RESPONSE TO EDITOR AND REVIEWER

RESPONSE TO THE EDITOR:

MAJOR POINTS:

COMMENT: I would suggest authors to add more details about the cancer registry and how a cancer case is defined. Could you tell be more about the population covered by the registry? Does it cover all the province? The authors mentioned that the registry reports « both population-based and hospital-based statistics ». This is unclear. How do a cancer case is defined? What is the date of incidence considered? How did authors consider cancer diagnosis based on death certificate only (DCO)?

RESPONSE: We added more detail about the Songkhla cancer registry and revised the unclear sentences (Study setting and data sources paragraph: 3-4).

“The Songkhla Cancer Registry is a population-based cancer registry that enrolled cancer patients residing in Songkhla Province. Case ascertainment began in 1988, and patients’ data were regularly supplied to the Cancer Incidence in Five Continents (CIV since vol. VIII) [15]. The cases were identified using active and passive case-finding methods and registered by trained staff. The sources of information included medical records and pathological records of all hospitals in the province. The status of the patients in the database is reported when deaths occur in the hospitals and healthcare network and is confirmed by the Bureau of Registration Administration Database, Department of Provincial Administration, Ministry of Interior.

The diagnosis date of cancer patients was obtained from the most reliable source, if possible. The diagnosis date was indicated as the date of biopsy, the date when the specimen was received at the pathological laboratory, or the report date. When the date of definitive diagnosis provided by the pathological laboratory was not indicated, the date of hospital admission due to this malignancy and other dates related to the occurrence of malignancy or death were considered [16].”

COMMENT: In this analysis, did authors apply an age criteria for inclusion?

RESPONSE: We included all breast cancer cases who were diagnosed in the study periods. However, from our data, the youngest patient who met our criteria was 24 years old. That is why we set the age group for calculating the age-specific incidence from age 20 to ≥85 years.

COMMENT: Also, I really like the discussion part about number of new cancer cases and estimated costs (lines 335-344). This would deserve to be part of the results part and to be presented as a secondary objective. This is an interesting point that may be of interest for policy makers. I would highlight that point. If authors decide to do so, they need to explain about they estimate the nb of new cancer cases in 2030 and how they estimate the excess costs in the method section.

RESPONSE: We decided to set the projection of additional cost due to the trastuzumab treatment in 2030 as the secondary objective of our study. We explained how to estimate the excess cost in the methodology part as subtopic “Trastuzumab cost projection” and added the outcome in the result part under the subtopic “Additional cost projection of trastuzumab treatment.”

COMMENT: Why did not the authors use the Rubin's rules to combine their estimates?

RESPONSE: In our analysis, we calculated the estimates and margin of error of the imputed data by three methods, median and its 95% probability interval, mean, and Rubin’s estimate of the 95% confidence interval and mean ±2 SD margins. All three methods gave very close values of the estimates and the margins of error. Thus, in the previous draft, we decided to show only the median proportion and 95%PI, but we forgot to explain the similarity of the results. So, in this revision, we showed the results from all methods in Table 2. (Table 2 and Results part in subtopic: Proportions of breast cancer M-IHC subtypes)

COMMENT: Because authors studied trends in cancer incidence, I would like to see a comment in the discussion on the possible change (or not) of recording system of new cancer cases. Also, authors showed that there is a decrease in incidence from the age of 70. Would not it be explained by a lower ascertainment of cancer cases at older ages? Older adults may be less likely to go through cancer diagnosis workups because of their age, the presence of other conditions, or frailty. This should be mentioned as possible reason.

RESPONSE: One study from six provincial cancer registries in Thailand found an effect of introducing a country-wide self-breast examination screening program under the universal health insurance, which covered over 90% of the Thai population increase capturing of the hidden breast cancer cases aged over 80. The capture rate declined after some years of the program's start even it has continued as many cases have been captured. So, we think that we captured the decline in the ascertainment rate during our study period and is becoming stabilized after the end of our study. In the paragraph, we discussed that “Thailand has promoted breast cancer screening programs since 2002, covering over 90% of the Thai population [3]. An analysis of six provincial cancer registries in Thailand reported the effect of introducing a country-wide self-breast examination screening program [3]. It increased the detection of breast cancer among individual aged >80 years. However, the detectable rate declined several years after that because few prevalent cases were reported. Our study also found a decline in the age-specific incidence rates of all breast cancer subtypes after the age of 70 years, which is consistent with the report of a previous study.” (Discussion: paragraph 3).

COMMENT: Another possible reason for changes in incidence is breastfeeding practices? Have they changed over the period covered by the study?

RESPONSE: We added the detail about the change in the breastfeeding rate in Thailand over time in the revised version (Discussion: paragraph 4).

“However, the 6-month exclusive breastfeeding rate in Thailand has changed over time. A series of national surveys reported that the rate was 14.5% in 2005 and increased to 23.1% in 2016, which was the highest; however, it sharply decreased to 14.0% in 2019 [27].”

27. Topothai C, Tangcharoensathien V. Achieving global targets on breastfeeding in Thailand: gap analysis and solutions. Int Breastfeed J. 2021 Dec;16(1):38. doi: 10.1186/s13006-021-00386-0. PMID: 33962645.

MINOR POINTS:

COMMENT: I would suggest to replace 10e5 by 100,000 as it is easier to read.

RESPONSE: We agree with the editor's comment and change text "105" to "100,000" in our revised version.

COMMENT: I strongly encourage authors to have an English-native speaker to check the grammar and sentence structure as there are several parts of text that are unclear. For instance, lines 223-231, 243, 259, 264-266, 196-299, 331-333, 355-359, 363. I encourage authors to reformulate.

RESPONSE: Before resubmission, we sent the revised manuscript to the Editage for checking the grammar and sentence structure.

COMMENT: The introduction may be shortened, in particular, the paragraph on racial and cultural disparities. Because the study is about incidence, the paragraph on treatment does not seem relevant in the introduction.

RESPONSE: We decided to delete the paragraph that describes the racial variations in Thailand. However, we remained the paragraph that described the treatment option in breast cancer patients. It shows why the knowledge of breast cancer incidence in terms of subtype is essential. In addition, it relates to our secondary objective that we added in the revised version.

COMMENT: Authors mentioned cancer stage several times but they did not define which staging system they used. I would then suggest to add the definition in the method section.

RESPONSE: Songkhla cancer registry records the breast cancer stage according to the AJCC-TNM classification. In a long-running cancer registry, cancer staging may change over time. The registries usually reclassify the extent of disease to the summary stage according to the SEER staging system. It categorized tumor stage to in situ, localized, regionalized, distant, and unknown stage.

COMMENT: Lines 304-305: is not tautological?

RESPONSE: We revised the sentences in Line 304-305 and described this issue in more detail as “However, the 6-month exclusive breastfeeding rate in Thailand has changed over time. A series of national surveys reported that the rate was 14.5% in 2005 and increased to 23.1% in 2016, which was the highest; however, it sharply decreased to 14.0% in 2019 [27].” (Discussion: paragraph 4).

COMMENT: Lines 311-312: authors mentioned an increase in teenage pregnancy. Would not it explain by a better reporting?

RESPONSE: We changed the last part of the discussion on reproductive behaviors in the Thai population to lessen the stress on teenage pregnancy and HR-positive breast cancer. The detail is, “Thai adolescents experienced a social dynamism in reproductive behavior, which possibly interfered with the overall change in internal estrogen exposure in this age group. From 2000 to 2012, the rate of teenage pregnancy has been increasing in Thai society [31], while the abortion rate due to unwanted pregnancies is high [32]. Such social effects on the reproductive age might have contributed to the incidence of HR-positive breast cancer.”

In addition, we also changed reference no. 31 (previous version no.29) to “Sukrat B. Thailand Adolescent Birth Rate: Trend and Related Indicators. Thai J Obstet Gynaecol. 2014 Jan 20;15–21”. (Discussion: paragraph 5)

COMMENT: Lines 315-317: I would invite caution with this interpretation.

RESPONSE: We revised the sentences, described them in more detail. The new text is “Exogenous hormone exposure, particularly combined estrogen/progesterone hormone replacement therapy, may have also positively increased the risk of HR-positive subtypes [33,34]. Two studies on female hormone use in Thailand demonstrated no association between exogenous hormonal use and breast cancer risk. However, these two studies did not specify the HR subtype of breast cancer [35-36].”

In addition, we changed the reference to “Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. The Lancet. 2019 Sep;394(10204):1159–68”. (Discussion: paragraph 6)

COMMENT: Lines 317: Are not there any data at all?

RESPONSE: Of course. We found only a few studies [35,36] on female hormone use and breast cancer risk. However, they are not specific on breast cancer subtypes or receptor status. They did not find the association between hormone use and breast cancer risk. We described more in the revised version. (Discussion: paragraph 6)

35. Poosari A, Promthet S, Kamsa-ard S, Suwanrungruang K, Longkul J, Wiangnon S. Hormonal Contraceptive Use and Breast Cancer in Thai Women. J Epidemiol. 2014 May 5;24(3):216–20.

36. Ratanawichitrasin A, Bhodhisuwan K, Reansuwan W, Kongpatanakul S, Ratanawichitrasin S. Risk of Breast Cancer in Post-Menopausal Women Using Hormone Replacement Therapy. J Med Assoc Thai. 2002 May;85(5):583-9.

COMMENT: Lines 320-323: Could authors include some figures in the text? What are the prevalences?

RESPONSE: We added more detail to the paragraph that described the BMI and positive-breast cancer risk and prevalence of obesity in Thai women as “The national surveys reported that the prevalence of overweight and obesity (BMI ≥ 25 mg/m2) among Thai women has increased [39-41]. The prevalence increased from 25.1 in 1994 to 34.4 and 41.8 kg/m2 in 2004 and 2014, respectively. In comparison, the prevalence trends of overweight and obesity in the Southern Thai women were 25.4, 36.3, and 43.7 kg/m2 in the same three years, respectively. Thus, the increasing trends of BMI in southern Thai women seemed to be higher than the average BMI of Thai women. This may partly explain the rising trends in HR-positive breast cancer in Thailand.” (Discussion: paragraph 7).

COMMENT: Figures: I would recommend to add confidence intervals around curves.

RESPONSE: We added the 95% confidence interval in Fig 1 following the editor’s suggestion and change y-scale from log- to normal scale.

COMMENT: Authors used both relative risk and rate ratios. I advise authors to pick one and stick with it throughout the manuscript. However, relative risk and rate ratios are not similar. Authors should probably clarify which one is estimated by APC models.

RESPONSE: We already clarified that the RR is the rate ratio like we notice in figure 2. We already revised the error text in our manuscript.

COMMENT: Line 109: what means stage 0 or extent 1?

Line 118: authors wrote « [the registry] collects cancer patients diagnosed or treated ». This is unclear. How does the cancer registry collect data on new cancer cases?

Line 161: Which period did authors consider as « recent »?

RESPONSE: Line 109: We included only invasive tumors, added “invasive” (subtopic: Study design and participants, paragraph 2) So, we can delete “in situ tumor (code as stage 0 or extent 1)”.

Line 118: We already added the detail about the cancer registry. (Setting and data sources: paragraph 3-4).

Line 161: we specified the period when we used the coefficients to project the future trend “coefficients from 2009-2018”. (Subtopic: Incidence rates, trends, and projection, paragraph 4)

RESPONSE TO REVIEWER 1:

COMMENT: The authors present the first population-based cancer registry data to summarize molecular-immune-histochemical subtypes. Overall, the authors provide a very rigorous analysis to interpret trends in hormone receptor status of primary breast cancer cases from 2009 to 2018. This is an important research topic, but I have some concerns, mainly related to the level of missing in the data.

RESPONSE: Our analysis found high percentages of missing data on ER, PR, and HER2 status, 45.6, 45.6, and 49.8%, respectively. Literature reviews found that multiple imputation could reduce bias and improved effect estimation at the high proportion of missing data. It is especially when imputation was conducted based on the auxiliary information, including variables predicting the complete set of the hormone and HER2 receptor statuses in the model. Thus, the replacement of the cases with missing values of the ER, PR, and HER2 statuses was random and conformed to the original construct of the association of the non-missing cases. The maximum of missing proportions that can hold by the multiple imputation method is different. However, the evidence shows that the multiple imputation by chained equation (MICE) method can handle up to 80% of missingness [3].

References.

1. Eisemann N, Waldmann A, Katalinic A. Imputation of missing values of tumour stage in population-based cancer registration. BMC Med Res Methodol. 2011 Dec;11(1):129.

2. Madley-Dowd P, Hughes R, Tilling K, Heron J. The proportion of missing data should not be used to guide decisions on multiple imputation. J Clin Epidemiol. 2019 Jun;110:63–73.

3. Souverein OW, Zwinderman AH, Tanck MWT. Multiple Imputation of Missing Genotype Data for Unrelated Individuals. Annals of Human Genetics. 2006;70(3):372–81.

COMMENT:

Introduction

I would suggest a little reorganizing of this paragraph "Since 2002, Thailand has implemented the universal health coverage (UHC) scheme [10]. It is the basic scheme for Thai citizens, covered health promotion, disease screening, treatment of basic and high-cost diseases under the Thai national list of essential medicines 5 (NLEM), and palliative/supportive care. The UHC scheme contributed approximately 79% of the Thai population's health insurance [11].".

Mainly, I would recommend mentioning that 79% of the population's health insurance is the basic covered should be mentioned after the fact it is the basic scheme for Thai citizens. I would also recommend switching covered to covers as the UHC appears to still be in place.

RESPONSE: We revised the sentence sequencing in the paragraph, “Since 2002, Thailand has implemented a universal health coverage (UHC) scheme [7]. This is the primary insurance scheme for Thai citizens. As of 2020, the UHC scheme has already provided health services to approximately 79% of the Thai population [8]. It covers health promotion, disease screening, treatment of basic and high-cost diseases under the Thai National List of Essential Medicines (NLEM), and palliative/supportive care.” following the suggestion from the reviewer. (Introduction: paragraph 3)

COMMENT:

The authors stated "Though a targeted therapy is cost-effective among early breast cancer cases, it increases the burden of cancer care costs as a whole and significantly contributes to the national health budget, especially when early patients are more detected ".

I am not exactly following your logic on how it would significantly increase the burden of cancer care costs as a whole if it is a cost-effective treatment. Can you please elaborate?

The authors state "Other targeted therapeutic drugs for breast cancer have been or are in Thai FDA". Can you please provide a few examples?

RESPONSE:

Though a targeted therapy is cost-effective among early breast cancer cases, it increases the sum of cancer care budget by 15560 USD per one patient to add a targeted therapy to the to the baseline treatment while the QALYs were expected to increase by 4.59 years. While an increased burden to the national health budget especially when early patients are more detected, in turn, it implies that the longer life gain to women benefited from a targeted therapy would make a return in terms of the GDP per capita greater than the budget spent by the UC scheme for the treatment cost per patient.

In addition, we added information about the other targeted drug that may include in the Thai national list of essential medicines (NLEM) in the future (Introduction: paragraph 6). It is the reason to show that why the estimated incidence in each breast cancer subtype is essential. The additional sentences are “Other targeted drugs approved by the Thai Food and Drug Administration for breast cancer treatment include pertuzumab and ribociclib. Currently, these are the only two drugs available to patients who are covered by the civil servant medical benefit scheme [12,13].”

COMMENT:

Methods

The authors mention that they excluded DCIS cases. Yet, DCIS can also be receptor-positive. Can the authors explain why this did not include this group?

RESPONSE: In our population-based cancer registry of Songkhla, it was not designed to collect in situ cases of breast cancer from the start of the registration since the standard of data collection for DCIS tumors is nonhomogeneous in hospitals in the province. It is possible in the future to collect this cancer at the best completeness after the province-wide data collection procedures are standardized.

COMMENT:

Management of missing data

The authors report using multiple imputation to account for missing outcome data, but more information would be valuable. Specifically, you mention that the missing in other variables is 22%, but what is the missing for your receptor statuses? This seems like a much bigger concern. It is also important to know how much change this imputation process had on your findings. Mainly, what does the results look like in the non-imputed dataset? How different is the population? I am also a little confused by the process. Did you enter the other missing variables as missing or did you use the imputed predictor variables to determine?

RESPONSE: In our study, we imputed only the missing values in outcome variables, which are ER, PR, and HER2 status. The proportion of missing values in each variable were 45.6, 45.6, and 49.8%, respectively. For the question that which of the missing values were addressed in the imputation, we transformed variables other than the three receptor statuses to factors and set the missing values to an ‘unknown’ class of that variable, so that the ‘unknown’ values have a predictive ability on the receptor statuses in the imputation. We also used the values of one of the three receptor statuses to predict the missing values of the other missing receptor statuses. The final set of the dataset consisted of 1000 imputed data set, a part of them were the known values from the original data, another part of them are imputed data filled into the missing (blank) values.

In Table 1, we added the characteristics of ER, PR, and HER2 status. For example, the numbers of HER2 negative/equivocal, positive, unknown were 1127, 319, 1437, after imputation, the mean of 1000 imputed data set were 2214, 669, and 0, while the SD of the imputed dataset were 38, 38 and 0. After we got the imputed values of the three receptor statuses, the Table 2 described the mean/median of the observed and imputed data with the range of prediction by the three methods. The difference in the observed and imputed proportion is on the third or second decimal places.

In addition, in our revised manuscript, we added the comparison baseline characteristics between observed and imputed data, as the Table 1 in the result part, and added a new table in the supplement (S1A and S1B Table).

COMMENT:

Results

Can you please include the range of age at breast cancer diagnosis in addition to the IQR?

RESPONSE: The range of age was 24-95 years. We added the range of age in table1.

COMMENT:

Results

It would also be good to see some comparison of demographics by HR status.

From reading the results section, it appears that almost 50% of the receptor status was missing. This is of great concern, especially given that there was an additional 22% of other missing variables. There really needs to be comparisons in the outcome and characteristics of those with and without receptor status, and the new sample with the imputed data to understand the impact.

It is great to see that you included observed data versus imputed data in the results section. I would ask that you include percent in the column "Number of cases". I still think there needs to be a comparison of how the demographics of the women looked before and after imputation.

RESPONSE: We added the percentage in column "Number of cases" of Table 2. The detail about the missing proportion and how we imputed the missingness is described in the previous comment. In addition, we added the baseline characteristic comparison between observed and imputed data according to the comment in table 1 and additional 2 tables (S1A S1B Table) in the supplement.

COMMENT:

Discussion

The sentence "In contrast, reproductive factors have an inconclusive influence on HR-negative cancers." Requires a reference

RESPONSE: We decided to revise this paragraph and delete the sentence according to the editor’s comment, making it a clearer comparison. From “In contrast, reproductive factors have an inconclusive influence on HR-negative cancers.” to “The reproductive characteristics of Thai women have been changing due to exposure to higher endogenous estrogen, such as younger age at menarche [28], later age at the first marriage [29], and a fall in the total fertility rate [30] from 4.9 in 1974–1976 to a fertility replacement rate of 2.1 in 1990 and down to 1.6 in 2011. These phenomena may explain the rise in the incidence of HR-positive breast cancer. Thai adolescents experienced a social dynamism in reproductive behavior, which possibly interfered with the overall change in internal estrogen exposure in this age group. From 2000 to 2012, the rate of teenage pregnancy has been increasing in Thai society [31], while the abortion rate due to unwanted pregnancies is high [32]. Such social effects on the reproductive age might have contributed to the incidence of HR-positive breast cancer.” (Discussion: paragraph 5)

Attachments

Attachment

Submitted filename: Response to reviewers.docx

Response to Reviewers

Comment for PONE-D-21-21989R1

Journal Requirements:

Suggestion: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response:

In manuscript version 2 (PONE-D-21-21989R1), revised from manuscript version 1(PONE-D-21-21989):

1. We removed the references from manuscript version 1 because the previous references were not relevant after we revised the text in the manuscript. The lists of removed references are as:

Hays J. People of Thailand: origin, different Thai groups and Siamese twins | facts and details. [cited 15 Jun 2021]. Available from: http://factsanddetails.com/southeast-asia/Thailand/sub5_8c/entry-3209.html

Srisontisuk DS, Katchamat P, Pakdee P. Poverty and the ethnic minority groups in Thailand. J Mekong Society. 2005;1: 151–189.

Reid LA. Benedict’s Austro-Tai hypothesis—an evaluation. Asian Perspect. 1984;26: 19–34.

Aekplakorn W, Inthawong R, Kessomboon P, Sangthong R, Chariyalertsak S, Putwatana P, et al. Prevalence and trends of obesity and association with socioeconomic status in Thai adults: national health examination surveys, 1991–2009. J Obes. 2014;2014: 410259. doi:10.1155/2014/410259. PMID: 24757561.

Sakboonyarat B, Pornpongsawad C, Sangkool T, Phanmanas C, Kesonphaet N, Tangthongtawi N, et al. Trends, prevalence and associated factors of obesity among adults in a rural community in Thailand: serial cross-sectional surveys, 2012 and 2018. BMC Public Health. 2020;20. doi:10.1186/s12889-020-09004-w. PMID: 32493314.

2. We added some references in manuscript version 2 because we added the new text in manuscript 2. The lists of added references are as:

Drug and Medical Supply Information Center, Ministry of Public Health. Medical Reimbursement Criteria for Cancer and Hematology Patients Who Need Expensive Drugs (Additional) (W 339, W 340) [Internet]. [cited 2021 Oct 29]. Available from: http://dmsic.moph.go.th/index/detail/7823

Drug and Medical Supply Information Center, Ministry of Public Health. Medical Reimbursement Criteria for Cancer and Hematology Patients Who Need Expensive Drugs (Additional) (W 278, W 279) [Internet]. [cited 2021 Oct 29]. Available from: http://dmsic.moph.go.th/index/detail/8221

Bray F, Colombet M, Ferlay J, Mery L, Piñeros M, Znaor A, et al. Cancer Incidence in Five Continents Volume XI [Internet]. [cited 2021 Oct 31]. Available from: https://publications.iarc.fr/Book-And-Report-Series/Iarc-Scientific-Publications

European Network of Cancer Registries (ENCR).pdf [Internet]. [cited 2021 Oct 31]. Available from: https://www.encr.eu/sites/default/files/pdf/incideng.pdf

Topothai C, Tangcharoensathien V. Achieving global targets on breastfeeding in Thailand: gap analysis and solutions. Int Breastfeed J. 2021 Dec;16(1):38. doi: 10.1186/s13006-021-00386-0. PMID: 33962645.

Poosari A, Promthet S, Kamsa-ard S, Suwanrungruang K, Longkul J, Wiangnon S. Hormonal Contraceptive Use and Breast Cancer in Thai Women. J Epidemiol. 2014 May 5;24(3):216–20.

Ratanawichitrasin A, Bhodhisuwan K, Reansuwan W, Kongpatanakul S, Ratanawichitrasin S. Risk of Breast Cancer in Post-Menopausal Women Using Hormone Replacement Therapy. J Med Assoc Thai. 2002 May;85(5):583-9.

Thai National Health Examination Survey 1994-1995, NHES I [Internet]. 1st ed. Nonthaburi: Health Systems Research Institute (HSRI); 1996 [cited 2021 Oct 31]. 271 p. Available from: https://www.hiso.or.th/hiso/picture/reportHealth/report/report5.pdf

Porapakkham Y, Boonyaratapan P, editors. Thai National Health Examination Survey 2003-2004, NHES III [Internet]. 1st ed. Nonthaburi: Health Systems Research Institute (HSRI); 2006 [cited 2021 Oct 31]. 267 p. Available from: https://www.hiso.or.th/hiso/picture/reportHealth/report/report2.pdf

Aekphakorn W, Pakjaroen H, Thaikla K, Satheannoppakao W. Thai National Health Examination Survey 2013-2014, NHES V [Internet]. 1st ed. Nonthaburi: Health Systems Research Institute (HSRI); 2016 [cited 2021 Oct 31]. 283 p. Available from: https://www.hiso.or.th/hiso/picture/reportHealth/report/report9.pdf

3. We change some of the references from manuscript version 1 as following lists:

Ref no 31. was changed from “UNFPA Thailand. [Where do teen mothers live in Thailand?]. [cited 22 May 2021]. Available from: https://thailand.unfpa.org/en/publications” to “Sukrat B. Thailand Adolescent Birth Rate: Trend and Related Indicators. Thai Journal of Obstetrics and Gynaecology. 2014 Jan 20;15–21.”.

The new reference was written in English, while the previous one was written in Thai. However, the information was similar.

Ref no 34. changed from “Kim S, Ko Y, Lee HJ, Lim J. Menopausal hormone therapy and the risk of breast cancer by histological type and race: a meta-analysis of randomized controlled trials and cohort studies. Breast Cancer Res Treat. 2018;170: 667–675. doi:10.1007/s10549-018-4782-2. PMID: 29713854.” to “Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. The Lancet. 2019 Sep;394(10204):1159–68. doi: 10.1016/S0140-6736(19)31709-X. PMID: 31474332.”.

The new reference is more relevant and more recent than the previous reference.

In manuscript version 3, (revised from manuscript version 2; PONE-D-21-21989R1):

We checked our references (from manuscript version 2). We revised the URL of reference no.18 from “http://web.nso.go.th/en/census/poph/cen_poph.htm” to “http://songkhla.old.nso.go.th/nso/project/search/index.jsp?province” because the previous URL cannot access presently. However, the information is the same as with the previous reference.

We revised the format of Ref no. 12, 13, 14, 40, 41, and 49 as the mark in “Revised Manuscript with Track Changes” file.

Additional Editor Comments:

Suggestion: I would advise deleting "and encourage all oncologists and health policymakers to manage breast cancer cases in Thailand." in line 20 as it seems not the right place to make this call.

Line 119: April 20, 2020, October 18, 2020. —> April 20, 2020, to October 18, 2020.

Line 125: The status of the patients —> the vital status of the patients

Line 128: The diagnosis date of cancer patients —> The date of incidence.

Response: We already revised the text in line No. 20, 119, 125 and 128 following the editor suggestion. (Revised version: Line 20, 119, 125, 129, and 130)

Suggestion: Lines 129-130: Because all these dates may not be the same, please, could you be more specific on how you choose the date? The earlier available?

Response: The incidence date was specified following the diagnosis date of cancer patients in the cancer registry database. The date of incidence was obtained from the most reliable source. The incidence date was firstly indicated as the date of biopsy, if not available, the date when the specimen was received at the pathological laboratory, or the report date. When the date of definitive pathological diagnosis was not indicated, the date of hospital admission due to this malignancy, radiological diagnosis, and other clinical diagnosis dates related to the occurrence of malignancy or death were considered. We already revised the paragraph. (Materials and Methods: Study setting and data sources, paragraph: 4)

Suggestion: Line 137: Does it means that the cancer registry can include patients from other province too? If so, the population covered is not only that of the Songkhla Province. Am I right?

Response: The Songkhla cancer registry is a population-based cancer registry. It includes only the cancer patients who are citizens of Songkhla province. The patients are identified from all hospitals in Songkhla province. Songklanagarind hospital is a hospital in Songkla province. The cancer patients of Songklanarind hospital who are the Songkhla citizen are registered to the Songkhla cancer registry and the hospital-based cancer registry of Songklanagarind hospital. While cancer cases, who are not Songkhla citizens, are not registered in the Songkla cancer registry. They are registered only in the hospital-based cancer registry of Songklanagarind hospital. We added more detail as “The hospital has been running both hospital-based CR the Songklanagarind hospital and population-based CR of Songkhla province. Subjects in this study were extracted from the population-based cancer registry.” (Materials and Methods: Study setting and data sources, paragraph: 5)

Suggestion: Line 431: what do you mean? Missing at random?

Response: Yes, we mean the missing at random. We already revised the sentence to more clear as “…In the MICE process, the missing process does not violate the missing at random assumption…”. (Discussion, paragraph 10)

Suggestion: Line 435: I am not sure to understand the link between this sentence and the following one.

Response: Southern Thai women slightly differ from women in other regions regarding genetic and cultural backgrounds. Though, we thought that the inference of this study to all Thai women was still relevant with no solid evidence to validate it.

Reviewers' comments:

Suggestion:

Introduction:

Please add a reference to the first line “Breast cancer is the most common cancer among women worldwide”.

Response: We already added the reference to that sentence. We wrote the sentence based on reference number 1. (Introduction, paragraph: 1)

Suggestion:

Methods:

If you one method to determine malignancy is based on death, wouldn’t this mean there may be an underestimation of the true prevalence of the disorder? I assume not everyone who dies undergoes an autopsy. This should be addressed in the limitations section.

Response: We would like to apologize not to address the diagnosis based on death certificate in the limitation section.

The percentage of the death certificate only (DCO) cases of Songkhla cancer registry was reported around 0.5% in the Cancer Incidence in Five Continents (CI5). Usually, the International Agency for Research on Cancer (IARC) doubts the quality of data when the DCO is zero as the registry might collect cases from pathology sources only. And none of the diagnosis was from autopsy. We are not sure how much pathology sources only bias occurred in diagnosis of breast cancer in the registry. However, the inclusion of cases diagnosed from death certificates ensures a better estimate of the incidence. The cancer registries model the prevalence of cancer based on the incidence and survival, not the count of existing cases in the registry. Since we were estimating the incidence of breast cancer by receptor status, the presence of DCO in cancer diagnosis would not affect the imputation process.

Reference: the International Agency for Research on Cancer (IARC). Indices of data quality of the Cancer Incidence in Five Continents (CI5) volume X. [cited 4 Feb 2022]. Available from: https://ci5.iarc.fr/CI5I-X/old/vol10/I_09.pdf

Suggestion:

You mention that your youngest case of breast cancer is in a women who is 24 years of age, yet use 5 year age groups to calculate the age-specific rates. What is the number of individuals who are 24 years of age? This group is likely very small, and unstable. How does the estimate change if you collapse the 24 year old into the upper age group?

Response: The number of individuals who are 24 years of age, were 2 cases from 2,883 cases. It estimated 0.1% of total cases.

The age-specific rates were calculated to the unit of cases per 100,000 population in a particular 5-year age group according to Boyle P. & Parkin D.M. in which age-specific rates were calculated from age group of 0–4 to 85+, which the formula as following.

a_i= (r_i⁄n_i )×100 000

Where ai is an age-specific rate per 100,000 population in each five-year age group, ri is the number of cases in the same five-year age group, and ni is the corresponding person-years of the observation.

The ultimate aim of stratifying into five-year strata is to calculate the age-standardized incidence rates (ASR) from the formula as follows:

ASR= ( ∑_(i=1)^A▒〖a_i w_i 〗)⁄(∑_(i=1)^A▒w_i )

Var (ASR) = (∑_(i=1)^A▒〖[a_i w_i^2 (100 000-a_i 〗)/n_i])⁄〖(∑_(i=1)^A▒w_i )〗^2

Where ai is an age-specific rate per 100,000 population in each five-year age group, wi is world standard population in the corresponding five-year age group, and ni is the person-years of sample population in the same five-year age group.

The variance of age-specific rate was still low in very young age groups in which the number of patients were small, while the person-years in the sample population were large, see Figure 1.

Reference: P. Boyle and D. M. Parkin, “Statistical Methods for Registries,” In: O. M. Jensen, D. M. Parkin, R. MacLennan, C. S. Muir and R. G. Skeet, Eds., Cancer Registration: Principles and Methods, IARC Scientific Publication No. 95, International Agency for Research on Cancer, Lyon, 1991, pp. 126-158.

Suggestion:

I was a little confused by this statement “including our projection of age-specific incidence rates of the HER2- 194 positive subtype in 18 age groups (0–4, 5–9, 10–14, ..., 80–84, and ≥85 years)”. How is this possible if you have the first case of cancer starting at 24 years? Wouldn’t the relative cost for each of these other groups be zero?

Response: The age-specific rates were calculated as described above. Even the age-groups with no case have their associated person-years (ni) and the 95%CI could be calculated by the following formula

ASR ± Z_(∝/2)× (s.e.(ASR))

s.e.(ASR)= √(Var (ASR))

The 95%CIs of age-specific rate in the very young age groups were narrow, since the number of patients were small, while the person-years in the sample population were large.

Suggestion:

Results:

Please include range of age in this sentence “The median age of the patients at diagnosis of breast cancer was 53.0 years 237 (interquartile range, IQR: 46.0–62.0)”.

Response: We already included the age range in this sentence. The new sentence is “The median age of the patients at diagnosis of breast cancer was 53.0 years (interquartile range, IQR: 46.0–62.0; range: 24–95),…” (Result: Participants and characteristics, paragraph: 2).

Suggestion:

Please also extend the table for age to show each 10 year age group from 20 to give an idea of the instability in estimates for the younger age groups.

Response: We already revised table1 to show each 10 ages group, starting from 20-29, 30-39, until 70 and over. (Table 1)

Suggestion:

Figure 3 title says 105, please change to 100,000. Same in the sentence “Over the study period, the ASRs of other subtypes were not greater than 5.5 cases per 105 women” And “. The ASR of this subtype in 2009 was 2.6 per 105 women.” And here “The overall ASR of HR-positive and HER2-positive (HR+/HER2+ and HR-/HER2+) breast cancer increase from 30-32 and 10-11 to 39 and 13-14 per 105 women in 2020 to 2030”

Response: We did not find the sentence that that reviewer suggested to revise in the second version (PONE-D-21-21989R1) of our manuscript. All of these sentences were in the first version (PONE-D-21-21989)? We already revised all of these sentences. (Figure 3 title, Result: Trends and projections of the age-standardized incidence rates, paragraph: 2)

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Response to Reviewers

comment on PONE-D-21-21989R3

We added the information of our data deposit in the Data Archiving and Networking Services (DANS) in subtopic “Population denominators” and “Management of missing data, paragraph 1”, and we added a reference No. 19 in the manuscript as “19. Chuaychai, A. 1000 imputed data set of receptor status for breast cancer. 2021. Data Archiving and Networking Services (DANS). https://doi.org/10.17026/dans-xn5-5286”.

1. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

Response: We already added captions of the supporting information files at the end of our manuscript.

comment on PONE-D-21-21989R2

Additional Editor Comments (if provided):

suggestion:

Line 178: (0–4, 5–9, 10–14, ..., 80–84, and ≥85 years) —> 20-25, …, ≥85 as you don’t have cases under 20 years old.

Same comment for line 207 as you don’t have cases under 20 so it will be zero anyway.

response: Yes, the cases under 20 year age group were zero cases in the result. However, in the method part, we wrote 18 age groups, including age group under 20 years, because our inclusion criteria included all cases and age groups. That is why we wrote 18 age-group in the methods part. We added the sentence “The count of cases/ estimated Songkhla population in each 5-year age group might result in the age-specific rate of zero in very young age groups.”. (Statistical analysis: Incidence rates, trends, and projection, paragraph: 1)

suggestion:

Lines 144-147: I appreciate that authors added details I suggested. However I would suggest another formulation: Instead « The hospital has been running both hospital-based of the Songklanagarind hospital and population-based cancer registry of Songkhla province. Subjects in this study were extracted from the population-based cancer registry. » I suggest: « In the present study, we included only cases living in Songkhla province and registered in the population-based cancer registry. »

response: We already revised following editor suggestion. (Study setting and data sources, paragraph: 5)

suggestion:

Line 224: instead of « manage », I would suggest using « impute ». This could give something such as « we imputed missing values of the receptor status using MICE R package. » I would also suggest mentioning clearly which variables you used to impute.

response: We already revised following editor suggestion. (Management of missing data, paragraph: 1)

suggestion:

Line 265-267: I would suggest deleting : « Since the raw dataset contained missing values for receptor status in approximately half of the cases, the MICE package was used to assign values to the “unknown” receptor status and classify the patients into four subtypes described in the Method section. » as it is not a result per se and was already described in the method section.

response: We already revised following editor suggestion. (Proportions of breast cancer M-IHC subtypes, paragraph: 1)

suggestion:

Line 441: I appreciate authors answered my comment. However, the sentence is not correct. You cannot say for sure that missing data pattern is at random. You can only assume it as it is not really verifiable. Author can consider something like: « We imputed missing data assuming missingness was at random and we properly modeled missing values. » instead of « In the MICE process, the missing process does not violate the missing at random assumption. »

response: We already revised following editor suggestion. (Discussion, paragraph: 10)

suggestion:

Authors did not really answer the comment of Reviewer 2 regarding diagnosis made via death certificate. The reviewer requested that authors acknowledge that some cancer cases may have been missed since not everyone has an autopsy. In addition, I would suggest authors to add %DCO in the method section where they mention it.

response: We added the information about the rules for reporting the incidence date of population-based cancer registry as “The rules for reporting the incidence date were according to the European Network of Cancer Registries (ENCR) [16], which was also used by the Thai Cancer Registry Network and the International Agency for Research on Cancer (IARC). The IARC allowed missing pathological diagnosis in capturing cancer cases for population-based cancer registration as a low percentage of patients migrating out of the captive area of a cancer registry usually occurred in long-surviving diseases and death might occur before diagnosis in very short surviving diseases.”. (Study setting and data sources, paragraph: 4)

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