Introduction
While not immediately practice changing, results from several clinically interesting trials in the field of breast cancer (BC) were presented at this year’s annual meeting of the American Society of Clinical Oncology (ASCO). This article is intended as a short review of some of the most pertinent data.
CDK4/6 inhibitors in early stage breast cancer
Two presentations focused on CDK4/6 inhibitors (CDKi) as component of adjuvant therapy in early stage BC. The prospective randomized phase III NATALEE trial evaluated the addition of ribociclib for a total duration of 3 years to standard endocrine therapy (ET) in hormone-receptor-positive/HER2-negative BC with high or intermediate recurrence risk [1]. A total of 5101 patients were included. In contrast to MONARCHe focusing on a high-risk population, 20% of the population accrued to NATALEE had anatomical stage II disease and nearly 30% no axillary lymph node involvement. At a median follow-up of 34 months, the 3‑year invasive disease-free survival (iDFS) improved from 87.1 to 90.4% (hazard ratio [HR] 0.748; 95% confidence interval [CI] 0.618–0.906; p = 0.014). Comparable results were obtained in terms of distant disease-free survival (HR 0.739; 95% CI 0.603–0.905; p = 0.0017); in addition, a numerical improvement of overall survival (OS) was reported. As ribociclib was administered at a dose of 400 mg per day, rates of QTc prolongation were lower compared to the metastatic setting. Grade 3/4 liver adverse events (AEs) were observed in 8.3% of patients. At the data cutoff, only 20% of patients had completed 3 years of adjuvant ribociclib; further analysis with longer follow-up must therefore be awaited to confirm a sustained benefit of ribociclib after treatment discontinuation. The question remains whether results will ultimately extend adjuvant CDKi therapy to a lower-risk population of node-negative patients. Given the added burden of intensified treatment in this group, data regarding the magnitude of the absolute benefit must be awaited.
Anzeige
From the MONARCHe trial, a subgroup analysis of patients with dose reductions and outcome in elderly patients was presented [2]. As already published, 4‑year iDFS improved from 79.4 to 85.8% with the addition of 2 years of abemaciclib to ET in a population of patients with HR-positive/HER2-negative early stage BC and high recurrence risk [3]. Dose reductions were reported in 44% of patients, with a higher rate in patients ≥ 65 years of age. Importantly, even a decrease of relative abemaciclib dose-intensity below 66% was not linked to higher recurrence risk. In addition, quality-of-life as analyzed by the FACT‑B score were similar across all arms and age groups.
Biomarkers in premenopausal patients
The prospective phase III SOFT trial randomized premenopausal patients to adjuvant endocrine therapy with tamoxifen, tamoxifen plus ovarian function suppression (OFS) or OFS in combination with the steroidal aromatase inhibitor (AI) exemestane. Outcomes have been previously published and benefit for intensified endocrine therapy was observed in the higher risk population [4]. In patients with available biospecimen, gene expression profiling with the PAM50 test was performed [5]. In the very young population (age < 40 years), a higher rate of patients with high PAM50 risk-of-recurrence (ROR) score was detected, irrespective of axillary lymph node involvement. In line with this observation, there was a higher rate of luminal B tumors in the very young group. Disappointingly, the PAM50 ROR score was not predictive for OFS benefit. These data are pertinent as they suggest a differential effect of OFS and chemotherapy in premenopausal patients and a benefit of chemotherapy beyond the induction of menopause.
PHERGain
A focus of clinical interest in HER2-positive breast cancer is the de-escalation of chemotherapy intensity. The randomized neoadjuvant phase II PHERgain trial aimed at identifying patients where chemotherapy can be safely foregone by PET metabolic response [6]. A total of 356 patients were randomized 1:4 to a control group receiving six cycles of standard neoadjuvant therapy consisting of trastuzumab, pertuzumab (TP), docetaxel and carboplatin (DCb) or a chemotherapy-free induction regimen consisting of two cycles of TP (group B). Before and after these two cycles, a PET-CT was performed. PET responders received another six cycles of antibody therapy alone, while nonresponders continued on TP plus DCb. In group B, 77% of patients had anatomically stage II disease and half of the population presented with nodal involvement. The majority of patients (79.6%) were PET responders; in this group, the rate of pathological complete remission (pCR) was 37.9%. These data have already been published [7] and at this year’s ASCO annual meeting, iDFS results (defined as the coprimary endpoint) were presented. In the overall experimental group randomized to PET-adapted therapy, 3‑year iDFS was 95.4 and 98.8% in patients achieving pCR. Results therefore indicate the feasibility of a dynamic biomarker-driven approach but a randomized comparison with a standard regimen appears desirable.
Adjuvant chemotherapy in small TNBC
While the role of chemotherapy is well established in early stage TNBC > 10 mm, there is an ongoing debate regarding the cut-off for chemotherapy in smaller tumors. Tarantino et al. identified 8601 patients from the SEER database with TNBC ≤ 20 mm without axillary lymph node involvement who underwent primary surgery with or without adjuvant chemotherapy [8]. During the retrospective observation period (2010–2019), an increase in the rate of patients receiving adjuvant chemotherapy was observed in pT1b and pT1c disease. Regarding breast cancer-specific survival (BCCS), no difference was seen between the chemotherapy and no-chemotherapy groups in pT1mi and pT1a tumors. In pT1b disease, the absolute benefit of chemotherapy was small (5-year BCSS 96.6% vs. 95.8%; HR 0.87; p = 0.619); a clear benefit was only reported in patients with pT1c tumors (5-year BCSS 94.5% vs. 91.2%; HR 0.64; p = 0.002). With all caveats of a retrospective analysis, results from this large dataset support foregoing chemotherapy in node-negative tumors ≤ 5 mm, in pT1b tumors (6–10 mm) the decision must be taken on an individual basis.
Anzeige
New data in metastatic breast cancer
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.
Take-home massage
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.
Conflict of interest
R. Bartsch: Advisory role: Astra-Zeneca, Daiichi, Eisai, Eli-Lilly, Gilead, Gruenenthal, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, Seagen, Stemline; lecture honoraria: Astra-Zeneca, BMS, Daichi, Eisai, Eli-Lilly, Gilead, Gruenenthal, MSD, Novartis, Pfizer, Pierre-Fabre, Roche, Seagen; research support: Daiichi, MSD, Novartis, Roche.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.