Clinical Characteristics of Patients With Pancreatic Cancer and Pathogenic <i>ATM</i> Alterations

Hannan, Zain M.; Yu, Shun; Domchek, Susan M.; Mamtani, Ronac; Reiss, Kim A.

doi:10.1093/jncics/pkaa121

Cited by 12 publications

(8 citation statements)

References 13 publications

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“…However, when we focused on PVs in specific genes, only patients carrying ATM PVs (N = 9) showed better OS compared to WT patients (N = 345) (HR = 0.33). Our results confirm previous reports that suggested ATM alterations as prognostic for improved outcomes in patients with PC [ 51 ].…”

Section: Discussionsupporting

confidence: 93%

Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients

Puccini

Ponzano

Dalmasso

et al. 2022

Cancers

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Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in 51 PC susceptibility genes in a real-world series of 422 Italian PC patients unselected for Family History (FH), compared the clinical characteristics and conducted survival analyses. 17% of patients had PVs (70/422), mainly in BRCA1/2 (4.5%, all <70 y), CDKN2A (4.5%, all >50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; p = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all p < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; p = 0.090), comprising ATM carriers (HR 0.33; p = 0.054). In the oxaliplatin-treated subset, PV carriers showed better control of the disease, although this was not statistically significant (67% vs. 56%). CDKN2A, BRCA2 and ATM were the most frequently altered genes. ATM PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried CDKN2A, BRCA2 or ATM PVs, had negative FH and would have been missed by traditional referral. Thus, CDKN2A and ATM should be added to BRCA1/2 testing regardless of FH.

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Section: Discussionsupporting

confidence: 93%

Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients

Puccini

Ponzano

Dalmasso

et al. 2022

Cancers

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“…However, no difference in PFS was seen between patients with ATM variation as compared to those who were ATM -wildtype [ 60 ]. Further, retrospective studies suggest that pathogenic ATM mutations may be prognostic in pancreatic cancer, rather than predictive of therapeutic sensitivity [ 61 ]. Consistent with these findings, in patients with prostate and breast cancer, mutations in ATM and CHEK2 are associated with minimal clinical activity of PARPi monotherapy [ 62 , 63 , 64 ].…”

Section: Tumor Intrinsic and Extrinsic Determinants Of Hrdmentioning

confidence: 99%

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Wattenberg

Reiss

2021

Cancers

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Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients.

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“…The prognostic nature of this mutation in various cancers has been mixed: in advanced urothelial cancers, ATM mutation was associated with worse OS, while in pancreatic and colorectal cancers, ATM mutation is associated with an improved OS compared to those who are ATM wildtype. [27][28][29] However, in terms of survival, ATM mutation has not been studied in those with core or noncore HRM. In our study, the majority of noncore HRM patients had colorectal cancer and an ATM mutation, but had worse OS compared to those with core HRM.…”

Section: Discussionmentioning

confidence: 99%

Core Homologous Recombination Mutations and Improved Survival in Nonpancreatic GI Cancers

Tan

Whiting²,

Knepper³

et al. 2022

American Journal of Clinical Oncology

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Introduction: Homologous recombination mutations (HRM) have led to increased responses to platinum chemotherapy in pancreatic cancer. However, HRMs’ role in nonpancreatic gastrointestinal (GI) cancers remains to be determined. Our objective was to evaluate the prognostic and predictive role of core (BRCA1, BRCA2, PALB2) and noncore HRM in nonpancreatic GI cancers receiving platinum therapy. Materials and Methods: This study performed at Moffitt Cancer Center included metastatic nonpancreatic GI cancer patients treated with platinum therapy. All patients had either a core or noncore HRM, determined by next generation sequencing. Response rates, median progression-free survival (PFS), and median overall survival (OS) were determined and compared between core versus noncore HRM patients. Results: In the study, 69 patients with one or more HRM were included: 63.8% were male, 87.0% were Caucasian, and 47.9% had colorectal cancer. Twenty-one (30.4%) patients had a core HRM and 48 (69.6%) had a noncore HRM. Among evaluable patients (n=64), there was no significant difference in objective response: 20.0% with core HRM versus 22.7% with noncore HRM responded to platinum therapy (P=0.53). Median PFS was 10.4 months versus 7.1 months for core HRM versus noncore HRM, respectively (P=0.039). Median OS was 68.9 months versus 24.3 months (P=0.026) for core HRM versus noncore HRM, respectively. Conclusions: Our study demonstrated response of core and noncore HRM to platinum therapy in metastatic nonpancreatic GI malignancies, suggesting benefit in both groups. Core HRM patients had significantly increased median OS and median PFS compared with those with noncore HRM, suggesting potential prognostic and predictive significance. Larger prospective studies are needed to confirm our findings.

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Clinical Characteristics of Patients With Pancreatic Cancer and Pathogenic ATM Alterations

Cited by 12 publications

References 13 publications

Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients

Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Core Homologous Recombination Mutations and Improved Survival in Nonpancreatic GI Cancers

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