

Staples

2017

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

Genome stability is maintained by a number of elegant mechanisms, which sense and repair damaged DNA. Germline defects that compromise genomic integrity result in cancer predisposition, exemplified by rare syndromes caused by mutations in certain DNA repair genes. These individuals often exhibit other symptoms including progeria and neurodegeneration. Paradoxically, some of these deleterious genetic alterations provide novel therapeutic opportunities to target cancer cells; an excellent example of such an approach being the recent development of poly (ADP-ribose) polymerase inhibitors as the first 'synthetic lethal' medicine for patients with BRCA-mutant cancers. The therapeutic exploitation of synthetic lethal interactions has enabled a novel approach to personalised medicine based on continued molecular profiling of patient and tumour material. This profiling may also aid clinicians in the identification of specific drug resistance mechanisms following relapse, and enable appropriate modification of the therapeutic regimen. This chapter focuses on therapeutic strategies designed to target aspects of the DNA damage response, and examines emerging themes demonstrating mechanistic overlap between DNA repair and neurodegeneration.

show abstract

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

Abstract: Intertumor and intratumor functional HR heterogeneity exists that cannot be detected using histological classification. This has implications for biomarker-directed treatment.

Cited by 10 publications

References 21 publications

A Functional Homologous Recombination Assay Predicts Primary Chemotherapy Response and Long-Term Survival in Ovarian Cancer Patients

A Functional Homologous Recombination Assay Predicts Primary Chemotherapy Response and Long-Term Survival in Ovarian Cancer Patients

Intratumoral Genomic Heterogeneity May Hinder Precision Medicine Strategies in Patients with Serous Ovarian Carcinoma

Approaches for Identifying Novel Targets in Precision Medicine: Lessons from DNA Repair

Contact Info

Product

Resources

About