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

Round  1

Reviewer 1 Report

In this manuscript the authors have performed a retrospective analysis on 5,143 families with family history of BRCA-related malignancies, in order to identify families with hereditary pancreatic cancer associated with breast and/or ovarian cancer which could provide information about the relationship between BRCA pathogenic variants and pancreatic cancer risk. This study showed that pancreatic cancer in BRCA-positive families with breast and/or ovarian cancer history may be diagnosed at younger age and shows better one-year OS.

This is an useful and interesting topic that makes the manuscript attractive and worthy of consideration, providing significant and useful information to current knowledge in the field. Also, the proposal provides multidisciplinary approaches, significantly integrating the fields of the oncology and oncological genetics. Therefore, this article should be of potential interest to a broad number of readerships interested to a better understanding of the oncological genetics underlying the onset of hereditary pancreatic cancers as well as breast and ovarian cancers.

This manuscript is readily intelligible because it is well-constructed, clear and well described with exhaustive figures and tables appropriate to the subject matter. The experimental design is technically sound. The scientific background and aims are clearly explained and seem to be appropriate to the investigation field. The conclusions are accurate and logically follow from the experimental results obtained from performed analyses. The references are updated and pertinent. The topic falls within the scope of the subject area of the journal.

For all these reasons, in my opinion, this paper is suitable for publication in “Cancers”, after minor revisions that will help the authors to further improve their manuscript.

 Minor revisions:

1) The authors should specify the acronym MFCC from its first use (page 2, “Results” section);

2) The authors should specify the abbreviation “GS” (Gleason score) in the footnotes of the Table 1;

3) In the Discussion section the authors wrote that they analyzed “…393 families with pancreatic cancer associated with breast and/or ovarian cancer”, whereas in the abstract and Results section they reported that these families are 392. Please, correct this typo.

Author Response



Reviewer 2 Report

The authors present a retrospective chart review of patients who underwent genetic testing in the Modena Family Cancer Clinic and draw conclusions about the relationship between BRCA pathogenic variants and pancreatic cancer risk.  They also propose regions in BRCA1 and BRCA2 which may confer pancreatic cancer risk.

Although this study has some merit, it does not significantly add to the body of literature.  It is well known that BRCA is a pancreas cancer risk. To have been more rigorous and to support their conclusions of BRCA variants in pancreas cancer, they needed to screen pancreas cancer patients without a family history of breast/ovarian.  The study is biased as these families were referred for a history of breast/ovary cancer, and not necessarily pancreas cancer.  This study will miss those patients who are BRCA positive with pancreas cancer, and did not have a family history of breast/ovary cancer.  The conclusion on the loci may be therefore skewed.

In terms of the testing criteria and figure 1, it is not clear how the NCCN arm and Modena arm are different.  Many of the NCCN criteria and Modena criteria overlap.  A 40% risk in an unaffected person is with BRCAPro is quite high.  Most other jurisdictions use 10%.  Perhaps that confounds the high detection rate.

Table 1 is not updated as many important characteristics of the 2019 NCCN are not included. 

for example:  Regardless of family history, some individuals with a BRCA-related cancer may benefit from genetic testing to determine eligibility for targeted treatment

Also a number of seminal studies in the BRCA testing space and pancreas genetic testing space were not discussed.

Stoffel et al: Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. PMID 30457921

Brand et al: Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma PMID 30067863

Hu et al: Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer PMID 29922827

Author Response

Please find attached our revision.

Author Response File: Author Response.docx

Round  2

Reviewer 2 Report

Modifications to the paper have more clearly defined the scope of this study and highlighted the difference between NCCN and Modena.  I would only suggest that the title be changed to include an Italian cohort reflecting it's population.

Author Response

Dear Reviewer,

the title has been modified accordingly.

Kind regards,

Angela Toss

Author Response File: Author Response.docx