Survival Comparisons between Breast Conservation Surgery and Mastectomy Followed by Postoperative Radiotherapy in Stage I–III Breast Cancer Patients: Analysis of the Surveillance, Epidemiology, and End Results (Seer) Program Database
Round 1
Reviewer 1 Report
Dear colleagues,
Your paper aimed two objectives:
- To compare the OS and BCSS in patients with conservative vs. radical surgery, followed by radiotherapy
- To propose a nomogram for 5, 10, 15 yrs- BCSS prediction
The first question (not identical) was address by Veronesi and Fisher in the ‘70s, Arriagada in ‘90s, Agarwal in 2010s and de Boniface in 2020s to cite only few. The answer was the same and it is the evidence for both European and American guidelines.
Your paper tried to replicate the data, and this could be appreciated. But the patients’ characteristics are missing, the statistical method used is not mentioned and the results are not clear.
I doubt that PSM is useful is large cohort. However, curiously, in your paper, after the matching, the groups are statistically significant different regarding PgR. Additionaly, in table 3, more than 75% are N2-N3 which is quite impossible for stage II breast cancer.
Finally the results are not reliable (even if I believe they reflect the truth).
I cannot have opinion on proposed nomogram, but it still is a secondary objective of your paper.
Author Response
Response to Reviewer 1 Comments
Dear reviewer,
Thank you for your careful reading and valuable suggestions for our manuscript. We have added a point-by-point response to your comments in the revised version of the manuscript. We have felt that the quality of our manuscript has improved greatly after incorporating the changes you suggested. All the changes we made were highlighted in red color in the revised manuscript.
Sincerely,
Dr. Haijun Yu
Comment #1:
Dear colleagues,
Your paper aimed two objectives:
- To compare the OS and BCSS in patients with conservative vs. radical surgery, followed by radiotherapy
- To propose a nomogram for 5, 10, 15 yrs- BCSS prediction
The first question (not identical) was address by Veronesi and Fisher in the ‘70s, Arriagada in ‘90s, Agarwal in 2010s and de Boniface in 2020s to cite only few. The answer was the same and it is the evidence for both European and American guidelines.
Response: Thank you for your insightful comment. We have intensively read these references. The randomized trials conducted by Veronesi and Fisher confirmed that the long-term survival rate of breast conservation surgery (BCS) plus radiotherapy (RT) is the same as that of radical mastectomy for female patients with small breast cancers. The randomized trial conducted by Arriagada provided trusted evidence supporting BCS plus RT as an alternative safe procedure for patients with small breast cancer. However, these studies did not directly compare the survival rate between the BCS plus RT group and the mastectomy plus RT group, which is the main objective of our work. The inclusion criteria in Agarwal’s paper were female patients with early-stage invasive ductal breast cancer with a tumor size of 4 cm or smaller with 3 or fewer positive lymph nodes from 1998 to 2008, whereas our study considered tumor size and lymph node infiltration as confounders to be processed with the propensity score matching to minimize selection bias. The difference between Boniface’s study and ours is that Boniface J analyzed Swedish female patients with invasive T1-2 N0-2 breast cancer from 2008 to 2017, whereas our cohort included all stage I-III American female breast cancer patients from 1990 to 2016. Not only early-stage patients but also T3-4(tumor size >5 cm)and N2-3(four or more node metastases)patients are analyzed in our data. Our study may provide sufficient additional evidence for guiding treatment for breast cancer. We have included all these relevant references (Ref) for sufficient introduction in the revised manuscript. Thank you for your valuable comments again.
Comment #2: Your paper tried to replicate the data, and this could be appreciated. But the patients’ characteristics are missing, the statistical method used is not mentioned and the results are not clear.
Response: Thank your appreciation for our work. The patients’ characteristics were presented in Supplementary Table 1, and we have moved it from supplementary to Table 1 of the results section to improve the readability in the revised manuscript. We have added the statistical methods we used to the methods and materials section (lines 349-350) and revised the results in the results section (lines539-543) for the results’ clear presentation in the revised manuscript.
Comment #3: I doubt that PSM is useful is large cohort.
Response: Sorry for our insufficient description of propensity score matching (PSM). PSM, proposed in 1983 by Rosenbaum and Rubin, estimates the treatment effect by modeling the relationship between confounders and treatment assignment, and it is not limited by the number of events. PSM works better in large samples, and it may be warranted when the number of confounders is large, or the number of outcomes is small(1, 2). We have added the introduction about PSM in our revised manuscript (Lines 339-341).
Comment #4: However, curiously, in your paper, after the matching, the groups are statistically significant different regarding PgR.
Response: Our study is a retrospective analysis, and unequal distribution of confounders may contribute to the difference in outcomes between BCS plus RT group and mastectomy plus RT group. For the patients in stage II, the nearest neighbor matching and the caliper distance (0.02) were performed in PSM. Significant imbalances of certain covariates may be unavoidable in PSM. We regret that the progesterone receptor status could not be perfectly matched, while other confounders presented no significant imbalance. Thanks for pointing out the limitations of the data itself and we added it to the study’s limitations in the revised manuscript. (Line1119-1121). Thank you for your valuable comments again.
Comment #5: Additionaly, in table 3, more than 75% are N2-N3 which is quite impossible for stage II breast cancer.
Response: We are sorry we attached the wrong title to Table 3, which presented the “clinical characteristics of patients for stage III before and after PSM.” We have corrected the title of Table 3 in our revised manuscript. we moved Supplementary Table 1 from supplementary to Table 1， so the initial table order is moved backward in turn.
Comment #6: Finally the results are not reliable (even if I believe they reflect the truth).
Response: Thank you for the comments.
Comment #7: I cannot have opinion on proposed nomogram, but it still is a secondary objective of your paper.
Response: Thank you for this suggestion.
References
- P. R. Rosenbaum, D. B. Rubin. The Central Role of the Propensity Score in Observational Studies for Causal Effects. Biometrika. 1983;70(1):41-55.
- U. Benedetto, S. J. Head, G. D. Angelini, E. H. Blackstone. Statistical primer: propensity score matching and its alternatives. Eur J Cardiothorac Surg. 2018;53(6):1112-1117.
Reviewer 2 Report
This is a concise article that presents a study comparing breast cancer survival between two forms of surgery after radiotherapy. The results show that breast cancer resection + radiation provided better survival outcomes compared to mastectomy + radiation, especially with stage II patients. There are several comments/concerns listed below for the author consideration in order to further improve the quality of the paper.
Minor comment: There are several errors in English and grammar that need to be corrected (see highlighted texts in the attached file). The services of an English editor may be solicited. Also, there are too many abbreviations in the paper. All abbreviations should be spelt out before their first use.
Major Comments:
1. Title: Correct the title to read "Survival comparisons between breast conservation surgery and mastectomy followed by postoperative radiotherapy in stage I-III breast cancer patients: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Program database.
2. Abstract: Line 11, the name of the database is incorrect, and presents the authors in bad light if they do not know the correct name of the database being analyzed by them. Correct "Surveillance, Epidemiology, and Final Results (SEER) database" to "Surveillance, Epidemiology, and End Results (SEER) Program database. In line 12, what was divided into BCS plus RT and mastectomy plus RT? Clarify. In line 14, and several other parts of the paper, sentences should begin with capital letters (not small letters as seen in this paper). Spell out "OS" before first use of the acronym. Which study is being referred to in line 25?
3. Background: Line 31, correct "existed" to "exists" and find another phrase for "high-quality". In line 41 and other parts of the paper, citations are poorly done and should be corrected. The statement in lines 41-44 is confusing and should be revised. What is "MRM+RT in line 48? Always spell out abbreviations before their first use. Line 55, the citation is poorly done. In line 57, mention the research properly instead of using the term "another research". In line 62, which study is being referred to as "The population-based study aimed...?"
4. Method: Mention the exact version of the SEER database that was used for this project. Was it SEER 17, SEER 18, etc? Line 71 correct the term "SEER's data is open to everyone" to "SEER data is publicly available". Line 98, correct "breast-specific survival (BCSS)" to "breast-cancer-specific survival (BCSS)". In line 100, correct to "BCSS refers to deaths from breast cancer".
4. Results: In line 130, correct "the general law of clinical practice" to "most clinical guidelines". Be consistent with reporting your findings. In line 135, correct to HR=0.8473(CI 0.7841-0.9155) p<0.001. It is difficult to read your figures. These should be done properly with the correct resolutions. Tables and figures should be placed next to the texts/narrative where they are mentioned in the results section. I do not understand why some of the tables are left out as supplementary. This does not make it easy for the reader. Also, I do not think that this study was only about stage II cancer, therefore the other findings should be presented properly in the main text. In line 143, correct "hint that stage was independent prognostic factors" to "suggest that stage was an independent prognostic factor". In line 146, include the value of the HR and CI. In the tables, is "RS" the same as mastectomy??? "RS" is not on the lists of abbreviations. Be consistent with abbreviations. The tables in the appendix should be moved to the manuscript next to where they are described.
5. Discussion: In line 293, what is "CTC-positive patients". Spell out CTC. In line 295, find a better word for "collaborate". In lines 308-309, the statement is confusing... Are you referring to the present study or SEER as a large sample size??? Clarify please. In line 313, find a better term for "which is a pity". Doesn't appear professional.
Best of luck!!!
Comments for author File: 
Comments.pdf
Author Response
Response to Reviewer 2 Comments
Dear reviewer,
We would like to thank you first for all the positive comments on our manuscript. We have added a point-by-point response to your comments in the revised version of the manuscript. We have felt that the quality of our manuscript has improved greatly after incorporating the changes you suggested. All the changes we made were highlighted in red color in the revised manuscript.
Sincerely,
Dr. Haijun Yu
This is a concise article that presents a study comparing breast cancer survival between two forms of surgery after radiotherapy. The results show that breast cancer resection + radiation provided better survival outcomes compared to mastectomy + radiation, especially with stage II patients. There are several comments/concerns listed below for the author consideration in order to further improve the quality of the paper.
Response: Thank you for your careful reading and valuable suggestions.
Minor comment:
Comment #1: There are several errors in English and grammar that need to be corrected (see highlighted texts in the attached file). The services of an English editor may be solicited.
Response: Thank you for reading carefully and providing the attached file thoughtfully. several errors in English and grammar that need to be corrected according to highlighted texts in the attached file. The manuscript has been thoroughly polished. Now the contexts have been presented in a better manner. Please see if the revised version met the English presentation standard.
Comment #2: Also, there are too many abbreviations in the paper. All abbreviations should be spelt out before their first use.
Response: Thank you for the suggestion. All abbreviations were spelt out before their first use in the revised manuscript.
Major Comments:
- Title:
Comment #1.1: Correct the title to read "Survival comparisons between breast conservation surgery and mastectomy followed by postoperative radiotherapy in stage I-III breast cancer patients: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Program database.
Response: Thank you for your suggestion. The title has been corrected.
- Abstract:
Comment #2.1: Line 11, the name of the database is incorrect, and presents the authors in bad light if they do not know the correct name of the database being analyzed by them. Correct "Surveillance, Epidemiology, and Final Results (SEER) database" to "Surveillance, Epidemiology, and End Results (SEER) Program database.
Response: Thank you for pointing this out. "Surveillance, Epidemiology, and Final Results (SEER) database" has been corrected to "Surveillance, Epidemiology, and End Results (SEER) Program database.
Comment #2.2: In line 12, what was divided into BCS plus RT and mastectomy plus RT? Clarify.
Response: Patients with available clinical information were divided into BCS plus RT and mastectomy plus RT. We have clarified this in our revised manuscript in line 18.
Comment #2.3: In line 14, and several other parts of the paper, sentences should begin with capital letters (not small letters as seen in this paper).
Response: Sorry for this bad. We have fixed it in the whole manuscript of the revised version.
Comment #2.4: Spell out "OS" before first use of the acronym.
Response: Thank you for the suggestion. "OS" was spelt out in line 24, and all abbreviations were spelt out before their first use in the revised manuscript.
Comment #2.5: Which study is being referred to in line 25?
Response: “The study” has been corrected to “Our study” in line 32.
- Background:
Comment #3.1: Line 31, correct "existed" to "exists" and find another phrase for "high-quality".
Response: Thank you for this suggestion. After polishing, we replaced the sentence expression. In the revised manuscript: Lines 38-41. “Breast-conserving surgery (BCS) plus postoperative radiotherapy (RT) was recommended as an alternative to mastectomy for early-stage breast cancer patients based on several randomized controlled trials, demonstrating that BCS followed by postoperative RT is as effective as mastectomy”. "high-quality" was replaced with “randomized controlled trials”.
Comment #3.2: In line 41 and other parts of the paper, citations are poorly done and should be corrected. The statement in lines 41-44 is confusing and should be revised.
Response: Thank you for pointing this out. We strengthened citations according to highlighted texts in the attached file. In the revised manuscript: Lines 181-206. “Veronesi U. et al. conducted a randomized trial in 1973, demonstrating the non-inferiority of BCS followed by RT compared with radical (Halsted) mastectomy for patients with a tumor size of 2 cm or smaller1. At the same time, a randomized controlled trial conducted by Fisher B. et al. confirmed the finding2. Therefore, BCS plus RT was recommended as an alternative to mastectomy for early-stage breast cancer patients18. Many recent studies (e.g., Hwang ES, 2013; Agarwal S, 2013; Fisher S,2015; Hartmann-Johnsen OJ,2015) have shown the superiority of BCS plus RT over mastectomy without RT5-11. However, fewer studies investigated whether BCS plus RT was still superior to mastectomy in the case of RT. Agarwal’s study demonstrated that female patients undergoing BCS plus RT have a better 5-year and 10-year disease-specific survival rate compared with those who received mastectomy with or without RT, and the number of the patients who underwent mastectomy plus RT accounted for 3%6. Besides, Hartmann-Johnsen OJ's study to compare the survival of BCS plus RT and mastectomy analyzed the Norwegian population of T1-2N0-1M0 from 1998 to 2008 and reported a worse disease-specific survival in the mastectomy group (30.7% of patients of the mastectomy group received postoperative RT)8. These studies showed that mastectomy plus RT seemed to be associated with worse survival compared with BCS plus RT group. In Lan XW's retrospective study of 196 pairs of stage T1-2N1M0 Chinese female patients, a lower 5-year distant metastasis rate and superior 5-year distant metastasis-free survival and disease-free survival and breast-cancer-specific survival（BCSS）with receipt of BCS plus RT compared with mastectomy plus RT were reported19. On the contrary, Sun GY.et al. compared 244 pairs of stage T1-2N1M0 Chinese patients, showing that the BCS plus RT group had comparable survival outcomes to the mastectomy plus RT group20. According to de Boniface J's analysis of Swedish female patients with invasive T1-2 N0-2 breast cancer from 2008 to 2017, BCS plus RT has a superior 5-year overall survival (OS) and 5-year BCSS than mastectomy with or without RT21.”.
Comment #3.3: What is "MRM+RT in line 48? Always spell out abbreviations before their first use.
Response: Thank you for the comment. "MRM+RT" is "mastectomy plus radiotherapy". The revised manuscript is in lines 189-192. All abbreviations were spelt out before their first use in the revised manuscript.
Comment #3.4: Line 55, the citation is poorly done.
Response: Thank you for pointing this out. For a clearer argument, we have added citations to high-impact papers and, in addition, analyzed and rewritten citations of existing papers.
Comment #3.5: In line 57, mention the research properly instead of using the term "another research".
Response: Thank you for this suggestion. As you suggested, we have corrected it. In the revised manuscript: Lines201-203, “On the contrary, Sun GY.et al. compared 244 pairs of stage T1-2N1M0 Chinese patients, showing that the BCS plus RT group had comparable survival outcomes to the mastectomy plus RT group”.
Comment #3.6: In line 62, which study is being referred to as "The population-based study aimed...?"
Response: Thank you for the comment. " The population-based study " has been corrected to " Our population-based study ".
- Method:
Comment #4.1: Mention the exact version of the SEER database that was used for this project. Was it SEER 17, SEER 18, etc?
Response: It was SEER 13, we added it in the methods and materials section(line 223).
Comment #4.2: Line 71 correct the term "SEER's data is open to everyone" to "SEER data is publicly available".
Response: Thank you for this suggestion. "SEER's data is open to everyone" was corrected to "SEER data is publicly available" in line 221 (prev. 71).
Comment #4.3: Line 98, correct "breast-specific survival (BCSS)" to "breast-cancer-specific survival (BCSS)".
Response: Thank you for the suggestion. "breast-specific survival (BCSS)" was corrected to "BCSS" in line 322 (prev. 98). It is mentioned first in Line 124.
Comment #4.4: In line 100, correct to "BCSS refers to deaths from breast cancer".
Response: Thank you for the suggestion. "BSCC refers to only died of breast cancer" was replaced with "BCSS refers to deaths from breast cancer" line 200 (prev. 100).
- Results:
Comment #5.1: In line 130, correct "the general law of clinical practice" to "most clinical guidelines". Be consistent with reporting your findings.
Response: Thank you for this suggestion. We have corrected "the general law of clinical practice" to "most clinical guidelines" in the revised manuscript. Line 530(prev.130) .
Comment #5.2: In line 135, correct to HR=0.8473(CI 0.7841-0.9155) p<0.001.
Response: Thank you for pointing this out, fixed. Line 535(prev.135).
Comment #5.3: It is difficult to read your figures. These should be done properly with the correct resolutions. Tables and figures should be placed next to the texts/narrative where they are mentioned in the results section. I do not understand why some of the tables are left out as supplementary. This does not make it easy for the reader.
Response: Thank you for this valuable suggestion. We have moved supplementary table 1 to Table 1 of the results section to improve the readability of the revised manuscript.
Comment #5.4: Also, I do not think that this study was only about stage II cancer, therefore the other findings should be presented properly in the main text.
Response: Thank you for your insightful comment. We have added Stratified Cox univariate regression analyses of stage III patients. Results have been appropriately supplemented (Line708-712). Additional pictures(SupplementaryFigure1) are placed at the end of the letter.
Comment #5.5: In line 143, correct "hint that stage was independent prognostic factors" to "suggest that stage was an independent prognostic factor".
Response: Thank you for this suggestion. We have corrected " hint that stage was independent prognostic factors " to " suggest that stage was an independent prognostic factor”. Line 563(prev.143) .
Comment #5.6: In line 146, include the value of the HR and CI.
Response: Thank you for pointing this out. We included the value of the HR and CI in lines 566-568 (prev. 146)
Comment #5.7: In the tables, is "RS" the same as mastectomy??? "RS" is not on the lists of abbreviations. Be consistent with abbreviations.
Response: Thank you for this suggestion. "RS" is the same as mastectomy, we have corrected " RS " to " mastectomy” in Table 2, Table 3, and Table 4.
Comment #5.8: The tables in the appendix should be moved to the manuscript next to where they are described.
Response: Thank you for the suggestion. The number of Figures and tables that can be displayed in the main text is limited. Currently, we prioritize important results for presentation. If the layout allows, we will make changes immediately.
- Discussion:
Comment #6.1: In line 293, what is "CTC-positive patients". Spell out CTC.
Response: Thank you for this suggestion. We have corrected " CTC-positive patients " to " circulating tumor cell-positive-positive patients”. Line 825-826(prev.293) .
Comment #6.2: In line 295, find a better word for "collaborate".
Response: Thank you for this suggestion. In the revised manuscript, Line 827:"collaborate" was replaced with "work".
Comment #6.3: In lines 308-309, the statement is confusing... Are you referring to the present study or SEER as a large sample size??? Clarify please.
Response: Thank you for the suggestion. We are referring to the present study as a large sample size. We are aware of the inappropriate of making a statement within the limitation and have removed this sentence.
Comment #6.4: In line 313, find a better term for "which is a pity". Doesn't appear professional.
Response: Thank you for this suggestion, In the revised manuscript, Line 1108-1111: Human epidermal growth factor receptor 2 (HER2) expression in breast cancer patients was only documented in the SEER database starting in 2010. Unfortunately, the follow-up time was insufficiently long to include HER2 in the study.
Best of luck!!!
Response: Thank you!!!
Round 2
Reviewer 1 Report
Thank you for clarifications!
Reviewer 2 Report
The authors have responded adequately to my comments/concerns from the initial review. There is still need to check out the MDPI recommended style for in text citation.
Best of luck!
