Hereditary Pancreatic Cancer: A Retrospective Single-Center Study of 5143 Italian Families with History of BRCA-Related Malignancies

Toss, Angela; Venturelli, Marta; Molinaro, Eleonora; Pipitone, Stefania; Barbieri, Elena; Marchi, Isabella; Tenedini, Elena; Artuso, Lucia; Castellano, Sara; Marino, Marco; Tagliafico, Enrico; Razzaboni, Elisabetta; Matteis, Elisabetta De; Cascinu, Stefano; Cortesi, Laura

doi:10.3390/cancers11020193

Cited by 15 publications

(23 citation statements)

References 36 publications

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“…This phenomenon occurs in approximately 6% of the overall PDAC population, with higher rates in those with a personal or family history of BRCA-related malignancies. [5][6][7][8][9][10] BRCA1 and BRCA2 are key proteins involved in homologous recombination, 11,12 and PALB2 is an essential regulator of BRCA2 function. 13 Loss of function of these genes leads to homologous recombination deficiency (HRD).…”

Section: Introductionmentioning

confidence: 99%

Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation

et al. 2019

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Background Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined. Methods Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS. Results The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25–0.74; 0.0068). Conclusion Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.

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Section: Introductionmentioning

confidence: 99%

Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation

et al. 2019

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“…Management of cancer prevention is crucial in HCSs. Cancer prevention can be divided into primary and secondary strategies [ 16 – 23 ]. The aim of the primary prevention is to avoid cancer development by strategies including health counselling and education, environmental controls, prophylactic surgery, and chemoprevention.…”

Section: Introductionmentioning

confidence: 99%

Secondary Prevention in Hereditary Breast and/or Ovarian Cancer Syndromes Other Than BRCA

Piombino

Cortesi

Lambertini

et al. 2020

Journal of Oncology

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BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndromes are among the best-known and most extensively studied hereditary cancer syndromes. Nevertheless, many patients who proved negative at BRCA genetic testing bring pathogenic mutations in other suppressor genes and oncogenes associated with hereditary breast and/or ovarian cancers. These genes include TP53 in Li–Fraumeni syndrome, PTEN in Cowden syndrome, mismatch repair (MMR) genes in Lynch syndrome, CDH1 in diffuse gastric cancer syndrome, STK11 in Peutz–Jeghers syndrome, and NF1 in neurofibromatosis type 1 syndrome. To these, several other genes can be added that act jointly with BRCA1 and BRCA2 in the double-strand break repair system, such as PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D. Management of primary and secondary cancer prevention in these hereditary cancer syndromes is crucial. In particular, secondary prevention by screening aims to discover precancerous lesions or cancers at their initial stages because early detection could allow for effective treatment and a full recovery. The present review aims to summarize the available literature and suggest proper screening strategies for hereditary breast and/or ovarian cancer syndromes other than BRCA.

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“…In line with this evidence, among the tumors reported in the analyzed DH BRCA1/2 families, the most frequent was OC (21.4%), followed by BC, prostate cancer (PC), and CC, with a percentage of 14.3%, and bBC, breast and ovarian cancer (BOC), bladder cancer (BLC), leukemia (LEU), and laryngeal cancer (LAC), with a percentage of 7.1% ( Figure 6). In a recent study, BRCA1/2 mutation carriers displayed an increased risk for PC (3.4-fold increased risk in BRCA1, 8.6-fold increased risk in BRCA2) [51]. Moreover, the BRCA2 mutations carriers have greater risk of bile duct, gall bladder, pancreatic, gastro-intestinal tumors, and melanoma [52], while the BRCA1 mutations carriers of CC [53].…”

Section: Discussionmentioning

confidence: 99%

Five Italian Families with Two Mutations in BRCA Genes

Vietri

Caliendo

Goletti

et al. 2020

Genes

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Double heterozygosity (DH) in BRCA1 and BRCA2 genes and double mutation (DM) in BRCA1 or BRCA2 are extremely rare events in the general population, and few cases have been reported worldwide so far. Here, we describe five probands, all women, with breast and/or ovarian cancer and their families. Particularly, we identified two probands with DH in the BRCA1/2 genes with a frequency of 0.3% and three probands with DM in the BRCA2 gene with a frequency of 0.5%. The DH BRCA1 c.547+2T>A (IVS8+2T>A)/BRCA2 c.2830A>T (p.Lys944Ter) and BRCA1 c.3752_3755GTCT (p.Ser1253fs)/BRCA2 c.425+2T>C (IVS4+2T>C) have not been described together so far. The DM in BRCA2, c.631G>A (p.Val211Ile) and c.7008-2A>T (IVS13-2A>T), found in three unrelated probands, was previously reported in further unrelated patients. Due to its peculiarity, it is likely that both pathogenic variants descend from a common ancestor and, therefore, are founder mutations. Interestingly, analyzing the tumor types occurring in DH and DM families, we observed ovarian cancer only in DH families, probably due to the presence in DH patients of BRCA1 pathogenic variants, which predispose one more to ovarian cancer onset. Furthermore, male breast cancer and pancreatic cancer ensued in families with DM but not with DH. These data confirm that BRCA2 pathogenic variants have greater penetrance to develop breast cancer in men and are associated with an increased risk of pancreatic cancer.

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Hereditary Pancreatic Cancer: A Retrospective Single-Center Study of 5143 Italian Families with History of BRCA-Related Malignancies

Cited by 15 publications

References 36 publications

Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation

Platinum response characteristics of patients with pancreatic ductal adenocarcinoma and a germline BRCA1, BRCA2 or PALB2 mutation

Secondary Prevention in Hereditary Breast and/or Ovarian Cancer Syndromes Other Than BRCA

Five Italian Families with Two Mutations in BRCA Genes

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