Systemic Therapy for Metastatic Pancreatic Cancer—Current Landscape and Future Directions
, Melissa Frizziero 1, Victoria Foy 1, Mairéad G. McNamara 1,2, Alison Backen 1,2 and Richard A. Hubner 1,2,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsExcellent review - please consider adding the following reference in the kRAS subsection:
A Phase 2 Randomized Placebo-Controlled Adjuvant Trial of GI-4000, a Recombinant Yeast Expressing Mutated RAS Proteins in Patients with Resected Pancreas Cancer.
J Pancreat Cancer. 2021 Mar 23;7(1):8-19. doi: 10.1089/pancan.2020.0021. eCollection 2021.PMID: 33786412Author Response
Reviewer 1:
Excellent review - please consider adding the following reference in the kRAS subsection:
A Phase 2 Randomized Placebo-Controlled Adjuvant Trial of GI-4000, a Recombinant Yeast Expressing Mutated RAS Proteins in Patients with Resected Pancreas Cancer.
Muscarella P, Bekaii-Saab T, McIntyre K, Rosemurgy A, Ross SB, Richards DA, Fisher WE, Flynn PJ, Mattson A, Coeshott C, Roder H, Roder J, Harrell FE, Cohn A, Rodell TC, Apelian D.J Pancreat Cancer. 2021 Mar 23;7(1):8-19. doi: 10.1089/pancan.2020.0021. eCollection 2021.PMID: 33786412
Response to reviewer 1:
Dear Reviewer, thank you for your response and suggestion to include the above phase 2 trial. As the trial assessed patients with resected pancreatic cancer and treated them in the adjuvant setting, we felt it beyond the scope of this article to include, whereby we focus our attention on the landscape of metastatic pancreatic cancer.
Reviewer 2 Report
Comments and Suggestions for AuthorsIn this review entitled “Systemic therapy for metastatic pancreatic cancer - current landscape and future directions” by Daniel Netto et al discussed the up-to-date therapeutic management of advanced pancreatic ductal adenocarcinoma (PDAC) in numerous clinical trials with focus on potential breakthrough compared to the current standard of care which are FOLFOX or Gemcitabine (Gem). The authors divided the therapeutic development into multiple categories, such as cytotoxic chemotherapy, targeted treatment, immune therapy etc and discussed them in great detail. Overall, the review is well written.
However, I suggest expanding the content (5.5) of targeting desmoplastic stroma. PDAC is well known for its desmoplastic stroma nature when compared to other common cancer types. The thick fibroblasts barrier has been known for contributing to chem- and radio- therapy resistance, immune desert and drug delivery, which were the key factors contributing to the clinical trial failure mentioned in this review. At the beginning, people tried Hedgehog inhibitors and the failure of trials led to targeting the stromal components, which are Hyaluronic acid etc. Providing such content will help readers understand the unique challenges of PDAC and the endless efforts our researchers have made.
Author Response
Reviewer 2:
In this review entitled “Systemic therapy for metastatic pancreatic cancer - current landscape and future directions” by Daniel Netto et al discussed the up-to-date therapeutic management of advanced pancreatic ductal adenocarcinoma (PDAC) in numerous clinical trials with focus on potential breakthrough compared to the current standard of care which are FOLFOX or Gemcitabine (Gem). The authors divided the therapeutic development into multiple categories, such as cytotoxic chemotherapy, targeted treatment, immune therapy etc and discussed them in great detail. Overall, the review is well written.
However, I suggest expanding the content (5.5) of targeting desmoplastic stroma. PDAC is well known for its desmoplastic stroma nature when compared to other common cancer types. The thick fibroblasts barrier has been known for contributing to chem- and radio- therapy resistance, immune desert and drug delivery, which were the key factors contributing to the clinical trial failure mentioned in this review. At the beginning, people tried Hedgehog inhibitors and the failure of trials led to targeting the stromal components, which are Hyaluronic acid etc. Providing such content will help readers understand the unique challenges of PDAC and the endless efforts our researchers have made.
Response to reviewer 2:
Dear Reviewer, thank you for your response and insights highlighting the importance of the desmoplastic stroma in tumourigensis and drug resistance. We agree that this important section should be further expanded and reflect some of the scientific challenges posed in treating pancreatic cancer.
We have therefore added further summaries of the difficulty in targeting CAF’s, particularly highlighting the lack of translational benefit from hedgehog inhibitors. We have also re-structured this section so that it reads more chronologically. We have also included ongoing clinical trials investigating novel ways of targeting the desmoplastic stroma.
