Management of early-stage triple-negative breast cancer: recommendations of a panel of experts from the Brazilian Society of Mastology

Abstract

Background

Triple-negative breast cancer (TNBC) is a heterogenous subtype involving different patterns of behavior and clinical course, demanding a complex, individualized sequence of treatment. The knowledge and attitudes of the affiliated members of the Brazilian Society of Mastology regarding TNBC were evaluated and a consensus regarding management and treatment was reached.

Methods

Affiliates completed a survey involving 44 objective questions. In addition, a specialist meeting was held with 27 experts and 3 ad hoc consultants. The panelists completed the survey before and after brainstorming. Answers achieving 70% of agreement were considered consensual. The chi-square test was used to compare answers between panelists and affiliates and the Kappa coefficient to calculate agreement.

Results

Consensus among the panelists increased from 26 (59.1%) to 32 questions (72.7%) following brainstorming (p = 0.17), including 7/10 questions on systemic treatment. Among the affiliates, consensus was achieved for 24 questions (54.5%), resulting in moderate agreement (κ = 0.445). Neoadjuvant chemotherapy should be indicated for almost all cases (except cT1a-b N0) and should include platinum agents. When indicated, immunotherapy is part of the standard of care. The panel reaffirmed the concept of no ink on tumor as indicative of adequate margins and the possibility of sentinel lymph node biopsy for cN1 patients who become cN0 following neoadjuvant therapy. Controversies remain on combining immunotherapy with capecitabine/olaparib in pertinent cases.

Conclusion

Expert consensus was achieved for > 70% of the questions, with moderate agreement between panelists and affiliates. Educational interventions on systemic breast cancer treatment affected decision-making in 60% of the questions.

Introduction

Triple-negative breast cancer (TNBC) is immunohistochemically defined as lacking expression of estrogen and progesterone receptors (ER, PR) and absence of over-expression of human epidermal growth factor receptor 2 (HER-2), and represents 10-20% of all cases of the disease [1, 2]. This heterogenous subtype involves different behaviors and clinical courses resulting from different profiles of gene expression and molecular biology [3, 4]. Specific medical knowledge is critical for adequate diagnosis, management and treatment of TNBC.

TNBC treatment has become progressively more complex and individualized [5]. In neoadjuvant therapy (NAT), combining pembrolizumab and chemotherapy improved pathologic complete response (pCR) and event-free survival (EFS), modifying clinical practice [6, 7]. Likewise, platinum agents [8] and poly adenosine diphosphate-ribose polymerase (PARP) inhibitors have been used in women with germline mutations in the BRCA1 and BRCA2 genes [9]. Controversies remain regarding clipping of axillary lymph nodes, sentinel lymph node biopsy (SLNB) following neoadjuvant chemotherapy (NAC), staging and initial disease management [5, 10, 11].

The Brazilian Society of Mastology (SBM) provides updated information and continued education to its affiliates [12] with a view to reducing breast cancer-related morbidity and mortality in the country [13, 14]. Nevertheless, the knowledge and attitudes of this Brazilian medical population may still reflect those of low-and-middle-income countries.

This study evaluated the knowledge and attitudes of SBM members regarding TNBC and drew up consensus guidelines on the diagnosis, management and treatment of the disease.

Methods

An email survey (December 2021 to January 2022) was sent to all 1400 active SBM members. All fully completed questionnaires were included in the analysis.

The 44-item questionnaire on the management and treatment of TNBC was developed using SurveyMonkey. Each question had three/four alternative answers, 28/44 being on a Likert-type scale. The American Association for Public Opinion Research recommendations were followed [15].

The demographic data surveyed included: the respondent’s sex; board-certification as a specialist in breast disease (yes/no), the geographical region of residence/work; and whether the respondent worked in an academic institute. Questions on TNBC diagnosis and locoregional treatment involved immunohistochemistry, staging, clipping of axillary lymph nodes, axillary management and post-mastectomy radiotherapy. Questions on systemic treatment focused particularly on NAT and immunotherapy. For standardization purposes, the questions considered patients with tumors over 1.0 cm in diameter, in good general health and with a life expectancy > 10 years.

A meeting of 27 experts was held on December 3, 2021 during a Breast Cancer Congress in Gramado, RS, Brazil, which also included 3 ad hoc consultants from the Brazilian Societies of Clinical Oncology, Pathology, and Radiotherapy, respectively. Only the breast surgeons, however, were allowed to vote.

The panelists answered the questions in the survey according to the Delphi method [16]. The answers reaching 70% of agreement were considered consensual. The questions for which no consensus was reached were then discussed based on a literature review (brainstorming session). Subsequently, a further round of voting was held for the 44 questions. Double consensus was defined as when agreement was > 70% in the first round of responses from the panelists and in the independent voting by the affiliates.

Ethical issues

The SBM review board approved the study protocol. Returning a completed questionnaire implied agreement to participate in the study and the consent to publish was obtained from all participants. The study procedures were conducted in compliance with current Brazilian legislation and the 1964 Helsinki Convention.

Statistical analysis

SPSS, version 26.0 (IBM Corporation, Armonk, NY) was used throughout the analysis. Answers were described as absolute (n) or relative frequencies (%). Pearson’s chi-square test was used to compare the answers given by the panelists before and after brainstorming, and to compare the initial panel answers with those given by the affiliates. A post hoc analysis was performed whenever pertinent [17]. Significance was set at p < 0.05.

The kappa coefficient was used to calculate agreement between the panelists and the affiliates. Agreement was defined as poor (κ < 0.00), slight (0.0 ≤ κ ≤ 0.2), fair (0.21 ≤ κ ≤ 0.4), moderate (0.41 ≤ κ ≤ 0.6), substantial (0.61 ≤ κ ≤ 0.8) or almost perfect (0.81 ≤ κ ≤ 1.0) [18].

Results

Mean age of the panelists was 51.7 ± 9.7 years. Most (81.5%) were male, 44.4% lived/worked in the southeast of the country, 96.3% lived in state capital cities and 92.6% were associated with academic institutions. The mean age of the 214 affiliates who completed the survey was 46.1 years (p = 0.05), 50.9% were female (p = 0.01) and 29.4% did not live in state capital cities (Additional file 1: Table S1).

Among the panelists, consensus was achieved for 26 questions (59.1%), increasing to 32 questions (72.7%) after brainstorming (p = 0.17) (κ = 0.465) (Additional file 1: Table S2, Additional file 2: Table S2, Additional file 3: Table S3, Additional file 4: Table S4). Disagreement was > 90% for three items in the survey: i) radiological evaluation of flap thickness following nipple-sparing mastectomy (NSM); ii) bilateral mastectomy for patients with the wild-type BRCA; and iii) radiotherapy following mastectomy in stage T1N0.

Among the affiliates, consensus was achieved for 24 questions (54.5%) (Additional file 5: Table S5). There was moderate agreement (κ = 0.445) and no significant difference (p = 0.661) in relation to the panelists prior to brainstorming. Tables 1, 2, 3 and 4 describe the agreement between panelists and affiliates, with differences being significant for nine questions (five related to systemic treatment) (Table 5).

Table 1 Agreement between the panelists and the SBM affiliated breast surgeons for the questions associated with diagnosis

Table 2 Agreement between the panelists and the SBM affiliated breast surgeons for the questions related to surgical treatment

Table 3 Agreement between the panelists and the SBM affiliated breast surgeons for the questions related to radiotherapy

Table 4 Agreement between the panelists and the SBM affiliated breast surgeons for the questions related to systemic treatment

Table 5 The nine questions for which the proportion of answers differed significantly between the panelists and the SBM affiliated breast surgeons

The panelists’ answers before and after brainstorming are shown in Additional file 6: Tables S6.1–S6.4. Consensus was achieved or modified following brainstorming for 7/10 questions on systemic treatment (Table 6) and for one question related to surgical treatment. Additional file 7: Tables S7.1–S7.4 describe the degree of consensus between panelists and affiliates. Finally, the main consensus recommendations are summarized in Tables 7 and 8, and the main controversies in Table 9.

Table 6 Responses of the panelists before and after brainstorming for the questions for which there was change in consensus

Table 7 Summary of main recommendations and how can practice change if they are applied

Table 8 Summary of main recommendations and how can practice change if they are applied

Table 9 Main remaining points of controversy and what additional data is needed to clarify them

Discussion and consensus

Participants

The panelists were nationally recognized experts in TNBC treatment. Most lived in major cities and worked in academic institutions. The current transition in the profile of Brazilian breast surgeons from being predominantly male in the past, as reflected in the panelists, to a female majority now, as reflected in the affiliates, may explain the gender differences between these two groups. The poor response rate found (15.5% of the affiliates) may be due to the questionnaire’s length and its items unrelated to surgery, as well as to the high number of SBM surveys performed recently.

We considered the sampling as a limitation of our study. However, we were satisfied with 15.5% response from affiliates because their answers enriched the debate together with the panelist experts. We consider that the Brazilian surgeons are initiating the participations in surveys [13, 14]. We also need to encourage breast surgeons to discuss unclear breast cancer management topics through surveys and discussions, educational events and production of national guidelines.

Pathology

In HER2-negative tumors, low-ER immunohistochemical expression (1-10%) still provokes controversy regarding diagnosis and treatment. Although representing < 5% of hormone-receptor-positive tumors, prognosis is poorer and the tumor often behaves similarly to TNBC [19]. Likewise, no consensus was reached regarding the treatment of ER+/HER2- tumors with a gene signature suggestive of the basal-like subtype. This concept became particularly important since no benefit in progression-free survival was found with the addition of ribociclib to standard endocrine therapy for patients with the basal-like Prediction Analysis of Microarray 50-gene set (PAM50) subtypes [20]. Nevertheless, due to the small sample size (n = 30) and the retrospective design of that analysis, further studies are required.

There was consensus regarding the need for further immunohistochemistry following NAT in cases of residual disease. Indeed, results can differ in relation to the percutaneous biopsy material in up to 5% of cases [21, 22]; therefore, confirming findings may significantly change the patient’s treatment and prognosis.

Diagnostic tests

Panelists and affiliates disagreed regarding axillary ultrasonography at the time of diagnosis. Although helpful in defining the need for adjuvant radiotherapy, this may have increased axillary lymph node dissection (ALND) rather than SLNB [23]. The panelists suggested individualizing axillary ultrasonography according to the potential for a change in treatment. Avoiding magnetic resonance imaging (MRI) was a double consensus. During brainstorming, MRI was prioritized in the context of NAT or when surgical planning remains uncertain.

Nineteen panelists (70.4%) initially agreed on requesting genetic testing for all TNBC cases. Following brainstorming, this number fell to 17 (63.0%). Although some international guidelines have already recommended the test irrespective of age [24], the Brazilian Supplementary Health Agency still restricts it to patients ≤60 years of age [25]. While 48.1% of affiliates would perform systemic staging in all asymptomatic women, 48.1% of panelists prioritized investigation from anatomic stage II onwards.

Nat

There was consensus regarding NAT for patients with clinically positive axilla, with agreement reaching 100.0% among the panelists. For patients with disease-free axilla, both the panelists (63.0%) and the affiliates (54.2%) recommended 1.0 cm as the cut-off tumor size for indicating NAT (no consensus).

In patients scheduled to undergo NAT and breast-conserving surgery (BCS), there was double consensus concerning clipping of the tumor or implantation of a radioactive iodine seed. If these techniques are unavailable, pigmentation of the skin over the tumor is also a viable option as indicated by > 20% of the affiliates. In fact, the absence of any marking on the tumor bed may prove detrimental for later surgical localization and could increase local recurrence rates [26]. Most panelists (70.4%) disagreed with the need for marking the axillary lymph node prior to NAT.

Following NAT, > 95.0% of the affiliates would request imaging tests to evaluate tumor response. However, the combination of mammography and MRI was indicated by 48.1% of the panelists and 60.3% of the affiliates (no consensus). Despite its poorer accuracy, ultrasonography can also be useful if MRI is unavailable [27]. If the disease had progressed, around 60.0% of the affiliates would also indicate further systemic staging.

Axillary surgery

Radiotherapy for locoregional control was indicated for patients undergoing upfront surgery who had a positive SLNB (double consensus). However, despite evidence in the literature [13, 28, 29], four panelists (14.8%) and 22% of the affiliates would still indicate ALND for patients with early disease and positive SLNB. If mastectomy were required, 40.2% of affiliates would recommend ALND. Likewise, in another SBM survey, 26% of respondents failed to apply the results of the ACOSOG Z0011 study to women with TNBC, particularly breast surgeons > 50 years of age, those not associated with academic institutions, and not board-certified [13].

ALND was indicated for patients undergoing BCS who had positive SLNB after NAT (double consensus). There was no consensus regarding ALND for SLNB-negative patients with initially positive axilla (without marking) and complete clinical response following NAT. Most affiliates would avoid ALND, while 30.0% would recommend it if < 3 lymph nodes were identified at SLNB. This difference corroborates another survey in which 63.7% of Brazilian surgeons would not take molecular profiling into consideration when defining axillary management following NAT [14].

Breast surgery

In women with TNBC and no pathogenic mutations, 100% of the panelists would avoid the unrestricted indication of bilateral mastectomy. When asked about the possible indications for a bilateral approach, there was also a double consensus for “under no circumstances”. Nevertheless, around 70% of the affiliates take family history into consideration when discussing the possibility of a bilateral mastectomy.

In cases of high penetrance germline mutations, almost 100% of the affiliates would consider bilateral mastectomy. For 48.1% of the panelists, bilateral mastectomy should be considered in women ≤60 years of age. Indeed, not only age, but also the affected gene, family history, staging of the disease, safety profile and possibilities of breast reconstruction should be taken into consideration [30, 31]. If indicated, 100.0% of the panelists would use NSM, while < 40% of the respondents would consider BCS.

In cases of patients with TNBC undergoing upfront BCS, 96.8% of the panelists and 83.2% of the affiliates considered “no ink on tumor” as being indicative of adequate surgical margins, as previously recommended [32]. The same definition of adequate margins was maintained for BCS following NAT (double consensus).

Radiotherapy

Affiliates would avoid radiotherapy following mastectomy in patients with T1N0 and T2N0 staging. Among the panelists, however, consensus was only reached following brainstorming (T2N0 from 66.7 to 77.8%). However, 100% of the panelists would indicate adjuvant radiotherapy for T1-2 N1-3 staging, even following NAT and pCR, and for T3N0 patients undergoing mastectomy (double consensus).

According to 92.6% of the panelists, evaluation of flap thickness using imaging methods should be avoided in women with T1-2 N0 tumors submitted to mastectomy. Although some studies have shown a greater amount of terminal duct lobular units and residual disease in flaps > 5.0 mm in thickness [33], no impact was detected on recurrence rates or overall survival rates [34]. Therefore, the consensus was that MRI evaluation of the mastectomy flap should be restricted to situations in which there is some doubt regarding the surgical technique performed.

Systemic therapy

Most of the affiliates recommended the addition of platinum agents to NAT regimens, irrespective of the presence of germline BRCA mutations. Consensus was only achieved among the panelists following brainstorming. The BrighTNess study detected an increase in the rates of pCR and EFS with the addition of carboplatin to the standard regimen of anthracycline and taxane [35], with the gain in pCR occurring irrespective of BRCA status [36].

Adding immune checkpoint inhibitors to NAT was recommended by 51.9% of the panelists and by only 30.4% of the affiliates. Nevertheless, consensus was reached among the panelists (81.5%) following discussion on the KEYNOTE-522 study (four cycles of anthracycline-based chemotherapy in a conventional 21-day regimen) [6, 7]. Nevertheless, around 75% of the affiliates recommended that anthracyclines be used in a dose-dense regimen when combining NAC and immunotherapy (double consensus). Following brainstorming, agreement was reversed towards the safety protocol [6, 7].

The presence of germline BRCA mutations did not affect the recommendation of NAT with immunotherapy (double consensus). On the other hand, 70.6% of the affiliates considered PD-L1 status to be an indication for neoadjuvant immunotherapy. Among the panelists, this line of thought decreased from 48.1 to 18.1% following discussion, since an increase in the pCR rate was found with the addition of pembrolizumab to NAC, irrespective of PD-L1 expression [6].

Continuing immunotherapy during adjuvant treatment remains controversial [11]. It was recommended that immunotherapy initiated at NAT be continued when there is residual disease (double consensus). However, with pCR, only 45.8% of the affiliates recommended maintaining immunotherapy. The percentage of panelists who agreed with this recommendation increased from 59.3 to 88.9% following brainstorming [6, 7].

For patients with wild-type BRCA who had received NAT with immunotherapy and failed to achieve pCR, most affiliates suggested maintaining immunotherapy plus capecitabine. Among the panelists, there was no consensus (51.9% of agreement). This combination of adjuvant therapy has yet to be evaluated in phase III prospective studies, although its safety profile is acceptable in cases of metastatic disease [37]. Conversely, most affiliates disagreed with the adjuvant combination of olaparib and immunotherapy for women with the BRCA mutation who achieved pCR following NAT. Despite the reported benefit in disease-free survival with the use of adjuvant olaparib in patients with TNBC and the BRCA mutation [9], the combination of iPARP and immunotherapy has yet to be tested as adjuvant therapy.

Conclusion

Consensus was reached among the experts for > 70% of the questions and agreement between the panelists and the affiliates was moderate. Neoadjuvant chemotherapy should be indicated for almost all cases (except cT1a-b N0) and should include platinum agents. When indicated, immunotherapy is part of the standard of care. The panel reaffirmed the concept of “no ink on tumor” as being indicative of adequate margins as well as the possibility of SLNB in cN1 patients who progressed to cN0 following NAT. Nevertheless, one in five of the affiliates still recommended ALND in patients eligible for the ACOZOG Z0011 study. Regarding adjuvant therapy, further prospective studies need to be performed to assess the efficacy and safety of the combination of immunotherapy and capecitabine/olaparib in pertinent cases. Educational interventions affected the panelists’ decision-making in 60% of the questions on systemic treatment, highlighting the relevance of continued education.