Retrospective Survival Analysis of Patients With Resected Pancreatic Ductal Adenocarcinoma and a Germline BRCA or PALB2 Mutation

Yu, Shun; Agarwal, Parul; Mamtani, Ronac; Symecko, Heather; Spielman, Kelsey; O’Hara, Mark H.; O’Dwyer, Peter J.; Schneider, Charles J.; Teitelbaum, Ursina R.; Nathanson, Katherine L.; Domchek, Susan M.; Reiss, Kim A.

doi:10.1200/po.18.00271

Cited by 32 publications

(35 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Response duration was also significantly longer compared to what has been reported, likely secondary to increased sensitivity to DNA-damaging drugs. The increased survival is comparable to previous research on DDR-related pancreatic cancer cohorts 3,12 .…”

Section: Discussionsupporting

confidence: 85%

“…Another study reported median time of survival of 11 months in the BRCA1/2-population (95% CI, 1.5-12) and 23.3 months in BRCA1/2+ group (95% CI, 3.8-30.2) with cisplatin, gemcitabine and veliparib 3 . Others found median survival was 46.6 months for those with a pathogenic BRCA1/2 or PALB2 variant following platinum exposure compared to 23.3 for those without a variant detected 12 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Outcomes in patients with DNA-damage repair related pancreatic cancer

Macklin¹,

Hines²,

Kasi³

2019

Preprint

View full text Add to dashboard Cite

Background: Patients with DNA-damage response genes (DDR)-related pancreas cancer (BRCA1/2 or other DNA-damage related genes) may have improved outcomes secondary to increased sensitivity to DNA-damaging drugs (platinum chemotherapy/ poly ADP ribose polymerase (PARP)-inhibitors). However, data is scarce pertaining to outcomes in this subset of patients. Our objective was to retrospectively identify DDR-related pancreas cancer patients and report on clinical outcomes. Methods: Pancreas cancer patients with either a somatic or germline BRCA1/2 or other DDR genes were identified retrospectively through review of medical records (medical genetics/oncology), germline and tumor-based genetic testing results at our institution. Data regarding clinical outcomes, therapy received, and survival was subsequently extracted. Results: A total of 11 patients with pancreas cancer were identified. Pathogenic DDR-variants detected were within BRCA1 (3), ATM (4), BRCA2 (2), PALB2 (1) and FANCC (1). Five of these individuals had prior history of other cancers. Clinically these tumors were localized (4), locally advanced (3), and metastatic (4) at diagnosis. Seven out of 11 patients were still alive at time of data review. Survival in the 3 patients who had died in the metastatic/advanced cohort was 23.5, 25.8 and 111.5 months. All patients with advanced disease had exposure to platinum chemotherapy. Conclusions: Historical survival in patients with advanced and metastatic pancreas cancer is poor. Results of this DDR-subset of patients do show significantly superior outcomes, likely secondary to exposure to platinum drugs. This data, alongside other similar cohorts, would favor the DDR-genes being a predictive marker with improved survival if exposed to these drugs and the new class of drugs, PARP-inhibitors.

show abstract

Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Outcomes in patients with DNA-damage repair related pancreatic cancer

Macklin¹,

Hines²,

Kasi³

2019

Preprint

View full text Add to dashboard Cite

show abstract

“…56 Finally, Yu et al (2018) reported a trend towards improved median OS with neoadjuvant platinum-based therapy in patients with resectable PDAC and pathogenic germline mutations in BRCA1/2 or PALB2 as compared to patients without pathogenic germline mutations (not met vs 23.1 months, p=0.07). 57 In a prospective Phase IB/II trial, Jameson et al (2019) studied gemcitabine, nab-paclitaxel, and cisplatin in an unselected cohort of 25 patients that included three patients with BRCA2, two with ATM and one with RAD51. 58 The median OS of the three patients harboring BRCA2 ranged from 39.8 to 45.3 months and all three patients experienced a partial radiographic response.…”

Section: Therapeutic Approaches Dna Damaging Agentsmentioning

confidence: 99%

“…85 PALB2 is currently considered an equivalent HRD biomarker to BRCA1/2 germline alterations. 54,56,57,59 Whether other germline mutations in the HRD pathway are equivalent HRD biomarkers to BRCA1/2 remains unknown. Germline mutations in PALB2, ATM, CHEK2 are currently being investigated in clinical studies testing PARP inhibitors (Table 3).…”

Section: Non-germline Brca Biomarkers Non-brca Germline Mutationsmentioning

confidence: 99%

BRCA Mutations in Pancreas Cancer: Spectrum, Current Management, Challenges and Future Prospects

Wong¹,

Raufi²,

Safyan³

et al. 2020

CMAR

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease to treat. Despite advances in surgical techniques, radiation, and medical therapies, the 5-year survival rate remains below 9%. Over the past decade, the genomic landscape of PDAC has been well studied and BRCA mutations have emerged as a target for the development of more effective therapies. Alterations in germline BRCA and PALB2 are detected in approximately 5-9% of patients with PDAC and can lead to homologous repair deficiency (HRD). PDAC with HRD is more susceptible to cytotoxic agents, such as platinum salts and topoisomerase inhibitors, that cause DNA damage. Furthermore, PARP inhibitors have emerged as an effective noncytotoxic approach to treating HRD-PDAC. In addition to BRCA and PALB2, germline mutations in other genes involved in the homologous DNA repair pathwaysuch as ATM and RAD51are potential targets, as are patients with the "BRCAness" phenotype and somatic mutations in the DNA repair pathway. Given the clinical implications of germline mutation related HRD in PDAC, universal germline testing is now recommended. In this review, we will discuss current and emerging biomarkers for HRD in PDAC, treatments, and the challenges associated with them.

show abstract

“…Another study reported median time of survival of 11 months in the BRCA1/2-population (95% CI, 1.5-12) and 23.3 months in BRCA1/2+ group (95% CI, 3.8-30.2) with cisplatin, gemcitabine and veliparib [2]. Others found median survival was 46.6 months for those with a pathogenic BRCA1/2 or PALB2 variant following platinum exposure compared to 23.3 for those without a variant detected [12].…”

Section: Introductionmentioning

confidence: 99%

Retrospective review of outcomes in patients with DNA-damage repair related pancreatic cancer

Macklin-Mantia

Hines

Kasi

2020

Hered Cancer Clin Pract

View full text Add to dashboard Cite

Background: Patients with DNA-damage response genes (DDR)-related pancreas cancer (BRCA1/2 or other DNAdamage related genes) may have improved outcomes secondary to increased sensitivity to DNA-damaging drugs (platinum chemotherapy/ poly ADP ribose polymerase (PARP)-inhibitors). However, data is scarce pertaining to outcomes in this subset of patients. Our objective was to retrospectively identify DDR-related pancreas cancer patients and report on clinical outcomes. Methods: Pancreas cancer patients with a germline pathogenic variant in BRCA1/2 or other DDR gene were identified retrospectively through review of medical records (medical genetics/oncology) and genetic testing results at our institution. Data regarding clinical outcomes, therapy received, and survival was subsequently extracted. Results: A total of 11 patients with pancreas cancer were identified to carry a pathogenic DDR-variant: BRCA1 (3), ATM (4), BRCA2 (2), PALB2 (1) and FANCC (1). Five of these individuals had prior history of other cancers. Clinically these tumors were localized (4), locally advanced (3), and metastatic (4) at diagnosis. Four out of 11 patients were still alive at time of data review. Survival in the 7 patients who had died was 13.7, 140.0, 20.5, 22.3, 23.5, 25.8, and 111.5 months. All patients with advanced disease had exposure to platinum chemotherapy. Conclusions: Historical survival in patients with advanced and metastatic pancreas cancer is poor. Results of this DDRsubset of patients do show significantly superior outcomes, likely secondary to exposure to platinum drugs. This data, alongside other similar cohorts, would favor the DDR-genes being a predictive marker with improved survival if exposed to these drugs and the new class of drugs, PARP-inhibitors.

show abstract

Retrospective Survival Analysis of Patients With Resected Pancreatic Ductal Adenocarcinoma and a Germline BRCA or PALB2 Mutation

Cited by 32 publications

References 15 publications

Outcomes in patients with DNA-damage repair related pancreatic cancer

Outcomes in patients with DNA-damage repair related pancreatic cancer

<p>BRCA Mutations in Pancreas Cancer: Spectrum, Current Management, Challenges and Future Prospects</p>

Retrospective review of outcomes in patients with DNA-damage repair related pancreatic cancer

Contact Info

Product

Resources

About