Abstract
The continuous availability of findings from new studies repeatedly results in updated treatment recommendations and guidelines. In the case of breast carcinoma in particular, several studies have been published in the last few years that have transformed how early and advanced breast carcinoma is being treated. However, this by no means means implies that there is agreement among all experts on specific issues. It is precisely the diversity of interpretation of guidelines and study findings that reflects the constantly changing available data and its complexity, as well as the availability of new drugs. In recent years, new substances such as pertuzumab, T-DM1, neratinib and capecitabine have become available to treat patients with early stages of breast carcinoma. Furthermore, the first results on the use of CDK4/6 inhibitors for adjuvant treatment have now been published. Last but not least, the use of multigene tests to avoid the necessity of chemotherapy in certain patients is still under discussion. This review summarises the state of the data and publishes the results of the survey completed by experts at the 2021 St. Gallen Breast Cancer Conference on early-stage breast cancer.
Key words: early breast cancer, therapy decisions, expert panel
Introduction
Every two years, following a multi-day conference in Vienna (formerly in St. Gallen), international experts complete a survey on current issues in clinical practice. The aim is to establish a snapshot of current opinion on national and international guidelines among an international panel of experts. The members of this yearʼs panel are listed in Table 1 . The questions were generally formulated in such a way as to apply to approximately 80% of typical female patients with the corresponding characteristics. It was explicitly stated that in all scenarios exceptions exist and that the questions should be answered with the most common 80% of concrete case studies in mind. The responses from this yearʼs St. Gallen Meeting are listed in Supplementary Table S1 . This review aims to present the current scientific background to selected sections of the survey.
Table 1 Members of the 2021 St. Gallen Expert Panel.
| Last name, first name, institute, country |
|---|
| Aebi Stefan, Tumorzentrum LUKS, Luzerner Kantonsspital, Lucerne, Switzerland |
| André Fabrice, Institut de Cancérologie Gustave Roussy, Villejuif, France |
| Barrios Carlos, Centro de Pesquisa em Oncologia, Hospital São Lucas, PUCRS, Porto Alegre, Brazil |
| Bergh Jonas, Karolinska Institutet and University Hospital, Stockholm, Sweden |
| Bonnefoi Herve, University of Bordeaux 2, Bordeaux, France |
| Bretel Morales Denisse, Oncosalud, Lima, Peru |
| Brucker Sara, Universitäts-Frauenklinik Tübingen, Tübingen, Germany |
| Burstein Harold, Dana-Farber Cancer Institute, Boston, United States |
| Cameron David, The University of Edinburgh, Edinburgh, United Kingdom |
| Cardoso Fatima, Champalimaud Cancer Center, Lisbon, Portugal |
| Carey Lisa, UNC – Lineberger Comprehensive Cancer Center, Chapel Hill, United States |
| Chua Boon, Prince of Wales Hospital, Randwick, Australia |
| Ciruelos Eva, University Hospital 12 de Octubre, Madrid, Spain |
| Colleoni Marco, European Institute of Oncology, Milano, Italy |
| Curigliano Giuseppe, European Institute of Oncology, Milano, Italy |
| Delaloge Suzette, Institut de Cancérologie Gustave Roussy, Villejuif, France |
| Denkert Carsten, Institute of Pathology, Charité – Universitätsmedizin Berlin, Berlin, Germany |
| Dubsky Peter, Brustzentrum Hirslanden Klinik St. Anna, Lucerne, Switzerland |
| Ejlertsen Bent, DBCG Secretariat and Dept. of Oncology, Rigshospitalet, Copenhagen, Denmark |
| Fitzal Florian, Medical University Vienna, Vienna, Austria |
| Francis Prudence, Peter McCallum Cancer Centre, Melbourne, Australia |
| Galimberti Viviana, European Institute of Oncology, Milano, Italy |
| Gamal Heba, National Cancer Institute, Cairo, Egypt |
| Garber Judy, Dana-Farber Cancer Institute, Boston, United States |
| Gnant Michael, Medical University Vienna, Vienna, Austria |
| Gradishar William, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, United States |
| Gulluoglu Bahadir, Marmara University School Of Medicine, Istanbul, Turkey |
| Harbeck Nadia, Frauenkliniken Maistrasse-Innenstadt und Großhadern, Munich, Germany |
| Huang Chiun-Sheng, National Taiwan University Hospital, Taipei, Taiwan |
| Huober Jens, Kantonsspital St. Gallen, St. Gallen, Switzerland |
| Ilbawi Andre, WHO Cancer Control Program, Switzerland |
| Jiang Zefei, 307 Hospital No. 8, Beijing, China |
| Johnston Steven, Royal Marsden Hospital, London, United Kingdom |
| Lee Eun Sook, National Cancer Center, Goyang-si, Korea |
| Loibl Sibylle, GBG Forschungs GmbH, Neu-Isenburg, Germany |
| Morrow Monica, Memorial Sloan-Kettering Cancer Center, New York, United States |
| Partridge Ann, Dana-Farber Cancer Institute, Boston, United States |
| Piccart Martine, Institut Jules Bordet, Brussels, Belgium |
| Poortmans Philip, Iridium Kankernetwerk & University of Antwerp, Antwerp, Belgium |
| Prat Aleix, Hospital Clinic of Barcelona, Barcelona, Spain |
| Regan Meredith, Dana-Farber Cancer Institute, Boston, United States |
| Rubio Isabella, Clinica Universidad de Navarra, Madrid, Spain |
| Rugo Hope, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States |
| Rutgers Emiel, Netherlands Cancer Institute, Amsterdam, Netherlands |
| Sedlmayer Felix, Paracelsus Medical University, Salzburg, Austria |
| Semiglazov Vladimir, N. N.Petrov Research Institute of Oncology, St. Petersburg, Russian Federation |
| Shao Zhiming, Fudan University Cancer Hospital, Shanghai, China |
| Spanic Tanja, Europa Donna, Ljubljana, Slovenia |
| Tesarova Petra, Charles University Hospital and 1st medical faculty, Prague, Czech Republic |
| Thürlimann Beat, Kantonsspital St. Gallen, St. Gallen, Switzerland |
| Tjulandin Sergei, N. N. Blokhin Cancer Research Center, Moscow, Russian Federation |
| Toi Masakazu, Graduate School of Medicine Kyoto University, Kyoto City, Japan |
| Trudeau Maureen, University of Toronto, Toronto, Canada |
| Turner Nicholas, The Royal Marsden Hospital, London, United Kingdom |
| Vaz Luis Ines, Institut de Cancérologie Gustave Roussy, Villejuif, France |
| Viale Giuseppe, Istituto Europeo di Oncologia, Milano, Italy |
| Watanabe Toru, Hamamatsu Oncology Center, Hamamatsu, Japan |
| Weber Walter, Klinik für Allgemeinchirurgie, Universitätsspital Basel, Basel, Switzerland |
| Winer Eric P., Dana-Farber Cancer Institute, Boston, United States |
| Xu Binghe, National Cancer Center, Beijing, China |
Breast Cancer Risk and Genetics
One topic that is typically discussed by this international panel of experts is the risk of developing the disease and the associated genetic tests and preventive measures. Only recently, two ground-breaking papers were published describing the lifetime risk associated with “panel genes” 1 , 2 . The publications confirmed that ATM, BRCA1, BRCA2, CHEK2 and PALB2 constitute risk genes. BRCA1, BRCA2 and PALB2 were also considered to be high-penetrance risk genes.
The SG-EBC Expert Panel did not advocate general testing of all breast cancer patients, despite the fact that almost a quarter of the experts were in favour of either offering panel testing to all breast cancer patients under 65 years of age or to all breast cancer patients regardless of age (Supplementary Table S1 , question 1). Recent research suggests that approximately 5 – 10% of all breast cancer cases involve a mutation in one of the known risk genes 1 , 2 , 3 , 4 , 5 .
While clear clinical recommendations for preventive measures have been established in the case of BRCA1 and BRCA2 6 , no data are yet available for PALB2 . Even though the described cumulative risk of disease associated with a confirmed PALB2 mutation is approximately 40% (similar to a BRCA2 mutation) 1 , it is unclear whether the measures employed in the case of a BRCA2 mutation are equally safe and effective in patients with a confirmed PALB2 mutation. Only (exactly) 50% of the panellists agreed with this assessment with regard to prophylactic mastectomy (Supplementary Table S1 , question 3).
The PARP inhibitors olaparib and talazoparib have already been approved for advanced breast cancer patients with germline mutations in BRCA1/2 7 , 8 . In a press release dated 17 February 2021, it was announced that the OlympiA trial had achieved its primary endpoint and that the findings of the study were positive 9 . Fifty per cent of the SG-EBC Expert Panel were in favour of testing in a scenario analogous to that of the OlympiA study (Supplementary Table S1 , question 4). If therapy with PARP inhibitors becomes standard in adjuvant scenarios this will result in a significant increase in testing, and additional testing capacity will need to be created.
The risk associated with the various risk genes has now been relatively well established (high penetrance vs. medium penetrance vs. low penetrance). This raises the question of how measures such as prophylactic surgery or intensified early detection should be implemented for the various risk groups. The responses of the panellists are summarised in Fig. 1 and Supplementary Table S1 , questions 5 – 10.
Fig. 1.
Recommended procedures (prophylactic or MRI-based screening) for healthy women with mutations in various risk genes.
Ductal Carcinoma in Situ
The 2021 St. Gallen Consensus Conference survey involved only a small number of questions on DCIS, most of which related to radiation therapy. Most panellists did not agree that boost radiation should be routinely given to all patients with DCIS. However, a significant number were in favour of giving a boost in high-risk (larger DCIS lesions, close margins, presence of comedonecrosis) cases (Supplementary Table S1 , questions 93 – 96). The merits of administering boost radiation therapy for DCIS need to be carefully weighed up. Improvements in local control are offset by the fact that giving a boost is detrimental to cosmetic outcomes and arm and shoulder functionality 10 , 11 .
There was, likewise, broad unanimity in the SG-EBC Expert Panel on the issue as to whether older patients and those with a lower risk of recurrence should undergo radiation therapy. The interesting finding here is that the panellists also considered a low biological or genomic risk, as established by a multigene assay, to be an indicator for not performing radiation therapy (Supplementary Table S1 ; questions 106 – 111). An analysis published this year likewise finds that the use of multigene assays is increasing and that this is reducing the number of patients at a low genomic risk undergoing radiotherapy for DCIS 12 , even if this finding has not yet been established in a prospective study. Interestingly, a majority of panellists rejected the use of multigene signatures for the various radiation therapy scenarios to treat invasive carcinoma (Supplementary Table S1 , questions 65 – 67).
The issue of hypofractionation in DCIS was not addressed in the 2021 St. Gallen survey. This is surprising, since up-to-date data on this issue have recently been published, and this is a highly relevant topic in clinical practice. In recently reported studies, moderate hypofractionation with a total treatment duration of three weeks yielded comparable results to conventional fractionation 11 , 13 .
DCIS and Endocrine Therapy
Asked whether endocrine therapy should be given to prevent DCIS recurrence and avoid radiation therapy, the response of the panellists was mixed. Only 16% responded that they would forego endocrine therapy altogether if radiation therapy was administered. The remaining panellists indicated that they would prescribe tamoxifen (5 or 20 mg) or an aromatase inhibitor. This is surprising, because to date no study investigating endocrine therapy as an alternative to radiation therapy has been published. Furthermore, no study on endocrine therapy in DCIS has yet demonstrated a survival benefit 14 , 15 , and the German Gynaecological Oncology Group (AGO), therefore, currently considers such treatment to be merely an option rather than a necessity (+/−).
Adjuvant radiation therapy
A majority of the St. Gallen panel generally considered moderate hypofractionation consisting of 15 – 16 doses over three weeks to be the standard of care for adjuvant radiation therapy for breast cancer (59%); this was true for breast-conserving therapy (72%) as well as for irradiation of the thoracic wall (90%) and of the regional lymphatic nodes (76%) following mastectomy (Supplementary Table S1 , questions 60 and 97 – 99). Last year, the first data from the FAST and FAST-Forward trials on ultra-hypofractionated whole-breast irradiation given in 5 doses over 5 weeks or 1 week were published 16 , 17 . Less than 10% of the St. Gallen panel considered this to constitute a recommended regimen, a view reflected by the AGO grade of recommendation (+/−) and the recommendation of the German Society for Radio-oncology (DEGRO) 18 .
Another subject that was addressed was the controversial question concerning the indication for regional node irradiation after neoadjuvant therapy. In the case of lymph node involvement prior to therapy and subsequent pCR, the majority of the panel recommended regional node irradiation in both triple-negative and HER2-positive disease, although a large majority did not consider it appropriate in patients with clinically unremarkable lymph nodes who had achieved pCR (Supplementary Table S1 , questions 100 – 104). Prospective data have not yet been published, although clinical studies are underway.
An overwhelming majority of panellists were opposed to using commercially available gene expression profiles to inform decisions on adjuvant radiation therapy (neither in the case of BCS, nor in that of PMRT or RNI) (Supplementary Table S1 , questions 65 – 67). Analogous to DCIS, panellists were asked whether radiation therapy should be reasonably omitted in older patients (> age 70) with a > 10 year life expectancy, after BCS for ER+ HER2− cancers). Nearly 90% were in favour of foregoing radiation therapy in patients with a tumour size of < 2.5 cm and a low-int grade/low genomic score (G1–2). This was not felt to be the case in patients with tumours larger than 2.5 cm, in patients with a positive sentinel lymph node or in patients whose tumours displayed aggressive biological features (Supplementary Table S1 , questions 106 – 111). The only long-term data available are from three studies, in each of which the risk of intra-mammary recurrence was significantly increased after a longer follow-up (approximately 10% after 10 years), although this had no negative impact on survival rates 19 , 20 , 21 .
Neoadjuvant Therapy in Triple-Negative Breast Cancer
Standard chemotherapy for triple-negative breast cancer (TNBC) is anthracycline/taxane-based. A dose-dense regimen of such therapy is more effective and is, therefore, preferable 22 . In contrast, there is no consensus on supplementary administration of carboplatin. Several meta-analyses and systemic reviews have now demonstrated that carboplatin supplementation is associated with significantly improved pCR rates 23 , 24 , 25 . Similarly, the GeparSixto trial has shown that carboplatin in addition to the standard regimen leads to an overall improved three-year disease-free survival (DFS) (86 vs. 76%; HR = 0.56; 95% CI: 0.34 – 0.93). Three-year overall survival, however, only demonstrated a trend (92 vs. 86%; HR = 0.60; 95% CI: 0.32 – 1.12) 26 . Interestingly, in this study, it was mainly the patients without a BRCA1/2 mutation who benefited from supplementary carboplatin, both in terms of pCR rate and DFS 27 . For this reason, the decision on whether to administer carboplatin should not be based on BRCA mutation status. In general, employment of carboplatin is likely to result in a higher grade 3/4 haematotoxicity as well as higher rates of therapy discontinuation, and this should be discussed with the patient 28 . This is the reason why practitioners are ambivalent about routinely using carboplatin in neoadjuvant therapy for all patients with triple-negative breast carcinoma (Supplementary Table S1 ; question 39).
In metastatic breast cancer, immune checkpoint inhibitors (ICPi) are used in TNBC as first-line therapy 29 , 30 . The results of studies on neoadjuvant treatment have now also been published. The phase 3 IMpassion031 study has revealed that the addition of atezolizumab to nab-paclitaxel followed by EC treatment led to a significant improvement in the pCR rate of 17% 31 . The effect on pCR rate was independent of PD-L1 status. Similarly, the KEYNOTE-522 study on the ICPi pembrolizumab observed similar effects in both PDL1-positive and PD-L1-negative patients. Weekly supplementation of pembrolizumab to pacliatxel and carboplatin followed by EC treatment increased the overall pCR rate by 14% 32 . Although in a later analysis involving more patients this difference was reduced to 7.5% in the KEYNOTE-522 study 33 , both studies demonstrated a trend towards improved event-free survival (EFS) 31 , 32 , 33 . However, data on overall survival have not yet been published. Furthermore, consideration must be given to the additional immunological side effects of ICPi (e.g. thyroiditis, hepatitis). Authorisation for pembrolizumab and atezolizumab in neoadjuvant treatment is currently pending in Germany. For this reason, ICPi should only be employed in the context of studies. The SG-EBC expert panellists took a similar view (Supplementary Table S1 ; question 40).
Neoadjuvant Therapy in HER2-positive Breast Cancer
Neoadjuvant therapy involving chemotherapy + trastuzumab + pertuzumab for HER2-positive breast carcinoma (N+ or NST) is an established approach due to its higher effectiveness 22 , 34 , 35 , 36 . However, the role of anthracyclines in simultaneous chemotherapy is increasingly being viewed in a critical light. A total of five studies involving anthracycline-free regimens that instead employed carboplatin in combination with dual inhibition have now been published. Overall, these studies reveal pCR rates that are comparable to rates associated with the use of anthracyclines (64% in TRYPHAENA and 68% in TRAIN-2), as well as outcome data with a three-year DFS of between 90% (TRYPHAENA) and 93.5% (TRAIN-2), with significantly lower cardiotoxicity and avoidance of AML (1% in the FEC arm of the TRAIN-2 study) 37 , 38 . In St. Gallen, discussion on anthracycline-free treatment was conducted with reference to lymph node status. A large majority of the panel considered anthracyclines not to be necessary in node-negative patients, whereas a majority considered anthracyclines to be necessary in node-positive patients. The opinion of the experts in this area is not founded on objective data; 68% of patients in the TRAIN-2 study, for instance, were node-positive. In summary, anthracycline-free, taxane-based chemotherapy with or without carboplatin in combination with dual inhibition with trastuzumab + pertuzumab is an effective alternative to an AT-based chemotherapy regimen and can be administered regardless of lymph node status (Supplementary Table S1 , questions 35 – 38).
Surgery After Neoadjuvant Therapy
Axillary staging has become ever less radical in recent decades. After successful implementation of sentinel lymph node biopsy (SLNB) and increasing use of neoadjuvant systemic therapy (NAST), the question has arisen as to whether axillary dissection after neoadjuvant systemic therapy is beneficial and appropriate. It is, for example, the accepted standard that if the axilla is initially negative (cN0) and a macrometastasis (ycN1) is discovered in the sentinel node (SLN), an axillary lymph node dissection (ALND) is indicated. If a micrometastasis or isolated tumour cells are detected in the SLN, the SG-EBC expert panellists agree that axillary dissection is not mandatorily indicated (Supplementary Table S1 ; questions 43 – 45). Prior to NAST, a suspicious axillary lymph node should be clarified by means of a core needle biopsy (CNB) and clipped/marked. If complete clinical remission of the axillary lymph nodes occurs after NAST, a targeted axillary dissection (TAD) to remove both the SLN and the targeted lymph node (TLN) can be performed, regardless of subtype, to eliminate the need for an ALND. It is entirely possible that the SLN will correspond to the TLN. This was also the view of the SG-EBC panellists (Supplementary Table S1 ; question 55 – 57). Both the study by Caudle et al. 39 and the German SENTA study 40 attest to a false negative rate respectively of 1.4% and 4.3% for TAD. As survival data on TAD are still pending, participation in the ongoing AXSANA trial is recommended 41 .
Post-neoadjuvant Therapy
Patients who do not achieve pathological complete remission (pCR) after neoadjuvant chemotherapy have a worse prognosis 42 , 43 , 44 , 45 , 46 . At the latest since the publication of the CreateX study, but especially now the results of the Katherine study have been presented, post-neoadjuvant systemic therapy has become established for treatment of early triple-negative or HER2-positive breast carcinoma 47 , 48 . As a result, the SG-EBC panellists discussed just a few, less contentious issues relating to this topic.
The first question incorporated two subordinate questions: whether (A) all patients who achieve pCR have a similar prognosis and whether (B) this also depends on the baseline clinical stage and the tumour subtype (Supplementary Table S1 , question 73). The panellists were only able to answer “yes” or “no” once in response to both subordinate questions. Since the two questions are contradictory in nature, we do not consider the responses to be representative of the panelʼs opinion (⅔ of the panellists responded “yes”). At this point, it is worth considering the research on the prognostic relevance of the CPS-EG scoring system, which, in addition to post-therapeutic tumour burden, also takes into account baseline clinical tumour stage and tumour biology (ER status and grading). In this context, patients experience different recurrence rates, even within the group of patients who achieve a pCR 49 , 50 . There is a debate as to whether one specific biomarker – BRCA1/2 status – might identify a group of patients who would not benefit from a pCR. Two studies have presented results supporting this hypothesis 51 , 52 , while two others did not support this 27 , 53 .
For the triple-negative breast carcinoma subgroup, the survey first asked to what extent patients with a pCR following neoadjuvant chemotherapy in combination with immunotherapy should receive adjuvant treatment with immuno-oncological substances/ICPi. As expected, the majority of panellists (85%) were not in favour of adjuvant immuno-oncological therapy (Supplementary Table S1 , question 76). Only 9% favoured such treatment, while 6% favoured it depending on initial disease extent. Actually, such responses should be viewed in the light of the fact that (post-neo-)adjuvant therapy with ICPi has not yet been approved in Europe. Moreover, no data yet exist for a stratified approach based on the baseline stage or response to neoadjuvant (immuno)chemotherapy.
In addition, the panel was asked to what extent all patients with triple-negative breast carcinoma and residual tumour disease (i.e. non-pCR) should receive post-neoadjuvant chemotherapy with capecitabine after neoadjuvant chemotherapy (Supplementary Table S1 , question 77). The majority of panellists were in favour of post-neoadjuvant therapy (88%), compared to only 12% who were not in favour. Indeed, the findings of the CREATE-X trial suggest there is no subgroup in which capecitabine therapy might not be expected to have an impact on disease-free survival 47 . However, an individualised approach taking into account the risk of recurrence and the expected spectrum of side effects is clearly justified.
With regard to patients with HER2-positive breast carcinoma who received neoadjuvant treatment, panellists were asked whether adjuvant HER2-targeted therapy should be continued after achieving a pCR (Supplementary Table S1 , questions 74 – 75). Consistent with the six-year follow-up data of the APHINITY study 54 , in the case of a clinically (i.e. pre-therapeutically) nodal-positive patient, 56% of panellists were in favour of blockade with trastuzumab + pertuzumab, while in the case of an initially nodal-negative patient, 70% were in favour of administration of trastuzumab alone 54 , 55 . In the presence of residual invasive tumour (non-pCR), 90% were in favour of the postneoadjuvant administration of trastuzumab-emtansine (T-DM1) in line with the data from the Katherine study 48 . In this regard, 77% were in favour of employing T-DM1 to treat patients with less than 5 mm of residual invasive cancer (Supplementary Table S1 , question 79).
Questions on treatment after neoadjuvant endocrine therapy can be found in Supplementary Table S1 , questions 81 – 85.
Adjuvant Therapy in HER2-positive Breast Cancer
Adjuvant treatment with trastuzumab and pertuzumab in patients with HER2/neu-positive breast carcinoma and affected axillary lymph nodes is standard and recommended by the Mamma commission of the AGO 22 . At present, the consensus is that node-negative breast cancer patients should not also be treated with the antibody therapy combination trastuzumab + pertuzumab. The APHINITY trial involving 4805 patients showed no benefit for patients with node-negative breast cancer after a median follow-up of 74 months 54 . The analysis to date considers invasive recurrences and metastases, as data on overall survival is currently lacking. A subgroup analysis of patients with 1 – 3 affected lymph nodes (38% of the total population) and patients with more than 4 affected axillary lymph nodes (25% of the total population) is, as yet, not available 54 .
Whether patients with HER2-positive breast cancer should receive adjuvant neratinib therapy following trastuzumab or trastuzumab + pertuzumab-based neoadjuvant or adjuvant therapy, or following post-neoadjuvant treatment with T-DM1, is a question that can be answered by the post-adjuvant ExteNET trial, the final results of which have recently been published 56 . In this trial, 2840 patients with HER2-positive breast cancer who had completed adjuvant therapy with trastuzumab were randomly assigned to receive one year of neratinib 240 mg/day or placebo. Neratinib was associated with a 5-year absolute benefit in invasive relapse-free survival compared to placebo of 5.1% and an 8-year absolute overall survival benefit of 2.1%. Thus, the numerical benefit in this trial was higher than in the APHINITY trial. Patients who had residual tumour after neoadjuvant therapy (non-pCR) had an absolute benefit of 7.4% in terms of invasive recurrence-free survival and an absolute benefit of 9.1% in terms of overall survival 56 . At the time of this study, supplementary treatment with pertuzumab was not standard. Similarly, post-neoadjuvant treatment of non-pCR patients with T-DM1, which is currently recommended, was also at the time non-standard, and, as such, it is impossible to definitively compare the risk reduction of adjuvant trastuzumab + pertuzumab with that of post-neoadjuvant T-DM1. However, the following conclusion by analogy can be assumed. In patients at very high risk of recurrence and metastasis in spite of treatment with trastuzumab + pertuzumab, for instance patients with more than four affected axillary lymph nodes, post-neoadjuvant therapy with neratinib may be considered in individual cases. Patients who have undergone post-neoadjuvant therapy with T-DM1 and who were diagnosed as high risk at the time of initial diagnosis, for instance those with a large primary tumour or multiple axillary lymph node involvement, may also benefit from post-T-DM1 treatment with neratinib. The European drug authorisation for neratinib places no restrictions on these treatment options. As such, this can be consciously discussed with patients at a very high risk of recurrence and metastases. This issue is addressed in Supplementary Table S1 , question 143.
The question as to whether adjuvant, anthracycline-containing chemotherapy is required in patients with HER2-positive breast carcinoma is currently a subject of intense debate, both nationally and internationally. The large adjuvant trials NCCTG/NSABP, HERA and BCIRG with over 20 000 patients demonstrated a significant benefit for chemotherapy plus anti-HER2 therapy with trastuzumab compared to chemotherapy alone. The only study to directly compare anthracycline-containing chemotherapy with anthracycline-free chemotherapy in line with the TCH regimen (docetaxel, carboplatin, trastuzumab) was the BCIRG 006 study 57 . The outcome with respect to recurrence and metastases was not statistically dissimilar, while the short-term cardiac effects were slightly higher with the anthracycline-containing regimen than with the anthracycline-free regimens. All long-term data available to date show no additional cardiac events after 10 – 12 years of follow-up 58 , 59 . The 10-year follow-up of the BCIRG 006 trial found five times as many cases of heart failure in the anthracycline-containing arms than in the anthracycline-free arm 60 . More recent studies, such as the TRAIN study with significantly fewer patients and pCR as the primary endpoint, reported similar results with regard to pCR, but revealed a different toxicity profile favouring anthracycline-free chemotherapy, especially in relation to cardiac events. However, such studies with well under 1000 patients are too small to establish a new anthracyline-free standard of treatment for patients with HER2-positive breast carcinoma, in particular because data on survival are unavailable for this study. The current AGO 2021 guideline supports this assessment 22 . Nevertheless, the risks of cardiac events suggest non-anthracycline therapy may be appropriate. This subject was picked up in question 144 (Supplementary Table S1 ).
Patients with a small (less than 2 cm), node-negative HER2-positive breast carcinoma are often treated with a combination of 12 weeks of paclitaxel weekly with 1 year of trastuzumab. Such therapy originated in a non-randomised phase II study 61 , 62 . However, this study has clear weaknesses: 50 patients withdrew from the study, and no follow-up data are available for 69 patients. As such, only data from 406 patients can be analysed. Of these, just one third were under 50 years old. Most patients had a tumour 1 – 2 cm in size, while only 9% had a tumour 2 – 3 cm in size. 70% of the patients were hormone receptor-positive, while only 30% were hormone receptor-negative. All patients were histologically node negative. In view of these weaknesses, this study should be considered with extreme caution as a basis for making decisions on neoadjuvant and post-neoadjuvant therapy. In other words, neither the addition of carboplatin nor the general abandonment of anthracyclines is advisable – and certainly not the replacement of chemotherapy with T-DM1 as sole treatment for patients with HER2-positive breast carcinoma. Large prospective randomised trials would need to be conducted to replace the current standard with such treatment involving less chemotherapy. However, in individual cases and depending on the individual risk of the patient, an anthracycline-free therapy can be considered.
Pathology
In the field of breast pathology, the main topics of discussion are currently Ki-67, multigene tests, immune markers such as tumour-infiltrating lymphocytes (TILs) and PD-L1 expression. The SG-EBC Expert Panel voted on these areas.
Ki-67 is a strong pathological prognostic marker for patients with early stages of breast carcinoma 44 , 63 , 64 , 65 . However, its clinical use and benefit is debated due to its inconsistent clinical assessment and variability. However, the International Ki67 in Breast Cancer Working Group (IKWG) found that for patients with a T1–2/N0–1 tumour stage, extreme thresholds of 5% and 30% could be employed to place patients relatively reliably into a group with a very good prognosis or a group with an unfavourable prognosis 66 . A majority of the SG-EBC Expert Panel likewise agreed with this for treatment of patients with an HER2-negative, hormone receptor-positive tumour (Supplementary Table S1 , question 11). Approximately 63% of panellists considered a cut-off above 20% to be acceptable to indicate chemotherapy. In a survey of 115 German decision-makers 67 , 87% considered that chemotherapy would be indicated at a cut-off of 20%.
Prognosis is best determined not merely by means of a static Ki-67 value before the start of therapy, but also by its (non-)reduction during anti-endocrine therapy 68 , 69 . This concept was also adopted in the German ADAPT trials and, along with a multigene assay, was able to identify patients with an excellent prognosis who did not require chemotherapy 70 . The SG-EBC Expert Panel responses can be found in Supplementary Table S1 , questions 14 and 15.
The main benefit of multigene tests, which are designed to identify patients with an excellent prognosis 71 , 72 , 73 , is to potentially eliminate the need for chemotherapy in this group of patients. In a (hypothetical) patient with an HER2-negative, hormone receptor-positive, 1 – 3 cm breast carcinoma, multigene tests seem most appropriate in the presence of 1 – 3 affected lymph nodes ( Fig. 2 ; Supplementary Table S1 , questions 16 – 25).
Fig. 2.
Percentage of SG-EBC experts who would perform a multigene test in selected patients with a 1 – 3 cm HER2-negative, hormone receptor-positive tumour.
Even though tumour-infiltrating lymphocytes (TILs) had been established as a prognostic parameter in breast carcinoma 74 , 75 , 76 , they are not routinely evaluated and have, so far, not been used to inform treatment decisions. Likewise, PD-L1 has not been proven to be a predictive marker for anti-PD-1/PD-L1 therapy 32 , 77 . Neither marker was recommended for routine use by the SG-EBC Expert Panel (Supplementary Table S1 , questions 26 – 27).
Adjuvant Endocrine Therapy
One of the first issues raised by the survey concerned how to define hormone receptor positivity (Supplementary Table S1 , question 113). 50% of panellists supported the concept that hormone receptor positive be defined as greater than or equal to 1%, while around 50% supported a figure of greater than or equal to 10%. This highlights the changing recommendations that have faced pathologists over the years 78 . More sensitive immunohistochemical staining techniques have resulted in increased positivity rates. Clinical analyses suggest that very weakly hormone receptor-positive tumours tend to behave similarly to triple-negative breast carcinomas 79 . The recommendations made by the Mamma commission of the AGO therefore refer to “questionably” endocrine-sensitive tumours within a range of 1 – 9% hormone receptor positivity 80 .
A whole series of issues voted on by the panellists addressed the topic of optimal endocrine therapy for premenopausal patients. Much discussion and controversy on this subject focussed on the use of GnRH analogues and, where appropriate, their combination with aromatase inhibitors. There was clear consent on the question of whether women with an increased risk of recurrence who receive chemotherapy should also undergo ovarian suppression: 94.3% of panellists were in favour, while only 5.7% were not. Compelling evidence exists that ovarian suppression is beneficial in patients who have undergone chemotherapy. The ASTRRA study revealed that administration of GnRH analogues for 2 years in addition to tamoxifen confers a benefit for recurrence-free survival and also, potentially, for overall survival 81 : The estimated 5-year DFS rate was 91.1% in the TAM + OFS group and 87.5% in the TAM-only group (HR = 0.69; 95% CI: 0.48 – 0.97; p = 0.033). The estimated 5-year overall survival rate was 99.4% in the TAM + OFS group and 97.8% in the TAM group (HR = 0.31; 95% CI: 0.10 – 0.94; p = 0.029). A further analysis of the SOFT and TEXT studies revealed that patients who had received chemotherapy due to unclearly defined risk factors likewise benefited from ovarian suppression as an adjunct to endocrine therapy: in total, about 92% experienced a DRFI of 8 years (194 DRs), and the absolute benefit of Exemestan + OFS vs. TAM + OFS was 3%. In conclusion, use of Exemestan + OFS yielded an absolute benefit of 10 – 15% compared to TAM + OFS or TAM alone in 8-year DRFI in premenopausal patients with hormone receptor-positive, HER2-negative breast cancer with a high risk of recurrence (as defined by clinicopathological features). The potential benefit from escalating endocrine therapy vs. tamoxifen alone is minimal in low-risk patients and, potentially, 4 – 5% in intermediate-risk patients 82 .
What is controversial, however, is whether chemotherapy is required in patients at an intermediate risk or whether ovarian suppression in addition to endocrine therapy is sufficient. The background to this discussion is the fact that in premenopausal patients chemotherapy triggers a loss of ovarian function, and hence at least part of the effectiveness of chemotherapy can be attributed to ovarian suppression. This hypothesis is supported by the fact that two earlier studies found that chemotherapy and ovarian suppression had a comparable effect in premenopausal patients 83 , 84 . In the TailorX trial, women under 50 with an intermediate risk score were shown to have benefited from chemotherapy based on a reduction in recurrence rate 73 , 85 . However, the patients in this study did not undergo ovarian suppression. The hypothesis that chemotherapy has an indirect effect in premenopausal women was also shared by a large majority of the panellists: only about 25% of panellists considered that premenopausal and nodal-negative patients with an intermediate risk based on a gene expression test, e.g. Oncotype DX ® , require chemotherapy; 22.5% considered tamoxifen alone was sufficient, and 53% preferred ovarian suppression plus endocrine therapy. On the question of the likely contribution of chemotherapy-induced ovarian suppression to the effectiveness of chemotherapy, around 56% of the panellists stated they estimated this contribution to be 75 or 100 per cent. In light of these considerations, the 2021 AGO recommendations do not consider that an indication for ovarian suppression should be linked to administration of chemotherapy but, instead, to the finding of an intermediate or increased risk 80 .
The St. Gallen Consensus 2021 only reached a general agreement on the optimal duration of adjuvant endocrine therapy for node-positive HR+/HER2− primary breast carcinoma: approximately 90% of panellists were in favour of therapy lasting longer than 5 years, while approximately 50% favoured 10 years. A consensus on therapy sequence and tolerability was not discussed. The AGO recommendations discuss prior therapy, sequence, risk and side effects in great detail in the corresponding chapter 80 .
At the St. Gallen consensus meeting, the expert panel was very divided on the use of adjuvant abemaciclib in hormone receptor-positive, HER2-negative primary breast carcinoma: 54% were not in favour of adjuvant abemaciclib in patients with 1 – 3 affected axillary lymph nodes, while the same number of experts were in favour of abemaciclib in patients with at least 4 affected axillary nodes (Supplementary Table S1 ; questions 121 – 122) 86 . Such survey findings are closely reflective of the AGO recommendation grade (+/−), which emphasizes a case-by-case approach and considers such therapy to be a viable option based on a consideration of all multifactorial decision criteria. In light of the negative findings of the PenelopeB and Pallas trials, neither St. Gallen nor the AGO recommend palbociclib use in primary breast cancer 80 .
Acknowledgements
This review was undertaken in part thanks to funding from onkowissen.de, Hexal, Pfizer, Lilly and Novartis. None of the companies played a role in reaching the recommendations made in this manuscript. The authors alone are responsible for the content of the manuscript.
Danksagung
Diese Arbeit entstand teilweise in Folge von Förderungen der Firmen onkowissen.de, Hexal, Pfizer, Lilly und Novartis. Keine der Firmen hatte einen Anteil an der Erstellung und den Empfehlungen dieses Manuskriptes. Für den Inhalt des Manuskriptes sind alleine die Autoren verantwortlich.
Footnotes
Conflict of Interest/Interessenkonflikt S. B. has no conflict of interest. A. B. has no conflict of interest. E. B. received honoraria from Novartis, Hexal, BMS, Lilly, Pfizer, Roche, MSD, Ipsen, BBraun and onkowissen.de for consulting, clinical research management or medical education activities. P. A. F. received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi-Sankyo, onkowissen.de, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma and Teva. His institution conducts research with funding from Novartis and Biontech. T. N. F. has participated on advisory boards for Amgen, Daiichi Sankyo, Novartis, Pfizer, and Roche and has received honoraria for lectures from Amgen, Celgene, Daiichi Sankyo, Roche, Novartis and Pfizer. A. D. H. received speaker and consultancy honoraria from AstraZeneca, Genomic Health, Roche, Novartis, Celgene, Lilly, MSD, Eisai, Teva, Tesaro, Daiichi-Sankyo, Hexal and Pfizer. W. J. has received research Grants and/or honoraria from Sanofi-Aventis, Daiichi-Sankyo, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Chugai, GSK, Eisai, Celgene and Johnson & Johnson. C. K.-L. has received honoraria from Roche, AstraZeneca, Celgene, Novartis, Pfizer, Lilly, Hexal, Amgen, Eisai, and SonoScape, honoraria for consultancy from Phaon Scientific, Novartis, Pfizer, and Celgene, research funding from Roche, Novartis, and Pfizer, and travel grants from Novartis and Roche. H.-C. K. has received honoraria from Pfizer, Novartis, Roche, Genomic Health/Exact Sciences, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, Teva, Theraclion, Janssen-Cilag, GSK, LIV Pharma, Lily, SurgVision, Onkowissen and MSD, travel support from Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi Sankyo, Tesaro and owns stock of Theraclion SA and Phaon Scientific GmbH. D. K. has received honoraria from Merck Sharp & Dohme outside of the submitted work. D. L. received honoraria from Amgen, AstraZeneca, Celgene, Lilly, Loreal, MSD, Novartis, Pfizer, Tesaro, Teva. V. M. received speaker honoraria from Amgen, Astra Zeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, Seattle Genetics and Nektar. Institutional research support from Novartis, Roche, Seattle Genetics, Genentech. Travel grants: Roche, Pfizer, Daiichi Sankyo. E. S. received honoraria from Roche, Celgene, AstraZeneca, Novartis, Pfizer, Tesaro, Aurikamed GmbH, MCI Deutschland GmbH, bsh medical communications GmbH, Onkowissen TV. A. S. received honoraria from Roche, Celgene, AstraZeneca, Novartis, Pfizer, Zuckschwerdt Verlag GmbH, Georg Thieme Verlag, Aurikamed GmbH, MCI Deutschland GmbH, bsh medical communications GmbH and promedicis GmbH. F. S. participated on advisory boards for Novartis, Lilly, Amgen and Roche and received honoraria for lectures from Roche, AstraZeneca, MSD, Novartis and Pfizer. C. T. Advisory boards, lectures: Amgen, AstraZeneca, Celgen, Daiichi-Sankyo, Eisai, Lilly, MSD, Mundipharma, Medapharm, Novartis, Pfizer, Pierre-Fabre, Roche, Tesaro, and Vifor. M. U. all honoraria went to the institution/employer: Abbvie, Amgen, Astra Zeneca, Celgene, Daichi Sankyo, Eisai, Lilly, MSD Merck, Mundipharma, Myriad Genetics, Pfizer, PUMA Biotechnology, Roche, Sanofi Aventis, Novartis, Pierre Fabre. M. W. has participated on advisory boards for AstraZeneca, Lilly, MSD, Novartis, Pfizer and Roche. A. W. participated on advisory boards for Novartis, Lilly, Amgen, Pfizer, Roche, Tesaro, Eisai and received honoraria for lectures from Novartis, Pfizer, Aurikamed, Roche, Celgene. R. W. has received personal fees/travel support from Agendia, Amgen, Aristo, Astra Zeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi Sankyo, Eisai, Exact Sciences, Genomic Health, GlaxoSmithKline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva, Veracyte and Viatris. M. T. has participated on advisory boards for AstraZeneca, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, GSK, Lilly, MSD, Neodynamics, Novartis, Pfizer, pfm medical, Pierre-Fabre, Roche and Sysmex and has received travel expenses and honoraria for lectures from Amgen, AstraZeneca, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, GSK, Hexal, Lilly, MSD, Novartis, Onkowissen, Pfizer, pfm medical Roche, Seagen, Sysmex, and Vifor and has received trial funding by Exact Sciences and Endomagnetics. He received manuscript support by ClearCut, pfm medical, Roche. The other authors have no conflict of interest to declare for this specific work. S. B. unterliegt keinem Interessenkonflikt. A. B. unterliegt keinem Interessenkonflikt. E. B. hat Honorare von Novartis, Hexal, BMS, Lilly, Pfizer, Roche, MSD, Ipsen, BBraun und onkowissen.de für Beratungsleistungen, klinisches Forschungsmanagement oder medizinische Fortbildungstätigkeiten erhalten. P. A. F. hat Honorare von Novartis, Pfizer, Roche, Amgen, Celgene, Daiichi Sankyo, onkowissen.de, AstraZeneca, Merck-Sharp & Dohme, Eisai, Puma und Teva erhalten. Sein Institut forscht mit finanzieller Unterstützung von Novartis und Biontech. T. N. F. war in Beratungsgremien für Amgen, Daiichi Sankyo, Novartis, Pfizer und Roche tätig und hat Honorare für Vorträge von Amgen, Celgene, Daiichi Sankyo, Roche, Novartis und Pfizer erhalten. A. D. H. hat Vortrags- und Beratungshonorare von AstraZeneca, Genomic Health, Roche, Novartis, Celgene, Lilly, MSD, Eisai, Teva, Tesaro, Daiichi Sankyo, Hexal und Pfizer erhalten. W. J. hat Forschungsgelder und/oder Honorare von Sanofi-Aventis, Daiichi Sankyo, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Chugai, GSK, Eisai, Celgene und Johnson & Johnson erhalten. C. K.-L. hat Honorare von Roche, AstraZeneca, Celgene, Novartis, Pfizer, Lilly, Hexal, Amgen, Eisai und SonoScape, Honorare für Beratung von Phaon Scientific, Novartis, Pfizer und Celgene, Forschungsgelder von Roche, Novartis und Pfizer sowie Reisekostenzuschüsse von Novartis und Roche erhalten. H.-C. K. hat Honorare von Pfizer, Novartis, Roche, Genomic Health/Exact Sciences, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, Teva, Theraclion, Janssen-Cilag, GSK, LIV Pharma, Lily, SurgVision, Onkowissen und MSD sowie Reisekostenzuschüsse von Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi Sankyo und Tesaro erhalten und besitzt Aktien von Theraclion SA und Phaon Scientific GmbH. D. K. hat unabhängig von der eingereichten Arbeit Honorare von Merck Sharp & Dohme erhalten. D. L. hat Honorare von Amgen, AstraZeneca, Celgene, Lilly, Loreal, MSD, Novartis, Pfizer, Tesaro, Teva erhalten. V. M. hat Vortragshonorare von Amgen, Astra Zeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seattle Genetics und Beratungshonorare von Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, Seattle Genetics und Nektar erhalten. Institutionelle Forschungsunterstützung von Novartis, Roche, Seattle Genetics, Genentech. Reisekostenzuschüsse: Roche, Pfizer, Daiichi Sankyo. E. S. hat Honorare von Roche, Celgene, AstraZeneca, Novartis, Pfizer, Tesaro, Aurikamed GmbH, MCI Deutschland GmbH, bsh medical communications GmbH und Onkowissen TV erhalten. A. S. hat Honorare von Roche, Celgene, AstraZeneca, Novartis, Pfizer, Zuckschwerdt Verlag GmbH, Georg Thieme Verlag, Aurikamed GmbH, MCI Deutschland GmbH, bsh medical communications GmbH und promedicis GmbH erhalten. F. S. hat an Beratungsgremien für Novartis, Lilly, Amgen und Roche teilgenommen und Honorare für Vorträge von Roche, AstraZeneca, MSD, Novartis und Pfizer erhalten. C. T. Beratungsgremien, Vorträge: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly, MSD, Mundipharma, Medapharm, Novartis, Pfizer, Pierre-Fabre, Roche, Tesaro und Vifor. M. U. alle Honorare gingen an die Institution/Arbeitgeber: AbbVie, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly, MSD Merck, Mundipharma, Myriad Genetics, Pfizer, PUMA Biotechnology, Roche, Sanofi Aventis, Novartis, Pierre Fabre. M. W. hat in Beratungsgremien für AstraZeneca, Lilly, MSD, Novartis, Pfizer und Roche mitgewirkt. A. W. hat an Beratungsgremien für Novartis, Lilly, Amgen, Pfizer, Roche, Tesaro, Eisai teilgenommen und Honorare für Vorträge von Novartis, Pfizer, Aurikamed, Roche und Celgene erhalten. R. W. hat persönliche Honorare/Reisekostenzuschüsse von Agendia, Amgen, Aristo, AstraZeneca, Boeringer Ingelheim, Carl Zeiss, Celgene, Clinsol, Daiichi Sankyo, Eisai, Exact Sciences, Genomic Health, GlaxoSmithKline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Seattle Genetics, Tesaro Bio, Teva, Veracyte und Viatris erhalten. M. T. hat in Beratungsgremien für AstraZeneca, ClearCut, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, GSK, Lilly, MSD, Neodynamics, Novartis, Pfizer, pfm medical, Pierre-Fabre, Roche und Sysmex mitgewirkt und hat Reisekosten und Honorare für Vorträge von Amgen, AstraZeneca, Clovis, Daiichi Sankyo, Eisai, Exact Sciences, GSK, Hexal, Lilly, MSD, Novartis, Onkowissen, Pfizer, pfm medical Roche, Seagen, Sysmex und Vifor erhalten. Zudem hat er Gelder für Studien von Exact Sciences und Endomagnetics erhalten. Er hat Manuskriptunterstützung von ClearCut, pfm medical, Roche erhalten. Die übrigen Autoren geben an, bezüglich dieser spezifischen Arbeit keinem Interessenkonflikt zu unterliegen.
Supporting Information
Supporting Information
References/Literatur
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