Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2

Barbosa, Alexandra; Pinto, Pedro; Peixoto, Ana; Guerra, Joana; Pinto, Carla; Santos, Catarina; Pinheiro, Manuela; Escudeiro, Carla; Bartosch, Carla; Silva, João; Teixeira, Manuel R.

doi:10.3390/cancers12102834

Cited by 9 publications

(10 citation statements)

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“…In the second group includes those patients from whom plasma samples were obtained after treatment (n=73). All patients included in this study were previously tested for germline variants in 10 genes in a study from our group that aimed to test the yield of germline variants using FFPE samples for NGS ( 19 ). The clinicopathological features of OC patients included in the study are presented in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

“…At least one variant per tumor sample was identified, except in four cases (OC13, OC29, OC48 and OC63), in which no variants were identified. In addition to the 26 variants identified as germline in our previous study (19), 11 variants with a VAF at nearly 50% in plasma samples were tested in peripheral blood samples and were confirmed to be germline. Excluding the 37 germline variants, we retained 172 somatic variants, among 90 patients and across 23 of the 27 genes included in the panel (Figure 1).…”

Section: Identification Of Somatic Variants In Tumor Samplesmentioning

confidence: 99%

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Next Generation Sequencing of Tumor and Matched Plasma Samples: Identification of Somatic Variants in ctDNA From Ovarian Cancer Patients

et al. 2021

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Genetic testing to detect somatic alterations is usually performed on formalin-fixed paraffin-embedded tumor samples. However, tumor molecular profiling through ctDNA analysis may be particularly interesting with the emergence of targeted therapies for ovarian cancer (OC), mainly when tumor is not available and biopsy is not viable, also allowing representation of multiple neoplastic subclones. Using a custom panel of 27 genes, next-generation sequencing (NGS) was performed on tumor and matched plasma samples from 96 OC patients, which were combined in two groups (treatment naive and post-treatment). Overall, at least one somatic variant present in the tumor sample was also detected in the matched plasma sample in 35.6% of the patients, a percentage that increased to 69.6% of the treatment naive patients and 83.3% of those with stage IV disease, showing the potential of ctDNA analysis as an alternative to identify somatic variants in these patients, namely those that have predictive value for targeted therapy. In fact, of the two treatment-naive patients with somatic BRCA1 variants identified in tumor samples, in one of them we detected in ctDNA a BRCA1 somatic variant that was present in the tumor with a VAF of 53%, but not in the one that had a VAF of 5.4%. We also showed that ctDNA analysis has a complementary role to molecular unraveling of inter- and intra-tumor heterogeneity, as exemplified by one patient diagnosed with bilateral OC in which different somatic variants from both tumors were detected in ctDNA. Interestingly, as these bilateral tumors shared a rare combination of two of the three variants identified in ctDNA, we could conclude that these morphologically different tumors were clonally related and not synchronous independent neoplasias. Moreover, in the post-treatment group of patients with plasma samples collected after surgery, those with detectable somatic variants had poor prognosis when compared with patients with no detectable somatic variants, highlighting the potential of ctDNA analysis to identify patients at higher risk of recurrence. Concluding, this study demonstrated that somatic variants can be detected in plasma samples of a significant proportion of OC patients, supporting the use of NGS-based ctDNA testing for noninvasive tumor molecular profiling and to stratify patients according to prognosis.

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Section: Methodsmentioning

confidence: 99%

Section: Identification Of Somatic Variants In Tumor Samplesmentioning

confidence: 99%

Next Generation Sequencing of Tumor and Matched Plasma Samples: Identification of Somatic Variants in ctDNA From Ovarian Cancer Patients

et al. 2021

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“…Consequently, p53 has long been considered undruggable. A vivid illustration of the scope of this problem is provided by cancer gene panel tests, increasingly being used to guide treatment decisions 1 . TP53 is included in all such panels, and TP53 alterations are often top hits.…”

Section: Introductionmentioning

confidence: 99%

Drugging p53 in cancer: one protein, many targets

Hassin

Oren

2022

Nat Rev Drug Discov

268

181

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Mutations in the TP53 tumour suppressor gene are very frequent in cancer, and attempts to restore the functionality of p53 in tumours as a therapeutic strategy began decades ago. However, very few of these drug development programmes have reached late-stage clinical trials, and no p53-based therapeutics have been approved in the USA or Europe so far. This is probably because, as a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered undruggable. Nevertheless, several promising approaches towards p53-based therapy have emerged in recent years, including improved versions of earlier strategies and novel approaches to make undruggable targets druggable. Small molecules that can either protect p53 from its negative regulators or restore the functionality of mutant p53 proteins are gaining interest, and drugs tailored to specific types of p53 mutants are emerging. In parallel, there is renewed interest in gene therapy strategies and p53-based immunotherapy approaches. However, major concerns still remain to be addressed. This Review re-evaluates the efforts made towards targeting p53-dysfunctional cancers, and discusses the challenges encountered during clinical development.

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“…[4] RAD51D analysis should be implemented into the multi-gene testing for high-risk ovarian cancer patients. [15,16] Currently, given the rarity of RAD51D mutations, the clinical characteristics and survival of RAD51D germline mutations carriers are not fully elucidated in Chinese ovarian cancer population. In the current study, we investigated the clinical characteristics and survival of Chinese ovarian cancer patients with RAD51D germline mutations.…”

Section: Introductionmentioning

confidence: 99%

Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations

Yuan

2022

Preprint

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ObjectivesWe aimed to describe the behavior among Chinese ovarian cancer patients with RAD51D germline mutations at our institution. MethodsNext-generation sequencing (NGS) was conducted for the entire coding regions and exon/intron boundaries of the RAD51D genes in 781 Chinese ovarian cancer patients treated at our institution from January 1, 2015 to August 1, 2021. Clinicopathological characteristics, treatment modalities, and outcomes were assessed for ovarian cancerpatients with RAD51D germline mutations. ResultsRAD51D germline pathogenic mutations were detected in 1.7% (13/781) of patients in this cohort. RAD51D c. 270_271dup (p. Lys91fs) mutation was the most common mutation which was found in 7 patients (7/13, 53.1%). Patients median age at diagnosis was 58 years (range: 45-69 years). 46.2% (6/13) of them were diagnosed after 60 years. Only 1 patient (1/13, 7.7%) had a family history of ovarian or breast cancer. And 1 patient (1/13, 7.7%) had a personal history of breast cancer. The FIGO 2014 distribution by stage was: stage II in 1 patient (7.7%), stage III in 9 patients (69.2%) and stage IV in 3 patient (23.1%).92.3% (12/13) patients had high-grade serous carcinoma. 2 patients (2/13, 15.4%) had a primary peritoneal cancer. The majority of patients in the entire cohort were reported to be platinum sensitive (92.3%, 12/13) with a platinum-free interval (PFI) of > 6 months.For patients who received PARPis for 2ndline maintenance treatment (n=5), 2 patients discontinued PARPis treatment after 33.5 and 8.1 months of duration. Other 3 patients are still on therapy with a duration of 2.4, 13.8 and 30.1 months at the date of data cutoff. 1 patient received PARPi as salvage treatment with a duration of only 1.2 months. 9 patients (9/13, 69.2%) relapsed during follow up and all of them relapsed within 2 years after diagnosis, among which 88.9% (8/9) were classi ed as platinum-sensitive recurrence (PSR), and only 1 patient was classi ed as platinum-resistant recurrence (PRR). Median PFS for the entire cohort was 17.3 months. Median PFS for the PSR subgroup was 15.9 months. 2 patients died during follow-up. The OS of these 2 patients was 17.2 and 39.6 months. The 5-year OS rate was 67.5%. ConclusionsRAD51D germline mutations are more frequent in Chinese ovarian cancer patients than other population. Few patients have a family history of ovarian or breast cancer, and personal history of breast cancer. Most patients are diagnosed after 50 years and tend to be associated with particularly aggressive phenotype. The sensitivity to PARP inhibitors of patients with RAD51D germline mutations need a further analysis.

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Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2

Cited by 9 publications

References 60 publications

Next Generation Sequencing of Tumor and Matched Plasma Samples: Identification of Somatic Variants in ctDNA From Ovarian Cancer Patients

Next Generation Sequencing of Tumor and Matched Plasma Samples: Identification of Somatic Variants in ctDNA From Ovarian Cancer Patients

Drugging p53 in cancer: one protein, many targets

Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations

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