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Dear Editor in Chief, Thanks considering our manuscript "Drug Metabolism and Pancreatic Cancer". I have c9onsideered all the suggestions and revised the paper accordingly. Hopefully now it will be accepted for publication. Once again, we appreciate for your consideration. Sincerely yours, M. Wasif Saif, MD Reviewer A: Flores et al. reviewed nicely the available data on predictive biomarkers for several chemotherapeutic agents in a early and metastatic pancreatic cancer. This is a well-written article by a group with experience in the field. I have some suggestions, however, that I believe will of be benefit both for the article and the readers. 1) The authors based their work mostly on reviewing the biomarker detection by IHC. There is available data on DNA polymorphisms for the genes that encode the same proteins. Please discuss the most important studies and report a summary of the data in a table form (e.g. gene, polymorphism, clinical outcome and reference). RESPONSE: though such data is beyond the scope of this paper but added few other related markers in this paper, such as Microsatellite Instability (MSI) Studies have also suggested that 5-fluorouracil (FU) may be less effective in patients with MSI pancreatic cancers, similar to data seen in the treatment of colon cancer, especially in the adjuvant setting. In a study by Nakata et al. 46 patients with pancreatic cancer who had undergone resection were evaluated for microsatellite variations 34. Univariate analysis showed that patients with MSI-positive tumors had significantly longer survival than those with MSI-negative tumors, although there were no significant differences in clinicopathological factors between the two groups (median survival, 62 months versus 10 months, respectively; p=0.011). Multivariate survival analysis indicated that MSI status had an independent predictive value (HR=5.577; p=0.007). The tumor-infiltrating leukocyte intensity in MSI-positive tumors was stronger than that in MSI-negative tumors, suggesting that MSI-positive tumors may induce stronger antitumor immunity. However, more data is needed to confirm its role as a marker in these patients. 2) A table that summarizes the presented data (in a similar fashion) will also be helpful for the readers. RESPONSE: Table 1: Potential Markers and Relevant Chemotherapeutic agents Chemotherapy agent Gemcitabine Representative candidate gene Irinotecan Cisplatin Oxaliplatin Erlotinib Fluorouracil Nab-paclitaxel Cytidine deaminase Deoxycytidine kinase Ribonucleotide reductase M1 subunit (RRM1) Dihydropyrimidine dehydrogenase (DPD) Thymidylate synthetase (TS) 5, 10-methylenetetrahydrofolate reductase (MTHFR) UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) Excision repair cross complementation group 1 and 2 (ERCC1 and ERCC2) Excision repair cross complementation group 1 (ERCC1) EGFR K-ras SPARC 3) Given that the readers of the journal are mostly GI specialists, I suggest an introduction on biomarkers (eg. definition, characteristics that a biomarker should have and some examples like HER2 in breast cancer). RESPONSE: We added a Figure in the beginning to self explain them. Biomarkers are generally considered as predictive or prognostic (Figure 1). Biomarkers can be measured in tumor tissue or other body fluids, such as plasma. Figure 1: How are biomarkers defined? 4) The biomarkers associated with 5FU (DPYD) and irinotecan (UGT1A1) toxicity need to be discussed. RESPONSE: Dihydropyrimidine dehydrogenase DPD: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the degradation of 5-FU. It is thought that intratumor expression of DPD may correlate with possible 5-FU resistance. The first study of DPD in pancreatic cancer was done by Nakayama et al. (15492566) retrospectively in 68 patients with resectable pancreatic adenocarcinoma 30 of which received 5-FU via a liver perfusion technique. They measured DPD by IHC and found that those with negative staining had longer survival if treated with intrahepatic 5-FU compared to those with positive staining. Intrahepatic 5-FU had no effect on survival in the DPD positive group. DPD was also studied in patients receiving S-1 by Kuramochi et al31. They evaluated DPD expression in patients with recurrent pancreatic cancer measured by RT-PCR. In 33 patients treated with S-1 and cisplatin after recurrence, they found that patients who responded to therapy (as measured by CA 19-9) had a mean lower intratumoral DPD expression. A larger study of DPD in the adjuvant setting was done by Kondo et al.32 in which 106 patients treated with adjuvant treatment were evaluated retrospectively. They observed high DPD expression in 37 percent of patients as measured by IHC. Those with low DPD expression were found to have increased median overall survival if they received S-1 (all these patients also received gemcitabine). No differences in survival were seen based on treatment in the high DPD group or in the group not treated by S-1 when divided by DPD expression. Interestingly, they also evaluated TS expression and did not find any correlation to OS by treatment. A similar study done by Kondo et al. evaluated both DPD and hENT1 by IHC in 86 patients treated with adjuvant S-1 and gemcitabine33. Low DPD and high hENT1 expression were observed as favorable factors in this study. Those with one or two favorable factors had an OS benefit when compared to those patients with no favorable factors. Like TS, DPD may be a useful marker to guide therapy with 5-FU based treatments, but prospective data are lacking for validation. 5) I would suggest a comment on the potential future role of BRCA1/2 mutations as predictive biomarkers for PARP inhibitors. This is not related to drug metabolism but since ERCC1 data was discussed, I will suggest so for BRCA1/2. RESPONSE: BRCA2 mutations: BRCA2 mutations are found in up to 17% of patients with familial pancreatic cancer. The protein product of the BRCA2 gene plays an important role in the repair of DNA crosslinking damage. It is located on chromosome 13q and is inactivated in fewer than 10 percent of pancreatic cancers. The gene is almost always inactivated by a germline (inherited) mutation coupled with somatic loss of the second allele 42. It has been suggested that this function of BRCA2 can be exploited therapeutically. In vitro studies suggest that pancreatic cancers with genetically inactivated BRCA2 are significantly more susceptible to DNA cross-linking agents then are pancreatic cancers with a genetically intact BRCA2. Indeed, several reports have documented remarkable therapeutic responses to DNA crosslinking agents such as mitomycin, cisplatin, or to poly ADP-ribose polymerase (PARP) 43,44. inhibitors in patients whose cancers have inactivated BRCA2 6) Irinotecan is being widely used in good PS patients (FOLFORINOX regimen) and some discussion on biomarkers will be appreciated. RESPONSE: Uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1): Irinotecan as a part of FOLFIRINOX regimen as well as a single agent or with 5-FU (FOLFIRI) is used by oncologists to treat patients with pancreatic cancer. A novel form of irinotecan, nanoliposomal irinotecan combined with fluorouracil/folinic acid is recently approved by FDA for second line treatment of patients who have failed gemcitabine-based chemotherapy 45. After intravenous administration, irinotecan is converted to its active metabolite, 7-ethyl-1 o-hydroxycamptothecin (SN-38) by a carboxylesterase. SN-38 is then detoxified by UGT1A1 enzyme to its inactive form SN-38 glucuronide (SN-38G) which is excreted into the bile and urine. UGT1A1 is found to be polymorphic and resulted in wide inter-individual variation in patient's response as well as toxic side effects. Based on this information, FDA had first approved irinotecan label with pharmacogenetics information in 2005. In 2010, new pharmacogenetic information was added to the label regarding the risk of neutropenia in patients who had genetic defect of (UGT1A1). Over 30 genetic variants in the promoter region and exon 1 of UGT1A1 have been identified which can decrease enzyme activities. These genetic variants have been linked to few syndromes, such as Gilbert syndrome and Criegler-Najjar. UGT1A1*28 has been reported to cause approximately 70 per cent reduction of UGT1A enzyme activity. Under-expression of UGT1A1 enzyme impaired the metabolism of SN-38 to its inactive form (SN-38G) and caused an excessive accumulation of toxic SN-38. The French Joint Work group developed a review on the impact of the deficient UGT1A1*28 variant on irinotecan efficacy and toxicity 46. In addition, there are inter-ethnicity variations. Therefore, physicians caring for these patients should be aware of these genetic abnormalities. The practical point is that normally we administer irinotecan doses at least equal to 180 mg/m2, but this dose should be reduced in patients who are known to be homozygous for theUGT1A1*28 allele. Reviewer B: Flores et al. present a review manuscript that addresses the role of tumor’s genomic profile and drug metabolism as predictive markers for response to each regimen. There are no major comments. Minor comment: 1) Introduction, lines 18-19: The phrase “...in the 2nd line setting after gemcitabine alone” should be corrected to “after gemcitabine-based therapy”, as more than half of the patients had received gemcitabine combination regimens, in the 1st line. RESPONSE: Most recently, nanoliposomal irinotecan plus fluorouracil and folinic acid has shown a survival benefit in the 2nd line setting after gemcitabine-based therapy. 2) It would be useful, if the authors will comment on irinotecan toxicity in relation to the genetic variations in UGT1A. RESPONSE: Uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1): Irinotecan as a part of FOLFIRINOX regimen as well as a single agent or with 5-FU (FOLFIRI) is used by oncologists to treat patients with pancreatic cancer. A novel form of irinotecan, nanoliposomal irinotecan combined with fluorouracil/folinic acid is recently approved by FDA for second line treatment of patients who have failed gemcitabine-based chemotherapy 45. After intravenous administration, irinotecan is converted to its active metabolite, 7-ethyl-1 o-hydroxycamptothecin (SN-38) by a carboxylesterase. SN-38 is then detoxified by UGT1A1 enzyme to its inactive form SN-38 glucuronide (SN-38G) which is excreted into the bile and urine. UGT1A1 is found to be polymorphic and resulted in wide inter-individual variation in patient's response as well as toxic side effects. Based on this information, FDA had first approved irinotecan label with pharmacogenetics information in 2005. In 2010, new pharmacogenetic information was added to the label regarding the risk of neutropenia in patients who had genetic defect of (UGT1A1). Over 30 genetic variants in the promoter region and exon 1 of UGT1A1 have been identified which can decrease enzyme activities. These genetic variants have been linked to few syndromes, such as Gilbert syndrome and Criegler-Najjar. UGT1A1*28 has been reported to cause approximately 70 per cent reduction of UGT1A enzyme activity. Under-expression of UGT1A1 enzyme impaired the metabolism of SN-38 to its inactive form (SN-38G) and caused an excessive accumulation of toxic SN-38. The French Joint Work group developed a review on the impact of the deficient UGT1A1*28 variant on irinotecan efficacy and toxicity 46. In addition, there are inter-ethnicity variations. Therefore, physicians caring for these patients should be aware of these genetic abnormalities. The practical point is that normally we administer irinotecan doses at least equal to 180 mg/m2, but this dose should be reduced in patients who are known to be homozygous for theUGT1A1*28 allele. Editor's comments: 1. Please consider to add tables as suggested by reviewer A as well as 1-2 figures RESPONSE: All considered; please see response above 2. The references are not according to Journal's style. Please check RESPONSE: Revised 3. The abstract could be improved, some more information is needed. RESPONSE: Revised