RESUMEN
Mutations in homologous recombination (HR) genes, including BRCA1, BRCA2, and the RAD51 paralog RAD51C, predispose to tumorigenesis and sensitize cancers to DNA-damaging agents and poly(ADP ribose) polymerase inhibitors. However, â¼800 missense variants of unknown significance have been identified for RAD51C alone, impairing cancer risk assessment and therapeutic strategies. Here, we interrogated >50 RAD51C missense variants, finding that mutations in residues conserved with RAD51 strongly predicted HR deficiency and disrupted interactions with other RAD51 paralogs. A cluster of mutations was identified in and around the Walker A box that led to impairments in HR, interactions with three other RAD51 paralogs, binding to single-stranded DNA, and ATP hydrolysis. We generated structural models of the two RAD51 paralog complexes containing RAD51C, RAD51B-RAD51C-RAD51D-XRCC2 and RAD51C-XRCC3. Together with our functional and biochemical analyses, the structural models predict ATP binding at the interface of RAD51C interactions with other RAD51 paralogs, similar to interactions between monomers in RAD51 filaments, and explain the failure of RAD51C variants in binding multiple paralogs. Ovarian cancer patients with variants in this cluster showed exceptionally long survival, which may be relevant to the reversion potential of the variants. This comprehensive analysis provides a framework for RAD51C variant classification. Importantly, it also provides insight into the functioning of the RAD51 paralog complexes.
Asunto(s)
Proteínas de Unión al ADN , Recombinación Homóloga , Neoplasias Ováricas , Recombinasa Rad51 , Proteínas Supresoras de Tumor , Adenosina Trifosfato/metabolismo , Proteínas de Unión al ADN/genética , Femenino , Humanos , Mutación , Neoplasias Ováricas/genética , Recombinasa Rad51/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms â³11 and â³11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.
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Proteína BRCA1 , Resistencia a Antineoplásicos , Exones , Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Sitios de Empalme de ARN , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Resistencia a Antineoplásicos/genética , Proteína BRCA1/genética , Femenino , Animales , Ratones , Neoplasias Ováricas/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Mutación , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular TumoralRESUMEN
BACKGROUND: Our preclinical work revealed tumour hypoxia induces homologous recombination deficiency (HRD), increasing sensitivity to Poly (ADP-ribose) polymerase inhibitors. We aimed to induce tumour hypoxia with ramucirumab thereby sensitising tumours to olaparib. PATIENTS AND METHODS: This multi-institution single-arm Phase 1/2 trial enrolled patients with metastatic gastroesophageal adenocarcinoma refractory to ≥1 systemic treatment. In dose escalation, olaparib was evaluated at escalating dose levels with ramucirumab 8 mg/kg day 1 in 14-day cycles. The primary endpoint of Phase 1 was the recommended Phase 2 dose (RP2D), and in Phase 2 the primary endpoint was the overall response rate (ORR). RESULTS: Fifty-one patients received ramucirumab and olaparib. The RP2D was olaparib 300 mg twice daily with ramucirumab 8 mg/kg. In evaluable patients at the RP2D the ORR was 6/43 (14%) (95% CI 4.7-25.6). The median progression-free survival (PFS) was 2.8 months (95% CI 2.3-4.2) and median overall survival (OS) was 7.3 months (95% CI 5.7-13.0). Non-statistically significant improvements in PFS and OS were observed for patients with tumours with mutations in HRD genes. CONCLUSIONS: Olaparib and ramucirumab is well-tolerated with efficacy that exceeds historical controls with ramucirumab single agent for gastric cancer in a heavily pre-treated patient population.
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Adenocarcinoma , Neoplasias Esofágicas , Piperazinas , Neoplasias Gástricas , Humanos , Ramucirumab , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Ftalazinas , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Unión Esofagogástrica , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Individuals with germline BRCA1 and BRCA2 pathogenic variants (BRCA carriers) are at high risk of developing high grade serous ovarian carcinoma (HGSC). HGSC is predominantly driven by TP53 mutations, but mutations in this gene are also commonly found in non-cancerous tissue as a feature of normal human aging. We hypothesized that HGSC predisposition in BRCA carriers may be related to increased TP53 somatic evolution, which could be detectable by ultra-deep sequencing of TP53 mutations in gynecological liquid biopsies. METHODS: Duplex sequencing was used to identify TP53 mutations with high sensitivity in peritoneal washes and cervical liquid-based cytology (LBC) collected at surgery from 60 individuals including BRCA1 and BRCA2 carriers, and non-carriers. TP53 mutation pathogenicity was compared across groups and with TP53 cancer mutations. RESULTS: TP53 mutations were more abundant in cervical LBC than in peritoneal washes but increased with age in both sample types. In peritoneal washes, but not in cervical LBC, pathogenic TP53 mutation burden was increased in BRCA1 carriers compared to non-carriers, independently of age. Five individuals shared identical pathogenic TP53 mutations in peritoneal washes and cervical LBC, but not in blood. CONCLUSIONS: Ultra-deep sequencing of TP53 mutations in peritoneal washes collected at surgery reveals increased burden of pathogenic TP53 mutations in BRCA1 carriers. This excess of pathogenic TP53 mutations might be linked to the elevated risk of HGSC in these individuals. In some patients, concordant TP53 mutations were found in peritoneal washes and cervical LBCs, but the cell of origin remains unknown and deserves further investigation.
RESUMEN
OBJECTIVE: Combination cediranib/olaparib has reported activity in relapsed ovarian cancer. This phase 2 trial investigated the activity of cediranib/olaparib in relapsed ovarian cancer and its association with homologous recombination deficiency (HRD). METHODS: Seventy patients were enrolled to cohorts of either platinum-sensitive or platinum-resistant ovarian cancer and received olaparib tablets 200 mg twice daily and cediranib tablets 30 mg once daily under a continuous dosing schedule. HRD testing was performed on pre-treatment, on-treatment and archival biopsies by sequencing key homologous recombination repair (HRR) genes and by genomic LOH analysis. The primary objective for the platinum-sensitive cohort was the association of HRD, defined as presence of HRR gene mutation, with progression-free survival (PFS). The primary objective for the platinum-resistant cohort was objective response rate (ORR), with a key secondary endpoint evaluating the association of HRD status with activity. RESULTS: In platinum-sensitive ovarian cancer (N = 35), ORR was 77.1% (95% CI 59.9-89.6%) and median PFS was 16.4 months (95% CI 13.2-18.6). Median PFS in platinum-sensitive HRR-HRD cancers (N = 22) was 16.8 months (95% CI 11.3-18.6), and 16.4 months (95% CI 9.4-NA) in HRR-HR proficient cancers (N = 13; p = 0.57). In platinum-resistant ovarian cancer (N = 35), ORR was 22.9% (95% CI 10.4-40.1%) with median PFS 6.8 months (95% CI 4.2-9.1). Median PFS in platinum-resistant HRR-HRD cancers (N = 7) was 10.5 months (95% CI 3.6-NA) and 5.6 months (95% CI 3.6-7.6) in HRR-HR proficient cancers (N = 18; p = 0.23). CONCLUSIONS: Cediranib/olaparib had clinical activity in both platinum-sensitive and -resistant ovarian cancer. Presence of HRR gene mutations was not associated with cediranib/olaparib activity in either setting.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Ftalazinas , Piperazinas , Quinazolinas , Humanos , Femenino , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Persona de Mediana Edad , Resistencia a Antineoplásicos/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Recombinación Homóloga , Supervivencia sin Progresión , Anciano de 80 o más Años , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , IndolesRESUMEN
BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.
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Carcinoma Epitelial de Ovario , Análisis Costo-Beneficio , Pruebas Genéticas , Mutación de Línea Germinal , Neoplasias Ováricas , Humanos , Femenino , Pruebas Genéticas/economía , Pruebas Genéticas/métodos , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/economía , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/economía , Predisposición Genética a la Enfermedad , Proteína BRCA2/genética , Proteína BRCA1/genética , Persona de Mediana Edad , Estados Unidos/epidemiología , Años de Vida Ajustados por Calidad de Vida , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/economía , ARN Helicasas/genética , Adulto , Reino Unido/epidemiología , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Proteínas de Unión al ADNRESUMEN
Polyguanine tracts (PolyGs) are short guanine homopolymer repeats that are prone to accumulating mutations when cells divide. This feature makes them especially suitable for cell lineage tracing, which has been exploited to detect and characterize precancerous and cancerous somatic evolution. PolyG genotyping, however, is challenging because of the inherent biochemical difficulties in amplifying and sequencing repetitive regions. To overcome this limitation, we developed PolyG-DS, a next-generation sequencing (NGS) method that combines the error-correction capabilities of duplex sequencing (DS) with enrichment of PolyG loci using CRISPR-Cas9-targeted genomic fragmentation. PolyG-DS markedly reduces technical artifacts by comparing the sequences derived from the complementary strands of each original DNA molecule. We demonstrate that PolyG-DS genotyping is accurate, reproducible, and highly sensitive, enabling the detection of low-frequency alleles (<0.01) in spike-in samples using a panel of only 19 PolyG markers. PolyG-DS replicated prior results based on PolyG fragment length analysis by capillary electrophoresis, and exhibited higher sensitivity for identifying clonal expansions in the nondysplastic colon of patients with ulcerative colitis. We illustrate the utility of this method for resolving the phylogenetic relationship among precancerous lesions in ulcerative colitis and for tracing the metastatic dissemination of ovarian cancer. PolyG-DS enables the study of tumor evolution without prior knowledge of tumor driver mutations and provides a tool to perform cost-effective and easily scalable ultra-accurate NGS-based PolyG genotyping for multiple applications in biology, genetics, and cancer research.
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Linaje de la Célula , ADN/genética , Guanina/química , Neoplasias/genética , Poli G/genética , Diferenciación Celular , Evolución Clonal , ADN/química , Genotipo , HumanosRESUMEN
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated metastatic breast cancer. However, studies evaluating PARP inhibitors plus platinum-based chemotherapy in germline BRCA1/2-wildtype triple-negative breast cancer are scarce. A large proportion of germline BRCA1/2-wildtype triple-negative breast cancer shows homologous recombination deficiency (HRD), resulting in a BRCA-like phenotype that might render sensitivity to PARP inhibitors. The S1416 trial assessed the efficacy of cisplatin combined with the PARP inhibitor veliparib in three predefined groups of metastatic breast cancer: germline BRCA1/2-mutated, BRCA-like, and non-BRCA-like. METHODS: S1416 was a randomised, double-blind, placebo-controlled, phase 2 trial conducted at 154 community and academic clinical sites across the USA. Eligible patients aged 18 years or older had metastatic or recurrent triple-negative breast cancer or germline BRCA1/2-associated metastatic or recurrent breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to one line of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) via the National Clinical Trials Network open interactive system with dynamic balancing on number of previous cytotoxic regimens for metastatic disease to receive intravenous cisplatin (75 mg/m2, day 1) combined with either veliparib or matching placebo (300 mg orally twice a day, days 1-14) on a 21-day cycle. Investigators, patients, and the sponsors were masked to treatment assignment; the study statisticians were unmasked. Central testing after ran domisation classified patients as having mutated or wildtype germline BRCA1/2. A biomarker panel established a priori was used to classify patients with wildtype germline BRCA1/2 into BRCA-like and non-BRCA-like phenotype groups, with BRCA-like status based on at least one of the biomarkers: genomic instability score (≥42), somatic BRCA1/2 mutations, BRCA1 promoter methylation, or non-BRCA1/2 homologous recombination repair germline mutations. The primary endpoint was investigator-assessed progression-free survival, analysed separately for the three predefined biomarker groups with a prespecified α value for each analysis. Efficacy analyses were done by intention to treat and included all eligible patients. Safety analyses of toxicities attributed to treatment included all patients who received at least one dose of veliparib or placebo. The study is ongoing and registered with ClinicalTrials.gov, NCT02595905. FINDINGS: Between July 7, 2016, and June 15, 2019, 335 patients were enrolled and randomly assigned. 320 patients (n=162 to cisplatin plus veliparib, all women; and n=158 to cisplatin plus placebo, 157 women and one man) were eligible for efficacy evaluation. 247 patients were classified into the three biomarker groups: germline BRCA1/2-mutated (n=37), BRCA-like (n=101), and non-BRCA-like (n=109). 73 patients could not be classified due to missing biomarker information. Median follow-up was 11·1 months (IQR 5·6-20·8). In the germline BRCA1/2-mutated group, median progression-free survival was 6·2 months (95% CI 2·3-9·2) in the cisplatin plus veliparib group and 6·4 months (4·3-8·2) in the cisplatin plus placebo group (HR 0·79 [95% CI 0·38-1·67]; log-rank p=0·54). In the BRCA-like group, median progression-free survival was 5·9 months (95% CI 4·3-7·8) in the cisplatin plus veliparib group versus 4·2 months (2·3-5·0) in the cisplatin plus placebo group (HR 0·57 [95% CI 0·37-0·88]; p=0·010). In the non-BRCA-like group, median progression-free survival was 4·0 months (95% CI 2·5-4·7) in the cisplatin plus veliparib group versus 3·0 months (2·2-4·4) in the cisplatin plus placebo group (HR 0·89 [95% CI 0·60-1·33]; p=0·57). The most common grade 3 or worse adverse events attributed to treatment were neutropenia (71 [46%] of 155 patients in the cisplatin plus veliparib group vs 29 [20%] of 147 in the cisplatin plus placebo group), leukopenia (42 [27%] vs 11 [7%]), anaemia (35 [23%] vs 12 [8%]), and thrombocytopenia (29 [19%] vs four [3%]). Serious adverse events attributed to treatment occurred in 48 (31%) patients in the cisplatin plus veliparib group and 53 (36%) patients in the cisplatin plus placebo group. Treatment-related adverse events led to death in one patient in the cisplatin plus veliparib group (sepsis) and one patient in the cisplatin plus placebo group (acute kidney injury due to cisplatin plus heart failure from previous doxorubicin exposure). INTERPRETATION: The addition of veliparib to cisplatin significantly improved progression-free survival in patients with BRCA-like metastatic triple-negative breast cancer, but not in patients with non-BRCA-like metastatic breast cancer. PARP inhibitors combined with platinum-based chemotherapy should be explored further in BRCA-like triple-negative breast cancer. FUNDING: National Cancer Institute and National Institute of General Medical Sciences (US National Institutes of Health); AbbVie; Myriad Genetics; the Biomarker, Imaging, and Quality of Life Studies Funding Program (awarded by the National Cancer Institute); and The University of Kansas Cancer Center.
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Antineoplásicos , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Cisplatino/efectos adversos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Calidad de Vida , Recurrencia Local de Neoplasia/patología , Antineoplásicos/efectos adversos , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Método Doble CiegoRESUMEN
OBJECTIVE: Underrepresented groups may be dissuaded from clinical trial participation without perceived value. We therefore comprehensively assessed gynecologic cancer clinical trial protocols for the inclusion of items of value most important to Black individuals. METHODS: ClinicalTrials.gov was queried for NCI-sponsored gynecologic cancer clinical trials in the US between Jan.1994 and Nov.2021. Pre-specified return of value (ROV) items were abstracted from each protocol. Inclusion proportions were calculated for each ROV item and temporal changes assessed with chi-square tests. Temporality of proportional trends was further assessed by slope and departure from linearity calculations. RESULTS: 279 gynecologic cancer clinical trials were included. Most commonly trials had first accrual in 2001-2007 (37%) and involved ovarian cancer (48%), phase II studies (53%), and chemotherapy (60%) or targeted therapy (34%). Trials often included ROV items in basic information (99%), medical record information (99%), and imaging (82%). 41% of trials included ROV items in biomarker testing, 20% genetic testing, and 20% in patient-reported outcome questionnaires. Over time, there were significant increases in the proportion of trials that included genetic (3% to 51%; p < 0.001) and biomarker testing (14 to 78%, p < 0.001). Information on lifestyle risk factors was rare (1%). No trials included ROV items in ancestry, how to connect with other participants, or remuneration. CONCLUSIONS: Gynecologic cancer clinical trials include few design elements that provide high value to Black individuals like lifestyle risk factors, ancestry, and remuneration. In any multi-pronged effort to improve diversity in clinical trial enrollment, inclusion of items valued by Black individuals should be considered.
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Neoplasias de los Genitales Femeninos , Neoplasias Ováricas , Selección de Paciente , Femenino , Humanos , Neoplasias de los Genitales Femeninos/diagnóstico , Neoplasias de los Genitales Femeninos/terapia , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Ensayos Clínicos como Asunto , Negro o AfroamericanoRESUMEN
BACKGROUND: Significant disparities exist in recruitment of minorities to clinical trials, with much of the prior literature focused on race/ethnicity only. Limited English proficiency (LEP) is a known barrier in healthcare that may also drive disparities in trial enrollment. We sought to determine participation rates in gynecologic oncology trials among patients with LEP and to explore barriers to their participation. METHODS: In a retrospective cohort study, electronic health record data from >2,700 patients treated over 2 years at one academic gynecologic oncology practice were abstracted and the primary exposure of having LEP was identified. The primary outcome was enrollment in a clinical trial. Demographic, financial, clinical, and healthcare access-related covariates were also abstracted and considered as potential confounders in a multivariable logistic regression model. Age, race, ethnicity, and insurance status were further examined for evidence of effect modification. In addition, a survey was administered to all gynecologic oncology research staff and gynecologic oncology providers (n=25) to assess barriers to research participation among patients with LEP. RESULTS: Clinical trial enrollment was 7.5% among fluent English speakers and 2.2% among patients with LEP (risk ratio, 0.29; 95% CI, 0.11-0.78; P=.007), and remained significantly lower in patients with LEP after adjusting for the identified confounders of Hispanic ethnicity and insurance payer (odds ratio, 0.34; 95% CI, 0.12-0.97; P=.043). There was a trend toward race and LEP interaction: Asian patients were equally likely to participate in research regardless of language fluency, whereas White and Black patients with LEP were less likely to participate than non-LEP patients in both groups (P=.07). Providers reported that the most significant barriers to enrollment of patients with LEP in research were unavailability of translated consent forms and increased time needed to enroll patients. CONCLUSIONS: Patients with LEP were 3.4 times less likely to participate in gynecologic oncology trials than fluent English speakers. De-aggregation of race, ethnicity, and language proficiency yielded important information about enrollment disparities. These findings offer avenues for future interventions to correct disparities.
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Neoplasias de los Genitales Femeninos , Dominio Limitado del Inglés , Femenino , Humanos , Barreras de Comunicación , Etnicidad , Neoplasias de los Genitales Femeninos/terapia , Estudios Retrospectivos , Ensayos Clínicos como AsuntoRESUMEN
BACKGROUND: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy. PRIMARY OBJECTIVE: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk. STUDY HYPOTHESIS: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) or 45-50 (BRCA2) years, compared with the current standard salpingo-oophorectomy at age 35-40 (BRCA1) or 40-45 (BRCA2) years, is non-inferior in regard to tubo-ovarian cancer risk. TRIAL DESIGN: In this international prospective preference trial, participants will choose between the novel salpingectomy with delayed oophorectomy and the current standard salpingo-oophorectomy. Salpingectomy can be performed after the completion of childbearing and between the age of 25 and 40 (BRCA1), 25 and 45 (BRCA2), or 25 and 50 (BRIP1, RAD51C, and RAD51D pathogenic variant carriers) years. Subsequent oophorectomy is recommended at a maximum delay of 5 years beyond the upper limit of the current guideline age for salpingo-oophorectomy. The current National Comprehensive Cancer Network (NCCN) guideline age, which is also the recommended age for salpingo-oophorectomy within the study, is 35-40 years for BRCA1, 40-45 years for BRCA2, and 45-50 years for BRIP1, RAD51C, and RAD51D pathogenic variant carriers. MAJOR INCLUSION/EXCLUSION CRITERIA: Premenopausal individuals with a documented class IV or V germline pathogenic variant in the BRCA1, BRCA2, BRIP1, RAD51C, or RAD51D gene who have completed childbearing are eligible for participation. Participants may have a personal history of a non-ovarian malignancy. PRIMARY ENDPOINT: The primary outcome is the cumulative tubo-ovarian cancer incidence at the target age: 46 years for BRCA1 and 51 years for BRCA2 pathogenic variant carriers. SAMPLE SIZE: The sample size to ensure sufficient power to test non-inferiority of salpingectomy with delayed oophorectomy compared with salpingo-oophorectomy requires 1500 BRCA1 and 1500 BRCA2 pathogenic variant carriers. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Participant recruitment is expected to be completed at the end of 2026 (total recruitment period of 5 years). The primary outcome is expected to be available in 2036 (minimal follow-up period of 10 years). TRIAL REGISTRATION NUMBER: NCT04294927.
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Neoplasias Ováricas , Salpingooforectomía , Humanos , Femenino , Adulto , Persona de Mediana Edad , Preescolar , Estudios Prospectivos , Calidad de Vida , Genes BRCA1 , Mutación , Ovariectomía/métodos , Salpingectomía/métodos , Proteína BRCA1/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Neoplasias Ováricas/epidemiología , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Cistadenocarcinoma Seroso/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/efectos adversos , Carboplatino/administración & dosificación , Terapia Combinada , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/cirugía , Método Doble Ciego , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Análisis de Intención de Tratar , Quimioterapia de Mantención , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugía , Paclitaxel/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Supervivencia sin Progresión , Calidad de VidaRESUMEN
OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (gBRCA) status. METHODS: Women with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and gBRCA status. RESULTS: 1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n = 586) versus Q3W (n = 546) paclitaxel (ITT: 20.5 vs 15.7 months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8 months, HR 0.64; BRCAwt: 18.0 vs 12.9 months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3 months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between gBRCAm (n = 211) and gBRCAwt (n = 902) subgroups. CONCLUSIONS: DD paclitaxel was tolerable and associated with longer PFS in the HR proficient and gBRCAwt groups, versus Q3W. gBRCA status did not impact safety.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bencimidazoles/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Síndrome de Cáncer de Mama y Ovario Hereditario/tratamiento farmacológico , Neoplasias Quísticas, Mucinosas y Serosas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Esquema de Medicación , Femenino , Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/patología , Humanos , Quimioterapia de Inducción , Quimioterapia de Mantención , Persona de Mediana Edad , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Supervivencia sin Progresión , Adulto JovenRESUMEN
OBJECTIVE: In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy. METHODS: Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks. RESULTS: Of 1140 patients randomized, 742 had BRCA wild type (BRCAwt) tumors (HRP, n = 373; HRD/BRCAwt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCAwt populations (HRD/BRCAwt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval [CI] 0.53-1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56-1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCAwt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control. CONCLUSIONS: These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Síndrome de Cáncer de Mama y Ovario Hereditario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Reparación del ADN por Recombinación/genética , Adulto , Anciano , Anciano de 80 o más Años , Desequilibrio Alélico/genética , Antígeno Ca-125/metabolismo , Carboplatino/administración & dosificación , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Procedimientos Quirúrgicos de Citorreducción , Femenino , Genes BRCA1 , Genes BRCA2 , Inestabilidad Genómica/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/metabolismo , Síndrome de Cáncer de Mama y Ovario Hereditario/patología , Humanos , Quimioterapia de Inducción , Pérdida de Heterocigocidad/genética , Quimioterapia de Mantención , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Adulto JovenRESUMEN
OBJECTIVE: ARIEL3 (NCT01968213) is a placebo-controlled randomized trial of the poly(ADP-ribose) polymerase inhibitor rucaparib as maintenance treatment in patients with recurrent high-grade ovarian carcinoma who responded to their latest line of platinum therapy. Rucaparib improved progression-free survival across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. METHODS: Patients were randomized 2:1 to receive rucaparib 600 mg twice daily or placebo. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were evaluated for association with exceptional benefit (progression-free survival ≥2 years) versus progression on first scan (short-term subgroup) and other efficacy outcomes. RESULTS: Rucaparib treatment was significantly associated with exceptional benefit compared with placebo: 79/375 (21.1%) vs 4/189 (2.1%), respectively (p < 0.0001). Exceptional benefit was more frequent among patients with favorable baseline clinical characteristics and with carcinomas harboring molecular evidence of homologous recombination deficiency (HRD). A comparison between patients who derived exceptional benefit from rucaparib and those in the short-term subgroup revealed both clinical markers (no measurable disease at baseline, complete response to latest platinum, longer penultimate platinum-free interval) and molecular markers (BRCA1, BRCA2, RAD51C, and RAD51D alterations and genome-wide loss of heterozygosity) significantly associated with exceptional benefit. CONCLUSIONS: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favorable clinical characteristics or molecular features associated with HRD. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of patients with recurrent high-grade ovarian carcinoma.
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Antineoplásicos , Carcinoma , Neoplasias Ováricas , Femenino , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Carcinoma/patología , Platino (Metal)/uso terapéutico , Antineoplásicos/uso terapéuticoRESUMEN
Mutations responsible for inherited disease may act by disrupting normal transcriptional splicing. Such mutations can be difficult to detect, and their effects difficult to characterize, because many lie deep within exons or introns where they may alter splice enhancers or silencers or introduce new splice acceptors or donors. Multiple mutation-specific and genome-wide approaches have been developed to evaluate these classes of mutations. We introduce a complementary experimental approach, cBROCA, which yields qualitative and quantitative assessments of the effects of genomic mutations on transcriptional splicing of tumor suppressor genes. cBROCA analysis is undertaken by deriving complementary DNA (cDNA) from puromycin-treated patient lymphoblasts, hybridizing the cDNA to the BROCA panel of tumor suppressor genes, and then multiplex sequencing to very high coverage. At each splice junction suggested by split sequencing reads, read depths of test and control samples are compared. Significant Z scores indicate altered transcripts, over and above naturally occurring minor transcripts, and comparisons of read depths indicate relative abundances of mutant and normal transcripts. BROCA analysis of genomic DNA suggested 120 rare mutations from 150 families with cancers of the breast, ovary, uterus, or colon, in >600 informative genotyped relatives. cBROCA analysis of their transcripts revealed a wide variety of consequences of abnormal splicing in tumor suppressor genes, including whole or partial exon skipping, exonification of intronic sequence, loss or gain of exonic and intronic splicing enhancers and silencers, complete intron retention, hypomorphic alleles, and combinations of these alterations. Combined with pedigree analysis, cBROCA sequencing contributes to understanding the clinical consequences of rare inherited mutations.
RESUMEN
OBJECTIVE: Routine genetic testing for ovarian cancer and identification of germline mutations can help improve early detection of cancer as well as guide treatment. Knowledge of genetic counseling and referral rates for genetic testing has been lower for Black patients, compared to White patients. We aimed to describe the demographics and presence of germline mutations in Black individuals with ovarian, fallopian tube or peritoneal carcinoma at two large academic institutions. METHODS: Fifty-one Black patients with invasive epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were identified via institutional tissue banks over a 20-year time-period. Germline DNA was sequenced using BROCA, a targeted capture and parallel sequencing assay that identified pathogenic germline mutations in ovarian carcinoma susceptibility genes. RESULTS: Germline mutations in ovarian cancer susceptibility genes were found in 25.5% of women, most commonly BRCA1 and BRCA2. This mutation frequency mirrors those previously described among predominantly White populations. Our data suggests there may be an advantage in survival among those with germline mutations, although this was not statistically significant. CONCLUSIONS: Given similar frequencies of germline mutations between Black and White patients with ovarian cancer, we conclude that there are not major differences in the genetic predisposition to ovarian carcinoma. Equitable access to genomic advancements including germline and tumor sequencing would facilitate equal access to PARP inhibitors, the standard of care for patients with BRCA mutated advanced ovarian cancer.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de las Trompas Uterinas/genética , Mutación de Línea Germinal , Neoplasias Ováricas/genética , Neoplasias Peritoneales/genética , Adulto , Anciano , Anciano de 80 o más Años , Población Negra , Neoplasias de las Trompas Uterinas/etnología , Neoplasias de las Trompas Uterinas/mortalidad , Femenino , Predisposición Genética a la Enfermedad , Recombinación Homóloga , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/etnología , Neoplasias Ováricas/mortalidad , Neoplasias Peritoneales/etnología , Neoplasias Peritoneales/mortalidad , Población BlancaRESUMEN
OBJECTIVE: In the phase 3 VELIA/GOG-3005 trial, veliparib added to carboplatin-paclitaxel and continued as maintenance improved progression-free survival (PFS) compared to carboplatin-paclitaxel alone in patients with newly diagnosed ovarian carcinoma. Primary analysis of PFS was by investigator (INV) assessment, with a supplemental analysis of PFS by blinded independent central review (BICR). METHODS: Patients received veliparib or placebo with carboplatin-paclitaxel (6â¯cycles) and as maintenance (30 additional cycles). The primary analysis compared PFS in the veliparib-throughout arm to the carboplatin-paclitaxel only arm in the BRCA mutation (BRCAm), homologous recombination deficiency (HRD), and intention-to-treat (ITT) populations. Exploratory analyses of PFS in BRCA wildtype (BRCAwt), homologous recombination proficient (HRP), and HRDâ¯+â¯BRCAwt populations were also performed. PFS per BICR and overall concordance rates between INV and BICR assessments were analyzed. RESULTS: Hazard ratios for PFS by INV and BICR were consistent in each of the primary analysis and exploratory populations. In the ITT population, median PFS per INV was 23.5â¯months in the veliparib-throughout arm versus 17.3â¯months in the control arm (hazard ratio [HR] 0.683, 95% confidence interval [CI] 0.562-0.831; Pâ¯<â¯0.001). Median PFS by BICR was 29.3â¯months versus 19.2â¯months (HR 0.687, 95% CI 0.504-0.806). In the ITT population, the overall concordance rates between INV and BICR were 78% and 75% for the veliparib-throughout and control arms, respectively. CONCLUSIONS: Hazard ratios for PFS per BICR and per INV were consistent, with no suggestion of investigator bias. These findings support the reliability of PFS by INV in ovarian cancer trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Carboplatino/uso terapéutico , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/mortalidad , Interpretación Estadística de Datos , Femenino , Humanos , Clasificación del Tumor , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/mortalidad , Paclitaxel/uso terapéutico , Supervivencia sin Progresión , Reproducibilidad de los Resultados , Proyectos de Investigación , Criterios de Evaluación de Respuesta en Tumores Sólidos , Análisis de SupervivenciaRESUMEN
OBJECTIVES: Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes. METHODS: We performed next generation sequencing on 393 cases of OC prospectively followed for survival. TP53 mutations were classified according to three schemes termed Structural, Functional, and Hotspot. Mutation distribution was compared between cases with and without BRCA mutations. In a subset of 281 cases of high grade serous carcinoma (HGSC), overall survival was compared using Kaplan-Meier curves, logrank testing, and multivariate Cox regression analysis, both stratified and adjusted for BRCA mutation status. Multivariate logistic regression was used to analyze the effects of TP53 mutation type on platinum resistance. RESULTS: TP53 mutations were identified in 76.8% of the total cohort (n = 302/393) and 87.9% of HGSC (n = 247/281). Cases with BRCA mutations demonstrated significantly higher TP53 mutation frequency overall (n = 84/91, 92.3% vs. n = 218/302, 72.2%, p < 0.001). TP53 mutations were not associated with overall survival, even when stratified by BRCA mutation. TP53 mutations were associated with platinum sensitivity, even after adjusting for BRCA mutation status (OR 0.41, p = 0.048). The choice of TP53 mutation classification scheme was not found to alter any significant outcome. CONCLUSIONS: BRCA mutations significantly co-occur with TP53 mutations. After adjusting for BRCA mutations, TP53 mutations are associated with platinum sensitivity, and this effect is not dependent on TP53 mutation type.
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Genes BRCA1/fisiología , Genes BRCA2/fisiología , Neoplasias Ováricas/genética , Proteína p53 Supresora de Tumor/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Persona de Mediana Edad , Mutación , Estudios Prospectivos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
OBJECTIVE: To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. METHODS: This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. RESULTS: Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10-0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations. CONCLUSION: Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.