Table 1.

Round one consensus

No	Recommendation	n/N	% Consensus	Grade [references]
A. General approach
A.1	Multidisciplinary assessment, including consultation with the following, (1) Medical oncologist, (2) Surgeon/surgical oncologist and where applicable, plastic surgeon (3) Radiation oncologist. A multidisciplinary tumor board/cancer conference discussion (or access to this forum if required.) Clinical trials/research protocol team, where applicable. Enrollment in clinical trials is encouraged. Nursing and other allied health support as required	105/107	98.13	Strong
B. Neoadjuvant therapy patient selection
B.1	Neoadjuvant chemotherapy (NAC) is the standard of care for all locally advanced breast cancers (LABC), defined as T3/T4 tumors and/or N2-3, and all inflammatory breast cancers, regardless of biomarkers	84/96	87.50	Strong
B.2	There is a suggestion that lobular carcinomas may not respond well to NAC; however, in the absence of level 1 evidence suggesting otherwise (and the potential for mixed histology tumors), LABCs that are lobular will still often be treated with NAC	77/88	87.50	Conditional
B.3	T1-2 tumors with upfront N1 disease that are ER-positive, HER-2 negative and deemed operable, can be considered for upfront surgery in many cases. However, patients may still be offered NAC, particularly to downstage to breast conservation and/or to allow for sentinel-lymph node biopsy	82/96	85.42	Conditional
B.4	NAC is the standard of care for all triple negative and HER-2 positive breast cancer patients, that have T2N0 or TxN1 disease, and are chemotherapy candidates. Tumors should ideally be evaluable for clinical response monitoring (i.e., palpable)	78/93	83.87	Strong [22, 23]
B.5	NAC for triple-negative or HER2-positive tumors that are T1N0 can be considered on a case-by-case basis Specific tumor characteristics (for instance higher grade or T1c lesions) may help better select patients; the main consideration is likely the choice of chemotherapy regimen that may be offered either pre- or post-operatively (for instance, anthracycline sparing for a T1a/b lesion). Please refer to NAC treatment section below	73/86	84.88	Conditional
B.6	NAC can be offered to any patient for tumor down-staging in order to facilitate breast-conservation (this may be determined by tumor-to-breast size ratio, and not necessarily upfront staging)	72/94	76.60	Conditional [24]
C. Pre-treatment assessment
C.1	All patients being considered for neoadjuvant chemotherapy should have pre-treatment breast and axillary imaging, including: Bilateral mammogram: further targeted imaging (i.e., additional mammographic views and ultrasound) of breast and lymph nodes should be performed based on initial findings. Breast magnetic resonance imaging (MRI) can be considered for all patients planned for neoadjuvant therapy (provided MRI-guided biopsy resources are available), especially for lobular carcinomas. Patients should ideally have access to a rapid-diagnostic unit (RDU) or expedited diagnostic examinations, particularly for urgent clinical presentations (example: rapidly growing breast mass, inflammatory breast changes, etc.)	81/95	85.26	Strong [25]
C.2	Biopsy and clips: Core biopsy should be performed of suspicious breast lesions using the most appropriate technique and modality. Fine needle aspiration for suspicious lymph nodes is generally adequate, although core biopsy is appropriate also. For invasive breast tumors that are eligible for breast conserving surgery, a marker clip should be placed to be used for pre-operative localization in the event of complete clinical and radiologic treatment response. Where a sentinel lymph biopsy after neoadjuvant therapy is being considered, a clip should also be placed in a biopsy-confirmed positive lymph node, if applicable	82/94	87.23	Strong
C.3	Staging: Cancer staging by imaging should be performed for all locally advanced breast cancers (T3/4 and/or any positive lymph nodes). This should include computed tomography (CT) of the chest, abdomen and pelvis, and a nuclear bone scan. Positron emission tomography (PET) imaging could also be considered as per local guidelines or research protocols. Patients of any initial clinical stage who have symptoms suggestive of metastatic disease should also receive targeted imaging (symptom directed)	78/92	84.78	Strong
C.4	Pathologic review by an experienced pathologist should be completed on all breast biopsy specimens to confirm an invasive cancer. The pathologist should also report: Histological type (WHO classification), if possible, Nottingham grade, if possible	91/94	96.81	Strong
C.5	Biomarkers should be reported on all core biopsies of invasive cancer, including: Estrogen receptor (ER), Progesterone receptor (PR), Human epidermal growth factor-2 (HER2) receptor status (by IHC and ISH when indicated)	94/97	96.91	Strong
C.6	Sampled lymph nodes should be reported, at minimum, as benign or containing malignant/metastatic cells (designation of breast as primary site is helpful, if possible)	97/98	98.98	Strong
C.7	Lymph nodes with carcinoma cells but no confirmed invasive disease in the breast should be re-sampled with a core biopsy to assess the histology and biomarkers, if applicable. Comprehensive breast imaging, including breast MRI, should be completed in these situations to look for an occult breast carcinoma	92/96	95.83	Strong
C.8	Multi-disciplinary assessment is important for most patients prior to initiation of NAC. Patients should be reviewed by both a medical oncologist and a surgeon prior to finalization of the initial NAC treatment plan. An early radiation oncology assessment should also occur in those patients who may require salvage radiation therapy (example: locally advanced breast cancer and/or inflammatory breast cancer) Multidisciplinary case conference (MCC) assessment should be considered for any patient deemed appropriate by treating physicians	84/97	86.60	Strong
C.9	Patients in whom breast reconstruction may be considered, consultation with a plastic surgeon and radiation oncologist early in treatment planning or initiation is ideal	89/94	94.68	Strong
C.10	A clinical care pathway disseminated to the entire care team can help standardize patient selection and management. In addition, a patient navigator (if resources are available), is often useful to coordinate initial investigations, multi-disciplinary communication, and subsequent patient follow up during key treatment milestones (example: completing chemotherapy, planning for surgery)	83/94	88.30	Strong
C.11	Assessment for fertility preservation (if applicable) should be done prior to the start of neoadjuvant chemotherapy, if applicable and reasonable based on clinical presentation	94/94	100.0	Strong
C.12	Genetics referral, counseling, and testing (if applicable) should be initiated early to permit inclusion of results into surgical planning *Added Note: Germline mutation testing for appropriate patients may also help select patients for certain adjuvant therapies; please see recommendation G.6 regarding the use of parp inhibitors in BRCA mutation carriers	92/95	96.84	Strong
D. Neoadjuvant systemic therapy
D.1	Chemotherapy is the standard of care for most invasive breast cancers being treated with pre-operative systemic therapy (neoadjuvant chemotherapy, NAC.) A third-generation chemotherapy regimen including anthracyclines and taxanes should be considered for 6–8 cycles total, in most patients	50/56	89.29	Strong [26]
D.2	Regarding specific NAC approaches: The sequence of agents (anthracycline or taxanes first) can be determined based on patient and disease characteristics, in order to optimize pCR. In general, anthracyclines are often given first. Anthracycline-sparing regimens should generally be reserved for patients at high risk for anthracycline toxicities. Shorter chemotherapy regimens, including taxane-based (such as TC or weekly-paclitaxel with trastuzumab for HER-2 positive) can be considered on a case-by-case basis, considering initial tumor staging (less than 2 cm, N0 disease) and grade (grade 1–2), patient preference, and toxicity considerations. The implications for potentially requiring further treatment post-operatively for residual disease should also be considered, if the initial regimen is not a standard anthracycline-taxane regimen (refer to section on additional adjuvant therapies) Dose-dense (biweekly) regimens are preferred for patients who can tolerate them, particularly for ER-negative cancers, due to the potential for modest improvement in outcomes compared to non-dose dense regimens	34/47	72.34	Conditional [26–33]
D.3	Regarding targeted therapies during NAC: The addition of a platinum to the taxane-containing portion of NAC can be considered for tumors with known BRCA-mutations, or for triple negative breast cancers; this is associated with an increase rate of pCR. The addition of platinums should also be considered if suboptimal or progressive disease is observed in these tumors on the anthracycline portion of NAC. Trastuzumab should be given during the taxane portion of NAC for HER-2 positive breast cancers. Pertuzumab (where accessible) should be considered in addition to trastuzumab, during the taxane portion of NAC for HER-2 positive breast cancers, particularly if there is node positive disease/locally advanced disease upfront. This is to improve the chance of pathologic complete response (pCR rate). 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 can be considered for such patients, if available	36/48	75.0	Conditional [28, 34–51]
D.4	Salvage* therapies for patients that progress on neoadjuvant chemotherapy include immediate surgery, if feasible. Switching to a non-cross resistant chemotherapy, especially platinum based as above for triple-negative cancers or those with known BRCA mutations. This should be followed by surgery, if possible. Radiation, followed by surgery, if possible *Added Note: The term “salvage” refers to a change in treatment meant to address tumour progression on initial therapy	70/75	93.33	Strong [39]
D.5	For patients receiving salvage* radiation (due to progression on NAC, see above), adding weekly cisplatin should be considered as a radiation-sensitizing agent, if the tumor is triple negative, and/or has a known BRCA mutation *Added Note: The term “salvage” refers to a change in treatment meant to address tumour progression on initial therapy	36/54	66.67	Conditional
D.6	Neoadjuvant endocrine therapy is NOT considered standard of care at this time. However, it can be considered for ER-positive, HER-2 negative breast cancer patients with a preference to avoid chemotherapy (due to patient age, co-morbidities or functional status). Chemotherapy candidates that may benefit from neoadjuvant endocrine therapy instead of neoadjuvant chemotherapy have high ER/PR expression and low Ki-67 score at baseline, and/or at the 4- and 12-week mark of therapy, and/or low genomic profiling scores. Research protocols, where appropriate, assessing serial tumor response (such as Ki-67 score) could be considered for these patients. The use of genomic profiling scores to select candidates for neoadjuvant endocrine therapy versus chemotherapy remains investigational at this time. The addition of CDK4/6 inhibitors to neoadjuvant endocrine therapy remains investigational at this time; early evidence suggests it does not improve endocrine-responsiveness or pathologic response rates. The efficacy of neoadjuvant endocrine therapy for down staging most patients with large ER positive tumors to allow for breast conservation, or node-positive patients to (targeted) sentinel lymph node biopsy is currently unknown	52/60	86.67	Conditional [52–64]
E. Neoadjuvant treatment response monitoring
E.1	Standard response monitoring remains by clinical examination at this time. Currently, the use of serial imaging modalities, biomarker analysis, or other novel response monitoring tools remains investigational. Patients should be considered for response monitoring studies where available, particularly where adaptive approaches (changing treatment based on response) can be facilitated, and the patient is a study candidate	75/81	92.59	Strong [25, 65–76]
E.2	Patients demonstrating clinical progression during NAC should have breast and lymph node imaging, ideally utilizing the same imaging modalities as performed pre-treatment	84/88	95.45	Strong [25]
E.3	Patients with documented clinical progression on NAC should have systemic staging (CT and bone scan) to screen for metastatic disease, and access to multidisciplinary discussion	84/85	98.82	Strong
E.4	Imaging to assess post-NAC response for clinical responders should be done on a case-by-case basis, and generally only for those considering breast-conservation, or if deemed useful by the care team for treatment planning. Imaging modalities use for post-NAC assessment should, in general, be the same as initial pre-NAC assessment modalities	79/86	91.86	Strong
F. Local–regional management after neoadjuvant systemic therapy
F.1	Breast conserving surgery (BCS) may be considered for patients with adequate tumor response, in combination with technical feasibility and acceptable cosmesis. In those patients with a hereditary breast cancer mutation, a mastectomy (or bilateral mastectomies) may be the preferred surgical modality, considering patient goals, preferences (including acceptance of chemoprevention), and competing health risks. Multi-disciplinary discussion may be useful in these cases	84/88	95.45	Strong [77–80]
F.2	Patients with extensive calcifications both pre- and post- NAC should be advised about the risks and benefits of surgical removal of all calcifications to ensure resection of possible in situ disease and reduce ambiguity on future surveillance	82/85	96.47	Strong
F.3	The pathologic goal for surgical margins is “no-tumor-on-ink” for resected viable in situ or invasive disease. The presence of residual tumor bed changes at the inked margin should be examined with multidisciplinary discussion to review the utility of any additional local–regional management	78/90	86.67	Conditional
F.4	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 biopsy proven lymph node was clipped prior to neoadjuvant therapy (if available) and dual tracer is used. At least two sentinel lymph nodes are removed AND pathologic nodal assessment with immunohistochemistry is available AND Patients are appropriately counseled regarding the risk of false negatives with sentinel lymph node biopsy and uncertainty of long-term outcomes	65/82	79.27	Conditional [81–84]
F.5	Axillary lymph node dissection post neoadjuvant chemotherapy should be considered if: Recommended by MCC and/or patients have palpable lymph nodes prior to definitive surgery and/or Initial N2 or N3 disease and/or Have an inflammatory cancer, regardless of chemotherapy response	74/82	90.24	Strong
F.6	The Residual Cancer Burden Index (RCBI) should be incorporated into synoptic pathology reporting of the final surgical breast and lymph node specimens after neoadjuvant therapy, if possible. This is to standardize assessment methods and to provide prognostic information to the clinician	70/77	90.91	Strong
F.7	Endocrine biomarkers (ER/PR) should be repeated on all residual disease specimens where the initial biomarkers were ER negative. HER2 can be repeated on the surgical specimen if there was uncertainty or heterogeneity in HER-2 analysis on initial biopsy	79/85	90.91	Strong
F.8	Clinical factors including stage, age, hormone receptor status, lymphovascular invasion, grade, extracapsular involvement, response to NAC in the primary tumor, and in regional lymph nodes, and initial (clinical) nodal involvement are important considerations for radiation planning following NAC	64/67	92.94	Strong
F.9	Adjuvant breast and regional (lymph node) radiotherapy following breast conserving surgery (BCS): Breast radiation should be offered to all patients following breast conserving surgery. There is currently a lack of evidence regarding the benefit of boost to the tumor cavity post-NAC and BCS. Boost should be considered according to age, grade, positive or close margins, receptor status and extent of residual disease following NAC	55/57	95.52	Strong
F.10	Regional radiation for patients after NAC who have positive lymph nodes on surgical pathology (regardless of upfront nodal status): Patients with 4 or more residual positive lymph nodes at the time of surgery should be offered local–regional radiotherapy Patients with 1–3 residual positive lymph nodes should also be strongly considered for local–regional radiotherapy. There is a lack of clear evidence of the benefit of local–regional radiotherapy for these patients after NAC and BCS	49/57	85.96	Conditional [85]
F.11	Regional radiation for patients with clinically positive nodes prior to NAC: Patients who have cN2-3 at presentation, or multiple high-risk features (age, tumor size, LVI, grade, ER-negative/HER2 positive receptor status, location) should be considered for local–regional radiation following NAC, irrespective of response on surgical pathology. Patients with initial N1 disease should also be considered for local–regional radiation, regardless of response to NAC Those with suspicious but indeterminate N1 disease prior to NAC, and negative nodal dissection at surgery (sentinel or axillary) can be considered for regional radiation on a case-by-case basis	52/54	96.30	Strong [85]
F.12	Treatment of N0 disease after NAC is controversial. Those patients with no residual nodal disease should have a discussion regarding benefits of regional radiotherapy based on presence of high-risk primary tumor features, nodal disease at presentation, and extent of response in lymph nodes and breast to NAC. A comment on fibrous scarring in the lymph nodes on final surgical pathology can be used as a marker of NAC effect, and potential targeting for regional radiation Ongoing trials seek to better define the role of regional RT for N0 disease after NAC, and to assess the benefit of local–regional radiation in patients with in-breast pCR but node-positive disease after NAC	55/58	94.83	Strong
F.13	Post-Mastectomy Radiation Therapy (PMRT): Patients with primary tumors with multiple high-risk features and N0 disease at surgery should also be considered for either local–regional radiotherapy or chest wall radiotherapy. Factors such as primary tumor size, grade, lymphovascular invasion (LVI), age, tumor location and margin status should be considered. Regional/nodal radiation should be considered in patients following mastectomy who have residual nodal disease following NAC: patients with 4 or more residual positive lymph nodes at the time of surgery should be offered local–regional RT. Patients with 1–3 residual positive lymph nodes should also be strongly considered for local–regional radiation. Patients with cN2-3 disease at presentation should be offered local–regional radiation after mastectomy, regardless of response to NAC. Patients with N1 disease at presentation should also be considered for local–regional radiation, regardless of NAC response. Primary tumor characteristics (as above) and extent of NAC response in lymph nodes at surgery should be considered in decision making. There is an absence of clear evidence in this area. Axillary radiation post-mastectomy of N0 disease after NAC is controversial. Those patients with no residual nodal disease should have a discussion regarding PMRT based on the presence of high-risk primary tumor features, nodal disease at presentation, and NAC response in lymph nodes and primary tumor. The presence of fibrous scarring in the lymph nodes on final pathology as a marker for NAC effect in the nodes can be considered (as above)	48/54	88.89	Conditional [86–88]
F.14	Other considerations for radiation treatment selection: Current evidence-based practice is to use conventional fractionation and dose (i.e., 50 Gy/25 fractions). Some institutions may use a hypofractionated regimen (i.e., 40–42.5 Gy/15–16 fractions) within this setting. There is ongoing debate regarding this approach. Ongoing trials seek to evaluate other adjuvant radiation regimens, including after NAC. Sequencing of RT in relation to further adjuvant systemic therapy should be determined based on patient and disease characteristics, and on discussion with the treating medical oncologist In patients who require further breast or axillary surgical management, adjuvant radiation should be initiated once final surgical treatment is complete, and on discussion with the treating surgeon. Stereotactic body radiation (SBRT) for residual in-breast disease in lieu of surgery remains investigational. Currently SBRT remains an option for those patients who are not considered candidates for surgery, in whom metastatic disease is diagnosed prior to surgery, or on clinical trial. Multi-disciplinary discussion is recommended in this setting	42/46	91.30	Strong
G. Additional adjuvant systemic treatment
G.1	Eligible patients who have any residual disease in breast or lymph nodes (RCB I or higher) after neoadjuvant therapy should be offered: Capecitabine for 6–8 cycles for triple negative breast cancer TDM-1 (where accessible) every three weeks for 14 cycles, for HER-2 positive breast cancer. The timing of additional systemic therapy in relation to any further local–regional management will depend on disease risk and phenotype, and patient tolerability of therapies	55/62	88.71	Strong [89–93]
G.2	Timing of adjuvant treatments should be carefully coordinated: Adjuvant TDM-1 for residual HER-2 positive disease can be administered alongside adjuvant radiation, as per the phase 3 clinical trial protocol. Adjuvant capecitabine can be administered before or after local–regional radiation, depending on individual patient and disease characteristics. MCC discussion can be considered for these patients. Decisions regarding the timing of further surgical management (for positive margins or axillary node dissection) in relation to further systemic or radiation therapy should be discussed at multidisciplinary case conference, unless further surgical intervention will help with adjuvant therapy decision-making (for instance: establishing nodal burden for systemic therapy or radiation planning)	59/62	95.16	Strong [89, 94]
G.3	Adjuvant endocrine therapy should be considered for all ER/PR positive cancers as per local practice; endocrine therapy should be maximized in strategy (agents and duration), particularly for high-risk pre-menopausal patients and those with residual disease. This can be given concurrently with adjuvant TDM-1 for eligible patients	73/74	98.65	Strong
G.4	Adjuvant bisphosphonate therapy should be considered for post-menopausal patients (natural or induced menopause)	57/62	91.94	Strong

Recommendations with results in bold did NOT meet the pre-specified threshold for consensus in Round 1 (>79%); these recommendations were modified and sent for a second round of consensus