Independent Relevance of Estrogen Receptor and Progesterone Receptor Statuses in DCIS on Risk of Subsequent Ipsilateral and Contralateral Invasive Breast Events in Absence of Endocrine Therapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript analyzes a large number of cases from the SEER database to examine the association between estrogen and progesterone receptor status and the occurrence of ipsilateral and contralateral invasive breast cancer after breast‑conserving surgery with or without adjuvant radiation therapy, and it presents several interesting findings. Please consider the following points.

Please enlarge the numbers on the x‑axis indicating the number of cases in Figures 1–4, as they are currently too small and difficult to read.
The number of cases in the ER–/PR+ group is presumed to be extremely small. Although this group does not appear to be described in the main text, the results for this group seem to have been combined with those of the ER+/PR– group in the analyses presented in Figures 3 and 4. Please verify this point. It would also be necessary to address the ER–/PR+ group explicitly in the main text.

Author Response

Reviewer #1

This manuscript analyzes a large number of cases from the SEER database to examine the association between estrogen and progesterone receptor status and the occurrence of ipsilateral and contralateral invasive breast cancer after breast‑conserving surgery with or without adjuvant radiation therapy, and it presents several interesting findings. Please consider the following points.

Please enlarge the numbers on the x‑axis indicating the number of cases in Figures 1–4, as they are currently too small and difficult to read.

 

Response: We thank Reviewer #1 for their thoughtful and thorough review of our manuscript and their excellent feedback. In response to this first point, we increased the size of the numbers on the x-axis indicating the number of cases in Figures 1-4 to make it more readable.

The number of cases in the ER–/PR+ group is presumed to be extremely small. Although this group does not appear to be described in the main text, the results for this group seem to have been combined with those of the ER+/PR– group in the analyses presented in Figures 3 and 4. Please verify this point. It would also be necessary to address the ER–/PR+ group explicitly in the main text.

 

Response: We thank Reviewer #1 for catching this—they are correct in that the ER-PR+ group is very small and we in fact did not include them in this analysis. The legend is incorrect and was from an attempt at combining the two to form a “mixed” hormone receptor status group, but as anticipated by Reviewer #1 there were very few ER-PR+ patients and the small number did not significantly change the trends so for the final analysis we restricted it to patients with ER+PR- disease for “mixed” hormone receptor status to keep it cleaner and to help make the results more interpretable.

 

We thank Reviewer #1 again for their very helpful feedback.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors evaluated the risk of invasive events in the breast cancer patients who were diagnosed with ductal carcinoma in situ, who underwent breast conserving surgery, in respect to the status of estrogen receptor (ER) and progesterone receptor (PR). They used data collected in Surveillance, Epidemiology and End Results (SEER) 17 registry. The number of cases included in the study was big enough to obtain statistical significance. The most important finding in this study was the comparison between ER+PR+ and ER-PR- groups showing that when the ER-PR- patients underwent also radiation therapy, their risk of developing invasive events did not differ from the ER+PR+ patients. This information is also very important for the patients who underwent breast conserving surgery and can still be at low risk of developing invasive events.

The authors point out also that their study was retrospective and they could not account for unobserved variables.

Author Response

Reviewer #2

The authors evaluated the risk of invasive events in the breast cancer patients who were diagnosed with ductal carcinoma in situ, who underwent breast conserving surgery, in respect to the status of estrogen receptor (ER) and progesterone receptor (PR). They used data collected in Surveillance, Epidemiology and End Results (SEER) 17 registry. The number of cases included in the study was big enough to obtain statistical significance. The most important finding in this study was the comparison between ER+PR+ and ER-PR- groups showing that when the ER-PR- patients underwent also radiation therapy, their risk of developing invasive events did not differ from the ER+PR+ patients. This information is also very important for the patients who underwent breast conserving surgery and can still be at low risk of developing invasive events.

The authors point out also that their study was retrospective and they could not account for unobserved variables.

 

Response: We thank Reviewer #2 for their careful review of our manuscript, their recognition of the importance of the work and its limitations, and their thoughtful review.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript investigated the prognostic importance of ER and PgR status on the outcome of a special cohort of DCIS breast cancer. ER and PgR are well-known prognostic markers and predictive for anti-estrogen treatments in breast cancer. The situation in DCIS is a bit different.

The retrospective (register-) cohort of this study includes patients having a DCIS with diverse receptor status, but patients with “known” HER2-status were excluded, as well as large DCIS cases and older patients. Patients underwent breast-conserving surgery with or without external beam radiation. The HER2-status will therefore segregate in the cohort as it is apparently not determined for DCIS, which I regard as another weakness of this study.

In this study, diverse combinations of ER and PgR in DCIS are investigated for relapses upon radiotherapy in the absence of anti-estrogen therapy. The cohorts were sufficiently matched.

As major outcome, patients receiving radiotherapy showed no differences for progression/relapses when stratified for receptor status. For patients without radiatio, the receptor status became prognostically relevant.

I am not aware of other published studies analyzing such an investigation. So. I think it is interesting for clinicians to read these data. The manuscript is also well written and sufficiently illustrated.

Minor point:

The rationale starts with the statement that ER is surprisingly not included in the Oncotype DX assays and other predictive scoring systems. It should not be forgotten and discussed in this manuscript, that ER in almost all cases drives PgR and it can therefore be assumed that PgR-positive cases are also ER-positive in more than 98% of cases. This should be dicussed.

Author Response

Reviewer #3

This manuscript investigated the prognostic importance of ER and PgR status on the outcome of a special cohort of DCIS breast cancer. ER and PgR are well-known prognostic markers and predictive for anti-estrogen treatments in breast cancer. The situation in DCIS is a bit different.

The retrospective (register-) cohort of this study includes patients having a DCIS with diverse receptor status, but patients with “known” HER2-status were excluded, as well as large DCIS cases and older patients. Patients underwent breast-conserving surgery with or without external beam radiation. The HER2-status will therefore segregate in the cohort as it is apparently not determined for DCIS, which I regard as another weakness of this study.

In this study, diverse combinations of ER and PgR in DCIS are investigated for relapses upon radiotherapy in the absence of anti-estrogen therapy. The cohorts were sufficiently matched.

 

Response: We thank Reviewer #3 for their thoughtful and helpful review of our manuscript. We agree that the lack of HER2 status is a limitation. Notably, HER2 status was not reported in SEER until 2010, so in addition to most patients with DCIS in SEER not having HER2 status, almost half of the patients included in this study would not have HER2 status included with their SEER data even if it were collected. We included the following statement to include this:

 

“HER2 status also was not included with SEER data until 2010.”

 

We also added under the discussion of limitations of the study:

 

“HER2 status, for which the prognostic relevance in DCIS has been debated, was also not included in this study, and is not available for the overwhelming majority of patients with DCIS in SEER in the time frame of the study.”

 

As major outcome, patients receiving radiotherapy showed no differences for progression/relapses when stratified for receptor status. For patients without radiatio, the receptor status became prognostically relevant.

I am not aware of other published studies analyzing such an investigation. So. I think it is interesting for clinicians to read these data. The manuscript is also well written and sufficiently illustrated.

Minor point:

The rationale starts with the statement that ER is surprisingly not included in the Oncotype DX assays and other predictive scoring systems. It should not be forgotten and discussed in this manuscript, that ER in almost all cases drives PgR and it can therefore be assumed that PgR-positive cases are also ER-positive in more than 98% of cases. This should be dicussed.

 

Response: This is a great point by Reviewer #3. We included this as an additional rationale beyond that provided in the Oncotype DX DCIS publication:

 

“This may also relate to the fact that most PR+ DCIS is driven by ER+ status, making ER-PR+ DCIS quite rare.”

 

We thank Reviewer #3 for their thoughtful and helpful review of our manuscript and their insightful feedback.

Reviewer 4 Report

Comments and Suggestions for Authors

The present retrospective study was undertaken to examine whether estrogen receptor (ER) and progesterone receptor (PR) have therapeutic and prognostic relevance in the context of breast-conserving surgery with or without radiation therapy and in the absence of endocrine therapy in patients with ductal carcinoma in situ (DCIS). The authors have carefully selected the patients and categorized them into four groups according to hormonal receptors status. They have found that the risk of subsequent invasive events was highly related to hormonal receptors status and radiation therapy. They concluded that stratifying DCIS patients by hormone receptor status (ER+PR+ vs. ER-PR-) confers prognostic and therapeutic value that extends beyond traditional clinicopathologic risk factors.

The study is very interesting and the manuscript is well-organized and written.

Author Response

Reviewer #4

The present retrospective study was undertaken to examine whether estrogen receptor (ER) and progesterone receptor (PR) have therapeutic and prognostic relevance in the context of breast-conserving surgery with or without radiation therapy and in the absence of endocrine therapy in patients with ductal carcinoma in situ (DCIS). The authors have carefully selected the patients and categorized them into four groups according to hormonal receptors status. They have found that the risk of subsequent invasive events was highly related to hormonal receptors status and radiation therapy. They concluded that stratifying DCIS patients by hormone receptor status (ER+PR+ vs. ER-PR-) confers prognostic and therapeutic value that extends beyond traditional clinicopathologic risk factors.

The study is very interesting and the manuscript is well-organized and written.

 

Response: We thank Reviewer #4 for their careful review of our manuscript and their recognition of the relevance of this manuscript. We are grateful for their review and feedback.