Mutant Ovarian Cancer Research Articles

Prevalence study of BRCA1/2 mutations in Portuguese patients diagnosed with non-mucinous ovarian cancer, fallopian tube invasive neoplasia or peritoneal primary cancer (PADOC)

<h3>Objectives:</h3> Family history is a representative risk factor for ovary cancer (OC), frequently associated with <i>BRCA1/2</i> mutations. The primary objective was to determine the prevalence of <i>BRCA1/2</i> mutations (somatic and germline) in patients with non-mucinous ovarian cancer (NMOC), invasive fallopian tube neoplasia (IFTN) or primary peritoneal carcinoma (PPC). <h3>Methods:</h3> National, interventional, retrospective and analytical study, with an estimated sample size of 261 women aged ≥18 years, diagnosed with NMOC, IFTN or PPC between 01/01/2014 and 31/12/2016 in the nine selected centers. <h3>Results:</h3> From 165 women eligible for analysis, the prevalence of <i>BRCA1/2</i> mutation was 20% (24.2% somatic, 75.8% germline). For patients with a mutation, 54.5% had a mutation in <i>BRCA1</i> (27.8% somatic, 72.2% germline), while 45.5% in <i>BRCA2</i> (20.0% somatic, 80.0% germline). Mean age of the sample was 61.1 years (mutated 60.3 years, non-mutated 61.3 years For patients with a mutation, the ages of the subgroups with somatic and germline were 70.5 and 57.0 years, respectively, with statistically significant difference. Furthermore, patients with somatic mutation were 68.1 years at diagnosis, whereas those with germline were 54.6 years, with statistically significant difference. In addition, 56.4% of patients with a mutation had disease in stage III and 18.8% in stage IV. Regarding family history, 20.6% of the total had confirmed family history of <i>BRCA</i> associated cancer, being that information unknown by 29.1%. In patients with <i>BRCA1/2</i> germline mutation, 48.0% confirmed family history of BRCA-associated tumors, in opposition to 15.2% in the non-mutated group. From the patients with mutation who reported familial history, 75.0% reported breast cancer, 33.3% ovarian cancer and 15.0% other tumors. <h3>Conclusions:</h3> PADOC study evaluated for the first time the nationwide prevalence of <i>BRCA1/2</i> germline and somatic mutations in ovarian cancer in Portugal, and the results suggest an estimated prevalence of 20.0%. These results highlight the importance of raising awareness for the disease in Portugal and the recommendation of broad genetic testing also bearing in mind the percentage of patients that have no information of <i>BRCA</i>-related cancers in family.

Abstract 1425: Synergistic antitumor efficacy of the dual RAF/MEK inhibitor VS-6766 with FAK inhibition for treatment of RAS-dependent solid tumors

Abstract The RAS/RAF/MEK/ERK pathway is the most mutated oncogenic pathway in cancer, and RAS pathway mutations often present with an overall worse prognosis. Although RAF and MEK have been validated as anticancer targets and several BRAF and MEK inhibitors (MEKi) are FDA approved, acquired resistance develops in most patients. Preclinically, inhibition of RAF or MEK has been found to activate focal adhesion kinase (FAK) signaling which may bypass RAS pathway blockade by driving tumor growth through activation of downstream pathways such as RhoA and YAP. VS-6766 is a unique dual RAF/MEK inhibitor which allows VS-6766 to block MEK signaling without the compensatory MEK activation that limits the efficacy of other MEK inhibitors. Defactinib is a selective FAK inhibitor (FAKi). Clinical studies are ongoing evaluating VS-6766 and defactinib for the treatment of various solid tumors. In 3D proliferation assays in vitro, defactinib was synergistic with VS-6766 or trametinib (MEKi) in reducing viability of several human tumor cell lines, including KRAS mutant (mt) ovarian cancer (TOV-21G) and KRAS-G12V mt non-small cell lung cancer (NSCLC; H441). We next investigated whether FAKi augments the efficacy of VS-6766 in solid tumor models. Combination of a FAKi with VS-6766 in a KRAS mt ovarian xenograft model (TOV21G) induced &amp;gt;30% tumor regression in 9/10 mice, whereas each agent alone induced mainly tumor stasis (&amp;gt;30% tumor regression with FAKi monotherapy or VS-6766 monotherapy in 1/10 and 3/10 mice, respectively) following 11 days of treatment. Similar results were observed in KRAS mt NSCLC (H2122) and GNAQ mt uveal melanoma (92.1) models in which the combination of FAKi with VS-6766 or trametinib induced tumor regression. In several patients with KRAS mt tumors, sequential biopsies showed that treatment with VS-6766 induced FAK activation (pY397) as a potential resistance mechanism, and this increased FAK activation was reversed in the presence of the defactinib/VS-6766 combination. Accordingly, the combination of VS-6766 with defactinib showed clinical activity in low grade serous ovarian cancer (LGSOC; ORR = 56% in KRAS-G12 mt and ORR = 41% in all 17 LGSOC patients; 8/17/20 data cut off). Importantly, the combination of defactinib with VS-6766 also induced responses in patients who had progressed on previous MEK inhibitor regimens. VS-6766 with defactinib also showed clinical activity in KRAS-G12V mt NSCLC. Furthermore, this combination regimen of VS-6766 with defactinib exhibited a manageable safety profile with no patients discontinuing for adverse events (NCT03875820). These preclinical and clinical data support the recent initiation of two registration-directed studies evaluating VS-6766 ± defactinib for the treatment of recurrent LGSOC with or without a KRAS mutation (NCT04625270) and recurrent NSCLC with KRAS-G12V or other KRAS mutation (NCT04620330). Citation Format: Silvia Coma, Justine S. Paradis, J Silvio Gutkind, Jonathan A. Pachter. Synergistic antitumor efficacy of the dual RAF/MEK inhibitor VS-6766 with FAK inhibition for treatment of RAS-dependent solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1425.

The Influence of Pre PARP-Inhibitor Platinum Chemotherapy in BRCA Mutated Ovarian Cancer, A Monocentric Experience

The Influence of Pre PARP-Inhibitor Platinum Chemotherapy in BRCA Mutated Ovarian Cancer, A Monocentric Experience

Platelet-Activating Factor Acetylhydrolase Expression in BRCA1 Mutant Ovarian Cancer as a Protective Factor and Potential Negative Regulator of the Wnt Signaling Pathway.

Aberrantly activated Wnt/β-catenin signaling pathway, as well as platelet-activating factor (PAF), contribute to cancer progression and metastasis of many cancer entities. Nonetheless, the role of the degradation enzyme named platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in ovarian cancer etiology is still unclear. This study investigated the functional impact of platelet-activating factor acetylhydrolase on BRCA1 mutant ovarian cancer biology and its crosstalk with the Wnt signaling pathway. PAF-AH, pGSK3β, and β-catenin expressions were analyzed in 156 ovarian cancer specimens by immunohistochemistry. PAF-AH expression was investigated in ovarian cancer tissue, serum of BRCA1-mutated patients, and in vitro in four ovarian cancer cell lines. Functional assays were performed after PLA2G7 silencing. The association of PAF-AH and β-catenin was examined by immunocytochemistry. In an established ovarian carcinoma collective, we identified PAF-AH as an independent positive prognostic factor for overall survival (median 59.9 vs. 27.4 months; p = 0.016). PAF-AH correlated strongly with the Wnt signaling proteins pGSK3β (Y216; nuclear: cc = 0.494, p < 0.001; cytoplasmic: cc = 0.488, p < 0.001) and β-catenin (nuclear: cc = 0.267, p = 0.001; cytoplasmic: cc = 0.291, p < 0.001). In particular, high levels of PAF-AH were found in tumor tissue and in the serum of BRCA1 mutation carriers. By in vitro expression analysis, a relevant gene and protein expression of PLA2G7/PAF-AH was detected exclusively in the BRCA1-negative ovarian cancer cell line UWB1.289 (p < 0.05). Functional assays showed enhanced viability, proliferation, and motility of UWB1.289 cells when PLA2G7/PAF-AH was downregulated, which underlines its protective character. Interestingly, by siRNA knockdown of PLA2G7/PAF-AH, the immunocytochemistry staining pattern of β-catenin changed from a predominantly membranous expression to a nuclear one, suggesting a negative regulatory role of PAF-AH on the Wnt/β-catenin pathway. Our data provide evidence that PAF-AH is a positive prognostic factor with functional impact, which seems particularly relevant in BRCA1 mutant ovarian cancer. For the first time, we show that its protective character may be mediated by a negative regulation of the Wnt/β-catenin pathway. Further studies need to specify this effect. Potential use of PAF-AH as a biomarker for predicting the disease risk of BRCA1 mutation carriers and for the prognosis of patients with BRCA1-negative ovarian cancer should be explored.

The importance of variants of unknown significance (VUS) in BRCA mutation.

e22507 Background: Genetic testing of patients for BRCA mutation may report variants of unknown significance (VUS). The use of multi-gene panels in clinical care has been increasing. Consequently, the reporting of variants of unknown significance has also increased. More than two decades of research and testing have elevated the status of BRCA1 and BRCA2 genes as the most well characterized genes. However, VUS are found even in BRCA1/2 testing. This raises many ethical and policy issues including communicating the significance of the results and possible clinical management options to patients. The practicing physicians would face the ethical and potential legal burden of contacting and explaining to patients, when any role of VUS changes and gets reclassified as potentially harmful. Methods: Data were collected retrospectively from medical records of patients tested for BRCA mutations. The results of fifty-two patients were analyzed. Eight patients had BRCA1 and BRCA2 mutations and twelve patients had variants of unknown significance. Results: When the results of thirteen patients with BRCA mutations with VUS were analyzed further, the variants included POLE, CHEK2, PALB2, MUTHYH, BR1P1, MSH3, ATM, RAD51C, GALNT12, etc. The age of these patients ranged from 39 years to 69 years. Four patients had ovarian cancer and eight patients had breast cancer, and one patient had both breast and ovarian cancers. The number of patients with stage IV, III, II, and I diseases were six, one, two, and two respectively. One patient had bilateral breast cancer and one patient had carcinoma in-situ. Eight patients had family histories of various cancers, including cancers of the breast, uterine, and prostate cancer. All patients were treated appropriately and three patients died due to their disease. Conclusions: Based on patients’ age, family histories, and disease characteristics BRCA mutation analyses were done. All patients tested positive for BRCA mutations and VUS were informed about their results. Variants of BRCA1 and BRCA2 occur in 2%-4% of tests depending on the laboratories, where the tests were performed. There is no concordance as to how VUS results were reported. There is conflicting evidence regarding the pathogenicity of VUS. These make clinical recommendations very complex. Based on existing guidelines, physicians can explain the details of the significance of BRCA! And BRCA2 mutations to patients with clarity. However, it is difficult and unclear to give recommendations regarding prophylactic measures, specific treatment options for BRCA mutation positive breast and ovarian cancer, follow-ups, and family testing in patients with VUS. Therefore, during BRCA testing, when VUS are reported routinely along with mutations of known significance, the treating physicians would need a better guidance to advise their patients without unduly increasing their anxiety, fear, and potential for misunderstanding.

ENGOT-ov60/GOG3052/RAMP 201: A phase 2 study of VS-6766 (dual RAF/MEK inhibitor) alone and in combination with defactinib (FAK inhibitor) in recurrent low-grade serous ovarian cancer (LGSOC).

TPS5603 Background: VS-6766 is a unique small molecule inhibitor that blocks MEK kinase activity and RAF phosphorylation of MEK. This mechanism of blockade has been shown to limit compensatory MEK activation, thereby potentially enhancing efficacy of MEK inhibition. Defactinib, (VS-6063), an orally active small molecule, is a potent adenosine 5'- triphosphate (ATP) competitive, reversible inhibitor of focal adhesion kinase (FAK). Defactinib has shown synergistic activity with BRAF and MEK inhibitors in both in vitro and in vivo solid tumor models. Prior molecularly unselected studies with single agent MEK inhibitors have shown response rates up to 26% in recurrent LGSOC. A third of patients with recurrent LGSOC harbor somatic KRAS mutations. FAK inhibition has been shown to induce tumor regression when combined with RAF, MEK or RAF/MEK inhibitors in in vivo models of KRAS mutant ovarian cancer. The combination of VS-6766 and defactinib is currently being evaluated in the ongoing Investigator Sponsored FRAME study (NCT03875820). In this proof of concept study, durable objective responses have been reported in recurrent LGSOC patients, particularly those with KRAS mutations including patients who have had a prior MEK inhibitor (Banerji et al AACR 2020). Based on preclinical studies demonstrating efficacy of both VS-6766 and the VS-6766/defactinib combination and preliminary results of the FRAME study, the phase II ENGOT-ov60/GOG3052 has been developed in recurrent LGSOC. Methods: This is a Phase II, adaptive, two-part, multicenter, parallel cohort, randomized, open label study designed to evaluate the efficacy and safety of VS-6766 versus VS-6766 in combination with defactinib (NCT04625270). The study will be conducted in two parts. Part A will determine the optimal regimen based on confirmed overall response rate (independent radiology review) in KRAS-mutated LGSOC. Part B will determine the efficacy of the optimal regimen identified in Part A in KRAS-mutated and KRAS wild-type LGSOC. The minimum expected enrollment is 52 subjects with KRAS-mutated tumors (32 subjects in Part A and 20 in Part B) and 36 with KRAS wild-type tumors in Part B. Patients will be randomized to receive VS-6766 (4.0 mg PO, twice weekly 3 weeks on, 1 week off) or VS6766 with defactinib (VS-6766 3.2 mg PO, twice weekly + defactinib 200 mg PO BID 3 weeks on, 1 week off) till progression. Key inclusion criteria include histologically confirmed LGSOC, presence of KRAS mutation (Part A), prior systemic therapy for metastatic disease and up to 1 prior line of MEK/RAF inhibitor therapy permitted. This international study is open to enrollment. Clinical trial information: NCT04625270.

Synergistic Effect of Bazedoxifene and PARP Inhibitor in the Treatment of Ovarian Cancer Regardless of BRCA Mutation.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are one of the targeted therapies proven to treat breast cancer gene (BRCA)-mutant ovarian cancer. Because most ovarian cancers are BRCA wild-type, it is necessary to extend the usage of PARPis. In the present study, we combined the PARPi, talazoparib, and the IL-6 inhibitor, bazedoxifene, for the treatment of human ovarian cancer cells. The human ovarian cancer cell lines, SKOV3, UWB1.289 (BRCA1-null) and OV75, were treated with talazoparib and bazedoxifene, as monotherapy or combination treatment. The effects of treatment on cell viability, migration, growth and colony formation were examined. Western blot was used to investigate pathways that may be involved in the antitumor effects of the two agents. The combination of talazoparib and bazedoxifene showed synergistic inhibition of cell viability, cell migration, cell growth, and cell colony formation on all the studied cell lines. The expression of p-AKT, c-myc, p-ERK, ERα was inhibited, and γ-H2AX expression was induced. Combined inhibition of PARP and IL-6 may be an efficacious treatment for ovarian cancer, independently of BRCA mutation status.

The G199X and V157fs mutations in the TP53 gene promote malignancy in serous ovarian cancer: an analysis using whole-exome sequencing.

BackgroundThe carcinogenic mechanisms underlying serous ovarian cancer are not fully understood.MethodsWhole-exome sequencing and targeted sequencing were performed in ovarian cancer samples to identify novel molecular markers involved in the process of cell malignancy in ovarian cancer. In vitro experiments, the oncogenic roles such as cell proliferation, migration and invasion of TP53 G199X and V157fs mutations were investigated deeply.ResultsThe present study identified the G199X and V157fs point mutations in the tumor protein P53 gene (TP53). The rate of TP53 mutation was 59.2% in a cohort of 76 ovarian cancer patients, compared with 9.0% in a cohort of 156 healthy women. Kaplan-Meier analysis showed that patients with a TP53 mutation had a lower 5-year overall survival (OS) rate compared with patients harboring wild type TP53. In vitro experiments in an ovarian cancer cell line demonstrated that the G199X and V157fs mutants inhibited P53 protein expression, enhanced proliferation, promoted migration and increased invasion.ConclusionsThis study identified two novel markers, TP53 G199X and V157fs mutations in TP53. Functional assays indicated that these mutations enhanced the malignant phenotype in ovarian cancer cells. These novel markers will assist in the diagnosis of ovarian tumors and represent potential targets for the treatment of TP53 mutant ovarian cancers.

The Prognostic and Predictive Role of Somatic BRCA Mutations in Ovarian Cancer: Results from a Multicenter Cohort Study.

Previous research involving epithelial ovarian cancer patients showed that, compared to germline BRCA (gBRCA) mutations, somatic BRCA (sBRCA) mutations present a similar positive impact with regard to overall survival (OS) and platinum and PARP (poly (ADP-ribose) polymerase) inhibitor sensitivity. Nevertheless, molecular testing in these studies did not include copy number variation (CNV) analyses of BRCA genes. The aim of this study was to explore the prognostic and predictive role of sBRCA mutations as compared to gBRCA mutations in patients who were also tested for CNVs. Among the 158 patients included in the study, 17.09% of patients carried a pathogenic or likely pathogenic gBRCA variant and 15.19% of patients presented pathogenetic or likely pathogenic sBRCA variants and/or CNVs. Overall, 81.6% of the patients included in this study were diagnosed with a serous histotype, and 77.2% were in advanced stages. Among women diagnosed in advanced stages, gBRCA patients showed better progression-free survival and OS as compared to sBRCA and wild-type patients, whereas sBRCA patients did not show any advantage in outcome as compared to wild-type patients. In this study, the introduction of CNV analyses increased the detection rate of sBRCA mutations, and the resulting classification among gBRCA, sBRCA and wild-type patients was able to properly stratify the prognosis of OC patients. Particularly, sBRCA mutation patients failed to show any outcome advantage as compared to wild-type patients.

PARP inhibition promotes ferroptosis via repressing SLC7A11 and synergizes with ferroptosis inducers in BRCA-proficient ovarian cancer

Pharmacologic inhibition of PARP is the primary therapeutic strategy for BRCA mutant ovarian cancer. However, most of patients carry wild-type BRCA1/2 with no significant clinical benefits from PARP inhibitors, calling for the needs to further understanding and developing new strategy when employing PARP inhibitors to treat ovarian cancer. Here, we show that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, is partly responsible for the efficacy of PARP inhibitor olaparib. Mechanistically, pharmacological inhibition or genetic deletion of PARP downregulates the expression of cystine transporter SLC7A11 in a p53-dependent manner. Consequently, decreased glutathione biosynthesis caused by SLC7A11 repression promotes lipid peroxidation and ferroptosis. Furthermore, ferroptosis perturbation results in significant resistance to olaparib without affecting DNA damage response, while boosting ferroptosis by ferroptosis inducers (FINs) synergistically sensitizes BRCA-proficient ovarian cancer cells and xenografts to PARP inhibitor. Together, our results reveal a previously unappreciated mechanism coupling ferroptosis to PARP inhibition and suggest the combination of PARP inhibitor and FINs in the treatment of BRCA-proficient ovarian cancer.

Germline and tumor BRCA1/2 mutations in Chinese high grade serous ovarian cancer patients.

BackgroundStudies on the prevalence of BRCA1/2 mutations in ovarian cancer mainly focused on germline single-nucleotide variant (SNV)/insertion/deletion (indel). The status of large genomic rearrangement (LRG) and somatic mutation were poorly investigated.MethodsPaired blood and tumor DNA from an unselected cohort of 115 Chinese high grade serous ovarian cancer (HGSOC) patients were collected and analyzed for BRCA1/2 SNV and indel by NGS. BRCA1/2 LRG was detected by MLPA. Clinicopathological characteristics including age at diagnosis, FIGO stage, family history and follow-up data were collected for further analysis.ResultsA total of 115 HGSOC patients were screened. Among them, 30 (26.1%) had germline BRCA1/2 mutations, including 19 (16.5%) SNV/indels, 5 (4.3%) LGRs in BRCA1, and 6 (5.2%) SNV/indels in BRCA2. Ten (8.7%) had somatic BRCA1/2 mutations, including 5 (4.3%) in BRCA1 and 5 (4.3%) in BRCA2. The entire tumor BRCA1/2 mutation frequency was 34.8%. No patients were found with two or more deleterious BRCA1/2 mutations. The proportion of germline (66.7%) and tumor (75%) mutation carriers was significantly increased for patients with family history when compared with those without (P<0.05). Patients with germline BRCA1/2 mutation appeared to be younger than non-carriers (mean age, 50.9 vs. 54.4 years, P=0.004) and somatic mutation carriers (mean age, 50.9 vs. 58.7 years, P=0.009). No significant association was found between BRCA1/2 status and clinicopathological characteristics including stage and family history of other cancer than breast and ovarian cancer. In univariate and Cox regression analysis, patients with tumor BRCA1/2 mutations had significant improvements than non-carriers in overall survival in the first two years after surgery (P<0.05). No significant impacts were found between various mutation status in PFS.ConclusionsThere is a high germline and tumor BRCA1/2 mutation incidences in Chinese HGSOC patients. Germline mutations were associated with family history and age at diagnosis, whereas somatic mutations were not. In our study, tumor BRCA1/2 mutations showed a time-depended improved survival outcome. A larger cohort should be examined to clarify the relation between BRCA1/2 mutation and survival outcomes.

PARP Theranostic Auger Emitters Are Cytotoxic in BRCA Mutant Ovarian Cancer and Viable Tumors from Ovarian Cancer Patients Enable Ex-Vivo Screening of Tumor Response

Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor, [125I]KX1, and show drug target specific DNA damage and subsequent killing of BRCA1 and non-BRCA mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic, [123I]KX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers.

RAD51AP1 promotes progression of ovarian cancer via TGF-β/Smad signalling pathway.

Ovarian cancer (OC) is one of the leading causes of female deaths. However, the molecular pathogenesis of OC has still remained elusive. This study aimed to explore the potential genes associated with the progression of OC. In the current study, 3 data sets of OC were downloaded from the GEO database to identify hub gene. Somatic mutation data obtained from TCGA were used to analyse the mutation. Immune cells were used to estimate effect of the hub gene to the tumour microenvironment. RNA‐seq and clinical data of OC patients retrieved from TCGA were used to investigate the diagnostic and prognostic values of hub gene. A series of in vitro assays were performed to indicate the function of hub gene and its possible mechanisms in OC. As a result, RAD51AP1 was found as a hub gene, which expression higher was mainly associated with poor survival in OC patients. Up‐regulation of RAD51AP1 was closely associated with mutations. RAD51AP1 up‐regulation accompanied by accumulated Th2 cells, but reduced CD4 + T cells and CD8 + T cells. Nomogram demonstrated RAD51AP1 increased the accuracy of the model. Down‐regulation of RAD51AP1 suppressed proliferation, migration and invasion capabilities of OC cells in vitro. Additionally, scatter plots showed that RAD51AP1 was positively correlated with genes in TGF‐β/Smad pathway. The above‐mentioned results were validated by RT‐qPCR and Western blotting. In conclusion, up‐regulation of RAD51AP1 was closely associated with mutations in OC. RAD51AP1 might represent an indicator for predicting OS of OC patients. Besides, RAD51AP1 might accelerate progression of OC by TGF‐β/Smad signalling pathway.

Cost-effectiveness of Maintenance Therapy Based on Molecular Classification Following Treatment of Primary Epithelial Ovarian Cancer in the United States

There are large randomized clinical trials-SOLO-1 (Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy [December 2018]), PRIMA (A Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy [September 2019]), and PAOLA-1 (Platine, Avastin and Olaparib in 1st Line [December 2019])-reporting positive efficacy results for maintenance regimens for women with primary, advanced epithelial ovarian cancer. The findings resulted in approval by the US Food and Drug Administration of the treatments studied as of May 2020. However, there are pressing economic considerations given the many eligible patients and substantial associated costs. To evaluate the cost-effectiveness of maintenance strategies for patients with (1) a BRCA variant, (2) homologous recombination deficiency without a BRCA variant, or (3) homologous recombination proficiency. In this economic evaluation of the US health care sector using simulated patients with primary epithelial ovarian cancer, 3 decision trees were developed, one for each molecular signature. The maintenance strategies evaluated were olaparib (SOLO-1), olaparib-bevacizumab (PAOLA-1), bevacizumab (PAOLA-1), and niraparib (PRIMA). Base case 1 assessed olaparib, olaparib-bevacizumab, bevacizumab, and niraparib vs observation of a patient with a BRCA variant. Base case 2 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination deficiency without a BRCA variant. Base case 3 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination proficiency. The time horizon was 24 months. Costs were estimated from Medicare claims, wholesale acquisition prices, and published sources. Probabilistic sensitivity analyses with microsimulation were then conducted to account for uncertainty and assess model stability. One-way sensitivity analyses were also performed. The study was performed from January through June 2020. Incremental cost-effectiveness ratios (ICERs) in US dollars per progression-free life-year saved (PF-LYS). Assuming a willingness-to-pay threshold of $100 000/PF-LYS, none of the drugs could be considered cost-effective compared with observation. In the case of a patient with a BRCA variant, olaparib was the most cost-effective (ICER, $186 777/PF-LYS). The third-party payer price per month of olaparib would need to be reduced from approximately $17 000 to $9000 to be considered cost-effective. Olaparib-bevacizumab was the most cost-effective in the case of a patient with homologous recombination deficiency without a BRCA variant (ICER, $629 347/PF-LYS), and bevacizumab was the most cost-effective in the case of patient with homologous recombination proficiency (ICER, $557 865/PF-LYS). Even at a price of $0 per month, niraparib could not be considered cost-effective as a maintenance strategy for patients with homologous recombination proficiency. The findings of this study suggest that, at current costs, maintenance therapy for primary ovarian cancer is not cost-effective, regardless of molecular signature. For certain therapies, lowering the drug price alone may not make them cost-effective.

Impact of tumor heterogeneity and microenvironment in identifying neoantigens in a patient with ovarian cancer.

Identification of neoepitopes as tumor-specific targets remains challenging, especially for cancers with low mutational burden, such as ovarian cancer. To identify mutated human leukocyte antigen (HLA) ligands as potential targets for immunotherapy in ovarian cancer, we combined mass spectrometry analysis of the major histocompatibility complex (MHC) class I peptidomes of ovarian cancer cells with parallel sequencing of whole exome and RNA in a patient with high-grade serous ovarian cancer. Four of six predicted mutated epitopes capable of binding to HLA-A*02:01 induced peptide-specific T cell responses in blood from healthy donors. In contrast, all six peptides failed to induce autologous peptide-specific response by T cells in peripheral blood or tumor-infiltrating lymphocytes from ascites of the patient. Surprisingly, T cell responses against a low-affinity p53-mutant Y220C epitope were consistently detected in the patient with either unprimed or in vitro peptide-stimulated T cells even though the patient's primary tumor did not bear this mutation. Our results demonstrated that tumor heterogeneity and distinct immune microenvironments within a patient should be taken into consideration for identification of immunogenic neoantigens. T cell responses to a driver gene-derived p53 Y220C mutation in ovarian cancer warrant further study.

Breast cancer (BRCA) gene testing in ovarian cancer.

The discovery of cancer-causing BRCA1/2 mutations and the emergence of genetic testing have brought precision in patient selection for poly-(ADP)-ribose polymerase inhibitor (PARPi) treatment. Interestingly, patients who are carriers of BRCA1/2 mutations have a higher risk for developing cancer, but respond better to DNA-damaging cytotoxic therapy, such as platinum-based chemotherapy. The distinctive biology of ovarian cancer involves high genomic instability consisting of gene amplification, gene deletion, oncogene hypomethylation, loss of heterozygosity, and tumor suppressor gene promoter hypermethylation in many of the DNA damage response (DDR) genes, including BRCA1/2. Several of these genetic abnormalities can impair high fidelity DNA damage repair increasing the therapeutic audience for PARPi's. This is especially important given the clinical development over the last decade of this group of agents and the dramatic increase in progression free survival among ovarian cancer patients who received PARPi, both in treatment or maintenance setting. In this review, we summarize our current understanding of the role of BRCA1/2 mutations in ovarian cancer and present relevant clinical trials in which BRCA1/2 was investigated as biomarker for therapy. We also outline the role of homologous recombination (HR) deficiency as biomarker by presenting the recent clinical development and recent approvals PARPi for firstline maintenance in ovarian cancer.

A novel signature of two long non-coding RNAs in BRCA mutant ovarian cancer to predict prognosis and efficiency of chemotherapy

BackgroundIn this study we aimed to identify a prognostic signature in BRCA1/2 mutations to predict disease progression and the efficiency of chemotherapy ovarian cancer (OV), the second most common cause of death from gynecologic cancer in women worldwide.MethodsUnivariate Cox proportional-hazards and multivariate Cox regression analyses were used to identifying prognostic factors from data obtained from The Cancer Genome Atlas (TCGA) database. The area under the curve of the receiver operating characteristic curve was assessed, and the sensitivity and specificity of the prediction model were determined.ResultsA signature consisting of two long noncoding RNAs(lncRNAs), Z98885.2 and AC011601.1, was selected as the basis for classifying patients into high and low-risk groups (median survival: 7.2 years vs. 2.3 years). The three-year overall survival (OS) rates for the high- and low-risk group were approximately 38 and 100%, respectively. Chemotherapy treatment survival rates indicated that the high-risk group had significantly lower OS rates with adjuvant chemotherapy than the low-risk group. The one-, three-, and five-year OS were 100, 40, and 15% respectively in the high-risk group. The survival rate of the high-risk group declined rapidly after 2 years of OV chemotherapy treatment. Multivariate Cox regression associated with other traditional clinical factors showed that the 2-lncRNA model could be used as an independent OV prognostic factor. Analyses of data from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) indicated that these signatures are pivotal to cancer development.ConclusionIn conclusion, Z98885.2 and AC011601.1 comprise a novel prognostic signature for OV patients with BRCA1/2 mutations, and can be used to predict prognosis and the efficiency of chemotherapy.

851P PLA2G7/PAF-AH as protective factor and potential negative regulator of the Wnt signaling pathway in BRCA1 mutant ovarian cancer

851P PLA2G7/PAF-AH as protective factor and potential negative regulator of the Wnt signaling pathway in BRCA1 mutant ovarian cancer

Abstract 2062: Delta prognosis: A novel clinical outcome based on automated analysis of unstructured cancer EHR data

Abstract Introduction: Efforts such as AACR Project GENIE pool genomic data across institutions to facilitate understanding of the clinical impact of genomic biomarkers in cancer. However, correlating genomic data with treatment outcomes is challenging, since outside clinical trials, outcomes such as improving or worsening cancer may be recorded only in electronic health record (EHR) free text. Automated methods could accelerate discovery by reliably characterizing treatment outcomes from unstructured EHR data. Methods: We analyzed unstructured imaging reports for patients with solid tumors (any stage) who participated in an institutional next generation sequencing study from 2013-2018 and received palliative-intent systemic therapy. A recurrent neural network was trained to predict overall survival (OS) following each report, using text from the report and the sequence of prior reports for the patient. Model performance was measured using the concordance (c)-index in a 10% held-out validation set. Next, the ‘delta prognosis, (ΔP)' was measured for each report. ‘Delta prognosis' (ΔP) captures the change in the number of months a patient is predicted to be alive out of the 12 months following each report, compared to the exponentially weighted moving average of prior prognostic predictions for that patient. Finally, a second neural network was trained to predict ΔP using each report. Ten-fold cross validation was used to annotate each report so ΔP measures for each patient would not be based on that patient's actual survival time. Using joint modeling of ΔP, biomarker status, and report frequency, associations were measured between ΔP and previously described prognostic biomarkers for cancer types in which prolonged survival with advanced disease is common, including BRAF mutations in colorectal cancer and BRCA1/2 mutations in ovarian cancer. Results: Model training was performed using 78,371 imaging reports for 4,512 patients with 273 cancer histologies. In a validation set of 9,306 reports for 595 patients, the c-index for survival prediction was 0.76. Within the first 6 months of palliative-intent therapy, among 597 patients with colorectal cancer, BRAF mutations were associated with worse mean ΔP (-0.33 months per report; 95% CI, -0.55 to -0.11 months; p = 0.003); among 395 patients with ovarian cancer, BRCA1/2 mutations were associated with better mean ΔP (+0.39 months per report; 95% CI, 0.17-0.61 months; p &amp;lt; 0.001). The latter association could not have been evaluated statistically using an overall survival endpoint, since no patients with BRCA1/2 mutations died within 6 months. Conclusion: Neural networks trained to identify shifts in prognosis using EHR text may enable ascertainment of improving and worsening cancer with no manual labeling, even if overall survival data are unavailable or immature at inference time. This technique could be relevant to any analysis of cancer outcomes using EHR data. Citation Format: Kenneth L. Kehl, Haitham A. Elmarakeby, Michael J. Hassett, Eliezer M. Van Allen, Deb Schrag. Delta prognosis: A novel clinical outcome based on automated analysis of unstructured cancer EHR data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2062.

Abstract 3432: Zinc metallochaperones for mutant p53 reactivation in cancer therapeutics

Abstract The p53 transcription factor functions as one of cancer's most potent tumor suppressors and is the most frequently mutated gene in human cancer. Restoration of wild type structure and function (so-called reactivation) of the high levels of the deficient mutant p53 protein with a small molecule is a highly sought after goal in anti-cancer drug development. We discovered a new class of small molecule zinc chelators named zinc metallochaperones (ZMCs) that reactivate zinc deficient mutant p53 through a novel mechanism by refolding p53 protein and inducing a p53 mediated apoptotic program. We identified the role of cellular zinc homeostasis as the OFF switch in ZMC pharmacodynamics indicating that a brief period of p53 mutant reactivation is sufficient for on-target efficacy. We conducted pre-clinical pharmacokinetic (PK), pharmacodymanic (PD) and efficacy studies in the murine pancreatic cancer (KPC) and BRCA1-deficient breast cancer models and found that ZMC1 and its new formulation of the drug in complex with zinc improved survival and inhibited tumor growth specifically for the zinc deficient allele. Using the BRCA1-deficient breast cancer model, we observed a highly synergistic effect of ZMC1 and the PARP inhibitor olaparib. Olaparib is now approved for the treatment of advanced BRCA1/2 mutant ovarian cancers, and recent clinical data also support its efficacy in BRCA1/2 mutant breast cancers. However acquired resistance to PARP inhibitors is inevitable in most advanced cancers. We investigated the ZMC therapeutic efficacy and found that the cell lines derived from olaparib resistant tumors are still sensitive to ZMC1 treatment. We are currently investigating the mechanism and testing the combination in vivo. In addition, we explored synergistic combinations of ZMC1 and other chemotherapy drugs based on its mechanism of action including ZMC1 with MDM2 antagonists and BCL2 antagonists. Overall, our findings indicate that the mutant p53 reactivational activity of ZMCs is governed by a unique ON/OFF switch mechanism that allows the compounds to be effective with a brief exposure to avoid the off target toxicities. The targeted and synergistic combinatorial treatments represent a significant departure from the traditional paradigm for developing a targeted molecular therapeutic in cancer. Citation Format: Xin Yu, Bing Na, Saif Zaman, Tracy Withers, John Gilleran, Alan J. Blayney, Anthony F. Bencivenga, Adam R. Blanden, Yue Liu, David A. Boothman, Stewart N. Loh, S. David Kimball, Shridar Ganesan, Darren R. Carpizo. Zinc metallochaperones for mutant p53 reactivation in cancer therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3432.