Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients with Gastric Cancer Associated with Hereditary Breast and Ovarian Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The study explored the possible connection between gastric cancer in HBOC background in Japanese population, H. pylori infection, and PARP inhibitor treatment. They provided evidence for the presence of connection between these factors, and support the use of PARP inhibitors to treat the gastric cancer in HBOC background of BRCA or HRD mutations.

 

Comments:

 

1.     Corresponding author: Takuma Hayashi, Cancer Medicine, National Hospital Organization Kyoto Medical 10 Center, Fushimi-ku, Kyoto 612-8555, Kyoto, e-mail: [email protected]: For scientific report, it is better to use professional email address.

2.     “It is presumed that cancer development occurs because of the accumulation of multiple cancer-related gene mutations within a single cell.”: This statement is not precise. It is well determined, not presumed……

3.     “Specific genetic pathogenic variants and driver genes have been identified for each type of cancer. Mutations in the gene for the epidermal growth factor receptor (EGFR) protein were first identified as the driver for lung cancer, which brought about a major paradigm shift in the treatment of lung cancer (4). EGFR gene mutations were detected in approximately half of the Japanese patients 55 with lung adenocarcinomas (5). Currently, the mutated KRAS proto-oncogene (KRAS) is 56 accepted as the most common oncogene in human cancers, accounting for approximately 30% of all solid tumors and pancreatic adenocarcinomas (the most common type of pancreatic cancer). KRAS is mutated in 95% of cases (6).”: The entire paragraph is not related with the gastric cancer, the focus of the study, it can be deleted.

4.     “the cytotoxin-associated gene A (CagA) antigen inhibits the nuclear migration of breast cancer susceptibility 1 (BRCA1) and BRCA2 genes (factors that repair damaged DNA and are strongly associated with the development of hereditary breast and ovarian cancer [HBOC]) (10). Thus, the physiological action of CagA causes an accumulation of mutations in multiple cancer-related genes within a single cell”: The description has a logical problem: the former is the inhibits nuclear migration of BRCA, which has nothing to do with mutation; the latter is the accumulation of mutation. As the entire study is around mutation, it will be better to remove the nuclear migration issue here

5.     “Therefore, our medical group compared the number of patients with gastric cancer in families with and without HBOC (n = 91 and 94, respectively) and found that families with HBOC had a greater proportion of patients with gastric cancer.” There is no citation for the authors’ own study on the subject.

6.     “poly-ADP-ribose-polymerase (PARP) inhibitor”: should be “inhibitors”. “to receive either olaparib plus paclitaxel or paclitaxel alone”: any control with conventional treatment without the use of PARPi?

7.     “gastric cancer with PVs, BRCA1/2, or HRD”: wrong writing.

8.     “2.1. Cancer Genome Profiling”: Should be 2.1. Cancer Gene Panel Profiling

9.     “panels were tested —OncoGuideTM NCC Oncopanel gene mutation analysis set 106 (Sysmex Corporation Kobe, Hyogo, Japan) and FoundationOne CDx’s cancer genome test 107 (Foundation One CDx, FoundationOne liquid CDx; Foundation Medicine, Inc., Cam-108 bridge MA, USA)”: a brief description for each panel should be provided, e.g., how many genes were included in each panel?

10.  Ethical description is repeated. Better to combine into a single paragraph.

11.  “In the United States, the incidence of gastric cancer is relatively low compared to 258 other types of cancer; however, globally, gastric cancer is the second most common cause 259 of cancer-related mortality. Gastric cancer is quite prevalent in Asian countries, such as 260 Korea, China, Taiwan, and Japan, and its treatment usually involves surgical removal of 261 the cancer, followed by chemotherapy, with or without radiation therapy. In Japan, gastric 262 cancer is associated with more than 50,000 deaths annually (20). H. pylori is a common 263 microbe found in East Asia, including Japan (20); as a result, it is believed that many pa-264 tients in East Asia develop gastric cancer because of H. pylori infection. The bacterium H. 265 pylori is broadly classified into CagA-positive and CagA-negative strains based on the 266 presence or absence of CagA secretion, with the CagA-positive strains inducing relatively 267 more severe gastric mucosal lesions (20-23). In Western countries, the ratio of CagA-posi-268 tive to CagA-negative strains is approximately 6:4 (21); however, CagA-positive H. pylori 269 strains are more common in East Asia, including Japan, are. Consequently, the incidence 270 of gastric cancer in the Japanese population (gastric cancer characteristic of East Asia) is 271 significantly higher (males = 6.07%; females = 2.11%) than in Western countries (USA: 272 males = 0.65%, females = 0.33%; UK: males = 0.66%, females = 0.28%) (24).” : the entire part can be moved to Introduction

Comments on the Quality of English Language

Substantial editing and revision are required to reach publication level

Author Response

R1 Comments:

Comment 1. Corresponding author: Takuma Hayashi, Cancer Medicine, National Hospital Organization Kyoto Medical 10 Center, Fushimi-ku, Kyoto 612-8555, Kyoto, e-mail: [email protected]: For scientific report, it is better to use professional email address.

Answer 1. We appreciate your comment.

In general, I think it is preferable for researchers to use the e-mail address of their research institute or the university to which they belong when publishing their manuscripts in academic journals. However, our email system of the national hospital organization Kyoto Medical Center is linked to the Electronic Medical Record (Karte), making it extremely difficult to send or receive emails outside the hospital. Therefore, the hospital director forces medical staff to use web-based email or free email services such as hotmail.com, outlook.com, and gmail, which allow email to be sent and received on mobile phones.

 

Comment 2. It is presumed that cancer development occurs because of the accumulation of multiple cancer-related gene mutations within a single cell.”: This statement is not precise. It is well determined, not presumed……

Answer 2. We appreciate your comment. We have rewritten the text as follows, based on your comments:

It has been demonstrated that cancer development occurs because of the accumulation of multiple cancer-related gene mutations within a single cell.

 

Comment 3. Specific genetic pathogenic variants and driver genes have been identified for each type of cancer. Mutations in the gene for the epidermal growth factor receptor (EGFR) protein were first identified as the driver for lung cancer, which brought about a major paradigm shift in the treatment of lung cancer (4). EGFR gene mutations were detected in approximately half of the Japanese patients 55 with lung adenocarcinomas (5). Currently, the mutated KRAS proto-oncogene (KRAS) is 56 accepted as the most common oncogene in human cancers, accounting for approximately 30% of all solid tumors and pancreatic adenocarcinomas (the most common type of pancreatic cancer). KRAS is mutated in 95% of cases (6).”: The entire paragraph is not related with the gastric cancer, the focus of the study, it can be deleted.

Answer 3. We appreciate your comment. We have rewritten the text as follows, based on your comments:

Specific genetic pathogenic variants and driver genes have been identified for each type of cancer. Mutations in the gene for the epidermal growth factor receptor (EGFR) protein were first identified as the driver for lung cancer, which brought about a major paradigm shift in the treatment of lung cancer (4). In solid cancers including lung adenocarcinoma and pancreatic cancer, mutant KRAS and mutant EGRF are known to function as driver factors (4,5,6). EGFR gene mutations were detected in approximately half of the Japanese patients 55 with lung adenocarcinomas (5). Currently, the mutated KRAS proto-oncogene (KRAS) is 56 accepted as the most common oncogene in human cancers, accounting for approximately 30% of all solid tumors and pancreatic adenocarcinomas (the most common type of pancreatic cancer). KRAS is mutated in 95% of cases (6).”.

 

Comment 4. The cytotoxin-associated gene A (CagA) antigen inhibits the nuclear migration of breast cancer susceptibility 1 (BRCA1) and BRCA2 genes (factors that repair damaged DNA and are strongly associated with the development of hereditary breast and ovarian cancer [HBOC]) (10). Thus, the physiological action of CagA causes an accumulation of mutations in multiple cancer-related genes within a single cell”: The description has a logical problem: the former is the inhibits nuclear migration of BRCA, which has nothing to do with mutation; the latter is the accumulation of mutation. As the entire study is around mutation, it will be better to remove the nuclear migration issue here

Answer 4. We appreciate your comment. We have rewritten the text as follows, based on your comments:

The cytotoxin-associated gene A (CagA) antigen inhibits the damaged DNA repair function of breast cancer susceptibility 1 (BRCA1) and BRCA2 (10). The cytotoxin-associated gene A (CagA) antigen inhibits the nuclear migration of breast cancer susceptibility 1 (BRCA1) and BRCA2 genes (factors that repair damaged DNA and are strongly associated with the development of hereditary breast and ovarian cancer [HBOC]) (10). Thus, the physiological action of CagA causes an accumulation of mutations in multiple cancer-related genes within a single cell”: The description has a logical problem: the former is the inhibits nuclear migration of BRCA, which has nothing to do with mutation; the latter is the accumulation of mutation. As the entire study is around mutation, it will be better to remove the nuclear migration issue here

 

Comment 5. Therefore, our medical group compared the number of patients with gastric cancer in families with and without HBOC (n = 91 and 94, respectively) and found that families with HBOC had a greater proportion of patients with gastric cancer.” There is no citation for the authors’ own study on the subject.

Answer 5. We appreciate your comment. We added an appropriate reference in the revised manuscript as follows, based on your comments:

Therefore, our medical group compared the number of patients with gastric cancer in families with and without HBOC (n = 91 and 94, respectively) and found that families with HBOC had a greater proportion of patients with gastric cancer (15).

15. Hayashi T, Sano K, Okada M, Ura T, Konishi I. Hereditary Gastric Cancer Is Linked with Hereditary Breast and Ovarian Cancer. World J Oncol. 2024 Aug;15(4):722-730. doi: 10.14740/wjon1871.

 

Comment 6. poly-ADP-ribose-polymerase (PARP) inhibitor”: should be “inhibitors”. “to receive either olaparib plus paclitaxel or paclitaxel alone”: any control with conventional treatment without the use of PARPi?

Answer 6. We appreciate your comment. We have rewritten the text as follows, based on your comments:

Therefore, combination therapy with paclitaxel and platinum drugs or oral administration of poly-ADP-ribose-polymerase (PARP) inhibitors, which are is an effective drug for patients with platinum-sensitive HBOC or ovarian cancer with HRD, may be used in patients with gastric cancer with BRCA1/2 with pathogenic variants (PVs) and/or HRD.

 

Comment 7. gastric cancer with PVs, BRCA1/2, or HRD”: wrong writing.

Answer 7. We appreciate your comment. We have rewritten the text as follows, based on your comments:

Naturally, clinical trials with large cohorts should be conducted to further verify the efficacy of olaparib in advanced/metastatic gastric cancer with PVs, BRCA1/2 with PVs, or HRD.

 

Comment 8. 2.1. Cancer Genome Profiling”: Should be 2.1. Cancer Gene Panel Profiling

Answer 8. We appreciate your comment. We have rewritten the text as follows, based on your comments:

2.1. Cancer Genome Profiling”: 2.1. Cancer Gene Panel Profiling:

 

Comment 9. panels were tested —OncoGuideTM NCC Oncopanel gene mutation analysis set 106 (Sysmex Corporation Kobe, Hyogo, Japan) and FoundationOne CDx’s cancer genome test 107 (Foundation One CDx, FoundationOne liquid CDx; Foundation Medicine, Inc., Cam-108 bridge MA, USA)”: a brief description for each panel should be provided, e.g., how many genes were included in each panel?

Answer 9. We appreciate your comment. We have rewritten the additional description for each panel as follows, based on your comments:

FoundationOne CDx cancer genome profile is a program that analyzes mutation information of 324 genes in genomic DNA extracted from tumor tissue samples (including cytology samples) obtained from patients with solid cancer.

FoundationOne Liquid CDx cancer genome profile is a program that analyzes mutation information of 324 genes in free DNA (cfDNA) extracted from plasma separated from whole blood obtained from patients with solid cancer.

OncoGuideTM NCC Oncopanel is a program that analyzes mutation information of 114 genes in genomic DNA extracted from tumor tissue specimens (including cytology specimens) obtained from patients with solid cancer. In addition, the program analyzes the mutation information of 114 genes in the cfDNA extracted from plasma separated from whole blood obtained from patients with solid cancer, and determines whether the genomic mutation information extracted from tumor tissue samples is a germline mutation.

 

Comment 10. Ethical description is repeated. Better to combine into a single paragraph.

Answer 10. I appreciate your comment. We agree with your comments. So, we have summarized the ethical explanation into one paragraph as follows.

2.3. Ethical Considerations with Human Study

Institutional Review Board (IRB) Approval and Consent to Participate: This research on human cancer genome information derived from results of cancer genome gene panels was conducted at the Kyoto University, its affiliated hospitals, and the National Hospital Organization Kyoto Medical Center in accordance with institutional guidelines (IRB approval no. 50-201504, NHOKMC-2023-2, and H31-cancer-2). This manuscript contains personal and/or medical information and a case report/case history about an identifiable individual; therefore, it has been sufficiently anonymized in line with our anonymization policy. All patients were briefed on the clinical study and agreed to take part in the present study by providing informed consent for participation. Our clinical research complied with the Helsinki Statement.

Ethics committee name: IRB of the National Hospital Organization Headquarters (approval code: H31-cancer-2; approval date: November 09, 2019, and June 17, 2013).

Ethics committee name: IRB of Kyoto University (approval code: R34005; approval date: August 01, 2022).

The authors attended research ethics education through the Education for Research Ethics and Integrity (APRIN e-learning program (eAPRIN)) agency. The completion numbers for the authors are AP0000151756, AP0000151757, AP0000151769, and AP000351128.

2.4. Ethical Compliance with Human Study

This study involves research with human participants and was approved by the institutional ethics committee(s) and IRBs. This manuscript contains personal and/or medical information and a case report/case history about an identifiable individual; therefore, it has been sufficiently anonymized in line with our anonymization policy. The authors obtained direct consent from the patient.

The authors attended research ethics education through the Education for Research Ethics and Integrity (APRIN e-learning program (eAPRIN)) agency. The completion numbers for the authors are AP0000151756, AP0000151757, AP0000151769, and AP000351128

 

Comment 11. In the United States, the incidence of gastric cancer is relatively low compared to 258 other types of cancer; however, globally, gastric cancer is the second most common cause 259 of cancer-related mortality. Gastric cancer is quite prevalent in Asian countries, such as 260 Korea, China, Taiwan, and Japan, and its treatment usually involves surgical removal of 261 the cancer, followed by chemotherapy, with or without radiation therapy. In Japan, gastric 262 cancer is associated with more than 50,000 deaths annually (20). H. pylori is a common 263 microbe found in East Asia, including Japan (20); as a result, it is believed that many pa-264 tients in East Asia develop gastric cancer because of H. pylori infection. The bacterium H. 265 pylori is broadly classified into CagA-positive and CagA-negative strains based on the 266 presence or absence of CagA secretion, with the CagA-positive strains inducing relatively 267 more severe gastric mucosal lesions (20-23). In Western countries, the ratio of CagA-posi-268 tive to CagA-negative strains is approximately 6:4 (21); however, CagA-positive H. pylori 269 strains are more common in East Asia, including Japan, are. Consequently, the incidence 270 of gastric cancer in the Japanese population (gastric cancer characteristic of East Asia) is 271 significantly higher (males = 6.07%; females = 2.11%) than in Western countries (USA: 272 males = 0.65%, females = 0.33%; UK: males = 0.66%, females = 0.28%) (24).” : the entire part can be moved to Introduction

Answer 11. We appreciate your comment. We have moved the sentence to introduction as follows, based on your comments:

1. pylori infection is a known cause of inflammation and ulcers in the stomach and small intestine, with 90% of all gastric cancer patients testing positive for H. pylori infection, making it a significant risk factor for the development of gastric cancer (8, 9). A previous study demonstrated that H. pylori infects gastric mucosal epithelial cells, and the cytotoxin-associated gene A (CagA) antigen inhibits the damaged DNA repair function of breast cancer susceptibility 1 (BRCA1) and BRCA2 (10). the cytotoxin-associated gene A (CagA) antigen inhibits the nuclear migration of breast cancer susceptibility 1 (BRCA1) and BRCA2 genes (factors that repair damaged DNA and are strongly associated with the development of hereditary breast and ovarian cancer [HBOC]) (10). Thus, the physiological action of CagA causes an accumulation of mutations in multiple cancer-related genes within a single cell; however, the molecular mechanism underlying the development of gastric cancer caused by H. pylori infection remains unclear.

In the United States, the incidence of gastric cancer is relatively low compared to 258 other types of cancer; however, globally, gastric cancer is the second most common cause 259 of cancer-related mortality. Gastric cancer is quite prevalent in Asian countries, such as 260 Korea, China, Taiwan, and Japan, and its treatment usually involves surgical removal of 261 the cancer, followed by chemotherapy, with or without radiation therapy. In Japan, gastric 262 cancer is associated with more than 50,000 deaths annually (20). H. pylori is a common 263 microbe found in East Asia, including Japan (20); as a result, it is believed that many pa-264 tients in East Asia develop gastric cancer because of H. pylori infection. The bacterium H. 265 pylori is broadly classified into CagA-positive and CagA-negative strains based on the 266 presence or absence of CagA secretion, with the CagA-positive strains inducing relatively 267 more severe gastric mucosal lesions (20-23). In Western countries, the ratio of CagA-posi-268 tive to CagA-negative strains is approximately 6:4 (21); however, CagA-positive H. pylori 269 strains are more common in East Asia, including Japan, are. Consequently, the incidence 270 of gastric cancer in the Japanese population (gastric cancer characteristic of East Asia) is 271 significantly higher (males = 6.07%; females = 2.11%) than in Western countries (USA: 272 males = 0.65%, females = 0.33%; UK: males = 0.66%, females = 0.28%) (24).

Previous studies have suggested that homologous recombination deficiency (HRD) of genes, including BRCA1 or BRCA2, may be linked to the development of gastric cancer (11-14). Therefore, our medical group compared the number of patients with gastric cancer in families with and without HBOC (n = 91 and 94, respectively) and found that families with HBOC had a greater proportion of patients with gastric cancer (15).

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The brief report entitled "Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients with Hereditary Gastric Cancer Linked to a Family History of Hereditary Breast and Ovarian Cancer (HBOC)" by T. Hayashi and colleagues aims to evaluate the efficacy of combination chemotherapy (olaparib and paclitaxel) in patients with gastric cancer (GC) with an HBOC background.

However, the report presents several major flaws that, in this Reviewer's opinion, cannot be rectified through revision:

Lack of experimental data on Helicobacter pylori (H. pylori): The role of H. pylori is emphasized throughout the manuscript, yet no experimental data are provided to substantiate the relevance of this bacterial infection in the study.

Repetitive data: Much of the data presented in Table 1 has already been published by the same authors, leading to concerns about the originality of the content.

 

Lack of novelty: The efficacy of the proposed combination therapy (olaparib and paclitaxel) in gastric cancer patients has already been evaluated by other researchers, diminishing the novelty of the findings.

Author Response

R2 Comments

The brief report entitled "Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients with Hereditary Gastric Cancer Linked to a Family History of Hereditary Breast and Ovarian Cancer (HBOC)" by T. Hayashi and colleagues aims to evaluate the efficacy of combination chemotherapy (olaparib and paclitaxel) in patients with gastric cancer (GC) with an HBOC background.

 

However, the report presents several major flaws that, in this Reviewer's opinion, cannot be rectified through revision:

 

Comment 1. Lack of experimental data on Helicobacter pylori (H. pylori): The role of H. pylori is emphasized throughout the manuscript, yet no experimental data are provided to substantiate the relevance of this bacterial infection in the study.

Answer 1: We appreciate your comment. We describe the following information regarding H. pylori infection in the manuscript.

A new treatment method was examined using cancer genome panel testing in 2361 Japanese patients with advanced/metastatic gastric cancer; of these, a total of 2340 patients (2340/2361; 99.11%) were found to be infected with H. pylori as a result of cancer genome testing and underwent cancer genome panel testing. Recent clinical studies have reported an incidence of 5%–10% for H. pylori infection in the Japanese population.

Our results, here, from analyzing cancer genomic medicine database are similar to those obtained in clinical research conducted by other research institutions.

Of 86 people with GC in HBOC families, 80 were infected with H. pylori (infection rate 80/86: 93.02%). Of 20 people with GC in non-HBOC families, 18 were infected with H. pylori (infection rate 18/20: 90.00%). Compared with the H. pylori infection rate (93.02%) in patients with GC in HBOC families, the H. pylori infection rate (90.00%) in patients with GC in non-HBOC families was almost the same.

 

We described the following information regarding H. pylori infection in the recent published manuscript.

Of 61 people with GC in HBOC families, 58 were infected with H. pylori (infection rate 57/61: 93.44%). Of 17 people with GC in non-HBOC families, 16 were infected with H. pylori (infection rate 16/17: 94.12%). Compared with the H. pylori infection rate (93.44%) in patients with GC in HBOC families, the H. pylori infection rate (94.12%) in patients with GC in non-HBOC families was almost the same.

 

Comment 2. Repetitive data: Much of the data presented in Table 1 has already been published by the same authors, leading to concerns about the originality of the content.

Answer 2. We appreciate your comment. We respond to your comment with the following:

Our research team previously published a report on the association between gastric cancer and HBOC. On this occasion, we received questions from readers and experts regarding "gender differences in the incidence of gastric cancer in HBOC families." We conducted a similar study to answer the questions of experts.

 

Sex-wise distribution of patients with gastric cancer

Total cases	Patients with GC in HBOC family (86 cases)		Patients with GC in No-HBOC family (20 cases)
	64 males with GC	74.41% males	11 males with GC	55.0% males with GC

 

In our previous report, we reported the results of a cohort study that included 78 HBOC families (2,070 cases) and 86 non-HBOC families (2,187 cases). This report presents the results of a cohort study that included 90 HBOC families (2,424 cases) and 94 non-HBOC families (2,377 cases). By increasing the number of participants in each cohort, gender differences in the incidence of advanced and metastatic gastric cancer in HBOC families were observed. By increasing the number of participants in each cohort, gender differences in the incidence of advanced and metastatic gastric cancer in HBOC families were observed. Previous research has shown that there is no difference between men and women in the infectivity of H. pylori. Therefore, factors that are differentially expressed between men and women may affect the fotr function of H. pylori CagA.

 

Comment 3. Lack of novelty: The efficacy of the proposed combination therapy (olaparib and paclitaxel) in gastric cancer patients has already been evaluated by other researchers, diminishing the novelty of the findings.

Answer 3. We appreciate your comment.

Previously reported clinical trials have investigated the efficacy of Olaparib in patients with gastric cancer in which ATM expression is very low or absent. Therefore, patients with gastric cancer were divided into cohorts with positive or negative expression of ATM in gastric cancer tissue.

A clinical trial conducted by our medical team was investigating the efficacy of Olaparib in patients with gastric cancer who had gBRCA1 PVs, gBRCA2 PVs, or HRD. Therefore, patients with gastric cancer were divided into cohorts with and without gBRCA1 PVs, gBRCA2 PVs, or HRD in their gastric cancer tissue. The content of the clinical trial protocol conducted by our medical staff is different from the content of clinical trial protocols that have already been reported.

 

Even for the same type of cancer, the genetic sequences are slightly different between Westerners, Asians, and Japanese. Even for the same type of cancer, the mechanism of onset differs slightly between Westerners and Asians/Japanese. Alternatively, the effect of the same antitumor agent on the same type of cancer differs between Westerners and Asians or Japanese. In other words, it has been revealed that certain gene mutations are VUS or benign in Westerners, but are pathogenic variants or likely pathogenic in Japanese people. Specifically, it has been revealed that BRCA2 S2616F is a VUS or benign variant in Westerners, but a pathogenic variant or likely pathogenic variant in Japanese people. If BRCA2 S2616F is detected in cancer genome profiling of Japanese patients, PARP inhibitors such as olaparib can be prescribed with insurance coverage. If the genetic mutation specific to Japanese people is thus a pathogenic variant, the efficacy of the drug will be specific to Japanese people. Similar clinical trials have already been conducted by other researchers and evaluations have been reported. However, the same clinical trial may produce different results depending on the race.

 

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

In the manuscript "Efficacy and Tolerability of Olaparib plus Paclitaxel lin Patients with Hereditary Gastric Cancer linked to a family History of Hereditary breast and Ovarian Cancer (HBOC)", the authors make the observation that there is increased incidence of Gastric cancer in males, with a family history of BRCA1/2 mutations, especially in light of infection by H. pylori.

All figures in this manuscript are required.

This manuscript was well written and easy to understand.

This manuscript of interest as it connects the infection of H. plyori with gastric tumor incidence. As H. plyori infection can alter the DNA damage response only by the release of cytotoxin-associated gene A (CagA) by inhibiting BRCA1/2 entry into the nucleus. This observation implies that any infection associated with H. plyori infection increases the possiblty for gastric cancer formation. This has important clinical implications for patients suffering from H. plyori infection with a family history of BRCA1/2 alteration. The authors also make the observation that PARP1 inhibitors, that are already in the clinic, are a viable treatment strategy.

Author Response

R3 Comment

In the manuscript "Efficacy and Tolerability of Olaparib plus Paclitaxel lin Patients with Hereditary Gastric Cancer linked to a family History of Hereditary breast and Ovarian Cancer (HBOC)", the authors make the observation that there is increased incidence of Gastric cancer in males, with a family history of BRCA1/2 mutations, especially in light of infection by H. pylori.

 

Comment

All figures in this manuscript are required.

 

This manuscript was well written and easy to understand.

 

This manuscript of interest as it connects the infection of H. plyori with gastric tumor incidence. As H. plyori infection can alter the DNA damage response only by the release of cytotoxin-associated gene A (CagA) by inhibiting BRCA1/2 entry into the nucleus. This observation implies that any infection associated with H. plyori infection increases the possiblty for gastric cancer formation. This has important clinical implications for patients suffering from H. plyori infection with a family history of BRCA1/2 alteration. The authors also make the observation that PARP1 inhibitors, that are already in the clinic, are a viable treatment strategy.

 

Answer

We would like to express our gratitude for the high evaluation of our submitted manuscript by the reviewer #3.

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

In general, the revision has addressed my comments with satisfaction.

 

The quality of English writing needs to be further improved. Multiple revised parts were directly copied from my comments, even for errors. E.g., in Comment 3: 55, 56 were copied from the lane number. But these numbers are also present in the revision. Similar issue was also present in other multiple locations.

Comments on the Quality of English Language

The revision is better, but the authors need to pay more attention to improve the quality of English writing to reach publication level.

Author Response

Manuscript ID: curroncol-3214931

R1

Comment: The revision is better, but the authors need to pay more attention to improve the quality of English writing to reach publication level.

Answer: We appreciate your comments. We agree with the content of your comments.

Based on the content of your comments, we have rewritten the entire English manuscript and polished the entire paper in native English.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The use of track changes significantly complicates the readability of the manuscript.

Authors poorly reply to my previous comments

H. plylori is not a nematode. Please remove.

iThenticate analysis reports a 65% match

Comments on the Quality of English Language

The manuscript should be edited by someone proficient in scientific English

Author Response

Manuscript ID: curroncol-3214931

R2

Comment 1: The use of track changes significantly complicates the readability of the manuscript.

Answer 1: We appreciate your comment. We understand your comments. The revised manuscript may be difficult to read because we are responding in balloons to editorial comments that are written in balloons within the manuscript. When you read the clean version of the manuscript, you may see that the manuscript has been revised.

 

Comment 2: Authors poorly reply to my previous comments.

Answer 2: We appreciate your comments. We agree with the content of your comments.

Based on the content of your comments, we have rewritten the entire English manuscript and polished the entire paper in native English.

 

Comment 3: H. plylori is not a nematode. Please remove.

Answer 3: We appreciate your comment. Based on the content of your comment, we removed the word.

 

Comment 4: iThenticate analysis reports a 65% match

Answer 4: Based on the content of your comments, we have rewritten the entire English manuscript and polished the entire paper in native English. We had a professional company check the similarity (percentage of plagiarism) between the content of our manuscript and other manuscripts. The plagiarism rate is 19.8%.

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Points to be addressed before publication:

2.1. Cancer Gene Panel Profiling. How many patients were involved in this study?

2.2. Clinical Trial. How many patients we involved in this study? 

2.3. Diagnostic Testing for H. pylori Infection. Which group of patients (2.1 or 2.2) has been tested?

 3. Results. 

Lines 186-197 should be moved and integrated into the introduction section.

Table 1. These patients and their families have not been described in materials and methods. Are they from the clinical trial (2.2) group? 

In the results section, authors jump mix the descriptions of different groups of patients and this could be misleading. The use of subsections could be useful. 

Lines 220-222: Please provide relevant references

Lines 222-223: To which group of patients this percentage is referred to?

Lines 226-227: In the same gruop of patients as the previuos point?

4. Discussion

Lines 289-292. Please provide adequate reference

Lines 293-295: Please clarify

 

Author Response

Manuscript ID: curroncol-3214931

Reviewer #2 comments

Comment 2.1. Cancer Gene Panel Profiling. How many patients were involved in this study?

Answer 2.1. We appreciate your comment. In accordance with your comments, we have added the number of participants in each cohort of the clinical study as follows.

HBOC 91 families: total 2424 participants, Patients with gastric cancer 86 patients.

Non-HBOC 94 families: total 2377 participants, Patients with gastric cancer 20 patients.

From December 2019 to June 2024, 36,211 novel treatments were investigated using cancer genome panel testing (FoundationOne® CDx test: n = 27,981; OncoGuide^TM NCC Oncopanel test, Riken Genesis, Yokohama, Kanagawa, Japan, n = 8,230) in cancer genomic medicine conducted at Japanese national universities. A novel treatment method was examined using cancer genome panel testing in 2,361 Japanese patients with advanced-stage/metastatic GC.

 

Comment 2.2. Clinical Trial. How many patients we involved in this study? 

Answer 2.2. We appreciate your comment. In accordance with your comments, we have added the number of participants in each cohort of the clinical study as follows.

All patients with GC: total participants n=132; patients treated with Olaparib + paclitaxel n=76, patients treated with placebo + paclitaxel n=65.

Patients with HRD-positive GC; total participants n=68; patients treated with Olaparib + paclitaxel n=35, patients treated with placebo + paclitaxel n=33.

 

Comment 2.3. Diagnostic Testing for H. pylori Infection. Which group of patients (2.1 or 2.2) has been tested?

Answer 2.3. We appreciate your comment. In accordance with your comments, we have added the number of participants in each cohort of the clinical study as follows.

Of the 86 patients with GC from families with HBOC, 80 (93.02%) had H. pylori infection. Of the 20 patients with GC from families without HBOC, 18 (90.00%) presented with H. pylori infection. The incidence of H. pylori infection was comparable between patients with GC from families with HBOC and those from families without HBOC.

 

3. Results.

Comment 3.1. Lines 186-197 should be moved and integrated into the introduction section.

Answer 3.1. We appreciate your comment. In accordance with your comments, we have moved and

integrated the section (Lines 186-197) into the introduction section as following.

BRCA1/2 suppresses tumor formation and progression, and recent studies have reported that CagA may prevent the inhibitory effect of BRCA1/2 on HBOC development (16-19). Previous studies have revealed that homologous recombination deficiency (HRD) of several genes, including BRCA1 and BRCA2, may be associated with the development of GC (16-19). Injection of H. pylori CagA into gastric mucosal epithelial cells significantly increased the accumulation of gene mutations that led to the development of GC (20,21). Furthermore, the CagA genotype was more likely to have a significant influence on the development of GC (21,22). Therefore, the action of CagA presumably results in the accumulation of genetic mutations in BRCA1/2 (i.e., PVs in BRCA1/2), which triggers the development and progression of GC by indirectly inducing the cancerous transformation of gastric mucosal epithelial cells. Furthermore, the incidence of GC in patients from families with HBOC harboring germline mutations in BRCA1/2 may be high (16-19). Therefore, this study compared the number of patients with GC from families with and without hereditary breast and ovarian cancer (HBOC) (n = 91 and 94, respectively). Results showed that families with HBOC had a greater proportion of patients with GC than those without (20). Therefore, treatment with oral poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors such as olaparib, which is an effective drug for patients with platinum-sensitive HBOC or HRD-positive ovarian cancer, can be used in patients with GC harboring BRCA1/2 mutations with PVs and/or HRD. Furthermore, this study revealed that GC was common in men from families with HBOC. Thus, combination therapy with paclitaxel and platinum drugs or oral treatment with PARP inhibitors, which are effective in patients with platinum-sensitive HBOC or HRD-positive ovarian cancer, can be utilized in patients with GC harboring germline BRCA1/2 mutations with PVs and/or HRDTo validate the efficacy of olaparib, patients with advanced-stage/metastatic GC in whom PVs were detected in any of the 10 homologous recombination genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, PALB2, RAD51C, and RAD51D) were randomized to receive either olaparib plus paclitaxel or paclitaxel alone. The safety and efficacy of olaparib plus paclitaxel and paclitaxel alone as a second-line chemotherapy for advanced-stage/metastatic GC were compared. Results showed that the olaparib plus paclitaxel group had a significantly longer overall survival (OS) than the paclitaxel alone group. Hence, large-scale clinical trials should be conducted to further verify the efficacy of olaparib in treating advanced-stage/metastatic GC harboring BRCA1/2 mutations with PVs or HRD. This study evaluated the results of previous studies (16-20). Moreover, the use of novel GC treatments in the future based on cancer gene panel testing was explored.

 

Comment 3.2 Table 1. These patients and their families have not been described in materials and methods. Are they from the clinical trial (2.2) group? 

Answer 3.2. We appreciate your comment. These patients and their families have been described in materials and methods as follows.

Material and methods:

HBOC 91 families: total 2424 participants, Patients with gastric cancer 86 patients.

Non-HBOC 94 families: total 2377 participants, Patients with gastric cancer 20 patients.

Result:

Therefore, the action of CagA presumably results in the accumulation of genetic mutations in BRCA1/2 (i.e., PVs in BRCA1/2), which triggers the development and progression of GC by indirectly inducing the cancerous transformation of gastric mucosal epithelial cells. Furthermore, the incidence of GC in patients from families with HBOC harboring germline mutations in BRCA1/2 may be high (16-19). Therefore, the incidence of GC in patients with (HBOC families n = 91) and without (non-HBOC families n = 94) a history of HBOC (families with 1–4 or 6 generations) was investigated. Results showed that the families with HBOC had a higher incidence of GC (3.55%) than those without (0.78%) (Table 1, S.Figure 1, S.Figure 2). Moreover, men constituted 74.41% of the patients with GC who were from families with HBOC and 55% of the patients with GC who were from families without HBOC (Table 1, S.Figure 1, S.Figure 2).

The detailed contents of Table 1 are shown in S.Figure 1 and S.Figure 2.

 

Comment 3.3. In the results section, authors jump mix the descriptions of different groups of patients and this could be misleading. The use of subsections could be useful. 

Answer 3.3. We appreciate your comment. In accordance with your comments, we have divided the results section into subsections and added subheadings to the manuscript.

3.1. Comparison of the number of gastric cancer cases between HBOC and non-HBOC families.

3.2. Detection of pathogenic variants in BRCA1 and BRCA2 genes in gastric cancer tissues by cancer genome panel testing in a population of gastric cancer patients

3.3. Antitumor efficacy and adverse events of the PARP inhibitor olaparib in patients with HRD-positive gastric cancer.

 

Comment 3.4. Lines 220-222: Please provide relevant references

Answer 3.4. We appreciate your comment. In accordance with your comments, we have added relevant reference (Ref. 23) to the manuscript.

 

Comment 3.5. Lines 222-223: To which group of patients this percentage is referred to?

Answer 3.5. We appreciate your comment. We have added the appropriate text to the manuscript following your comments.

In our study with cancer genome panel testing, BRCA2 with germline PVs (gPVs) and/or somatic PVs (sPVs) was detected in 395 (395/2361; 16.73%) patients with advanced-stage/metastatic GC.

 

Comment 3.6 Lines 226-227: In the same gruop of patients as the previuos point?

Answer 3.6. We appreciate your comment. We convey the following to our readers:

The results of our clinical study detected ERBB2 mutations as a factor associated with the onset or progression of human gastric cancer. Previously, a clinical study conducted by He et al. also detected ERBB2 mutations as a factor associated with the onset or progression of human gastric cancer. Both clinical studies revealed that ERBB2 mutations are associated with the onset and progression of gastric cancer.

 

4. Discussion

Comment 4.1. Lines 289-292. Please provide adequate reference

Answer 4.1. We appreciate your comment. In accordance with your comments, we have added relevant reference (Ref. 26) to the manuscript.

Kawai S, Wang C, Lin Y, Sasakabe T, Okuda M, Kikuchi S. Lifetime incidence risk for gastric cancer in the Helicobacter pylori-infected and uninfected population in Japan: A Monte Carlo simulation study. Int J Cancer. 2022 Jan 1;150(1):18-27. doi: 10.1002/ijc.33773.

 

Comment 4.2. Lines 293-295: Please clarify

Answer 4.2. We appreciate your comment. In accordance with your comments, we have rewritten the sentence as follows:

Both events occurred in the olaparib/paclitaxel arm during the combination phase; one event was grade 3 by Common Terminology Criteria for Adverse Events (the other was grade 2) and led to dose modification.

 

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