Author's response to reviews

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1 Author's response to reviews Authors: Marit Synnestvedt Elin Borgen Erik Wist Gro Wiedswang Kjetil Weyde Terje Risberg Christian Kersten Ingvil Mjaaland Lise Vindi Cecilie Schirmer Jahn Martin Nesland Bjørn Naume Version: 3 Date: 5 November 2012 Author's response to reviews: see over

2 Version: 1 Reviewer number: 1 This is a very interesting study on the use of bone marrow DTCs as a tool to select patients for secondary adjuvant treatment strategies in early breast cancer. The authors provide data only about the detection of DTCs since the follow-up data are not yet mature. Major Strengths: 1. The authors have performed bone marrow biopsies in a prospective series of more than 1000 patients with early breast cancer at two time points (3 and 9 months after treatment). These data provide important information about the fate of DTCs and the reproducibility of the DTC detection overtime. Moreover, the have used DTC detection as a tool to decide for a secondary adjuvant treatment strategy and have monitor DTCs after docetaxel treatment. The authors should be praised for using this novel treatment approach. 2. The authors have detected DTCs following appropriate methodology based on international guidelines. Major weaknesses: 1. The authors come to a conclusion that is not fully supported by their data. Since they did not use a randomization design, they cannot state in the abstract conclusion that After docetaxel rescue treatment, the majority of patients experience disappearance of the DTCs. Instead, they should mention that since this is not a randomized trial, the observed results could be either due to limitations of the detection technology for DTCs or due to the effect of concomitant trastuzumab or endocrine treatment or due to docetaxel itself. This statement in the conclusion of the abstract is now modified in line with reviewer # 1 comments (page 5). Among the 72 BM2-positive, docetaxel-treated patients, 15 (20.8%) had persistent DTCs at BM3 and 4. The same or even higher conversion rate was observed in patients not receiving docetaxel. Indeed, among the 94 BM1 positive patients, only 15 (16%) had persistent DTCs at BM2 without receiving any docetaxel treatment. What was the effect of endocrine treatment or trastuzumab in these BM1-positive patients? Have any of these patients received

3 bisphosphonates that have been shown to affect DTC detection? The authors need to provide specific information about the administration of endocrine treatment and/or trastuzumab and/or bisphosphonates between BM1 and BM2 but also between BM2 and BM3 or BM4. The authors need to provide a supplementary table with complete DTC status at all timepoints for BM1-positive patients. For each BM1-positive patient, they need to provide information about the administration or not of endocrine treatment and /or trastuzumab and/or bisphosphonates. Similarly, in sup table 2 for each BM2 positive patient, they need to provide information about the administration or not of endocrine treatment and /or trastuzumab and/or bisphosphonates. The change in BM status between BM1 and BM2 can be affected by the recent administration of the standard adjuvant chemotherapy (this was the rationale for using the BM2 time point for selection of patients to docetaxel treatment, as described in the introduction). A change from BM1 positive to BM2 negative DTC-status was observed in 82.4% (61/74) of the endocrine treated patients, in 87.5% (7/8) of the trastuzumab treated patients (4 of the patients were treated with both endocrine therapy and trastuzumab) and in 85.7%(6/7) of the patients that did not receive endocrine treatment or trastuzumab. This point and these results have now been included in the Result section (page 12) According to reviewer # 1 comments, we have provided a supplementary table with information about the administration of endocrine treatment and/or trastuzumab in addition to information about complete BM status for each BM1 positive patient and/or BM2 positive patient (also see the Results section, page 13). None of the patients in the study received bisphosphonates. We have also added a section in Methods (in the Patients section, page 8) for further clarification of the adjuvant treatment given in this study, 2. They authors need to discuss other randomized trials of bisphosphonate administration and DTC detection such as the studies by Aft et al Lancet Oncology 2010 and Solomayer et al Annals of Oncology We agree that the discussion about bisphosphonate administration and DTC detection is an important point. We have added a section about this issue in the Discussion (page 17). Minor comment: The authors need to update ref 21 and 22. The references have been updated (Reference list, ref 17 and 18 in reviced reference list).

4 Version: 2 Reviewer number: 2 This manuscript presents descriptive data on 1121 patients with pn1-3 or pt1c/t2g2-3pn0 breast cancer. Bone marrow-aspiration was performed 8-12 weeks after chemotherapy (bone marrow1), followed by a second bone marrow-aspiration 6 months later (bone marrow2). DTC-status was determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells, which can be considered as gold standard. The prevalence of positive bone marrow status and its correlation to tumor characteristics is presented. Major comments: This manuscript focuses on a clinical interesting topic with lack of data: the fate of disseminated tumor cells after primary systemic treatment and its relevance for further clinical management The main weakness of this manuscript is that no follow-up data is being presented We have not presented clinical follow-up data, because we are not allowed to perform survival analyses vs BM results before the last follow-up has been completed in the study and the clinical follow-up data have been finally monitored. This is in accordance with the apriori statistical considerations for the study. The follow-up is still ongoing. This has been clarified in the Methods (page 9), and also mentioned in the Introduction (Background) (page 7) and Discussion (page 18). We still feel that the descriptive results from the study is of importance, because there is great need for tools to monitor the effect of adjuvant treatment in order to test alternative treatment approaches for patients that are insufficiently treated. This novel approach gives information that can be helpful for the scientific community in preparing studies addressing this topic. Also, our study compares DTC results with clinicopathological parameters that gives clinically relevant information, which we feel support the publication of our results so far. The second major weakness of this study is that no randomization for pts with positive BM2 was performed, i.e. that all these pts received docetaxel. This study design will not lead to meaningful results on the benefit of treatment after positive BM2 We are aware of the weakness of the lack of randomization in the present study and we have already discussed this issue in a section in the Discussion of the manuscript.

5 Whether the study design will lead to meaningful treatment-related results, in our opinion, is dependent upon the final clinical data. But this study also presents a principle for monitoring of treatment, which is supported by a recent randomized study by Solomayer et al (Annals of Oncology 2012). Introduction: the first paragraph is general knowledge and little enlightening in the context of this study The introduction in general is lengthy and should be more concise We have shortened the Introduction (Background) to make it more concise, including removal of most of the first paragraph. Methods: recruitment ended in 2008: why are there no FU-data being presented? We have not presented clinical follow-up data, because we are not allowed to perform survival analyses vs BM results before the last follow-up has been completed in the study and the clinical follow-up data have been finally monitored. This is in accordance with the statistical considerations described for the study. The follow-up is still ongoing. Discussion: the above mentioned weaknesses are no addressed adequately in the discussion, i.e. phrasing clearly suggest a true change in the tumor cell load after the intervention is by far too speculative We have modified the text in the Discussion in accordance with the reviewer # 2 comments (page 14). Minor comments: docetaxel rescue treatment: this terminology is not correct in primary treatment We have removed the term rescue in the text in the Conclusion section in the Abstract (page 5) and in Conclusions (page 19). Table 3: percentages should be presented We have added precentages in Table 3.

6 Version: 2 Reviewer number: 3 The manuscript by Sennestvedt et al reports the results of bone marrow disseminated tumor cells detection at several time points after the primary treatment of localized brest cancer. This study included non-randomized administration of a second adjuvant chemotherapy in patients who had DTC after the end of anthracycline-baseed chemotherapy. This is a prospective study, headed by a recognized research team focused on DTC & CTC, and the patient compliance is astonishing. The final survival results are not disclosed in this report but the changes in BM DTC detection are interesting, supporting the use of a second adjuvant chemotherapy in BM DTC+ patients. The article is clear and well written, the discussion adresses the main issues of this study. So, I recommend this article for publication without any major changes. small things to be fixed: Reference #35 : "Alix" instead of "ix" Reference #36 has no clear interest & can be removed Reference #43 may be replaced by Vincent-Salomon & al Br J Cancer 2007 (FISH being more relevant than immunocytostaining for HER2). All these points have been corrected.

7 Version: 2 Reviewer number: 4 The authors are presenting interesting data on disseminated tumor cells as a surrogate of minimal residual disease. The disappearance of DTCs after docetaxel-rescue-treatment one year after diagnosis shows that DTCs are indeed not a phenomenon of the primary tumor but play an important role in breast cancer as a systemic disease. This offers the possibility to monitor effectivity of adjuvant treatment and to offer non-responders extended adjuvant therapy. I am excited about the follow-up data to prove the clinical importance of these observations.