Table 2.

Round 2 consensus

No	Revised Recommendation	n/N	% Consensus	Grade [references]
Neoadjuvant therapy patient selection
B.6-R	NAC can be offered primarily* for tumor down staging, to select patients who are eligible for breast conservation (considering tumor focality, tumor to breast size ratio, and implications for radiation/reconstruction). The likelihood of tumor response based on biomarkers (example: lower chance in ER positive, HER2 negative) should be considered, in addition to the risk of over-treatment with chemotherapy in certain patients *Added Note- Clarification of the term “primary”: in select patients NAC may be offered for down-staging of the tumour as the “primary” goal, however in other patients, NAC is recommended beyond the goal of potentially decreasing clinical tumour burden (example: for HER2 + /triple negative phenotypes	61/68	91.18	Strong
Neoadjuvant therapy regimen selection
D.2-R.1	Patient and disease characteristics are always considered when choosing NAC. Regarding the specific neoadjuvant chemotherapy regimens: a. The sequence of agents (anthracycline or taxanes first) can be determined based on patient and disease characteristics, in order to optimize pCR. HER-2 directed therapies are generally given with the taxane-component (see targeted agent section)	35/43	81.40	Conditional
D.2-R.2	Patient and disease characteristics are always considered when choosing NAC. Regarding the specific neoadjuvant chemotherapy regimens: b. Anthracycline-sparing regimens can be considered particularly for patients with a high risk for cardiotoxicity. Docetaxel, carboplatin and trastuzumab (TCH) for 6 cycles is a reasonable anthracycline-sparing NAC regimen for HER2-positive disease. *Added note: It should be considered that the evidence for TCH being equivalent in efficacy to an anthracycline-taxane based neoadjuvant regimen is with the addition of pertuzumab (TCHP); access to pertuzumab is not uniform across Canada at this current time.	39/40	97.50	Strong 45
D.2-R.3	Patient and disease characteristics are always considered when choosing NAC. Regarding the specific neoadjuvant chemotherapy regimens: c. When using anthracycline/taxane (third generation) regimens, dose-dense (biweekly) regimens may be considered for patients who can tolerate them, particularly for ER-negative cancers (due to modest improvements in outcome.) Tolerability and toxicities should be considered	39/41	95.12	Strong
D.2-R.4	Patient and disease characteristics are always considered when choosing NAC. Regarding the specific neoadjuvant chemotherapy regimens: d. Shorter chemotherapy regimens, including taxane-based (such as TC or weekly-paclitaxel with trastuzumab for HER-2 positive) are sometimes considered on a case-by-case basis, considering initial tumor staging, patient preference, and toxicity considerations. The lack of data in this realm should be noted, as well as the implications for potentially requiring further treatment post-operatively for residual disease, and eligibility criteria for these additional therapies (example: adjuvant TDM-1 data is in HER-2 positive patients with 6 or more cycles of NAC.)Refer to section on additional adjuvant therapies	29/36	80.56	Conditional
D.3-R.1	Pathologic complete response (pCR) has been established as a meaningful prognostic surrogate for particular subtypes of breast cancer, particularly triple negative and ER-negative, HER-2 positive (with the use of anti-HER2 therapy.) Additional systemic therapies improve outcomes for triple negative and HER-2 positive cancers that have residual disease (lack of pCR) after NAC. Therefore, improving pCR rates means less patients with these subtypes may require additional systemic therapy after surgery. Considering these principles; regarding targeted therapies during NAC: a. Trastuzumab should be given during the taxane portion of NAC for HER-2 positive breast cancers	38/39	97.44	Strong [95]
D.3-R.2	Regarding targeted therapies during NAC: b. The evidence at this time shows the addition of Pertuzumab to NAC for HER-2 positive disease does not improve survival outcomes; however, it does improve PCR from NAC when given alongside trastuzumab and a taxane. If accessible, it can be considered to improve pCR (rationale as above). This approach may be preferred for LABC or lymph node positive patients, given the burden of disease, and adjuvant data. However, Pertuzumab is currently not considered standard of care in Canada either for NAC or adjuvant therapy. Access and resource implications should be considered when considering Pertuzumab therapy	35/42	83.33	Conditional [49, 96, 97]
D.3-R.3	Regarding targeted therapies during NAC: c. NAC with immunotherapy (PD-1 or PDL-1 inhibitors) is considered investigational at this time, and most likely to benefit* triple negative breast cancers. Clinical trials should be considered for such patients, if available *Added note: increased pCR rates have been demonstrated with atezolizumab and pembrolizumab in the neoadjuvant setting; pembrolizumab given in the neoadjuvant setting and continued in the adjuvant setting has also most recently demonstrated increased EFS. However, overall survival data is premature. These therapies are currently not standard practice in Canada	54/55	98.18	Strong [98–100, 105, 108]
D.3-R.4	Regarding targeted therapies during NAC: d. There is conflicting evidence regarding the addition of a platinum to the taxane-containing portion of a third-generation NAC regimen; however, if accessible and tolerable, a platinum agent can be considered for triple negative breast cancers, in order to potentially improve PCR. There is evidence that BRCA-associated tumors may not benefit from the addition of a platinum, and therefore ideal patient selection without the knowledge of BRCA-status may be challenging. There is data to support platinums for NAC as an anthracycline-sparing approach. Access remains an issue in many Canadian regions. The addition of a platinum agent to a taxane can also be considered if suboptimal or progressive disease is observed in triple negative tumors during the anthracycline portion of NAC	29/36	80.56	Conditional [101]
D.5-R.1	For patients in whom tumor progression on NAC is treated with radiation, the addition of a radio-sensitizing systemic agent is reasonable to enhance radiotherapy response, with the primary goal of achieving tumor respectability. There is some practice-based data available for the use of weekly platinum agents with radiation for the treatment of triple negative tumors progressing on NAC. This approach can be considered for eligible patients (considering the balance with modestly increased toxicities)	39/49	79.59	Conditional
Local–regional management after neoadjuvant systemic therapy
F.4-R.1	Patients with initial N1 disease can be considered for (targeted) sentinel lymph node biopsy if: Patients are clinically (by physical exam) node negative prior to definitive surgery, AND dual tracer is used, AND At least 3 sentinel lymph nodes are removed. At institutions where lymph nodes are clipped at diagnosis, it is recommended that they are localized at surgery, and excised along with the sentinel nodes. Pathologic nodal assessment with immunohistochemistry should be available. Patients should be counseled that the risk of false negatives is low with a sentinel-lymph node approach that meets the criteria above, but that long term outcomes are still uncertain. Multi-disciplinary discussion with a radiation oncologist prior to finalizing the axillary surgical approach (as with the primary breast tumor) is also encouraged	58/66	87.88	Conditional
Additional adjuvant systemic treatment
G.5	Data regarding the use of adjuvant CDK4/6 inhibitors for high-risk ER positive, HER2 negative patients continues to accumulate. Long term patient outcome data is important before routinely recommending particular agents, including to patients with residual disease after NAC. Clinical trial enrollment in these patients is encouraged	46/47	97.87	Strong [103]

*Added notes were not integrated into the consensus statements, and were included to provide further context and clarity after manuscript review