scholarly journals F-Box Protein-Mediated Resistance to PARP Inhibitor Therapy

2019 ◽  
Vol 73 (2) ◽  
pp. 195-196 ◽  
Author(s):  
Aleksandra I. Adamovich ◽  
Amanda Ewart Toland ◽  
Jeffrey D. Parvin
Keyword(s):  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
F Box Protein

PALB2 mutation as a predictive biomarker for immunotherapy in patients with advanced melanoma: Results from (a pooled analysis of) five multicenter, randomized clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21537-e21537
Author(s):  
Changxuan You ◽  
Yating Zheng ◽  
Mengli Huang
Keyword(s):  
Randomized Clinical Trials ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Pooled Analysis ◽  
Advanced Melanoma ◽  
Inhibitor Therapy ◽  
Study Cohort ◽  
Platinum Based Chemotherapy ◽  
Palb2 Mutation ◽  
Inhibitor Treatment

e21537 Background: PALB2, a gene in the homologous recombination repair (HRR) pathway, has been shown to be associated with the efficacy of platinum based chemotherapy, and PARP inhibitor therapy in breast, prostate, ovarian, and pancreatic cancers. However, their predictive value of PALB2 remained unknown in patients with advanced melanoma. Methods: Five independent cohorts (Miao2018, Samstein2018, Allen 2015, Hugo2016, and Synder2014. study cohort) with data from 672 patients with advanced melanoma were used to analyze the correlation with immunogenic marker, and the prognostic effect of PALB2 on immunotherapy. Results: A pooled analysis of five independent cohorts of 672 advanced patients melanoma show that 31 (4.6%) harbored PALB2 mutation ( PALB2mut). PALB2mut (72.63Muts/Mb) was associated with higher tumor mutation burden (TMB) (P < 0.001) than PALB wild-type ( PALB2wt) (19.71Muts/Mb). The same phenomenon has also been observed in TNB, PALB2mut (1983 counts) was associated with higher tumor neoantigen burden (TNB) than PALB2wt (603.5 counts) (P = 0.0147). The objective response rate (ORR) of immunotherapy was 53.33% for the patients with PALB2mut and 24% for the PALB2wt subgroup (P = 0.027). The PALB2mut patients had significantly improved median overall survival (mOS) than the PALB2wt group (Not reach versus 29 months, hazard ratio (HR) = 0.38, 95%CI 0.19−0.73, P = 0.003). A subgroup analysis of CTLA4 inhibitor treatment found that PALB2mut was associated with better ORR (50% versus 18.3%, P = 0.016) on immunotherapy, and mOS in the PALB2mut group was significantly better than that in the PALB2wt group (Not reach versus 21 months, HR = 0.3, 95%CI 0.13−0.68, P = 0.002). However, in the subgroup receiving PD-L1 inhibitor treatment, no ORR benefit was found in the PALB2mut group (66.67% versus 56.76%, P = 1), and there was no difference on mOS between PALB2mut and PALB2wt (Not reach versus 31 months, HR = 0.45, 95%CI 0.11−1.8, P = 0.254). Conclusions: PALB2 mutations was associated with a higher TMB and TNB level. PALB2 may serve as a positive predictor of immunotherapy (CTLA4 inhibitor therapy) in patients with advanced melanoma and their clinical value warrants further investigation.

The impact of live education on the competence and performance of oncology practitioners who care for patients with ovarian cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e23010-e23010
Author(s):  
Vanessa Carranza ◽  
Bryan Carson Taylor ◽  
Susan H. Gitzinger ◽  
Joan B. Fowler ◽  
Jessica Hall
Keyword(s):  
Ovarian Cancer ◽  
Genetic Testing ◽  
Cancer Patients ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Community Based ◽  
Educational Initiatives ◽  
Post Test ◽  
Chi Square Analysis

e23010 Background: About a third of ovarian cancer patients in the US have limited access to a gynecologic oncologist (GO) due to geographic disparities. A survey by The Society of Gynecologic Oncology (SGO) found that the majority of GOs found it was vital to coordinate local access to care, from diagnosis to survivorship, for patients living in areas of disparity. This allows rural/underserved patients broader access to novel therapies, as they increasingly become standard of care. It is critical for not only GOs to be current on the latest ovarian cancer data, but all clinicians who care for these patients. Methods: CEC Oncology developed two educational initiatives focused on PARP inhibitor therapy in ovarian cancer, which was targeted to all US healthcare professionals caring for ovarian cancer patients. Evaluations were collected from attendees attending an SGO Symposium and Ground Round (GR) series to assess impact on practice, increased competency, and intent to make a change in practice. Learning, knowledge, and competence was objectively assessed by analyzing pre-test, post-test, and follow-up survey data (sent 4-6 weeks post-activity). Chi-square analysis was conducted with a priori significance set at 0.05. Results: A total of 830 clinicians were educated, with SGO attendees primarily practicing in academic settings and GR attendees mostly from community practices. SGO attendees were asked case questions at baseline, immediately after the activity, and 4-6 weeks after the activity. Knowledge increased from pre- to post-test regarding current genetic testing recommendations (23% increase; P= .004) and appropriate selection of PARP inhibitor therapy (25% increase; P= .017). Knowledge was sustained at follow-up analysis. At follow-up, 90% of SGO and 84% of GR attendees made a change as a result of attending the activities. More attendees were able to incorporate germline multigene testing into practice, than originally intended; increase of 29% for SGO and 7% for GR audiences. All attendees experienced the barrier lack of patient education about the importance of genetic testing/counseling more than anticipated; increase of 7% for SGO and 13% for GR audiences. At follow-up, there was a 9% increase in GR attendees listing staying current with trial data and practice guidelines as a barrier. Conclusions: There were some notable differences seen in competence/performance among attendees of the two ovarian cancer educational initiatives. Differences may be attributed to practice setting (SGO primarily academic; GR primarily community.) Overall, GR attendees were more likely to face barriers, suggesting that community-based clinicians have fewer resources and experience more barriers to implementing best practices. Thus, it is vital to offer education for clinicians in community-based practices, particularly in areas that are considered ‘geographically disparate’.

Abstract 4093: Drug combinations that can overcome resistance to PARP inhibitor therapy for BRCA1-associated breast cancer

2020 ◽  
Author(s):  
Dina Mohamed Abd El Aziz Moustafa ◽  
Maha Abd Elwahed ◽  
Hanaa El Said ◽  
Jeffrey Parvin
Keyword(s):  
Breast Cancer ◽  
Parp Inhibitor ◽  
Drug Combinations ◽  
Inhibitor Therapy

Doubling down on tumor suppressor deletion

2020 ◽  
Vol 12 (524) ◽  
pp. eaba2903
Author(s):  
Adam G. Sowalsky
Keyword(s):  
Prostate Cancer ◽  
Tumor Suppressor ◽  
Parp Inhibitor ◽  
Inhibitor Therapy

Codeletion of BRCA2 and RB1 increases prostate cancer sensitivity to PARP inhibitor therapy.

scholarly journals Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency

2016 ◽  
pp. e259-e268 ◽  
Author(s):  
Rebecca S. Kristeleit ◽  
Rowan E. Miller ◽  
Elise C. Kohn
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Molecular Therapy ◽  
Parp Inhibition ◽  
Gynecologic Cancers ◽  
Brca Mutations ◽  
Individual Gene

The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed “ BRCAness”). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined. They include individual gene defects (e.g., RAD51 mutation, CHEK2 mutation), homozygous somatic loss, and whole genome properties such as genomic scarring. Testing this knowledge is possible when selecting patients to receive molecular therapy targeting DNA repair, not only for patients with ovarian cancer but also endometrial and cervical cancers. The validity of HRD assays and multiple gene sequencing panels to select a broader population of patients for treatment with PARP inhibitor therapy is under evaluation. Other non-HRD targets for exploiting DNA repair defects in gynecologic cancers include mismatch repair (MMR), checkpoint signaling, and nonhomologous end-joining (NHEJ) DNA repair. This article describes recent evidence supporting strategies in addition to BRCA mutation for selecting patients for treatment with PARP inhibitor therapy. Additionally, the challenges and opportunities of exploiting DNA repair pathways other than homologous recombination for molecular therapy in gynecologic cancers is discussed.

scholarly journals HP1β Is a Biomarker for Breast Cancer Prognosis and PARP Inhibitor Therapy

PLoS ONE ◽  
2015 ◽  
Vol 10 (3) ◽  
pp. e0121207 ◽  
Author(s):  
Young-Ho Lee ◽  
Xiyong Liu ◽  
Fuming Qiu ◽  
Timothy R. O’Connor ◽  
Yun Yen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Breast Cancer Prognosis ◽  
Cancer Prognosis

scholarly journals Breast cancer brain metastases show increased levels of genomic aberration based homologous recombination deficiency scores relative to their corresponding primary tumors

2018 ◽  
Author(s):  
M. Diossy ◽  
L. Reiniger ◽  
Zs. Sztupinszki ◽  
M. Krzystanek ◽  
K. M. Timms ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Brain Metastases ◽  
Primary Breast Cancer ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Published Data ◽  
Data Set ◽  
Primary Tumors ◽  
Homologous Recombination Deficiency

AbstractDue to its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Various measures of genomic scarring based HRD scores were developed as a companion diagnostic in order to correlate it with PARP inhibitor sensitivity. We compared a variety of HRD scores in primary tumors and their corresponding brain metastases and found a significant increase in this measure in brain metastases for all measures of HRD that were tested. This discrepancy warrants further investigation to assess whether this observation is common to other metastatic sites, and potentially a significant adjustment of strategy in the application of HRD measures in clinical trials for the prioritization of patients for PARP inhibitor therapy.Key messageWe quantified homologous recombination deficiency (HRD) in paired primary breast cancer and brain metastases samples based on a previously published data set. We showed that HRD significantly increases in the brain metastases relative to its paired primary tumor. An independent validation was also performed on another set of primary breast cancer and brain metastasis pairs using the “my choice” HRD score in collaboration with Myriad Genetics.These confirmatory results suggest that brain metastases of breast cancer tend to have significantly higher HRD scores, which would prioritize those patients for PARP inhibitor therapy with those agents that cross the blood brain barrier such as veliparib and niraparib.

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