scholarly journals Germline PALB2 Variants and PARP Inhibitors in Endometrial Cancer

2021 ◽  
Vol 19 (11) ◽  
pp. 1212-1217
Author(s):  
Michael A. Cilento ◽  
Nicola K. Poplawski ◽  
Sellvakumaram Paramasivam ◽  
David M. Thomas ◽  
Ganessan Kichenadasse
Keyword(s):  
Endometrial Carcinoma ◽  
Treatment Options ◽  
Parp Inhibitors ◽  
Response To Treatment ◽  
Parp Inhibition ◽  
Ovarian Cancer Risk ◽  
Additional Question ◽  
Prostate Cancers ◽  
Risk Reducing ◽  
Female Carriers

PARP inhibitors are orally administered antineoplastic agents that affect the homologous recombination (HR) repair pathway, and are approved by the FDA for the treatment of ovarian, breast, pancreatic, and prostate cancers. This report presents a case of recurrent endometrial carcinoma occurring in a woman with a germline pathogenic PALB2 whole-exon deletion. This uncommon finding in a patient with endometrial carcinoma provided the opportunity to use a management strategy of PARP inhibition with olaparib, resulting in a prolonged response to treatment; however, disease progression eventually occurred. Further studies are required to elucidate the mechanisms underlying resistance to PARP inhibition, and the potential future treatment options in this setting. Current recommendations for risk management of female carriers of PALB2 variants focus on breast and ovarian cancer risk. This case raises the additional question of a potential role for risk-reducing hysterectomy in female carriers of PALB2 variants.

Results of a deep-dive survey on practice patterns of oncologists and advanced practice providers utilizing PARP inhibitors as maintenance therapy for patients with ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18044-e18044
Author(s):  
Wendy Turell ◽  
Tariqa Ackbarali ◽  
Robert L. Coleman ◽  
Shannon Neville Westin ◽  
Judith Ann Smith
Keyword(s):  
Ovarian Cancer ◽  
Online Education ◽  
Maintenance Therapy ◽  
Patient Outcomes ◽  
Treatment Options ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Deep Dive ◽  
Barriers To Change ◽  
Education Activity

e18044 Background: Often diagnosed at an advanced stage, most patients with ovarian cancer will relapse. As several PARP inhibitors (PARPi) have recently been approved as maintenance, patients are presented with treatment options that extend the interval of disease remission. However, novel challenges exist as oncology teams are apprehensive of integrating PARPi in practice. Emphasis on building this competence is essential for patients to obtain the maximum benefit of maintenance PARP therapy. Methods: Oncology teams were invited to participate in a 1-hour live and online education activity broadcast from 2018-2019 at OMedLive.com for 12 months. The activity addressed clinical data on the use of PARPi as maintenance therapy, management of adverse events, and emerging strategies utilizing PARP inhibition. A deep-dive survey, including structured and open-ended questions, was conducted 2 to 4 months after participation and focused on changes in practice, barriers to change, and observed patient outcomes. Results: In total, 915 clinicians participated in the video-based activity. Sixty physicians and advanced practitioners opted to complete the deep-dive survey, 70% of whom have used PARP inhibitors as maintenance therapy. Practice improvements were reported for identifying patients likely to benefit from PARPi (90%), differentiating among approved PARPi (86%), counseling patients (85%), and team-based side effect management (95%). The top 3 barriers to utilization of PARPi were lack of reimbursement (23%), inability to anticipate patient outcomes (15%), and unfamiliarity with clinical guidelines (15%). Variations in responses to open-ended questions included persistent questions (n = 47) in need of responses before adopting PARPi, data needed to better inform decision-making (n = 49), major concerns about PARPi (n = 55), and the most challenging aspects of current patient management with PARPi (n = 39). Conclusions: Patient education yielded improvements in practical application and management of PARP inhibitors for patients with ovarian cancer. The thematic variations in open-ended responses may inform the design of tailored interventions to improve clinical integration of PARP inhibitors as maintenance therapy and different lines of treatment.

scholarly journals Response to Olaparib in a Patient with Germline BRCA2 Mutation and Breast Cancer Leptomeningeal Carcinomatosis

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Pedro Exman ◽  
Robert M. Mallery ◽  
Nancy U. Lin ◽  
Heather A. Parsons
Keyword(s):  
Breast Cancer ◽  
Metastatic Cancer ◽  
Parp Inhibitor ◽  
Treatment Options ◽  
Brca2 Mutation ◽  
Leptomeningeal Metastasis ◽  
Complete Response ◽  
Parp Inhibitors ◽  
Leptomeningeal Carcinomatosis ◽  
Response To Treatment

AbstractLeptomeningeal carcinomatosis (LC) is a devastating complication of metastatic cancer that disproportionately affects patients with advanced breast cancer. Moreover, those with BRCA1/2-mutated disease more often experience leptomeningeal metastasis. Treatment options for LC are limited and often include significant toxicities. PARP inhibitors offer an important potential treatment for patients with BRCA1/2-mutated breast and ovarian cancers, but clinical studies excluded patients with central nervous system (CNS) metastases, including LC. Efficacy data in this area are therefore limited, although a phase I study of olaparib in glioblastoma did show CNS penetration. Here we report a case of a patient with BRCA2-mutated breast cancer and solitary recurrence in the leptomeninges with ongoing complete response to treatment with the PARP inhibitor olaparib. PARP inhibitors may be an important treatment option for patients with BRCA-mutated disease and LC, and warrant further study.

scholarly journals Zebrafish Xenografts Unveil Sensitivity to Olaparib beyond BRCA Status

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1769 ◽  
Author(s):  
Ana Beatriz Varanda ◽  
Ana Martins-Logrado ◽  
Miguel Godinho Ferreira ◽  
Rita Fior
Keyword(s):  
Triple Negative ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Treatment Options ◽  
Xenograft Model ◽  
Response To Treatment ◽  
Parp Inhibition ◽  
Wild Type ◽  
Zebrafish Model ◽  
Cytotoxic Effects

Poly (ADP-ribose) polymerase (PARP) inhibition in BRCA-mutated cells results in an incapacity to repair DNA damage, leading to cell death caused by synthetic lethality. Within the treatment options for advanced triple negative breast cancer, the PARP inhibitor olaparib is only given to patients with BRCA1/2 mutations. However, these patients may show resistance to this drug and BRCA1/2 wild-type tumors can show a striking sensitivity, making BRCA status a poor biomarker for treatment choice. Aiming to investigate if the zebrafish model can discriminate sensitivities to olaparib, we developed zebrafish xenografts with different BRCA status and measured tumor response to treatment, as well as its impact on angiogenesis and metastasis. When challenged with olaparib, xenografts revealed sensitivity phenotypes independent of BRCA. Moreover, its combination with ionizing radiation increased the cytotoxic effects, showing potential as a combinatorial regimen. In conclusion, we show that the zebrafish xenograft model may be used as a sensitivity profiling platform for olaparib in monotherapy or in combinatorial regimens. Hence, this model presents as a promising option for the future establishment of patient-derived xenografts for personalized medicine approaches beyond BRCA status.

scholarly journals Pin1 plays a key role in the response to treatment and clinical outcome in triple negative breast cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592090604 ◽  
Author(s):  
Catherine Knowlson ◽  
Paula Haddock ◽  
Victoria Bingham ◽  
Stephen McQuaid ◽  
Paul B. Mullan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Standard Of Care ◽  
Parp Inhibitors ◽  
Response To Treatment ◽  
Increased Sensitivity

Background: Triple negative breast cancer (TNBC) is the subset of breast cancer associated with the poorest outcome, and currently lacks targeted treatments. Standard of care (SoC) chemotherapy often consists of DNA damaging chemotherapies ± taxanes, with a range of responses observed. However, we currently lack biomarkers to predict this response and lack alternate treatment options. Methods: Pin1 expression was modulated in vitro and proliferation and treatment response was studied. Pin1 expression was analysed in patient samples and correlated with clinical outcome. Results: In this study, we have shown that the prolyl isomerase, Pin1, which is highly expressed in TNBC, plays a key role in pathogenesis of the disease. Knockdown of Pin1 in TNBC resulted in cell death while the opposite is seen in normal cells. We revealed for the first time that loss of Pin1 leads to increased sensitivity to Taxol but only in the absence of functional BRCA1. Conversely, loss of Pin1 results in decreased sensitivity to DNA-damaging agents independent of BRCA1 status. Analysis of Pin1 gene or IHC-based expression in over 200 TNBC patient samples revealed a novel role for Pin1 as a TNBC-specific biomarker, with high expression associated with improved outcome in the context of SoC chemotherapy. Preliminary data indicated this may be extended to other treatment options (e.g. Cisplatin/Parp Inhibitors) that are gaining traction for the treatment of TNBC. Conclusions: This study highlights the important role played by Pin1 in TNBC and highlights the context-dependent functions in modulating cell growth and response to treatment.

scholarly journals Plasma Protein Biomarkers Associated with Higher Ovarian Cancer Risk in BRCA1/2 Carriers

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2300
Author(s):  
Hee-Sung Ahn ◽  
Jung Yoon Ho ◽  
Jiyoung Yu ◽  
Jeonghun Yeom ◽  
Sanha Lee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Plasma Protein ◽  
Normal Subjects ◽  
Genetic Alterations ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ovarian Cancer Risk ◽  
Protein Markers ◽  
Protein Biomarkers ◽  
Proteomics Approach ◽  
Risk Reducing

Ovarian cancer (OC) is the most lethal gynecologic malignancy and in-time diagnosis is limited because of the absence of effective biomarkers. Germline BRCA1/2 genetic alterations are risk factors for hereditary OC; risk-reducing salpingo-oophorectomy (RRSO) is pursued for disease prevention. However, not all healthy carriers develop the disease. Therefore, identifying predictive markers in the BRCA1/2 carrier population could help improve the identification of candidates for preventive RRSO. In this study, plasma samples from 20 OC patients (10 patients with BRCA1/2 wild type (wt) and 10 with the BRCA1/2 variant (var)) and 20 normal subjects (10 subjects with BRCA1/2wt and 10 with BRCA1/2var) were analyzed for potential biomarkers of hereditary OC. We applied a bottom-up proteomics approach, using nano-flow LC-MS to analyze depleted plasma proteome quantitatively, and potential plasma protein markers specific to the BRCA1/2 variant were identified from a comparative statistical analysis of the four groups. We obtained 1505 protein candidates from the 40 subjects, and SPARC and THBS1 were verified by enzyme-linked immunosorbent assay. Plasma SPARC and THBS1 concentrations in healthy BRCA1/2 carriers were found to be lower than in OC patients with BRCA1/2var. If plasma SPARC concentrations increase over 337.35 ng/ml or plasma THBS1 concentrations increase over 65.28 mg/ml in a healthy BRCA1/2 carrier, oophorectomy may be suggested.

scholarly journals Establishment of a Pretreatment Nomogram to Predict the 6-Month Mortality Rate of Patients with Advanced Biliary Tract Cancers Undergoing Gemcitabine-Based Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3139
Author(s):  
Chiao-En Wu ◽  
Wen-Kuan Huang ◽  
Wen-Chi Chou ◽  
Chia-Hsun Hsieh ◽  
John Wen-Cheng Chang ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Mortality Rate ◽  
Biliary Tract ◽  
Mortality Risk ◽  
Treatment Options ◽  
Univariate Analysis ◽  
Cytotoxic Agents ◽  
Response To Treatment ◽  
Tract Cancer ◽  
Additional Information

Background: The estimation of mortality risk among patients diagnosed with advanced cancer provides important information for clinicians and patients in clinical practice. Currently, gemcitabine-based chemotherapy regimens are the standard treatment for patients with advanced biliary tract cancer (BTC). We aimed to develop a nomogram to predict the 6-month mortality rate among patients with advanced BTC to help physicians evaluate treatment options and outcomes. Patients: We conducted a retrospective analysis to evaluate the 6-month mortality rate among patients with advanced BTC who underwent gemcitabine-based chemotherapy from 2012 to 2018. Data regarding pretreatment factors and the clinical response to treatment were collected. Univariate and multivariate analyses were performed to identify independent factors for nomogram creation. Results: A total of 202 advanced BTC patients who were treated with gemcitabine-based chemotherapy were included in this analysis. No difference in survival was identified between patients undergoing gemcitabine monotherapy and those treated with gemcitabine combined with other cytotoxic agents. The univariate analysis revealed 10 significant factors, while the multivariate analysis identified four independent factors, including gender, monocyte to lymphocyte ratio (MLR), alkaline phosphatase (ALP), and liver metastasis, which were used to establish the nomogram. The performance of this nomogram for the prediction of 6-month mortality risk was found to be promising and feasible based on logistic regression. Conclusion: A nomogram based on four independent pretreatment factors, including gender, MLR, ALP, and liver metastasis, was established to predict the 6-month mortality risk in patients with advanced BTC; it can provide clinicians and patients with additional information when evaluating treatment outcomes.

Endometriumkarzinom: Kombination aus Lenvatinib und Pembrolizumab zeigt Wirksamkeit unabhängig vom Mikrosatellitenstatus

2021 ◽  
pp. 1-2
Author(s):  
Sarah Matz
Keyword(s):  
Endometrial Carcinoma ◽  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Efficacy Analysis ◽  
Duration Of Response ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Prior Systemic Therapy ◽  
Grade 3

<b>Purpose:</b> Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors. <b>Methods:</b> Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24); secondary efficacy end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Tumor assessments were evaluated by investigators per immune-related RECIST. <b>Results:</b> At data cutoff, 108 patients with previously treated endometrial carcinoma were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)-high tumors (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumors (n = 94). For previously treated patients, regardless of tumor MSI status, the median DOR was 21.2 months (95% CI, 7.6 months to not estimable), median PFS was 7.4 months (95% CI, 5.3 to 8.7 months), and median OS was 16.7 months (15.0 months to not estimable). Grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients. <b>Conclusion:</b> Lenvatinib plus pembrolizumab showed promising antitumor activity in patients with advanced endometrial carcinoma who have experienced disease progression after prior systemic therapy, regardless of tumor MSI status. The combination therapy had a manageable toxicity profile. <b>Trial registration:</b> ClinicalTrials.gov NCT02501096.

CBIO-22. PARP INHIBITION SYNERGIZES WITH DNA DAMAGING DRUGS IN PEDIATRIC CNS TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi31-vi31
Author(s):  
Anna Laemmerer ◽  
Dominik Kirchhofer ◽  
Sibylle Madlener ◽  
Daniela Loetsch-Gojo ◽  
Carola Jaunecker ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Predictive Biomarkers ◽  
High Grade Glioma ◽  
Parp Inhibitors ◽  
Cns Tumors ◽  
Parp Inhibition ◽  
Tumor Subtypes ◽  
Synergistic Cytotoxicity ◽  
Anti Cancer

Abstract BACKGROUND Central nervous system (CNS) tumors are the second most common childhood cancer. Despite innovations in surgery and chemo-/radiotherapy, CNS tumors remain the major cause of cancer-related death in children. Previous sequencing analyses in a pediatric cancer cohort identified BRCA and DSB repair signatures as potentially targetable events. Based on these findings, we propose the use of PARP inhibitors (PARPi) for aggressive CNS tumor subtypes, including high-grade glioma (HGG), medulloblastoma (MB) and ependymoma (EPN). METHODS We tested multiple PARPi in tumor cell lines (n=8) as well as primary patient-derived models (n=11) of pediatric HGG, MB, EPN and atypical teratoid/rhabdoid tumors (ATRTs). Based on PARPi sensitivity, selected models were further exposed to a combination of PARPi and DNA-damaging/modifying agents. The mode of action was investigated using Western blot and flow cytometry. RESULTS We show that a fraction of pediatric MB, EPN and ATRT demonstrate sensitivity towards PARP inhibition, which is paralleled by susceptibility to the DNA damaging drugs cisplatin and irinotecan. Interestingly, talazoparib, the most potent PARPi, showed synergistic cytotoxicity with DNA-damaging/modifying drugs. In addition, cell cycle blockade and increased DNA damage combined with reduced DNA repair signaling, such as activation of the ATR/Chk1 pathway were observed. Corroboratively, talazoparib exhibited a synergistic anti-cancer effect in combination with inhibitors of ATR, a major regulator of DNA damage response. CONCLUSION/OUTLOOK To sum up, we demonstrate that PARP inhibition synergizes with DNA damaging anti-cancer compounds or DNA repair inhibitors and, thus, represents a promising therapeutic strategy for a defined subgroup of pediatric high-risk CNS tumors patients. More in depth characterization of the underlying molecular events will most likely allow the identification of predictive biomarkers for most efficient implementation of this strategy into clinical application.

scholarly journals Predictors of risk-reducing surgery intentions following genetic counseling for hereditary breast and ovarian cancer

2018 ◽  
Vol 10 (2) ◽  
pp. 337-346 ◽  
Author(s):  
Mary Kathleen Ladd ◽  
Beth N Peshkin ◽  
Leigha Senter ◽  
Shari Baldinger ◽  
Claudine Isaacs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Genetic Counseling ◽  
Cancer Risk ◽  
Prophylactic Surgery ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Affective Factors ◽  
Risk Reducing

Abstract Risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) are increasingly used to reduce breast and ovarian cancer risk following BRCA1/BRCA2 testing. However, little is known about how genetic counseling influences decisions about these surgeries. Although previous studies have examined intentions prior to counseling, few have examined RRM and RRSO intentions in the critical window between genetic counseling and test result disclosure. Previous research has indicated that intentions at this time point predict subsequent uptake of surgery, suggesting that much decision-making has taken place prior to result disclosure. This period may be a critical time to better understand the drivers of prophylactic surgery intentions. The aim of this study was to examine predictors of RRM and RRSO intentions. We hypothesized that variables from the Health Belief Model would predict intentions, and we also examined the role of affective factors. Participants were 187 women, age 21–75, who received genetic counseling for hereditary breast and ovarian cancer. We utilized multiple logistic regression to identify independent predictors of intentions. 49.2% and 61.3% of participants reported intentions for RRM and RRSO, respectively. Variables associated with RRM intentions include: newly diagnosed with breast cancer (OR = 3.63, 95% CI = 1.20–11.04), perceived breast cancer risk (OR = 1.46, 95% CI = 1.17–1.81), perceived pros (OR = 1.79, 95% CI = 1.38–2.32) and cons of RRM (OR = 0.81, 95% CI = 0.65–0.996), and decision conflict (OR = 0.80, 95% CI = 0.66–0.98). Variables associated with RRSO intentions include: proband status (OR = 0.28, 95% CI = 0.09–0.89), perceived pros (OR = 1.35, 95% CI = 1.11–1.63) and cons of RRSO (OR = 0.72, 95% CI = 0.59–0.89), and ambiguity aversion (OR = 0.79, 95% CI = 0.65–0.95). These data provide support for the role of genetic counseling in fostering informed decisions about risk management, and suggest that the role of uncertainty should be explored further.

scholarly journals Women’s intentions to engage in risk-reducing behaviours after receiving personal ovarian cancer risk information: an experimental survey study

2019 ◽  
Author(s):  
Ailish Gallagher ◽  
Jo Waller ◽  
Ranjit Manchanda ◽  
Ian Jacobs ◽  
Saskia Sanderson
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Risk Stratification ◽  
Perceived Risk ◽  
Lifestyle Factors ◽  
Cancer Risk Assessment ◽  
Survey Study ◽  
Ovarian Cancer Risk ◽  
Risk Reducing ◽  
Experimental Survey

Risk stratification using genetic and/or other types of information could identify women at increased ovarian cancer risk. The aim of this study was to examine women’s potential reactions to ovarian cancer risk stratification. 1,017 women aged 45-75 years took part in an online experimental survey. Women were randomly assigned to one of three experimental conditions describing hypothetical personal results from ovarian cancer risk stratification, and asked to imagine they had received one of three results: (a) 5% risk due to SNPs and lifestyle factors; (b) 10% risk due to SNPs and lifestyle factors; (c) 10% risk due to a rare mutation in BRCA2. 83% of women indicated interest in having ovarian cancer risk assessment. After receiving their hypothetical risk estimates, 29% of women stated they would have risk-reducing surgery. Choosing risk-reducing surgery over other behavioural responses was associated with having higher surgery self-efficacy and perceived response-efficacy, but not with perceptions of disease threat, i.e. perceived risk or severity, or with experimental condition. A substantial proportion of women age 45-75 years may be open to the idea of surgery to reduce risk of ovarian cancer, even if their absolute lifetime risk is only increased to as little as 5 or 10%.

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