POSNOC—POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy: a randomised controlled trial of axillary treatment in women with early-stage breast cancer who have metastases in one or two sentinel nodes

Introduction ACOSOG-Z0011(Z11) trial showed that axillary node clearance (ANC) may be omitted in women with ≤2 positive nodes undergoing breast conserving surgery (BCS) and whole breast radiotherapy (RT). A confirmatory study is needed to clarify the role of axillary treatment in women with ≤2 macrometastases undergoing BCS and groups that were not included in Z11 for example, mastectomy and those with microscopic extranodal invasion. The primary objective of POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant therapy plus Clearance or axillary radiotherapy (POSNOC) is to evaluate whether for women with breast cancer and 1 or 2 macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment, in terms of 5-year axillary recurrence. Methods and analysis POSNOC is a pragmatic, multicentre, non-inferiority, international trial with participants randomised in a 1:1 ratio. Women are eligible if they have T1/T2, unifocal or multifocal invasive breast cancer, and 1 or 2 macrometastases at sentinel node biopsy, with or without extranodal extension. In the intervention group women receive adjuvant therapy alone, in the standard care group they receive ANC or axillary RT. In both groups women receive adjuvant therapy, according to local guidelines. This includes systemic therapy and, if indicated, RT to breast or chest wall. The UK Radiotherapy Trials Quality Assurance Group manages the in-built radiotherapy quality assurance programme. Primary endpoint is 5-year axillary recurrence. Secondary outcomes are arm morbidity assessed by Lymphoedema and Breast Cancer Questionnaire and QuickDASH questionnaires; quality of life and anxiety as assessed with FACT B+4 and State/Trait Anxiety Inventory questionnaires, respectively; other oncological outcomes; economic evaluation using EQ-5D-5L. Target sample size is 1900. Primary analysis is per protocol. Recruitment started on 1 August 2014 and as of 9 June 2021, 1866 participants have been randomised. Ethics and dissemination Protocol was approved by the National Research Ethics Service Committee East Midlands—Nottingham 2 (REC reference: 13/EM/0459). Results will be submitted for publication in peer-reviewed journals. Trial registration number ISRCTN54765244; NCT0240168Cite Now


GENERAL COMMENTS
The POSNOC trial is a highly rewarded study, which has been expected to complement evidence of previous ACOSOG-Z0011(Z11) trial on axillary management of early breast cancer. It evaluates whether for women with early breast cancer and one or two macrometastases, adjuvant therapy alone is non-inferior to adjuvant therapy plus axillary treatment (ANC or ART), in terms of 5-year axillary recurrence. The strengths of this study are extended population, large sample size, complete data of participants and time-dependent outcomes. However, the following issues still require attention.
1. The POSNOC includes women with T1 or T2, unifocal or multifocal invasive breast cancer, undergoing mastectomy or breast conserving surgery (BCS), one or two macrometastases at sentinel node biopsy, and with or without extranodal extension, which extended target population compared to the ACOSOG-Z0011(Z11) trial and provided a full-fledged evidence. However, the inclusion criteria of Z0011 trial regarding positive SLNs was less than three SLNs containing metastatic breast cancer documented under the premise of taking at least three SLNs during surgery. In POSNOC trial, patients with one or two macrometastases of SLNs were identified and included, but how many SLNs in total were taken during operation? It should be noted that different proportions of positive SLN have different meanings on disease stage and prognosis, and omission of axillary management for all patients with one or two macrometastases of SLNs was debatable. The authors need to address it.
2. According to the inclusion criteria of POSNOC, patients with early breast cancer received sentinel node biopsy prior to neoadjuvant therapy were included and randomized to either intervention group or control group. As for these patients, did they receive sentinel node biopsy again during operation? If they did and were assigned to intervention group, but with macrometastases of SLNs found at the end, didn't they undergo any further axillary treatment with ANC or ART?
3. As mentioned in the protocol, allocation of the study is stratified by recruiting site and minimised by age, type of surgery, estrogen receptor status, number of positive nodes, and intra-operative sentinel assessment using OSNA. What is the reason for choosing "intra-operative sentinel assessment using OSNA "as one of the stratifications? The five stratifications for randomization seemed difficult to perform intra-operatively, please explain how to execute it.
4. In this study, the longest follow-up period was five year, which was rather sufficient and acceptable for evaluation of axillary recurrence and local recurrence. As for overall survival, diseasefree survival, and other assessment of morbidity, further long-term follow-up was strongly recommended.

Magnoni, Francesca
European Institute of Oncology, Breast Cancer Surgery REVIEW RETURNED 20-Jul-2021

GENERAL COMMENTS
-Pending the results of the 5-year outcome, the manuscript is presented as an updated report of the ongoing randomised, multicentre, non-inferiority POSNOC trial which recruitment started on 1 August 2014 and as of 09 June 2021, with 1866 participants randomised and an estimated enrolment of 1900. Primary endpoint is the 5 years axillary recurrence's rate in early breast cancer patients presenting one or two nodes with macrometastases undergone adjuvant therapy alone compared to adjuvant therapy plus axillary treatment. -Significant study in the current scientific perspective that aims to increasingly enhance an axillary conservative approach, in this case underlining the role of adjuvant therapies, given the growing prominence of tumor biology in the management of breast cancer.
-Some of points of strength: • it includes women undergoing mastectomy and those with extranodal invasion • it includes multi-focal invasive tumour ≤5 cm in its largest dimension -In the Introduction Authors underlined several limitations of Z0011 trial: "...Z11 has not changed clinical practice because of several limitations. The study did not meet its recruitment goal, approximately 40% of participants had micrometastases, many were lost to follow-up (19.4%), and there was a lack of radiation therapy quality assurance. …". These considerations would not seem so crucial in the overall premise of the scientific role of POSNOC trial in axillary management for breast cancer. It would be advisable to emphasize as a premise that the Z0011 finding "…are not applicable to subgroups that were not included such as those with mastectomy and microscopic extranodal invasion…", as written by Authors below.
-In relation to this sentence, the presence of microscopic extranodal invasions considered as an inclusion criteria could be clearly specified in the inclusion criteria in the web site https://clinicaltrials. 1. The POSNOC includes women with T1 or T2, unifocal or multifocal invasive breast cancer, undergoing mastectomy or breast conserving surgery (BCS), one or two macrometastases at sentinel node biopsy, and with or without extranodal extension, which extended target population compared to the ACOSOG-Z0011(Z11) trial and provided a full-fledged evidence. However, the inclusion criteria of Z0011 trial regarding positive SLNs was less than three SLNs containing metastatic breast cancer documented under the premise of taking at least three SLNs during surgery. In POSNOC trial, patients with one or two macrometastases of SLNs were identified and included, but how many SLNs in total were taken during operation? It should be noted that different proportions of positive SLN have different meanings on disease stage and prognosis, and omission of axillary management for all patients with one or two macrometastases of SLNs was debatable. The authors need to address it.
The POSNOC protocol does not require the surgeons to remove at least 3 nodes during sentinel node biopsy. Surgeons are advised to perform sentinel node biopsy in a standard manner.
Z0011 trial did not require surgeons to remove at least 3 nodes. The median number of nodes removed in Z0011 study was 2 (IQR 1-4). 2. According to the inclusion criteria of POSNOC, patients with early breast cancer received sentinel node biopsy prior to neoadjuvant therapy were included and randomized to either intervention group or control group. As for these patients, did they receive sentinel node biopsy again during operation? If they did and were assigned to intervention group, but with macrometastases of SLNs found at the end, didn't they undergo any further axillary treatment with ANC or ART?
These patients did not undergo sentinel node biopsy again after neoadjuvant chemotherapy.
3. As mentioned in the protocol, allocation of the study is stratified by recruiting site and minimised by age, type of surgery, estrogen receptor status, number of positive nodes, and intra-operative sentinel assessment using OSNA. What is the reason for choosing "intra-operative sentinel assessment using OSNA "as one of the stratifications? The five stratifications for randomization seemed difficult to perform intra-operatively, please explain how to execute it.
OSNA analyses and amplifies mRNA from solubilised biopsy samples of sentinel lymph node tissue. It detects the level of expression of the CK19 gene, an epithelial marker associated with breast cancer. There is more than 95% concordance between OSNA and histopathology, however, to minimise the imbalance between the trial arms, minimisation was used. Patients undergoing sentinel node assessment by OSNA were randomised intra-operatively.
4. In this study, the longest follow-up period was five year, which was rather sufficient and acceptable for evaluation of axillary recurrence and local recurrence. As for overall survival, disease-free survival, and other assessment of morbidity, further long-term follow-up was strongly recommended.
We agree with the reviewer. Long-term follow up is planned. This is reported on page 10 (section -Flagging with NHS Digital).
Reviewer: 2 Dr. Francesca Magnoni, European Institute of Oncology Comments to the Author: -In the Introduction Authors underlined several limitations of Z0011 trial: "...Z11 has not changed clinical practice because of several limitations. The study did not meet its recruitment goal, approximately 40% of participants had micrometastases, many were lost to follow-up (19.4%), and there was a lack of radiation therapy quality assurance. …". These considerations would not seem so crucial in the overall premise of the scientific role of POSNOC trial in axillary management for breast cancer. It would be advisable to emphasize as a premise that the Z0011 finding "…are not applicable to subgroups that were not included such as those with mastectomy and microscopic extranodal invasion…", as written by Authors below.
-In relation to this sentence, the presence of microscopic extranodal invasions considered as an inclusion criteria could be clearly specified in the inclusion criteria in the web site https://clinicaltrials.gov/ct2/show/NCT02401685, in particular in case of selected cases of neoadjuvant therapy in patients with early breast cancer.
This has now been added to the text under target population on page 5. See below: Target population: Women with unifocal or multifocal invasive breast cancer with the largest lesion ≤5cm, who have 1 or 2 sentinel nodes with macrometastases (>2mm), with or without extranodal invasion.

GENERAL COMMENTS
All the comments have been addressed by the author.