A huge number of abstracts concerning metastatic breast cancer (mBC) were presented as well; while again not immediately practice-changing, several of these abstracts merit discussion.

In the phase II PALMIRA trial, patients progressing on first-line ET in combination with the CDKi palbociclib or with recurrent disease after adjuvant palbociclib-based therapy were randomized 2:1 to ET consisting of fulvestrant or letrozole with or without palbociclib palbociclib [9]. A total of 198 patients were accrued; no difference was observed in terms of investigator-assessed progression-free survival (PFS), which was defined as the primary study endpoint. Therefore, the MAINTAIN trial of ribociclib after progression on first-line CDKi still remains the only positive phase II study in the CDKi beyond progression setting so far [10].

The PADA-1 study evaluated the strategy of treatment adaption once rising ESR1 mutation levels became detectable in the peripheral blood (bESR1mut) of patients with mBC receiving first-line aromatase inhibitor (AI) therapy plus palbociclib. Primary results have already been presented [11]: in patients with measurable bESR1mut without radiological progression, switching from AI + palbociclib to fulvestrant + palbociclib prolonged PFS over continuing AI despite a potential cross-over upon radiological progression. At the 2023 ASCO annual meeting, an update on PFS and bESR1mut dynamics was presented. At 28.2 months median follow-up, median PFS was 12.8 months in the group switching to fulvestrant + palbociclib vs. 5.8 months in the group continuing AI (HR 0.54; 95% CI 0.38–0.75). Out of 84 patients in the AI + palbociclib group, 49 patients crossed over to fulvestrant + palbociclib upon documented progression. In this subset, PFS was 3.5 months. When analyzing also for the next subsequent treatment line (PFS2 from randomization), the benefit for the fulvestrant + palbociclib group was maintained (PFS2 29.4 months vs. 14.0 months; HR 0.37; 95% CI 0.24–0.56). Upon progression, a higher frequency of polyclonal mutations and Y537S mutations was observed. In addition, the bESR1mut undetectability rate at 2 months in patients crossing over to fulvestrant + palbociclib upon progression was low at 27%. In summary, these data again indicate the relevance of ESR1 mutations as mechanism of resistance to AI-based therapy, but also suggest a benefit of early intervention targeting the emerging resistance clone and in general point at the opportunity of adapting treatment according to dynamic biomarkers analyzed by repeated liquid biopsies.

The first phase II data were presented for patritumab deruxtecan (HER3-DXd), an antibody–drug conjugate (ADC) targeting HER3, a member of the HER/EGFR receptor tyrosine kinase family [12]. In part A of a single-arm phase II trial, 61 patients with pretreated HER2-negative mBC were included and 60 patients received HER3-DXd at a dose of 5.6 mg/kg once every 3 weeks. Objective response (ORR) in the entire population was 35.0%, and irrespective of HER3 expression; numerically lower ORR were observed in TNBC compared with luminal BC (21.1% vs. 41.1%). The most common adverse events (AEs) where nausea, fatigue and diarrhea, but mostly mild to moderate in severity. These data support the concept of ADC therapy in mBC in principle but point at the urgent need to understand mechanism of resistance to ADC-based therapy and generate clinical data on the potential activity of ADCs after ADCs with every new agent investigated. At this year’s ASCO annual meeting, a retrospective single-center analysis evaluated activity of an ADC after another ADC in 32 patients with HER2-negative mBC. PFS on ADC1 was 7.55 months, and 2.53 months on ADC2, suggesting a relatively high degree of cross-resistance which may depend upon target and/or payload [13].

In the context of treatment sequencing, a pertinent question is the optimal approach in patients with HER2-positive mBC progressing on T‑DXd. A French retrospective multicenter trial evaluated outcome of 101 patients receiving the third-generation tyrosine kinase inhibitor (TKI) tucatinib in combination with trastuzumab/capecitabine (TTC) as next subsequent treatment line [14]. Patients had received a median of four prior treatment lines for mBC and median duration of T‑DXd therapy was 8.9 months, suggesting this to be a heavily pretreated population. At a median follow-up of 11.6 months, median PFS on TTC was 4.7 months, and median OS 13.4 months. In patients with brain metastases, median PFS was comparable but longer in patients discontinuing T‑DXd due to toxicity instead of progression (7.3 months vs. 4.4 months). With the caveat of a relatively small retrospective cohort, these data indicate the potential activity of further HER2-directed treatment in HER2-positive mBC patients after T‑DXd and suggest that administering TTC as next subsequent line is a reasonable approach. This hypothesis is also strengthened by an analysis of HER2-expression and ERBB2 gene amplification in pre- and posttreatment specimen from HER2-positive and HER2-low metastatic breast cancers and HER2-positive gastrointestinal cancers [15]. In the majority of patients with HER2-positive BC, HER2 remained detectable after T‑DXd, suggesting target-independent mechanisms of T‑DXd resistance.

Addition of ribociclib to endocrine therapy reduced recurrence risk in patients with high and intermediate risk HR-positive/HER2-negative early stage BC in the phase III NATALEE study; to allow for full appraisal of these results, longer follow-up is required. Long-term outcome of the neoadjuvant phase II PHERgain trial suggests that chemotherapy de-escalation based upon dynamic biomarkers holds promise in HER2-positive disease. PAM50 risk-of-recurrence score was not predictive for benefit of ovarian function suppression in a biomarker analysis from the SOFT trial. A retrospective analysis questions the need for adjuvant chemotherapy in very small node-negative triple-negative breast cancer. In metastatic breast cancer, the PADA-1 study points at the potential role of repeated liquid biopsies for treatment guidance. A phase II trial of patritumab deruxtecan reported promising response rates with yet another next-generation antibody–drug conjugate. With further innovative treatment options becoming available, the question of sequencing becomes even more pertinent.