Abstract
Purpose
The neoadjuvant treatment of breast cancer (NABC) is a rapidly changing area that benefits from guidelines integrating evidence with expert consensus to help direct practice. This can optimize patient outcomes by ensuring the appropriate use of evolving neoadjuvant principles.
Methods
An expert panel formulated evidence-based practice recommendations spanning the entire neoadjuvant breast cancer treatment journey. These were sent for practice-based consensus across Canada using the modified Delphi methodology, through a secure online survey. Final recommendations were graded using the GRADE criteria for guidelines. The evidence was reviewed over the course of guideline development to ensure recommendations remained aligned with current relevant data.
Results
Response rate to the online survey was almost 30%; representation was achieved from various medical specialties from both community and academic centres in various Canadian provinces. Two rounds of consensus were required to achieve 80% or higher consensus on 59 final statements. Five additional statements were added to reflect updated evidence but not sent for consensus.
Conclusions
Key highlights of this comprehensive Canadian guideline on NABC include the use of neoadjuvant therapy for early stage triple negative and HER2 positive breast cancer, with subsequent adjuvant treatments for patients with residual disease. The use of molecular signatures, other targeted adjuvant therapies, and optimal response-based local regional management remain actively evolving areas. Many statements had evolving or limited data but still achieved high consensus, demonstrating the utility of such a guideline in helping to unify practice while further evidence evolves in this important area of breast cancer management.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Background
Breast cancer is the most commonly diagnosed malignancy globally, with 2.3 million new cases in 2020 [1]. Outcomes have generally improved particularly in higher income nations, including Canada [2]. This is largely attributed to better screening, improved local therapies, and advances in systemic treatment. In addition, a further appreciation of the breast cancer subtypes and associated disparate biology has facilitated several new approaches to multidisciplinary care that have changed the paradigm of breast cancer management [3]. In particular, practice-changing data available in the last several years has resulted in an increased momentum for the pre-operative, or neoadjuvant chemotherapy (NAC) approach to breast cancer treatment [4,5,6,7,8].
A Canadian national consortium for the neoadjuvant treatment of breast cancer (NABC) has existed since 2010. The most recent meeting of this group of national multidisciplinary experts was in May 2019 (Ontario, Canada). This group assembles national multidisciplinary experts in breast cancer to discuss and disseminate emerging evidence-based guidance across the country, and in particular focus on areas that have incomplete evidence and require expert opinion to help direct practice. Various members of this group have previously published meeting reports and one expert consensus guideline, with a significant focus on the utility of NAC for locally advanced breast cancer (LABC) [4,5,6]. However, over the last few years, research has increasingly demonstrated the important prognostic and predictive implications of treating certain subtypes of early breast cancer (HER2 positive and triple negative) with NAC [3], irrespective of upfront clinical stage or operability. The routine use of NAC for early stage breast cancer that is operable on presentation is a paradigm shift of great importance, with significant therapeutic and resource implications [7, 8]. Rapidly evolving evidence, the paucity of long-term data in some studies, the use of variable patient endpoints, and drug funding disparities within the country, can create some uncertainty in therapeutic approaches, but also opportunities for ongoing clinical trials [9]. Considering all this, there is an ongoing need for expert opinion to help consolidate the approach to NABC patient management. This is paramount to achieving the best possible uniform outcomes for Canadian breast cancer patients, particularly considering the publicly funded healthcare landscape. International breast oncology guidelines often embed the use of NAC within larger documents pertaining to breast cancer management [10]. In addition, some of the NAC recommendations are resource and practice-setting specific; there also remains some debate around the impact of certain research findings on clinical care (example using pathologic complete response rate as a practice-changing endpoint). Finally, most guidelines, including the recently published American Society of Clinical Oncology (ASCO) document, focus on systemic therapy alone [11], and do not include the subsequent implications of systemic therapy on surgical and radiation therapy decision-making. We, therefore, developed a contemporary, evidence-based Canadian National Consensus on the Neoadjuvant Treatment of Breast Cancer, using validated consensus methodology. This is meant to capture the most up-to-date evidence on optimal patient management throughout the entire treatment journey, while aligning multidisciplinary expert opinion with practice-based consensus from clinicians across the country.
Guideline type: Evidence Based Consensus.
Intended users: Practitioners who treat invasive breast cancer (pathology, radiology, surgery, medical oncology, radiation oncology, and other involved health professions.)
Applicable resource setting: Upper middle to high income nations with access to advanced screening, diagnostic, pathologic, surgical, radiation, and systemic therapy options.
Methods
Expert guideline panel
An expert guideline steering committee was established at the most recent Canadian National NABC Consortium meeting (May 2019, Ontario, Canada). The committee was comprised of academic and clinical experts in breast cancer management in the following specialties: medical oncology, surgical oncology, radiation oncology, breast radiology and anatomic pathology. All committee experts practice in academic cancer centres for more than 5 years, treat more than 100 unique breast cancer patients per year, and have demonstrated research and academic impact in NABC (peer-reviewed publications, research grants/projects, clinical trials involvement, and/or academic meeting presentations.) Representation from multiple Canadian provinces was sought.
Systematic evidence review
A systematic review of the literature was performed. As management for the neoadjuvant treatment of locally advanced breast cancer and general treatment principles of early breast cancer are well-established [5, 10, 11], the focus of the review was to update established principles of NABC care and highlight areas of new or evolving evidence that in particular would benefit from consensus to help improve practice. The overall focus was defined as the comprehensive management of breast cancer with a neoadjuvant therapy approach, including specific attention to the domains of multi-disciplinary assessment, diagnosis, monitoring, systemic therapy and local treatment. To maintain scope and feasibility, a single database search (PUBMED) was performed with the following parameters: invasive breast cancer, neoadjuvant, limited to phase 3 or 4 studies, meta-analysis, systematic review, or guidelines published in the English language. To focus mainly on new developments in this area, the search was limited to the past 5 years (initially October 2015 to October 2020 inclusive); the search was then repeated for November 2020 to May 2021 prior to manuscript preparation, to ensure no new relevant evidence had been published (Fig. 1). In December 2020, July 2021, October 2021, and December 2021, a targeted online gray literature search was completed to review any updated evidence as presented at four high impact oncology meetings (San Antonio Breast Cancer Symposium 2020 and 2021, American Society of Clinical Oncology 2021, European Society of Medical Oncology 2021), and any new published guidelines. The guideline panel decided it was important to capture any relevant new evidence with a select few additional recommendations, to ensure the guideline was most up-to-date. It was decided a priori that if the new evidence did not change the relevance or accuracy of existing recommendations, or greatly change the guideline’s scope or impact, these few select recommendations would not be sent for consensus to prevent delays in final guideline submission.
Consensus statements and consensus process
The steering committee developed recommendations for consensus based on the evidence review and discussion of important principles of NABC care, as established during and since the last Canadian NABC consensus statement in 2015 [5]. Discussions were held virtually (telephone), and via email correspondence. The statements were further reviewed by five additional clinical experts in breast surgical, radiation, and medical oncology; these expert reviewers were identified from past Canadian NABC Consortium involvement. Representation from multiple provinces was again ensured.
The Modified-Delphi approach is well recognized as a robust consensus methodology, particularly for consensus development in healthcare [12, 13]. This anonymous, survey-based consensus guideline model has several advantages compared to more traditional expert-based or nominal group methods; the latter rely solely on the opinions of a select group of individuals, and can be more subject to bias or the influence of the most vocal members of a guideline committee. Using the modified-Delphi approach, final statements were emailed to potential physician respondents using a secure online survey platform (Survey Monkey Inc., San Mateo, California, USA). Potential respondents were identified as being probable breast cancer clinicians by national or provincial medical society membership, provincial cancer centre affiliation, description of medical practice as available in public domain (example: institutional websites), recommendation by invited colleagues, and/or previous attendance at Canadian National NABC Consortium meetings. Invited participants were instructed only to respond if they had enough clinical expertise and experience in the neoadjuvant treatment of breast cancer to have an opinion. To achieve a broad practice-based consensus on expert recommendations, the guideline committee preferred not to restrict responses by years of practice or number of patients, and assumed respondents would only engage in the survey if they felt comfortable with the subject matter. Invitation to participate in the consensus process was carried out using email addresses for these individuals, as available in the public domain or through personal solicitation from the steering committee, or as shared by invited colleagues. Given the focus of this guideline was an practice-based physician consensus, other health care disciplines, and patient representatives were not included in the statement development or consensus process itself. Widespread physician representation was targeted, including multidisciplinary providers in both academic and community centers and in all Canadian provinces with comprehensive cancer programs.
Responses were anonymous; only respondent demographics including discipline, geographic area of practice, and years in practice were collected. Respondents were asked to indicate agreement, disagreement, or neutrality (i.e., "no opinion") to each statement. Given that multiple oncology specialties were involved, respondents were asked to indicate "no opinion" only if the statement was outside of their area of direct practice and not because they had no opinion about a statement related to their specialty. Reminders were sent twice over an 8-week period. Respondents were required to provide detailed qualitative feedback regarding statements they disagreed with. Specifically, respondents were instructed that if they did not agree with a statement in its entirety, to indicate disagreement, and provide detailed feedback regarding the elements they did not agree with. As per Modified-Delphi process, statements that did not achieve consensus were reviewed by the steering committee and modified based on the qualitative feedback as collected by the survey. These statements were emailed for a second round of survey; this was emailed to the same participants. Participants were instructed to respond only if they had responded to the first survey; one reminder was sent over 6 weeks. A third round was planned if required (Fig. 2).
Consensus analysis
Agreement statistics were calculated for each statement based on the total number of responses. The denominator for each statement (N, Agree + Disagree) was calculated as the sum of respondents who agreed and disagreed. Blank responses and those who indicated "no opinion" were excluded from the total number of responses for each question. The numerator (n, Agree) corresponded to the number of respondents who indicated "agree" for each statement. The proportion (n/N) was converted to a percent value (%) to determine the consensus value. A threshold value was determined a priori; consensus was defined as statements with 80% or more of respondents in agreement; statements with consensus > 79.5% were rounded up to 80%. Statements with less than an 80% (i.e., ≤ 79.5%) agreement level were marked for modification in the next round of survey, as per Modified Delphi methodology. Qualitative feedback was collected from respondents who indicated disagreement with particular statements; this feedback was utilized to modify statements that did not achieve consensus with the initial round.
Grading of recommendations
The final statements were ranked using the GRADE recommendations for guidelines (Strong or Conditional) [14], with consideration of the four domains within the framework for a recommendation’s direction and strength, which include: estimates of effect for desirable and undesirable outcomes of interest, confidence in the estimates of effect, estimates of values and preferences, and resource use [15]. In considering this framework, recommendations were generally considered strong if they were based on positive data and had level 1 or 2 evidence as per the GRADE framework for ranking evidence [14], and met the threshold for consensus. If a recommendation was lacking updated level 1–2 evidence in the last 5 years (acknowledging the review was limited to this timeframe), was deemed imperative to patient care and received a very high level of consensus (> 89%), it was also rated as strong. Recommendations deemed less impactful to patient care, with level 3 or 4 evidence, with preliminary (short term) level 1 or 2 evidence, high resource implications/lack of public funding, or with no published evidence and consensus < 90%, were marked as conditional. The term conditional was preferred over “weak” to indicate these statements may have evolving data thatmay strengthen the recommendation over time) and/or the statement may still be impactful for patient care, particularly in certain contexts. Available evidence was linked to recommendations in the “Grading” column (Tables 1 and 2). As the consensus statements may have been based on several sources of evidence with varying strengths, and to illustrate the grading of recommendations was not based on the strength of evidence alone (as discussed above), formal grading of the evidence was not integrated into the guideline table. Finally, additional statements added by the panel (Table 3) were all graded as “conditional” to reflect that they were not sent for consensus.
Engagement of further stakeholders
The final guideline was reviewed by a pharmacist, breast cancer patient representative, and a neoadjuvant nurse navigator, all affiliated with the Sunnybrook Health Sciences Centre. Their feedback on the premise of the guideline, agreement with recommendations, and on implementation was sought.
Results
A total of 47 recommendations were initially created by the steering committee and integrated into a consensus survey. Email invitations to complete the survey were sent to 391 clinicians in October 2020. There were 109 participants who completed the survey, for a response rate of 28%. Surgical oncology represented the largest respondent group (41/109; 37.6%), followed by medical oncology (29/109; 26.61%) and radiation oncology (21/109; 19.27%) (Fig. 3). Respondents were predominantly within their mid-career level of practice. Geographical representation was achieved from across several Canadian provinces, although the majority of respondents were located in central Canada (66.0% Ontario and Quebec), and at academic health institutions (77.0%). A summary of all respondent profiles is presented in Fig. 3.
Consensus agreement: round 1
During the first survey round, 89.4% of questions (42/47) achieved 80% or greater consensus (agreement). A summary of all statements with the levels of consensus is presented in Table 1. Consensus was not reached for five statements under the following domains: patient selection, neoadjuvant systemic therapy, and local–regional management after neoadjuvant systemic therapy. The five statements that did not receive 80% agreement were modified based on qualitative feedback from the survey. These five statements were re-structured into 12 statements and sent for a second round of survey in December 2020. One additional new statement was integrated into the second survey to encompass new data regarding adjuvant therapy that became available as part of the targeted gray literature search in at that time.
Consensus agreement: round 2
In the second round, there were 81 respondents (81/109; 74.3% of respondents from round 1). A summary of the modified statements in round 2 is outlined in Table 2. All of the modified statements reached ≥ 80% consensus. The new statement on adjuvant therapy achieved consensus. A third round of survey was therefore not required, given the second round achieved complete consensus on this new statement, and all revised statements.
Systematic review
There were 389 citations found on systematic review; 311 were excluded based on abstract review; criteria are shown in Fig. 1. There were many early phase studies, and those focused on biomarker assessment, a rapidly evolving area of research in the neoadjuvant realm. As much of this data is exploratory or early, these studies were excluded. There were also many studies evaluating imaging response modalities for neoadjuvant therapy; some of these were included and matched to the statement regarding their investigational use. In general, studies that had negative results or did not meet primary efficacy endpoints, or with early phase data only, or therapies that had subsequent or conflicting data demonstrating a lack of meaningful impact on patient care, were excluded. The 78 included citations were fully reviewed and matched with guideline statements. For ease of readability and clarity, detailed descriptions of the evidence were not included in the recommendation table itself. Some recommendations did not have associated citations, as they were based on data published before the systematic review timeframe.
Further evidence review and additional statements
Targeted gray literature review did not demonstrate any impact on the accuracy or relevance of existing consensus statements. However, five additional recommendations were created by the expert guideline panel to reflect important areas of practice deemed not to be captured in the initial or revised statements This included statements on sentinel lymph node biopsy for N0 disease [16], nab-paclitaxel for neoadjuvant therapy [17, 18], and two additional adjuvant therapies, neratinib [19] and olaparib [20]. Finally, the rapidly evolving impact of molecular gene profiling on NABC was decided to be more clearly addressed after final external review. The five additional statements are presented in Table 3. Footnotes were included for a few consensus recommendations to clarify concepts as suggested by external review.
Additional stakeholder feedback
The nursing, patient, and pharmacist feedback sought demonstrated agreement with the recommendations overall, and in particular with the multi-disciplinary approach to NAC care. Suggestions to disseminate the guideline in patient, nursing, and pharmacy forums were made.
Discussion
There was a high level of agreement on 59 final statements encompassing the complex, multidisciplinary care pathway of neoadjuvant breast cancer patients. Five additional statements were not sent for consensus but were integrated to reflect the most up-to-date evidence pertaining to NABC at the time of manuscript preparation. Important highlights of this guideline include the recommendation to use neoadjuvant systemic therapy for early (operable) stage HER-2 positive and triple negative breast cancer, and the subsequent use of additional adjuvant therapies for those patients with residual disease after definitive surgery. In addition, this guideline demonstrates the importance of multi-disciplinary collaboration throughout the patient care journey. Finally, this consensus guideline demonstrates a balance between improving patient outcomes in an evidence-based manner while seeking to minimize toxicities, with a focus on individualized decision making, including clinical trial enrollment, particularly where evidence is less robust or still accumulating. This is particularly relevant for local–regional treatment approaches where evidence continues to accumulate from ongoing studies.
Assessment of resource implications
Given the broad scope of this guideline, including many treatment modalities, formal assessment of cost-effectiveness for individual therapies was outside the scope of this guideline. The committee acknowledged that most of the recommendations were applicable to High-middle and High income countries. Due to the robust health technology assessment for cancer drug funding recommendations nationally (pan-Canadian Oncology Drug Review through CADTH) [21], provincially funded systemic therapies for cancer generally have a cost-effectiveness backing within the Canadian healthcare landscape. Therefore, Health Canada approved agents that do not have wide-spread public funding or remain under evaluation (such as pertuzumab) were acknowledged within the recommendations as potentially having resource constraints at this current time. Corresponding statements suggested that accessibility and resources should be considered in particular for these drugs.
Limitations
Limitations of this guideline include only a 29% response rate to the consensus survey, and potential sampling and non-response bias. Primarily academic physicians responded to the survey, as such, the opinion of breast cancer clinicians in community practice settings may be under-represented. In addition, medical oncologists and surgeons comprised the largest group of respondents, and the opinion of other specialties may not completely be captured. There were also approximately 25% of initial participants who did not respond to the second round of survey, potentially impacting the results. However, this is unlikely, given the high levels of initial consensus on these statements with the first round (range 66–79%). Patient and other health care professionals were not engaged in the initial development of recommendations; their feedback was only sought on the final guideline and implementation plan. Five additional statements were created but not sent for consensus to prevent delay on the timely dissemination of this guideline; however, they are unlikely to impact on the scope and relevance of the guideline in general.
Summary and knowledge dissemination plan
This work represents an updated Canadian National Consensus on the Neoadjuvant treatment of breast cancer, across all parts of the therapeutic patient journey. A systematic review of recent literature and formal grading of recommendations was also achieved. The evidence was reviewed several times during guideline preparation, ensuring the most updated data was incorporated in a meaningful manner. The neoadjuvant treatment of breast cancer is a rapidly evolving area of clinical and academic interest; data can change quickly and uptake in clinical settings can falter based on sub-optimal knowledge dissemination or hesitancy to change practice. We believe our approach demonstrates Canadian consensus on key areas of neoadjuvant care, integrating available evidence, expert opinion, and practice-based consensus. We believe this guideline can help optimize patient outcomes across the country, by synthesizing the evidence into comprehensive recommendations for clinical care. Furthermore, the presence of national practice guidelines may help to foster clinical and policy change within healthcare organizations and health networks, with the hope of achieving uniformity of practice and thus patient outcomes. Given the importance of ensuring patient management is aligned with best practice, and to help optimize the use of resources and expertise in this area, we hope to achieve broad dissemination of this consensus guideline. A particular strength of this work is the inclusion of all elements of the patient treatment journey, formal grading of recommendations, and also achieving high levels of consensus, particularly in areas where evidence is lacking or evolving. This may help implementation and uptake of practice elements that can standardize Canadian breast cancer care as the neoadjuvant landscape continues to rapidly evolve. This guideline will be disseminated at the next Canadian National NABC Consensus meeting (planned for mid-2022), and ideally at national and international academic forums. There is also much interest in this document from national, provincial and hospital-based cancer programs in Canada to help guide local practice and resource allocation. We hope this guideline will be a strong addition to the published literature in this important area.
Data availability
Not applicable.
Code availability
Not applicable.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 71(3):209–249
Canadian Cancer Society (2021) No title. https://www.cancer.ca/en/cancer-information/cancer-type/breast/prognosis-and-survival/survival-statistics/?region=on. Accessed 8 Mar 2021
Prat A, Pineda E, Adamo B, Galván P, Fernández A, Gaba L et al (2015) Clinical implications of the intrinsic molecular subtypes of breast cancer. The Breast 24:S26-35
Brackstone M, Robidoux A, Chia S, Mackey J, Dent R, Boileau J et al (2011) Canadian initiatives for locally advanced breast cancer research and treatment: inaugural meeting of the Canadian Consortium for LABC. Curr Oncol 18(3):139–144
Simmons CE, Hogeveen S, Leonard R, Rajmohan Y, Han D, Wong A et al (2015) A Canadian national expert consensus on neoadjuvant therapy for breast cancer: linking practice to evidence and beyond. Curr Oncol 22(Suppl 1):S43-53
Arnaout A, Lee J, Gelmon K, Poirier B, Lu FI, Akra M et al (2018) Neoadjuvant therapy for breast cancer: updates and proceedings from the seventh annual meeting of the Canadian Consortium for Locally Advanced Breast Cancer. Curr Oncol 25(5):490–498
Caparica R, Lambertini M, Pondé N, Fumagalli D, de Azambuja E, Piccart M (2019) Post-neoadjuvant treatment and the management of residual disease in breast cancer: state of the art and perspectives. Ther Adv Med Oncol 11:175883591982771
Simmons C (2018) The changing role of neoadjuvant therapy in breast cancer: considering systemic treatment for patients with operable as well as inoperable disease. BC Med J 60(2):103–108
White J, DeMichele A (2015) Neoadjuvant therapy for breast cancer: controversies in clinical trial design and standard of care. Am Soc Clin Oncol Educ B 35:e17-23
NCCN (2021) NCCN clinical practice guidelines. Breast cancer 2021. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 26 Mar 2021
Korde LA, Somerfield MR, Carey LA, Crews JR, Denduluri N, Hwang ES et al (2021) Neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer: ASCO guideline. J Clin Oncol 39(13):1485–1505
Dalkey NC (1969) The Delphi method: an experimental study of group opinion. RAND Corporation PP, Santa Monica
Niederberger M, Spranger J (2020) Delphi technique in health sciences: a map. Front Public Health. https://doi.org/10.3389/fpubh.2020.00457/full
Andrews J, Guyatt G, Oxman AD, Alderson P, Dahm P, Falck-Ytter Y et al (2013) GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol 66(7):719–725
Andrews JC, Schünemann HJ, Oxman AD, Pottie K, Meerpohl JJ, Coello PA et al (2013) GRADE guidelines: 15. Going from evidence to recommendation—determinants of a recommendation’s direction and strength. J Clin Epidemiol 66(7):726–735
Brackstone M, Baldassarre FG, Perera FE, Cil T, Chavez Mac Gregor M, Dayes IS et al (2021) Management of the Axilla in early-stage breast cancer: Ontario health (Cancer Care Ontario) and ASCO guideline. J Clin Oncol. https://doi.org/10.1200/JCO.21.00934
Liu M, Liu S, Yang L, Wang S (2021) Comparison between nab-paclitaxel and solvent-based taxanes as neoadjuvant therapy in breast cancer: a systematic review and meta-analysis. BMC Cancer 21(1):118
Li Y, Lu X, Lin Q, Li W (2020) Is nab-paclitaxel better than conventional taxanes as neoadjuvant therapy for breast cancer? A meta-analysis. J Int Med Res 48(8):030006052094347
Chan A, Moy B, Mansi J, Ejlertsen B, Holmes FA, Chia S et al (2021) Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer 21(1):80-91.e7
Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P et al (2021) Adjuvant olaparib for patients with BRCA1—or BRCA2—mutated breast cancer. N Engl J Med 384(25):2394–2405
How pCODR Works (2021) https://www.cadth.ca/how-pcodr-works. Accessed 20 July 2021
Broglio KR, Quintana M, Foster M, Olinger M, McGlothlin A, Berry SM et al (2016) Association of pathologic complete response to neoadjuvant therapy in HER2-positive breast cancer with long-term outcomes. JAMA Oncol 2(6):751
Xia L-Y, Hu Q-L, Zhang J, Xu W-Y, Li X-S (2020) Survival outcomes of neoadjuvant versus adjuvant chemotherapy in triple-negative breast cancer: a meta-analysis of 36,480 cases. World J Surg Oncol 18(1):129
Volders JH, Negenborn VL, Spronk PE, Krekel NMA, Schoonmade LJ, Meijer S et al (2018) Breast-conserving surgery following neoadjuvant therapy-a systematic review on surgical outcomes. Breast Cancer Res Treat 168(1):1–12
Kim R, Chang JM, Lee H-B, Lee SH, Kim S-Y, Kim ES et al (2019) Predicting axillary response to neoadjuvant chemotherapy: breast MRI and US in patients with node-positive breast cancer. Radiology 293(1):49–57
Pathak M, Dwivedi SN, Deo SVS, Thakur B, Sreenivas V, Rath GK (2018) Neoadjuvant chemotherapy regimens in treatment of breast cancer: a systematic review and network meta-analysis protocol. Syst Rev 7(1):89
Zaheed M, Wilcken N, Willson ML, O’Connell DL, Goodwin A (2019) Sequencing of anthracyclines and taxanes in neoadjuvant and adjuvant therapy for early breast cancer. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD012873.pub2
Pathak M, Deo SV, Dwivedi SN, Thakur B, Sreenivas V, Rath GK (2020) Regimens of neo-adjuvant chemotherapy in the treatment of breast cancer: a systematic review & network meta-analysis with PRISMA-NMA compliance. Crit Rev Oncol Hematol 153:103015
Petrelli F, Coinu A, Lonati V, Cabiddu M, Ghilardi M, Borgonovo K et al (2016) Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs 27(7):702–708
Conte B, Bruzzone M, Lambertini M, Poggio F, Bighin C, Blondeaux E et al (2020) Effect of dose-dense adjuvant chemotherapy in hormone receptor positive/HER2-negative early breast cancer patients according to immunohistochemically defined luminal subtype: an exploratory analysis of the GIM2 trial. Eur J Cancer 136:43–51
Ding Y, Ding K, Yang H, He X, Mo W, Ding X (2020) Does dose-dense neoadjuvant chemotherapy have clinically significant prognostic value in breast cancer? A meta-analysis of 3,724 patients. PLoS ONE 15(5):e0234058
Goldvaser H, Majeed H, Ribnikar D, Šeruga B, Ocaña A, Cescon DW et al (2018) Influence of control group therapy on the benefit from dose-dense chemotherapy in early breast cancer: a systemic review and meta-analysis. Breast Cancer Res Treat 169(3):413–425
Vriens BEPJ, Vriens IJH, Aarts MJB, van Gastel SM, van den Berkmortel FWPJ, Smilde TJ et al (2017) Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer. Breast Cancer Res Treat 165(3):593–600
Li Y, Yang D, Chen P, Yin X, Sun J, Li H et al (2019) Efficacy and safety of neoadjuvant chemotherapy regimens for triple-negative breast cancer: a network meta-analysis. Aging 11(16):6286–6311
Pathak M, Dwivedi SN, Deo SVS, Thakur B, Sreenivas V, Rath GK (2019) Effectiveness of added targeted therapies to neoadjuvant chemotherapy for breast cancer: a systematic review and meta-analysis. Clin Breast Cancer 19(6):e690-700
Huober J, Holmes E, Baselga J, de Azambuja E, Untch M, Fumagalli D et al (2019) Survival outcomes of the NeoALTTO study (BIG 1–06): updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur J Cancer 118:169–177
Loibl S, Jackisch C, Schneeweiss A, Schmatloch S, Aktas B, Denkert C et al (2017) Dual HER2-blockade with pertuzumab and trastuzumab in HER2-positive early breast cancer: a subanalysis of data from the randomized phase III GeparSepto trial. Ann Oncol 28(3):497–504
Sheikh F, Nazir A, Yasmeen S, Badar F, Ahmad U, Siddiqui N (2019) Pathologic complete response in HER2-positive breast cancer patients receiving trastuzumab in neoadjuvant setting. J Coll Physicians Surg Pak 29(2):159–163
Firouzabadi D, Dehghanian A, Rezvani A, Mahmoudi L, Talei A (2021) Addition of carboplatin-gemcitabine as second-line neoadjuvant chemotherapy in non-responsive locally advanced breast cancer patients to standard neoadjuvant chemotherapy and evaluation of factors affecting response: a randomized controlled trial. BMC Cancer 21(1):47
Iwase M, Ando M, Aogi K, Aruga T, Inoue K, Shimomura A et al (2020) Long-term survival analysis of addition of carboplatin to neoadjuvant chemotherapy in HER2-negative breast cancer. Breast Cancer Res Treat 180(3):687–694
Nakashoji A, Hayashida T, Yokoe T, Maeda H, Toyota T, Kikuchi M et al (2018) The updated network meta-analysis of neoadjuvant therapy for HER2-positive breast cancer. Cancer Treat Rev 62:9–17
Wang D, Feng J, Xu B (2019) A meta-analysis of platinum-based neoadjuvant chemotherapy versus standard neoadjuvant chemotherapy for triple-negative breast cancer. Future Oncol 15(23):2779–2790
Zhang P, Yin Y, Mo H, Zhang B, Wang X, Li Q et al (2016) Better pathologic complete response and relapse-free survival after carboplatin plus paclitaxel compared with epirubicin plus paclitaxel as neoadjuvant chemotherapy for locally advanced triple-negative breast cancer: a randomized phase 2 trial. Oncotarget 7(37):60647–60656
Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A et al (2020) Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer. JAMA Oncol 6(5):676
van Ramshorst MS, van der Voort A, van Werkhoven ED, Mandjes IA, Kemper I, Dezentjé VO et al (2018) Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19(12):1630–1640
Pandy JGP, Balolong-Garcia JC, Cruz-Ordinario MVB, Que FVF (2019) Triple negative breast cancer and platinum-based systemic treatment: a meta-analysis and systematic review. BMC Cancer 19(1):1065
Tarantino P, Gandini S, Trapani D, Criscitiello C, Curigliano G (2021) Immunotherapy addition to neoadjuvant chemotherapy for early triple negative breast cancer: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 159:103223
Shao Z, Pang D, Yang H, Li W, Wang S, Cui S et al (2020) Efficacy, safety, and tolerability of pertuzumab, trastuzumab, and docetaxel for patients with early or locally advanced ERBB2-positive breast cancer in Asia. JAMA Oncol 6(3):e193692
Squires H, Pandor A, Thokala P, Stevens JW, Kaltenthaler E, Clowes M et al (2018) Pertuzumab for the neoadjuvant treatment of early-stage HER2-positive breast cancer: an evidence review group perspective of a NICE single technology appraisal. Pharmacoeconomics 36(1):29–38
Chen S, Liang Y, Feng Z, Wang M (2019) Efficacy and safety of HER2 inhibitors in combination with or without pertuzumab for HER2-positive breast cancer: a systematic review and meta-analysis. BMC Cancer 19(1):973
Li Z-Y, Zhang Z, Cao X-Z, Feng Y, Ren S-S (2020) Platinum-based neoadjuvant chemotherapy for triple-negative breast cancer: a systematic review and meta-analysis. J Int Med Res 48(10):030006052096434
Spring LM, Gupta A, Reynolds KL, Gadd MA, Ellisen LW, Isakoff SJ et al (2016) Neoadjuvant endocrine therapy for estrogen receptor-positive breast cancer. JAMA Oncol 2(11):1477
Cottu P, D’Hondt V, Dureau S, Lerebours F, Desmoulins I, Heudel P-E et al (2018) Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol 29(12):2334–2340
Chae SY, Kim S-B, Ahn SH, Kim HO, Yoon DH, Ahn J-H et al (2017) A randomized feasibility study of 18 F-fluoroestradiol PET to predict pathologic response to neoadjuvant therapy in estrogen receptor-rich postmenopausal breast cancer. J Nucl Med 58(4):563–568
Bear HD, Wan W, Robidoux A, Rubin P, Limentani S, White RL et al (2017) Using the 21-gene assay from core needle biopsies to choose neoadjuvant therapy for breast cancer: a multicenter trial. J Surg Oncol 115(8):917–923
Du L, Yau C, Brown-Swigart L, Gould R, Krings G, Hirst GL et al (2021) Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2−) breast cancer before chemo-endocrine therapy. Ann Oncol 32(5):642–651
Dubsky PC, Singer CF, Egle D, Wette V, Petru E, Balic M et al (2020) The EndoPredict score predicts response to neoadjuvant chemotherapy and neoendocrine therapy in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer patients from the ABCSG-34 trial. Eur J Cancer 134:99–106
Zhang T, Feng F, Yao Y, Qi L, Tian J, Zhou C et al (2019) Efficacy and acceptability of neoadjuvant endocrine therapy in patients with hormone receptor-positive breast cancer: a network meta-analysis. J Cell Physiol 234(8):12393–12403
Kim HJ, Noh WC, Lee ES, Jung YS, Kim LS, Han W et al (2020) Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer. Breast Cancer Res 22(1):54
Whitworth P, Beitsch P, Mislowsky A, Pellicane JV, Nash C, Murray M et al (2017) Chemosensitivity and endocrine sensitivity in clinical luminal breast cancer patients in the prospective neoadjuvant breast registry symphony trial (NBRST) predicted by molecular subtyping. Ann Surg Oncol 24(3):669–675
Huang L, Xu A-M (2017) Short-term outcomes of neoadjuvant hormonal therapy versus neoadjuvant chemotherapy in breast cancer: systematic review and meta-analysis of randomized controlled trials. Expert Rev Anticancer Ther 17(4):327–334
Iwata H, Masuda N, Yamamoto Y, Fujisawa T, Toyama T, Kashiwaba M et al (2019) Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study. Breast Cancer Res Treat 173(1):123–133
Stafford A, Williams A, Edmiston K, Cocilovo C, Cohen R, Bruce S et al (2020) Axillary response in patients undergoing neoadjuvant endocrine treatment for node-positive breast cancer: systematic literature review and NCDB analysis. Ann Surg Oncol 27(12):4669–4677
Wang Y, He L, Song Y, Wu Q, Wang H, Zhang B et al (2020) The tumour response of postmenopausal hormone receptor-positive breast cancers undergoing different types of neoadjuvant therapy: a meta-analysis. BMC Womens Health 20(1):17
Li H, Yao L, Jin P, Hu L, Li X, Guo T et al (2018) MRI and PET/CT for evaluation of the pathological response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. The Breast 40:106–115
Gao W, Guo N, Dong T (2018) Diffusion-weighted imaging in monitoring the pathological response to neoadjuvant chemotherapy in patients with breast cancer: a meta-analysis. World J Surg Oncol 16(1):145
Banys-Paluchowski M, Gruber IV, Hartkopf A, Paluchowski P, Krawczyk N, Marx M et al (2020) Axillary ultrasound for prediction of response to neoadjuvant therapy in the context of surgical strategies to axillary dissection in primary breast cancer: a systematic review of the current literature. Arch Gynecol Obstet 301(2):341–353
Liu YH, Xue LB, Yang YF, Zhao TJ, Bai Y, Zhang BY et al (2018) Diffuse optical spectroscopy for monitoring the responses of patients with breast cancer to neoadjuvant chemotherapy. Medicine 97(41):e12683
Tang S, Xiang C, Yang Q (2020) The diagnostic performance of CESM and CE-MRI in evaluating the pathological response to neoadjuvant therapy in breast cancer: a systematic review and meta-analysis. Br J Radiol 93(1112):20200301
Tian F, Shen G, Deng Y, Diao W, Jia Z (2017) The accuracy of 18F-FDG PET/CT in predicting the pathological response to neoadjuvant chemotherapy in patients with breast cancer: a meta-analysis and systematic review. Eur Radiol 27(11):4786–4796. https://doi.org/10.1007/s00330-017-4831-y
Kirshner JJ, McDonald MC, Kruter F, Guinigundo AS, Vanni L, Maxwell CL et al (2018) NOLAN: a randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim. Support Care Cancer 26(4):1323–1334
Jun W, Cong W, Xianxin X, Daqing J (2019) Meta-Analysis of quantitative dynamic contrast-enhanced MRI for the assessment of neoadjuvant chemotherapy in breast cancer. Am Surg 85(6):645–653
Han S, Choi JY (2020) Prognostic value of 18F-FDG PET and PET/CT for assessment of treatment response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. Breast Cancer Res 22(1):119
Chen L, Yang Q, Bao J, Liu D, Huang X, Wang J (2017) Direct comparison of PET/CT and MRI to predict the pathological response to neoadjuvant chemotherapy in breast cancer: a meta-analysis. Sci Rep 7(1):8479
Sheikhbahaei S, Trahan TJ, Xiao J, Taghipour M, Mena E, Connolly RM et al (2016) FDG-PET/CT and MRI for evaluation of pathologic response to neoadjuvant chemotherapy in patients with breast cancer: a meta-analysis of diagnostic accuracy studies. Oncologist 21(8):931–939
Jia K, Li L, Wu XJ, Hao MJ, Xue HY (2019) Contrast-enhanced ultrasound for evaluating the pathologic response of breast cancer to neoadjuvant chemotherapy. Medicine 98(4):e14258
Sun Y, Liao M, He L, Zhu C (2017) Comparison of breast-conserving surgery with mastectomy in locally advanced breast cancer after good response to neoadjuvant chemotherapy. Medicine 96(43):e8367
Dubsky P, Pinker K, Cardoso F, Montagna G, Ritter M, Denkert C et al (2021) Breast conservation and axillary management after primary systemic therapy in patients with early-stage breast cancer: the Lucerne toolbox. Lancet Oncol 22(1):e18-28
Golshan M, Loibl S, Wong SM, Huober JB, O’Shaughnessy J, Rugo HS et al (2020) Breast conservation after neoadjuvant chemotherapy for triple-negative breast cancer. JAMA Surg 155(3):e195410
Li X, Dai D, Chen B, Tang H, Wei W (2017) Oncological outcome of complete response after neoadjuvant chemotherapy for breast conserving surgery: a systematic review and meta-analysis. World J Surg Oncol 15(1):210
Simons JM, van Nijnatten TJA, van der Pol CC, Luiten EJT, Koppert LB, Smidt ML (2019) Diagnostic accuracy of different surgical procedures for axillary staging after neoadjuvant systemic therapy in node-positive breast cancer. Ann Surg 269(3):432–442
Tee SR, Devane LA, Evoy D, Rothwell J, Geraghty J, Prichard RS et al (2018) Meta-analysis of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with initial biopsy-proven node-positive breast cancer. Br J Surg 105(12):1541–1552
El Hage CH, Headon H, El Tokhy O, Heeney J, Kasem A, Mokbel K (2016) Is sentinel lymph node biopsy a viable alternative to complete axillary dissection following neoadjuvant chemotherapy in women with node-positive breast cancer at diagnosis? An updated meta-analysis involving 3,398 patients. Am J Surg 212(5):969–981
Geng C, Chen X, Pan X, Li J (2016) The feasibility and accuracy of sentinel lymph node biopsy in initially clinically node-negative breast cancer after neoadjuvant chemotherapy: a systematic review and meta-analysis. PLoS ONE 11(9):e0162605
Krug D, Baumann R, Budach W, Dunst J, Feyer P, Fietkau R et al (2018) Individualization of post-mastectomy radiotherapy and regional nodal irradiation based on treatment response after neoadjuvant chemotherapy for breast cancer. Strahlenther Onkol 194(7):607–618
Li L, Han D, Wang X, Wang Q, Tian J, Yao J et al (2017) Prognostic values of Ki-67 in neoadjuvant setting for breast cancer: a systematic review and meta-analysis. Future Oncol 13(11):1021–1034
Recht A, Comen EA, Fine RE, Fleming GF, Hardenbergh PH, Ho AY et al (2017) Postmastectomy radiotherapy: an American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology focused guideline update. Ann Surg Oncol 24(1):38–51
Stauder MC, Caudle AS, Allen PK, Shaitelman SF, Smith BD, Hoffman KE et al (2016) Outcomes of post mastectomy radiation therapy in patients receiving axillary lymph node dissection after positive sentinel lymph node biopsy. Int J Radiat Oncol 96(3):637–644
von Minckwitz G, Huang C-S, Mano MS, Loibl S, Mamounas EP, Untch M et al (2018) Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 5:617
Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I et al (2017) Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376(22):2147–2159
Conte P, Schneeweiss A, Loibl S, Mamounas EP, Minckwitz G, Mano MS et al (2020) Patient-reported outcomes from KATHERINE: a phase 3 study of adjuvant trastuzumab emtansine versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for human epidermal growth factor receptor 2–positive breast cancer. Cancer 126(13):3132–3139
Natori A, Ethier J-L, Amir E, Cescon DW (2017) Capecitabine in early breast cancer: a meta-analysis of randomised controlled trials. Eur J Cancer 77:40–47
Huang M, O’Shaughnessy J, Zhao J, Haiderali A, Cortés J, Ramsey SD et al (2020) Association of pathologic complete response with long-term survival outcomes in triple-negative breast cancer: a meta-analysis. Cancer Res 80(24):5427–5434
Piroth MD, Krug D, Sedlmayer F, Duma M-N, Baumann R, Budach W et al (2021) Post-neoadjuvant treatment with capecitabine and trastuzumab emtansine in breast cancer patients—sequentially, or better simultaneously? Strahlenther Onkol 197(1):1–7
Yee D, DeMichele AM, Yau C, Isaacs C, Symmans WF, Albain KS et al (2020) Association of event-free and distant recurrence-free survival with individual-level pathologic complete response in neoadjuvant treatment of stages 2 and 3 breast cancer. JAMA Oncol 6(9):1355
Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang C-S, Thompson AM et al (2018) Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 19(1):115–126
Gianni L, Pienkowski T, Im Y-H, Tseng L-M, Liu M-C, Lluch A et al (2016) 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol 17(6):791–800
Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R et al (2020) Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 tria. Lancet 396(10257):1090–1100
Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J et al (2020) Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382(9):810–821
Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer J-U et al (2019) A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 30(8):1279–1288
Poggio F, Bruzzone M, Ceppi M, Pondé NF, La Valle G, Del Mastro L et al (2018) Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. Ann Oncol 29(7):1497–1508
Zong Y, Wu J, Shen K (2017) Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: a systematic review and meta-analysis. Oncotarget 8(10):17360–17372
Johnston SRD, Harbeck N, Hegg R, Toi M, Martin M, Shao ZM et al (2020) Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol 38(34):3987–3998
Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H et al (2017) Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(12):1688–1700
Schmid P, Cortes J, Dent R et al (2021) KEYNOTE-522: Phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann Oncol 32(9):1198–1200. https://doi.org/10.1016/j.annonc.2021.06.014
Sparano JA, Gray RJ, Makower DF et al (2018) Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 379:111–121
Piccart M, van t’Veer LJ, Poncet C et al (2021) 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol 22(4):476–488
Kalinsky K, Barlow WE, Gralow JR et al (2021) 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med 385:2336–2347
Acknowledgements
Ivan Tyono (pharmacist), Althea Van Massop (nurse navigator), Shelyna Khalfan (patient).
Funding
Existing academic funds of primary author.
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
Conflicts of Interest
Primary Authors: SG—advisory board (Roche, Novartis, Lilly, Pfizer, Exact Science, and Agendia). External Reviewer: JFB—speaking honoraria (Roche, Novartis, Genomic Health, Pfizer, Allergan and Merck), consultant (Roche), Grants (Roche, Novartis, Pfzier, Abbvie), advisory board (Roche, Genomic Health, Nanostring Technologies, Pfizer, Lilly, Novartis and Merck). None of these COI were deemed impactful on the development or review of specific guideline recommendations.
Ethical approval
Not applicable.
Research involving humans and animal participants
Not applicable.
Informed consent
Not applicable.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Gandhi, S., Brackstone, M., Hong, N.J.L. et al. A Canadian national guideline on the neoadjuvant treatment of invasive breast cancer, including patient assessment, systemic therapy, and local management principles. Breast Cancer Res Treat 193, 1–20 (2022). https://doi.org/10.1007/s10549-022-06522-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-022-06522-6