Triple-negative breast cancer (TNBC), representing 10% to 15% of breast cancer cases, is characterised by the absence of oestrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) amplification or overexpression. It is associated with higher rates of recurrence, metastasis, and worse overall survival (OS) than other subtypes.1 2 Given its high immune infiltration rate, with over 50% tumour-infiltrating lymphocytes in histological samples,3 4 TNBC is amenable to immunomodulation through immunotherapy.

Immunotherapies directed against programmed death receptor 1 (PD-1) or programmed death receptor ligand 1 (PD-L1) have shown promising and positive results in patients with metastatic TNBC (mTNBC), based on the phase III randomised KEYNOTE-355 and IMpassion130 trials.5 6 7 Addition of the anti–PD-1 antibody pembrolizumab to chemotherapy significantly improved progression-free survival and OS by 4.1 months and 6.9 months, respectively, in patients with mTNBC whose tumours expressed PD-L1 (combined positive score [CPS] ≥10).5 6

The effectiveness of neoadjuvant pembrolizumab in combination with neoadjuvant chemotherapy (NAC) was demonstrated in the KEYNOTE-5228 9 and NeoImmunoBoost trials.10 The pathological complete response (pCR) rate significantly increased from 51.2% among patients receiving NAC alone to 64.8% among those receiving pembrolizumab–chemotherapy in the former study, independent of PD-L1 status.8 Event-free survival (EFS) at 36 months also increased from 76.8% to 84.5%.9 Although pembrolizumab demonstrated favourable results in the KEYNOTE-522 study, several important questions regarding patient selection, types and schedules of chemotherapy, and treatment plans for patients with residual disease after surgery remain in real-world practice. Therefore, the Hong Kong Breast Cancer Foundation (HKBCF) convened a multidisciplinary consensus to guide the practical use of pembrolizumab locally.

The results of this consensus were partially presented during the Hong Kong Breast Cancer Symposium in November 2023 and in abstract form at the American Society of Clinical Oncology Annual Meeting 2024.11 Here, we present the full results.

To explore the perioperative use of immunotherapy and provide expert guidance for routine clinical practice in the treatment of early triple-negative breast cancer (eTNBC), the HKBCF established a consensus panel comprising seven breast surgeons, six clinical oncologists, and three medical oncologists, each with at least 15 years of clinical experience.

A modified Delphi panel was conducted on seven topics encompassing 45 statements, covering the workup for TNBC as well as neoadjuvant and adjuvant treatment for eTNBC. Statements relating to surgery were prepared by breast surgeons, whereas statements concerning non-surgical interventions were developed by oncologists. The statements were generated with reference to established guidelines and clinical trials, after a non-systematic search of databases for literature published in English without time restrictions. The levels of evidence and strength of recommendations were determined using a two-level grading system.12

In the first round, votes from 64 practising healthcare professionals in Hong Kong—including surgeons (n=21), clinical oncologists (n=36), and medical oncologists (n=7)—were collected through an online form using a six-point Likert scale: Strongly disagree = 1; Disagree = 2; Slightly disagree = 3; Slightly agree = 4; Agree = 5; Strongly agree = 6. No midpoint or neutral option was provided to encourage definitive responses. Consensus to accept (CTA) was defined as a median score ≥5 with an interquartile range (IQR) ≤1.75. Consensus to reject (CTR) was defined as a median score ≤2 with an IQR ≤1.75. The results, including statements that did not reach consensus, were discussed further by 16 senior panellists, who voted anonymously during a consensus meeting. All panellists were invited to review the manuscript contents to confirm the final statements, as described in later sections. The first-and second-round voting results are summarised in the Table and online supplementary Tables 1 and 2. All voting data were analysed using SPSS (Windows version 28.0; IBM Corp, Armonk [NY], United States) to determine consensus. Recommendations were graded using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system as strong (grade 1) or weak (grade 2); the quality of evidence was classified as high (grade A), moderate (grade B), or low (grade C).12 This manuscript follows the AGREE (Appraisal of Guidelines Research and Evaluation) reporting guideline.

Respondents and panellists agreed that all women with clinical suspicion of breast cancer should be offered mammography, with or without ultrasound, and that imaging should be scored according to the BI-RADS (Breast Imaging Reporting and Data System) by a qualified and experienced radiologist. The definition of TNBC was also highlighted, referring to breast cancer that lacks expression of ER and PR and does not exhibit overexpression of HER2. Two key statements relating to the histopathology of TNBC are presented below:

It was agreed that assessment of ER/PR expression and HER2 overexpression in breast cancer is essential to facilitate treatment planning and should be confirmed before treatment initiation. The panel regarded ER-low–positive (1%-9% ER expression) breast cancer as a biologically distinct subgroup for which treatment consensus has not yet been established, due to the uncertain benefit of endocrine therapy.13 A prospective multicentre registry study of 516 patients conducted between 2011 and 2019 showed that demographic and clinical characteristics, as well as BRCA1/2 mutation status, were comparable between ER-low breast cancer and TNBC.14 The respondents therefore believed that breast cancer exhibiting low ER expression on immunohistochemistry should be treated as TNBC.

The importance of neoadjuvant therapy (NAT) for downstaging non–metastatic TNBC (non-mTNBC) was generally agreed upon by respondents and panellists. Patients with stage II to III disease or node-negative cases with a primary tumour size between 1 and 2 cm should be considered for NAT. Definitive surgery should be performed within 3 to 6 weeks after completion of the final cycle of NAT. Two key statements relating to NAC use for eTNBC are discussed below:

The St Gallen Consensus Conference recommends adding carboplatin to neoadjuvant paclitaxel, followed by anthracyclines and cyclophosphamide, for stage II to III TNBC.15 The National Comprehensive Cancer Network Guidelines state that preoperative systemic therapy is preferred for TNBC patients at clinical stage ≥cT2 or ≥cN1 and can also be considered for cT1cN0.16 The American Society of Clinical Oncology recommends offering an anthracycline- and taxane-containing regimen in the neoadjuvant setting for patients with TNBC at clinical stage cT1cN0M0,17 whereas the European Society for Medical Oncology guidelines suggest NAT for TNBC patients with cT1cN0 disease or greater.18 After reviewing these guidelines, the panellists agreed on the use of NAT for TNBC patients with a clinical tumour size of 1 to 2 cm and no palpable lymph nodes (LNs).

The panellists also noted that, in clinical practice, establishing a multidisciplinary team comprising surgeons and oncologists is essential when developing a treatment plan, particularly for patients who may be eligible for breast conserving surgery (BCS) after NAT. Patient adherence to treatment plans proposed by a multidisciplinary team is reportedly higher, according to a retrospective study conducted in Europe.19

Anthracycline/cyclophosphamide/taxane-based chemotherapy is the standard NAT regimen for stage II to III TNBC.20 In addition to standard chemotherapy, respondents and panellists agreed that other regimens may be considered as clinically indicated or according to patient preferences. The addition of platinum agents and immune checkpoint inhibitors should also be considered, given the improved EFS observed in stage II or III TNBC patients in recent clinical trials.9 21 Based on the results of the KEYNOTE-522 trial, respondents and panellists supported the addition of pembrolizumab to NAT for TNBC, regardless of PD-L1 expression level.8 9 Three key statements concerning the use of pembrolizumab are highlighted below:

Respondents and panellists emphasised the importance of adding carboplatin to backbone chemotherapy in the NAT of TNBC. A meta-analysis and systematic review of platinum-based NAT across 11 randomised controlled trials involving 2946 patients suggested that platinum-based chemotherapy was associated with a higher pCR rate (40%) compared with platinum-free chemotherapy (27%).22 Subgroup analysis showed that taxane plus platinum chemotherapy increased the pCR rate to 44.6% vs 27.8% for platinum-free treatment, supporting the neoadjuvant use of carboplatin plus taxane chemotherapy.22

The phase III KEYNOTE-522 trial demonstrated that preoperative pembrolizumab plus chemotherapy achieved a significantly higher pCR rate (64.8% vs 51.2%; P<0.001) than chemotherapy alone in untreated stage II to III TNBC patients.8 These promising findings were further supported by the trial’s 60-month EFS rates, which were 81.3% and 72.3% in the pembrolizumab and control groups, respectively.23

Patients with cT1a or cT1bN0 TNBC should not be routinely offered NAT outside clinical trials; guidelines suggest a case-by-case approach to NAT for treating cT1cN0M0 disease.16 Although combinations of immune checkpoint inhibitors and chemotherapy have been extensively studied in three phase II and III neoadjuvant trials (KEYNOTE-522,8 IMpassion031,24 and NeoImmunoBoost10), none included cT1cN0 patients. Thus, the panel concluded that there is insufficient evidence to justify extrapolating the addition of immunotherapy to chemotherapy for this patient group.

Panellists were divided on the use of immune checkpoint inhibitors, such as pembrolizumab, in all cT1N0 disease. Some noted that evidence from phase III studies is currently limited, whereas others supported the use of pembrolizumab in cT1N0 disease given its inclusion in the NeoPACT trial.25 Nonetheless, individualised discussions and multidisciplinary team consultations are encouraged for each case before treatment.

Dosing schedules may influence treatment response, safety outcomes, and patient compliance. Respondents and panellists were open to various dosing regimens combining pembrolizumab with platinum and taxane, followed by anthracyclines.6 10 25 Dose-dense anthracycline was not considered an alternative to the 3-weekly schedule when neoadjuvant pembrolizumab is administered. Two key statements on 3-weekly and weekly dosage schedules are highlighted below for further discussion:

The National Health Service London Cancer Alliance recommends administering paclitaxel once every 3 weeks (Q3W) for four cycles in early breast cancer.26 However, the E1199 trial investigated the optimal dosing of docetaxel or paclitaxel after anthracycline plus cyclophosphamide in 4954 patients with axillary LN-positive or high-risk LN-negative breast cancer, including 1025 TNBC patients.27 Although no difference was observed in the primary comparisons of taxane type (docetaxel vs paclitaxel) or schedule (3-weekly vs weekly), a secondary analysis with a 10-year update reported that weekly paclitaxel produced more favourable survival outcomes than the 3-weekly schedule. In TNBC patients, higher 10-year disease-free survival (DFS) and OS were noted with weekly paclitaxel (Q1W) compared with Q3W (69% vs 58.7%; hazard ratio [HR]=0.69; P=0.01 and 75.1% vs 65.6%; HR=0.69; P=0.019, respectively), supporting the adjuvant use of weekly paclitaxel.27 In the recent phase II NeoPACT trial, the neoadjuvant combination of pembrolizumab, carboplatin, and docetaxel Q3W achieved a pCR rate of 58% (95% confidence interval [95% CI]=48%-67%) and a 3-year EFS of 86% for all patients.25 If validated in a phase III randomised study, this combination may represent a future 3-weekly anthracycline-free chemoimmunotherapy option for TNBC patients.25

The efficacy of paclitaxel Q3W remains controversial. Although consensus was not reached, all panellists participating in the discussion preferred weekly paclitaxel (Q1W), considering its long-term data on efficacy, tolerability, and toxicity, as well as its consistency with the KEYNOTE-522 regimen, which utilises weekly paclitaxel in combination with pembrolizumab.8 9 The panellists did not consider paclitaxel Q3W to be an optimal alternative to weekly regimens but agreed that 3-weekly taxane (docetaxel or paclitaxel) regimens may provide a practical treatment schedule for selected patients.

Respondents and panellists agreed that the addition of immunotherapy to chemotherapy improves pCR rates in patients who wish to undergo BCS after NAT. For patients with clinically negative LNs at diagnosis who achieve a complete response after NAT, extensive axillary surgery may be omitted if sentinel LN dissection reveals negative nodes. However, the panellists did not support applying the same approach to patients who had clinically positive LNs at diagnosis.

One statement concerning the option of offering BCS before the initiation of treatment was discussed:

According to the National Comprehensive Cancer Network Guidelines,16 early-stage (≤cT1cN0) operable breast cancer patients may undergo upfront BCS or mastectomy with adjuvant systemic therapy where indicated, whereas patients with clinical stage ≥cT2 or ≥cN disease should be treated with NAT. The European Society for Medical Oncology guidelines state that BCS is the preferred local treatment option for most early breast cancer patients, but aggressive phenotypes such as eTNBC should receive NAT first28; BCS should only be offered when the response to NAT is satisfactory.28 The 17th St Gallen International Guidelines also recommend dose-dense anthracycline- and taxane-based NAT for stage II or III eTNBC but do not comment on stage I disease.29

The panellists declined to endorse the statement, noting that NAT is a treatment option for eTNBC patients but not a prerequisite for BCS in stage I or II disease. However, it is noteworthy that in-breast recurrences represent 5% to 15% of all recurrence events in early-stage breast cancer under contemporary BCS and RT management.30 31 Recurrence rates have continued to improve with advances in therapy. In a recent meta-analysis of 14 studies involving 19 819 TNBC patients who underwent BCS (plus radiotherapy) or mastectomy, the pooled odds ratio for locoregional recurrence was 0.64 (95% CI=0.48-0.85; P=0.002), the pooled odds ratio for distant metastasis was 0.70 (95% CI=0.53-0.94; P=0.02), and the pooled HR for all-cause mortality was 0.78 (95% CI=0.69-0.89; P<0.001) among patients who underwent BCS relative to mastectomy.32 Another retrospective study of 12 761 patients with T1-2N0M0 TNBC also revealed significantly higher 5-year OS (89% vs 84.5%; P<0.001) and breast cancer–specific survival (93% vs 91%; P<0.001) in patients receiving BCS and radiotherapy compared with those undergoing mastectomy alone.33 Both meta-analyses did not report outcome differences between adjuvant therapy with upfront BCS and NAT followed by BCS in eTNBC. Given these encouraging data, the panellists regarded the statement as unclear but raised no objection to recommending upfront BCS for selected patients with ≤cT1cN0 eTNBC. Risk factors, including age, tumour grade, and disease stage, should be considered when offering this treatment option.

For patients with residual disease after neoadjuvant pembrolizumab plus chemotherapy, adding capecitabine to adjuvant pembrolizumab was considered acceptable. However, consensus was not reached among panellists regarding the combined use of a poly (ADP-ribose) polymerase inhibitor and pembrolizumab in the adjuvant setting for patients with residual disease and a known germline BRCA1/2 mutation (gBRCA1/2m), due to variations in local testing practices for gBRCA1/2m. Discussions of scenarios that may benefit from the adjuvant use of pembrolizumab are summarised in the two statements below:

According to the KEYNOTE-522 trial, patients receiving perioperative pembrolizumab and NAC demonstrated better EFS than those treated with NAC alone (84.5% vs 76.8%, HR=0.63; 95% CI=0.48-0.82) at a median follow-up of 39.1 months.9 Further EFS analysis based on pCR outcomes showed that patients who did not achieve pCR also benefited from the KEYNOTE-522 regimen (67.4% vs 56.8%, HR=0.7; 95% CI=0.52-0.95).9 The panellists agreed that for patients who did not achieve pCR after neoadjuvant pembrolizumab plus chemotherapy, adjuvant pembrolizumab—or pembrolizumab combined with capecitabine—should be administered.

Based on the CREATE-X (Capecitabine for Residual Cancer as Adjuvant Therapy)34 and EA1131 trials,35 patients without a pCR after NAT may benefit from adjuvant capecitabine. The phase III CREATE-X study enrolled 910 HER2-negative breast cancer patients with residual disease after NAT containing anthracycline, taxane, or both. Those who received standard treatment with capecitabine demonstrated better long-term survival outcomes than the control (capecitabine-free) group. Among 286 patients with residual TNBC, those receiving adjuvant capecitabine achieved higher DFS (69.8% vs 56.1%; HR=0.58; 95% CI=0.39-0.87) and OS (78.8% vs 70.3%; HR=0.52; 95% CI=0.30-0.90) than those in the control group at 5 years.34 Another phase III EA1131 study of 410 patients with residual TNBC after NAT also showed better 3-year invasive DFS among those receiving adjuvant capecitabine (49.4%; 95% CI=39.0%-59.0%) than among those receiving adjuvant platinum (42.0%; 95% CI=30.5%-53.1%), although the difference was not statistically significant.35

Despite the lack of mature data regarding the adjuvant use of capecitabine in combination with pembrolizumab, the KEYNOTE-522 study demonstrated the additional benefit of perioperative pembrolizumab with NAC without increasing chemotherapy-related adverse effects in the neoadjuvant setting.8 9 The panellists considered that adding capecitabine to pembrolizumab in patients without pCR after NAT plus pembrolizumab represents a clinically feasible option to improve long-term survival outcomes in cases where residual disease is observed after pembrolizumab-based NAT. They noted that the combination of pembrolizumab and capecitabine has been reported to be safe and tolerable in mTNBC.36 However, further prospective studies are required to determine the long-term survival and safety benefits, as well as the optimal dosing schedule, in eTNBC. The panellists ultimately reached a consensus to accept this statement, adding that adjuvant capecitabine with pembrolizumab may be considered on a case-by-case basis.

Respondents and panellists reached consensus on all statements relating to treatment toxicities without requiring further discussion in the second round. In summary, for patients receiving immunotherapy plus chemotherapy, clinicians should monitor for potential immunotherapy-related adverse events, which are generally mild in most patients but may be life-threatening in some cases. Thyroid function should be proactively monitored, given that reversible destructive thyroiditis and overt hypothyroidism commonly occur in patients receiving pembrolizumab.37

The development of these consensus statements on the management of eTNBC involved a multidisciplinary panel of oncologists and breast surgeons from public, private, and academic institutions, providing a comprehensive overview of clinical practice in Hong Kong. These statements offer guidance to clinicians regarding the general work-up, treatment, and use of immunotherapy for TNBC patients who do not fit the patient profile enrolled in the KEYNOTE-522 study.

Concept or design: PSY Cheung, W Yeo.
Acquisition of data: All authors.
Analysis or interpretation of data: PSY Cheung, W Yeo.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: PSY Cheung, W Yeo, YHY Chan, RCY Leung.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

CC Yau received speaker’s honoraria from Novartis and Eli Lilly. AKC Leung is the Second Vice President of the Hong Kong Breast Oncology Group. All other authors have disclosed no conflicts of interest.

The authors acknowledge and thank all breast surgeons, clinical oncologists, and medical oncologists in Hong Kong who supported this consensus by voting during the first round of the Delphi methodology.

The consensus statement results were presented at The Chinese University of Hong Kong Breast Cancer Meeting (28-29 October 2023, Hong Kong) and as a poster presentation at the American Society of Clinical Oncology Annual Meeting 2024 (31 May to 4 June 2024, Chicago, United States).

The study was funded by the Hong Kong Breast Cancer Foundation Limited with the support of Merck Sharp and Dohme (Asia) Limited. Medical writing support was provided by MediPaper Medical Communications Limited. The funders had no role in the study design, data collection/analysis/interpretation, or manuscript preparation.

The supplementary material was provided by the authors and some information may not have been peer reviewed. Accepted supplementary material will be published as submitted by the authors, without any editing or formatting. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by the Hong Kong Academy of Medicine and the Hong Kong Medical Association. The Hong Kong Academy of Medicine and the Hong Kong Medical Association disclaim all liability and responsibility arising from any reliance placed on the content.

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