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  • American Society of Clinical Oncology (ASCO)  (3)
  • 1
    Online Resource
    Online Resource
    Association of tumor homologous recombination deficiency (HRD) score with immune checkpoint inhibitor benefit in metastatic clear cell renal cell carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e16538-e16538
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e16538-e16538
    Abstract: e16538 Background: Genomic aberrations resulting in homologous recombination repair deficiency (HRD) can be successfully targeted with poly (ADP-ribose) polymerase (PARP) inhibitors. Tumors with HRD also have a higher tumor mutation burden (TMB) and immunogenic phenotypes, prompting PARP inhibitor + immune checkpoint inhibitor (ICI) trials across cancer types. Clear cell renal cell carcinoma (ccRCC) rarely harbors canonical genomic aberrations associated with HRD. However, a “BRCA-like” HRD phenotype can be detected from next-gen DNA- or RNA-sequencing using models trained on tumors with BRCA1/2 bi-allelic loss. We hypothesized that this novel HRD phenotype is associated with ICI benefit in metastatic ccRCC. Methods: Patients with metastatic ccRCC who underwent nephrectomy and were treated with anti-PD-1/L1 ICI monotherapy +/- ipilimumab were identified in an institutional database (N = 52), and outcomes were determined by chart review. Progression free survival (PFS) and overall survival (OS) were calculated from the start date of ICI treatment. Targeted next generation DNA and whole transcriptome sequencing were performed from archived nephrectomy specimens using the Tempus xT platform. HRD scores were calculated using DNA (HRD-DNA) and RNA (HRD-RNA) based methods as previously described (Liebowitz BD et al. BMC Cancer 2022). HRD status was analyzed as a continuous rather than binary variable, as biologically relevant cutoff thresholds have not been established for ccRCC. Multivariable Cox regression models were used to evaluate the association between HRD scores and PFS or OS when demographic/pathologic covariates were adjusted. Results: The cohort was predominantly white (n = 48; 92%) and male (n = 37; 71%) with good performance status (ECOG 0-1: n = 47; 90%). Half (n = 26) were current/former smokers; median age 67 years and BMI 28. Twenty-four (46%) nephrectomies were cytoreductive. Most tumors were staged pT3/4 (85%) and grade 3/4 (90%) including 18 (35%) with sarcomatoid histology. ICI monotherapy or ICI + ipilimumab were received by 32 (62%) and 20 (38%) patients, respectively, in the 1st (40%), 2nd (40%), 3rd (17%), or 4th (2%) line. Median PFS and OS for the cohort were 6.4 months (95% CI 4.4-11.1) and 62.7 months (95% CI 32.8-not applicable). HRD-DNA and HRD-RNA could be calculated for 47 and 46 subjects, respectively. HRD-DNA was not found to be associated with PFS nor OS. High HRD-RNA score was associated with improved PFS (HR 0.92 per unit increase; 95% CI 0.85-1.00, p = 0.052) in the multivariable model, but not OS. Conclusions: High HRD-RNA was associated with longer PFS for metastatic ccRCC patients undergoing ICI-treatment. A “BRCA-like” transcriptomic signature may be predictive of ICI benefit in ccRCC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e16538
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Germline thrombophilia gene alterations and thrombosis rates among patients with advanced germ cell tumors treated with chemotherapy.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e17023-e17023
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e17023-e17023
    Abstract: e17023 Background: Men with advanced germ cell tumors (GCT) treated with cisplatin-based chemotherapy are at high risk of venous thromboembolism (VTE). Validated predictors of VTE would allow development of targeted prophylactic anticoagulation strategies in this population. We hypothesized that a high genomic risk score from a previously identified panel of germline single nucleotide polymorphisms (SNPs) in thrombophilia genes would be associated with an increased risk of VTE within 6 months of chemotherapy initiation for GCT. Methods: Men with stage IIA or higher GCT who received 3-4 cycles of cisplatin-based chemotherapy were identified at two centers with available tissue for germline sequencing. High genomic risk was defined as having 4 or more risk alleles from an established 5 SNP germline panel composed of ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914). Univariable and multivariable logistic regression were used to evaluate the impact of genomic risk on VTE incidence within six months of chemotherapy initiation. Results: 123 patients were identified with 72% having non-seminoma histology and 28% categorized as IGCCCG intermediate or poor risk. The VTE rate was 26% (32/123), and the incidence of high genomic risk was 21% (26/123). Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5 – 3.5, p = 0.54). A multivariable model identified Khorana score, N3 status and elevated LDH as predictors for VTE (Table). The association between high genomic risk and VTE strengthened when adjusting for clinical variables, but remained non-significant, adjusted OR 2.1 (95% CI 0.7 – 6.5, p = 0.18). The optimal threshold to define high genomic risk in this cohort was 3 or more risk alleles, adjusted OR 2.5 (95% CI 0.9 – 6.8, p = 0.08). ABO (non-O blood type) was the only individual SNP significantly associated with VTE (p 〈 0.01). Conclusions: In this multi-institutional cohort, a previously established germline thrombophilia panel was not clearly associated with increased VTE risk among patients with GCT receiving chemotherapy. Khorana score, elevated LDH, clinical nodal stage, and non-O blood type were the strongest predictors of VTE. Exploratory analysis of the association between VTE risk and 76 additional SNPs is ongoing. Prospective studies of prophylactic anticoagulation are warranted in high-risk patients with advanced GCT undergoing chemotherapy.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e17023
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Interrelation of functional homologous recombination deficiency and hrr pathway alterations in prostate cancer.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 151-151
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 151-151
    Abstract: 151 Background: The use of PARP inhibitors (PARPi) may trigger synthetic lethality of tumor cells in the context of deficient homologous recombination repair (HRR). Approximately 10-20% of patients with prostate cancer harbor mutations in the HRR pathway, but HRR-associated mutations do not consistently predict the response to PARPi. Considering alternative methods to define Homologous Recombination Deficiency (HRD)—the inability to repair double strand breaks—may aid in identifying additional tumors that are sensitive to PARPi. Here, we evaluate the relationship between HRD status and HRR mutations amongst a large cohort of patients with prostate cancer. Methods: Retrospective analysis of 1,022 de-identified patients with prostate cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, whole-exome capture RNA-seq) was performed. Comparison groups were defined based on HRR alterations—either mono- or bi-allelic alterations of BRCA1 or BRCA2 ( BRCA1/2), ATM, or other HRR pathway genes. HRD status was determined via the Tempus RNA-based HRD algorithm. Results: Among this cohort, mono (-/+) or biallelic (-/-) alterations of HRR genes were found in 432 patients: BRCA1/2 -/- (n = 31), BRCA1/2 -/+ (n = 87), ATM-/- (n = 24), ATM-/+ (n = 67), other HRR-/- (n = 54), other HRR-/+ (n = 169) or no HRR alterations (n = 590). The BRCA1/2-/- group had a higher frequency of Asians (17% vs. 〈 7% in all other groups) and were diagnosed at younger ages (median 62 years vs. 〉 65 for all other groups). We identified 130/1022 (13%) patients with prostate cancer to be HRD-positive (HRD+) and observed significant differences in HRD positivity according to the type of HRR alteration observed (Table). Notably, 54% (70/130) of HRD+ patients had no mutations in any genes associated with the HRR pathway. Conversely, 89% (278/314) of patients with non- BRCA1/2 HRR mutations were HRD negative. Amongst all individuals with biallelic loss of any HRR gene, HRD positivity was most enriched for BRCA2-/- (16/29, p 〈 0.001) and PALB2-/- (3/4, p = 0.082). Conclusions: By using an RNA-based HRD algorithm, we found 13% of patients with prostate cancer are HRD+. This RNA-based HRD signature not only captures patients with HRR mutations but also identifies a substantial population of HRD+ patients who are currently undetectable by methods based solely on sequencing HRR genes. Further research is needed to assess the clinical response to PARPi in this HRD+ population, as well as the response to PARPi in the HRD negative population who harbor HRR gene alterations.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.151
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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    Online Resource
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