Leo: There were three presentations that I would consider the most practice-changing: The data from INSEMA presented by Toralf Reimer, the data from AXSANA presented by Torsten Kühn and the data from the PATINA trial presented by Otto Metzger.

In the INSEMA trial, 5,500 patients with clinically node-negative, T1 or T2 invasive breast cancer were randomized to either no sentinel lymph node biopsy (SLNB) or SLNB. After a median follow-up of 6 years, omission of SLNB was noninferior to SLNB with regard to invasive disease-free survival (iDFS). 5-year overall survival (OS) was 98.2% in the no SLNB arm versus 96.9% in the SLNB arm. The occurrence of axillary recurrences was very low in both arms (1.0% in the no SLNB arm and 0.3% in the SLNB group).

Torsten Kühn presented data from the prospective multicenter AXSANA/EUBREAST 3 study that investigated upstaging of the nodal stage by diagnostic axillary lymph node dissection in patients with isolated tumor cells or micrometastases in the sentinel or target lymph node after neoadjuvant chemotherapy. The upstage rate to higher nodal stage was extremely low, especially in patients achieving a pathological complete remission (pCR) in the breast.

The third trial that needs to be mentioned here is PATINA, a phase 3 trial in metastatic hormone receptor (HR)-positive/HER2-positive breast cancer. In this trial, palbociclib was added to maintenance endocrine therapy and anti-HER2 therapy after 1st line treatment with taxane, trastuzumab, and pertuzumab. The addition of palbociclib resulted in a significant and clinically meaningful improvement of median progression-free survival (PFS): 44 months in the palbociclib arm versus 29 months in the control arm. The HR was 0.74, which translates into a 26% reduction in having a PFS event in the palbociclib arm. The median OS has not yet been reached in the palbociclib arm and was 77 months in the control arm. The PATINA study shows that by adding a CDK4/6 inhibitor – in this case palbociclib – resistance to anti-HER2 therapy and endocrine therapy can be overcome and outcome can be significantly improved.

Reinisch: In my view, there were also three practice-changing results. The most significant and practice-changing trial presented at this year’s SABCS was the German INSEMA trial (Reimer et al., GS2-07). I think, we have to add that, although the study was open to all patients, the majority had tumors smaller than 2 cm (>90%), with grades 1 or 2 (>95%), and over 98% were HR-positive, making the results, particularly applicable to this patient population. The significance of these practice-changing results was underscored by their publication in the New England Journal of Medicine shortly after the presentation (https://www.nejm.org/doi/full/10.1056/NEJMoa2412063).

We should inform our patients about this study and consider omitting the SLNB when patients present with low-risk factors (tumors <2 cm, grade 1/2, HR-positive) following a biopsy. In metastatic breast cancer, the most practice-changing result was the PATINA trial (Metzger et al., GS2-12), which also recruited participants in Germany. The trial demonstrated that palbociclib significantly improved PFS by 15.2 months compared to anti-HER2 therapy and endocrine therapy alone, with median PFS of 44.3 months in the palbociclib group versus 29.1 months in the control group. Additionally, the palbociclib arm exhibited a higher overall response rate and clinical benefit rate, although it was associated with increased rates of neutropenia, fatigue, stomatitis, and diarrhea. Despite a similar incidence of grade 4 adverse events across both arms, the trial’s safety profile was deemed manageable.

It is important to highlight the positive selection of the study cohort: patients who experienced tumor growth while undergoing chemotherapy were excluded from the PATINA study. As a result, the PFS outcomes in the comparator arm are better than those observed in the CLEOPATRA study.

Last but not least, the EMBER-3 trial (Jhavi et al., GS1-01) is also noteworthy. This three-arm, prospective randomized trial investigated the potential of the oral selective estrogen receptor degrader (SERD) imlunestrant. Patients with HR-positive metastatic breast cancer were included and received treatment until disease progression or unacceptable toxicity occurred.

Imlunestrant was evaluated as a single agent compared to fulvestrant endocrine therapy and imlunestrant combined with abemaciclib. The trial found that imlunestrant outperformed fulvestrant in patients with ESR1 mutations, showing a median PFS of 5.5 months versus 3.8 months, with 30% of the patients having an ESR1 mutation. However, imlunestrant was not superior to fulvestrant in the intent-to-treat population, with median PFS of 5.6 months for imlunestrant compared to 5.5 months for fulvestrant.

In the intent-to-treat populations, the combination of abemaciclib and imlunestrant demonstrated superiority over imlunestrant alone, with median PFS of 9.4 months versus 5.5 months. This was also seen in the ESR1 mutant subgroup, where median PFS was 11.1 months for the combination compared to 5.5 months for imlunestrant alone. OS data were not mature at the time of the data cutoff. The safety profile was comparable to previous studies of fulvestrant plus abemaciclib, with a low discontinuation rate of 6%.

Rinnerthaler: I agree that the results of the INSEMA trial (surgical de-escalation), the EMBER-3 trial and the PATINA trial are particularly noteworthy.

Leo: We will definitely do less SLNB in cN0 patients, a development that started with the choose wisely campaign in the USA, was encouraged with the data from the SOUND study and is now solidly confirmed with INSEMA: In most patients undergoing breast-conserving surgery that are >50 years (and postmenopausal), having G1 or G2, HR-positive/HER2-negative breast cancer and a tumor size of up to 2 cm, SLNB can safely be omitted. For this situation we do have robust data now.

Also, with the data presented by Torsten Kühn, the body of evidence is now so strong that we can safely omit completion axillary surgery in patients with isolated tumor cells or micromets in axillary lymph nodes after neoadjuvant chemotherapy in patients that achieved a pCR.

Reinisch: And we certainly will discuss in the multidisciplinary tumor board adding palbociclib to maintenance ET and dual blockade in patients with metastatic HR-positive/HER2-positive breast cancer but as palbociclib is approved for the indicated combination or indication, we will not be able to offer these treatments immediately. Interdisciplinary tumor conferences should evaluate the addition of palbociclib on an individual basis, and requests for cost coverage should be submitted.

Rinnerthaler: I will implement the results of the PATINA trial immediately. In patients where lymph node status would escalate adjuvant treatment decisions, the omission of SLNB, as suggested by the INSEMA trial, must be carefully considered. However, the implementation of imlunestrant as in the EMBER-3 trial is not yet relevant, as this medication is neither approved nor commercially available.

Leo: The results of the GeparDouze trial were reported at SABCS2024. In this trial, atezolizumab plus neoadjuvant chemotherapy, followed by adjuvant atezolizumab did not significantly improve event-free survival (EFS) in 1,550 triple-negative breast cancer (TNBC) patients when compared to placebo. This lack of benefit was consistent across all patient subgroups except clinical nodal status, in which a significant difference favoring atezolizumab was detected for those with positive nodes. Despite a higher pCR rate, no OS benefit was observed with atezolizumab at 4 years. So for now, it is not expected that neoadjuvant treatment strategies will change and the KN-522 regimen, which investigated the PD-1 inhibitor pembrolizumab in early high-risk TNBC, stays standard of care.

Reinisch: Unfortunately, GeparDouze was a negative trial, showing no improvement in invasive disease-free survival (iDFS) or OS. The reasons for the differing results between the GeparDouze and the KN-522 remain speculative. One possibility is the different effects of the PD-1 inhibitor (pembrolizumab) used in KN-522 compared to the PD-L1 inhibitor (atezolizumab) in GeparDouze. Additionally, the lack of an effect from atezolizumab in a dose-dense regimen in GeparDouze may contrast with the three weekly anthracycline schedule employed in KN-522. The study population in GeparDouze included more node-negative patients and smaller tumors, suggesting that patients with these tumor characteristics may not require intensified chemotherapy with the addition of immune checkpoint inhibition. This is further supported by subgroup analyses, which indicated that node-positive patients or those with tumors larger than 3 cm benefited more from treatment.

Moreover, capecitabine was allowed in GeparDouze after an amendment, which may have diluted the efficacy of the immune checkpoint inhibitor. A post hoc subgroup analysis of patients who did not receive capecitabine also did not demonstrate any differences in survival outcomes. Further investigations are needed to fully understand these discrepancies and the impact of treatment regimens on patient outcomes.

Rinnerthaler: The results of KN-522 have established the addition of pembrolizumab to neoadjuvant chemotherapy as a standard of care for higher risk TNBC patients. In an exploratory biomarker analysis of this trial (Joyce O’Shaughnessy et al., LB1-07), no predictive markers for pembrolizumab benefit were identified among a selection of immune biomarkers. The biomarker analysis of the A-BRAVE trial (Maria Vittoria Dieci et al., RF3-02), conducted in patients who did not achieve a pCR and were treated with avelumab, yielded unexpectedly inconclusive results. Together with the negative findings of the GeparDouze trial, these analyses highlight the urgent need for a better understanding of optimal patient selection for immunotherapy to avoid overtreatment and unnecessary toxicities. Moreover, a presentation of tumor-infiltrating lymphocyte (TIL) analysis data from the KN-522 study is urgently needed.

Leo: I would like to comment on the COMET trial and the TRAIN-3 trial. The COMET trial presented by Dr. Hwang investigated de-escalation of local therapy for low-risk DCIS. In this trial, patients with low-risk DCIS were randomized and either received guideline concordant care (surgery ± radiation therapy) or active monitoring (mammography every 6 months). In the standard therapy arm, 66% of patients started with an endocrine therapy and in the active-monitoring arm, 71% initiated endocrine treatment. Women in the active-monitoring arm did not have a higher rate of invasive ipsilateral breast cancer at 2 years (5.9% in the surgery group vs. 4.2% in the monitoring group). The COMET trial also investigated patient-reported outcomes and Dr. Partridge showed that there were no significant differences between the two groups, including anxiety and depression. Although follow-up is still short with only 2 years, the results are encouraging and active surveillance might become a true option for patients with low-risk DCIS in the future.

Another interesting trial reporting data on de-escalation was the multicenter phase-II TRAIN-3 study (BOOG 2018-01): in this study patients with stage II–III HER2+ breast cancer were enrolled, and image-guided optimization of neoadjuvant chemotherapy duration was performed. Patients received up to nine cycles of paclitaxel, carboplatinum, trastuzumab, and pertuzumab and every three cycles the response to therapy was evaluated by MRI and biopsies. In case of radiological complete response the patient underwent surgery. If pCR was achieved, patients got completion of 1 year of dual blockade. If pCR was not achieved, patients received 14 cycles of T-DM1. The 3-year EFS for patients with only three cycles of neoadjuvant therapy was excellent (96.0% for TNBC, 97.1% for HR+). This study shows an interesting therapeutic approach that can result in significant reduction of treatment-related toxicity.

Reinisch: I really think that this congress was filled with discussions on de-escalating local therapy strategies, focusing on less surgery, reduced endocrine therapy, and/or less radiotherapy. I think the SUPREMO study (Kunkler et al., GS2-03) should be commented, too.

The SUPREMO trial, a phase 3 randomized controlled trial, investigated the impact of chest wall irradiation (CWI) following mastectomy in patients with intermediate-risk breast cancer, including those with 1–3 positive nodes (pN1) or node-negative disease (pN0) with additional risk factors. After a median follow-up of 9.6 years, the trial found no significant difference in OS at 10 years between patients who received CWI and those who did not. Although CWI slightly reduced chest wall recurrence (hazard ratio: 0.45), this had minimal clinical impact. Overall, CWI did not improve OS in this population.

The EUROPA trial, a phase 3 study involving women aged 70 years or older with stage I luminal A-like breast cancer, investigates health-related quality of life (HRQOL) in patients receiving either radiotherapy (whole breast irradiation or partial breast irradiation) or endocrine therapy. The study found that at 24 months, endocrine therapy was associated with a greater reduction in HRQOL compared to radiotherapy, with an adjusted mean difference favoring the radiotherapy group. Additionally, treatment-related adverse events were more frequent in the endocrine therapy group, suggesting that radiotherapy appeared to better preserve HRQOL. The initial reported results did not show any differences in survival parameters (local or distant recurrences) between the two groups. However, as these data are immature, based on a median follow-up of only 24 months, further data on disease control outcomes are needed to confirm these interim findings.

Rinnerthaler: The most compelling data on de-escalation come from the INSEMA trial. The investigators demonstrated that omitting sentinel lymph node extirpation does not impact outcomes in patients with low-risk breast cancers undergoing primary breast-conserving surgery. However, as surgical staging and lymph node status influence decisions regarding adjuvant therapy, this concept is unlikely to be broadly applicable without careful patient selection.

Reinisch: I found it quite surprising that weekly patient-reported outcome monitoring with an automated alert system led to a 20% reduction in mortality compared to a control group. These results were presented in the German PRO-B trial (Karsten et al., GS1-06), a multicenter randomized controlled study in 924 metastatic breast cancer patients across 52 centers. Patients in the intervention group completed weekly surveys that triggered clinic alerts when symptoms worsened, facilitating timely contact and intervention. This approach significantly reduced fatigue, improved physical functioning and quality of life, and as I already mentioned resulted in a 20% reduction in mortality compared to the control group, which received surveys every 3 months. The study supports the integration of alert-based patient-reported outcome monitoring into routine care for advanced breast cancer patients and highlights the importance of physician-patient contact and guidance.

The Chinese FASCINATE trial (Li et al., GS1-04) showed the potential of a new antibody drug-conjugate (ADC). SHR-A1811, this ADC consisting of a HER2-targeting antibody linked to a topoisomerase I inhibitor was administered to a subgroup of patients with HER2-positive breast cancer. SHR-A1811 was administered every 3 weeks for eight cycles and was compared to standard-of-care (SOC) chemotherapy, which consisted of six cycles of nab-paclitaxel, carboplatin, trastuzumab, and pertuzumab. A third arm examined the combination of the ADC with the tyrosine kinase inhibitor pyrotinib. The primary endpoint was the pCR rate. The patient population included 90% with nodal positivity, 70% in stage III, and 55% with HR-negative disease. SHR-A1811 achieved a pCR rate of 63.2%, which was comparable to 64.4% in the SOC arm. The addition of pyrotinib did not provide any benefit to the pCR rate.

This study marks the first presentation of an ADC’s potential in the neoadjuvant setting. Remarkably, SHR-A1811 achieved the same pCR rate with just one drug as the four-drug regimen used in the SOC arm. Whether this translates into comparable or improved DFS will need to be determined in future evaluations. The significance of this trial lies in its demonstration of the results we might expect from other ADCs currently under investigation in early breast cancer settings, such as the DESTINY-Breast11 study, which explores T-DXd in a neoadjuvant context for HER2-positive breast cancer.

Rinnterthaler: For me, the results of the NSABP B-59/GBG-96-GeparDouze trial, which investigated the addition of atezolizumab to standard anthracycline-containing chemotherapy, were disappointing, as the primary endpoint was not met. The addition of atezolizumab did not result in a statistically significant improvement in EFS.

Leo: The integration of circulating tumor DNA (ctDNA) into the clinical management of patients is of high clinical need. Although not basic science anymore, I want to briefly mention the ZEST trial that was reported by Nicholas Turner. It was designed to evaluate the PARP inhibitor niraparib for the prevention of breast cancer recurrence in patients with ctDNA occurring after completion of neo/adjuvant therapy. Patients with stage I–III triple-negative or BRCA-mutated, HR-positive breast cancer were eligible. ctDNA was measured by a personalized test that examined blood samples for 16 mutations specific to each patient’s tumor. Of note, 49% of patients with a positive ctDNA sample had already clinical detectable metastases upon imaging. Unfortunately, the study failed to accrue enough patients positive for ctDNA. Although the ZEST study yielded negative results, the concept of tailoring treatment based on minimal residual disease remains a promising approach. The conclusion for now is that the patient population for such trials requires further refinement and that the minimal residual disease testing method, which relied on ctDNA detection in the ZEST study, needs thorough validation and standardization.

Reinisch: A central approach in basic research was the search for biomarkers that either predict therapeutic response or have a predictive character. The importance of TILs and other immunological factors was emphasized to better understand responses to and resistances against immune checkpoint inhibitors. An example of different approaches is multi-omic prognostic models, which incorporate genetic and immunological features alongside tumor stage to improve survival predictions.

Rinnerthaler: MHC class I expression is essential for T-cell-mediated antitumor immunity. Paula Gonzalez-Ericsson et al. (GS3-08) presented an analysis of in situ detection of individual classical MHC-I gene products. Their findings demonstrated that antigen presentation is both gene- and subtype-specific. This work has the potential to impact response prediction to immunotherapy and support the development of more effective immunotherapeutic strategies in breast cancer.

Cornelia Leo received consultancy fees and honoraria from Roche, AstraZeneca, Eli Lilly, MSD, Daiichi Sankyo, Gilead, Novartis, Pfizer, Exact Sciences, and Sirius Medical. Mattea Reinisch received honoraria for consultancy from MSD, Lilly, Roche, Stemline, AstraZeneca, Novartis, Eli Lilly, Daiichi Sankyo, Gilead, Seagen, and Somatex, and travel support from Roche, Novartis, Stemline, Gilead, and AstraZeneca. Gabriel Rinnerthaler received honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Roche, Seagen, Stemline, and BMS; for consulting or advisory role from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Roche, and Stemline; and travel support from Amgen, Daiichi Sankyo, Gilead, Pfizer, and Roche. Isabell Witzel received honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Roche, and Seagen; for consulting or advisory role from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, MSD, Novartis, Pfizer, and Roche; and travel support from Pfizer and Roche.

This study was not supported by any sponsor or funder.

Prof. Dr. med. Isabell Witzel

Department of Gynecology

Universitatsspital Zürich

University Zurich

Rämistrasse 100

Zürich, Switzerland

[email protected]

Prof. Dr. med. Cornelia Leo

Interdisziplinäres Brustzentrum

Kantonsspital Baden

Baden, Switzerland

[email protected]

PD Dr. med. Mattea Reinisch

Brustzentrum der Frauenklinik

Universitätsklinikum Mannheim

Mannheim, Germany

[email protected]

Prof. Dr. med. Gabriel Rinnerthaler

Klinische Abteilung für Onkologie

Medizinische Universität Graz

Graz, Austria

[email protected]