1017 Background: Endocrine therapy (ET) plus Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) is the standard 1 st line treatment for patients (pts) with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative, advanced Breast Cancer (HR+/HER2- aBC). ET+CDK4/6i continuation beyond progressive disease (PD) detection, plus/minus locoregional therapies, is often used in clinical practice for selected pts with oligoprogressive disease or minimal PD. However, the effectiveness of this approach has never been investigated in large studies. Methods: In this analysis of the multicenter, real-world study PALMARES-2 (NCT06805812), we evaluated clinical characteristics and outcomes in HR+/HER2- aBC pts who continued 1 st line ET+CDK4/6i after detection of PD, as defined by physicians based on clinical-radiological assessment. The primary endpoint was real-world progression-free survival (rwPFS) beyond PD, defined as the time between the detection of the first PD event during 1 st line ET+CDK4/6i and the occurrence of subsequent PD leading to definitive ET+CDK4/6i discontinuation, or patient death. We used multivariable Cox regression models to explore the association of 15 covariates with rwPFS beyond PD. We also assessed real-world overall survival (rwOS), as defined as the time between 1 st line ET+CDK4/6i initiation and patient death. Results: Of 4,236 consecutive pts who initiated ET+CDK4/6i between January 2016 and September 2024 in 27 Italian Institutions, 2,434 pts experienced a PD event. Of these pts, 454 (18.7%) continued the same ET+CDK4/6i beyond PD and underwent radiotherapy (n = 306; 67%), surgery (n = 39; 9%), other locoregional treatments (n = 28; 6%) or no local therapies (n = 81; 18%). Pts continuing ET+CDK4/6i beyond PD were more likely to be younger and premenopausal, to have higher tumor estrogen receptor (ER) and/or progesterone receptor (PgR) expression, to have bone/lymph node metastases, and less likely to have liver metastases (p < 0.05 for all covariates). Median rwPFS beyond PD was 10.5 months (95% CI: 9.7-12). At multivariable analysis, higher tumor ER (p = 0.031)/PgR (p = 0.001) or lower Ki-67 (p < 0.001) expression, better ECOG Performance Status (p = 0.009) and the use of locoregional treatments (p < 0.001) were associated with longer rwPFS beyond PD. Pts continuing ET+CDK4/6i therapy beyond PD had better median rwOS than those discontinuing it after first PD detection (71.3 and 44.7 months, respectively; p < 0.001). Conclusions: This is the largest real-world study to show the effectiveness of 1 st line ET+CDK4/6i continuation beyond PD in HR+/HER2- aBC pts. Our findings support the use of this well-tolerated and effective approach in selected pts, such as those with less biologically aggressive tumors and/or amenable to locoregional therapies. Clinical trial information: NCT06805812 .

Breast cancer (BC) is the second leading cause of brain metastases (BMs). The incidence of BMs has increased over the last decades as results of both the improvement in imaging detection power and the longer life expectancy of patients with metastatic disease. In human epidermal growth factor receptor 2-positive (HER2 + ) advanced BC, the incidence of BMs is especially high and is associated with poor prognosis. The central nervous system (CNS) has historically been considered a sanctuary site since the blood-brain barrier prevents the penetration of most therapeutic agents. Therefore, loco-regional therapies, such as surgery or radiotherapy, have largely represented the only effective strategies for treating intracranial disease. However, the development of several anti-HER2 agents with proven CNS efficacy has resulted in unprecedented disease control, raising the question of the optimal strategy to adopt in the management of both extracranial and intracranial disease. Here, we provide a comprehensive narrative review of the therapeutic management of HER2 + BMs and leptomeningeal disease, highlighting recent advances in the efficacy of both locoregional and systemic strategies and briefly discuss brain imaging screening and biomarkers for BMs risk stratification. Building on this evidence, we propose an updated, integrated treatment algorithm designed to optimize clinical decision-making.

BACKGROUND:Trastuzumab deruxtecan (T-DXd) reshaped clinical practice in human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC). The impact of clinical characteristics and drug-drug interactions (DDIs) on outcomes in patients receiving T-DXd is still under investigation. METHODS:We retrospectively analyzed data of patients from the Italian DE-REAL study. Clinical features including age, body mass index (BMI), toxicity and DDIs were assessed and correlated with clinical outcomes. The Drug-PIN software was used to evaluate DDIs. RESULTS:Among 143 patients, age did not significantly affect progression-free survival (PFS) but influenced overall survival (OS), with younger patients (<65 years) showing better outcomes (median overall survival [mOS]: 12 vs. 10 months, P = 0.02). Patients with BMI >25 demonstrated significantly longer PFS (11 vs. 9 months, P = 0.04), which was confirmed as independent predictor of better PFS at multivariate analysis (P ≤0.05), but experienced higher toxicity rates, particularly nausea (P = 0.019). Drug-PIN classification showed no impact on survival outcomes, although patients with high-risk DDIs experienced more nausea and asthenia compared to those with low-risk interactions (P = 0.0018 and P = 0.003, respectively). CONCLUSION:T-DXd efficacy appears consistent across different age groups, although elderly patients showed reduced OS. Higher BMI was associated with improved PFS but increased toxicity. While DDIs did not affect survival outcomes, they influenced specific adverse events. Our results reinforce the efficacy and favorable safety profile of T-DXd in a broad real-world population, including patients with polypharmacy or comorbidities, while highlighting that personalized monitoring and supportive care strategies may be particularly beneficial for elderly patients and those with higher BMI.

BACKGROUND:Preclinical evidence suggests that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation. RANKL inhibition with denosumab could disrupt tumor-bone microenvironment crosstalk and potentially limit metastatic progression. We evaluated the association between denosumab and real-world progression-free survival (rwPFS) in germline BRCA1/2-mutated hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) with bone metastases. METHODS:We performed a retrospective, multicenter study across 24 Italian hospitals including HR+/HER2- bone mBC patients treated in first- or second-line with a CDK4/6 inhibitor plus endocrine therapy. rwPFS was estimated by Kaplan-Meier and compared with log-rank tests. Center-stratified multivariable Cox models adjusted for clinically relevant covariates were used to assess the association between denosumab exposure and rwPFS. Effect modification by BRCA status was evaluated using a denosumab×BRCA1/2 mutation status. RESULTS:Among 1399 patients, 46 harbored germline BRCA1/2 mutations (13 BRCA1, 33 BRCA2), and 21 of these patients received denosumab. Among patients not receiving denosumab, BRCA1/2-wild-type/unknown patients had better rwPFS than BRCA1/2-mutated patients (median 28 vs 13 months; hazard ratio (HR) 0.48, 95% CI 0.32-0.73; p = 0.001). Among BRCA1/2-wild-type/unknown patients, denosumab use did not affect rwPFS (HR 0.98, 95% CI 0.85-1.12). Conversely, denosumab use was associated with longer rwPFS among patients with BRCA1/2 mutations (median 35 months, 95% CI 24-NR vs 13 months, 95% CI 9-27; HR 0.34, 95% CI 0.16-0.74; p = 0.006), with no significant difference between BRCA1 and BRCA2-mutated subgroups. Multivariable analysis confirmed the rwPFS benefit of denosumab in BRCA1/2-mutated patients (adjusted HR 0.45, 95% CI 0.21-0.99; p = 0.048). CONCLUSION:In this real-world cohort, denosumab use was associated with longer rwPFS in germline BRCA1/2-mutated HR+/HER2- mBC with bone metastases.

1129 Background: Sacituzumab govitecan (SG) has reshaped the treatment landscape of metastatic triple-negative breast cancer (mTNBC), demonstrating superior survival outcomes compared with standard chemotherapy in the ASCENT trial. Despite the overall poor prognosis of mTNBC, a subset of patients experiences remarkably durable responses and prolonged survival, far exceeding the median progression-free survival (PFS) observed in pivotal trial. However, the clinical characteristics and prognostic determinants of these "long-term responders" (LTRs) remain poorly defined, and real-world evidence specifically addressing this population is currently lacking. This multicenter study aims to characterize outcomes and identify potential predictors of long-term benefit from SG in a real-world setting. Methods: This multicenter observational analysis included 271 patients with mTNBC treated with SG across 18 Italian cancer centers, within a study incorporating both retrospective and prospective cohorts (NCT02284581). LTRs were defined as patients achieving a real-world PFS (rwPFS) ≥ 9 months. The primary endpoint was rwPFS, while secondary endpoints included real-world overall survival (rwOS) and objective response rate (ORR). Survival outcomes were estimated using the Kaplan-Meier method, and independent prognostic factors were identified using Cox proportional hazards models. Results: Seventy-four of 271 patients (27.3%) were identified as LTRs. Within this cohort, median rwPFS was 14 months (95% CI: 13.3–16.3) and median rwOS was 25.6 months (95% CI: 21.0–NR). The ORR was 68.9% (all partial responses; n=51), while 29.7% of patients (n=22) achieved stable disease. On multivariable analysis, previous therapy with immune checkpoint inhibitors (ICI) was independently associated with a reduced risk of progression (HR 0.47; 95% CI: 0.22–0.98; p=0.04). De novo metastatic disease also showed a trend towards a lower risk of progression (HR 0.44; 95% CI: 0.16–1.17; p=0.10). Conversely, treatment with SG in the third line compared with the second line was associated with a higher risk of progression (HR 2.04; 95% CI: 1.02–4.07; p=0.04). No significant association were observed for brain metastases (p=0.37), BRCA mutation status (p=0.33), or visceral involvement (p=0.27). Conclusions: In real-world setting, more than 25% of mTNBC patients experience a durable benefit from SG. Prior exposure to immunotherapy and earlier use of SG in the second-line setting were associated with a higher likelihood of LTR, while de novo disease showed a favourable trend. Notably, the presence of brain or visceral metastases did not preclude prolonged benefit. These findings suggest that a subset of patients with mTNBC may derive sustained clinical benefit from SG and support its use earlier in the treatment sequence. Clinical trial information: NCT02284581 .

BACKGROUND:Bone-only HR+/HER2 - metastatic breast cancer generally has a favourable prognosis, but some patients develop visceral metastases. We aimed to quantify visceral conversion and identify reproducible baseline correlates during CDK4/6 inhibitor (CDK4/6i) therapy. METHODS:This multicentre retrospective cohort included 692 patients treated with palbociclib, ribociclib, or abemaciclib plus endocrine therapy as first- or second-line treatment across 24 Italian centres. Visceral conversion was analysed in a competing-risks framework, with skeletal progression or death without prior visceral conversion as competing events. Eighteen baseline candidate predictors derived from a 35-variable dataset were evaluated using Fine-Gray modelling, ridge penalisation, bootstrap stability assessment, and cause-specific Cox sensitivity analyses. RESULTS:Over a median follow-up of 31 months, 162 patients (23.4%) developed visceral conversion after a median of 17.0 months. Cumulative incidence was 8.8%, 17.5%, and 24.5% at 12, 24, and 36 months, respectively; median overall survival after visceral conversion was 18.0 months. Progesterone receptor (PR) expression was the most stable tumour-biological correlate, with complete sign concordance and a median absolute coefficient rank of 1 across 500 bootstrap resamples. In the mutually adjusted Fine-Gray model, higher PR expression was associated with lower visceral-conversion risk (sHR per 10-percentage-point increase, 0.929; 95% CI, 0.889-0.971; p = 0.0012), with consistent direction across complementary analyses. However, stand-alone PR prediction remained modest (24-month IPCW AUC, 0.585; Brier score, 0.142; IPA, 1.1%; O:E, 1.00), limiting individual-level clinical utility. CONCLUSIONS:Broad baseline-variable profiling identified PR expression as the most reproducible tumour-biological correlate of visceral conversion, although its stand-alone predictive performance was modest.

BACKGROUND:Metastatic (m) HR-positive/HER2-negative special-type breast cancer (STBC) exhibits distinct biological behaviors compared with no special-type BC (NSTBC), yet their management is largely extrapolated from trials dominated by NSTBC. To improve understanding of real-world (rw) clinical outcomes, this study evaluated the effectiveness of CDK4/6 inhibitors (i) specifically in patients with mSTBC, providing clinical relevant insights into their therapeutic impact. PATIENTS AND METHODS:This retrospective cohort study included patients with mSTBC treated with first- or second-line CDK4/6i plus endocrine therapy (ET). Real-world progression-free survival (rwPFS) and overall survival (rwOS) were estimated using the Kaplan-Meier method, and differences between subgroups were evaluated using log-rank tests. RESULTS:From April 2016 to December 2024, 181 patients received CDK4/6i-based therapy. Median rwPFS was 18.2 months (95% CI, 16-22.1) and median rwOS was 58.1 months (95% CI, 49.4-77.4). A statistically significant difference in rwOS was observed between patients treated with aromatase inhibitors + CDK4/6i versus fulvestrant + CDK4/6i (77.4 vs. 42.4 months; unadjusted HR = 2.2; P = .002). No other subgroup analyses demonstrated statistically significant differences. Common adverse events included neutropenia, anemia, and diarrhea; 32% of patients required dose reductions, which did not adversely affect survival outcomes. Following CDK4/6i progression, overall rwPFS2 was 29.7 months (95% CI, 25.9-32.2). Chemotherapy was the most frequently used post-CDK4/6i treatment, while ET combined with an mTOR-inhibitor provided the longest rwPFS2. CONCLUSION:CDK4/6i represent a safe and effective therapeutic option for mSTBC. Nevertheless, dedicated studies and tailored treatment strategies are warranted to optimize post-CDK4/6i treatment in these subgroups.

Supplementary Data of correlation analysis

Purpose: This phase IIIb study prospectively evaluated the prognostic and predictive value of baseline and dynamic circulating tumor DNA (ctDNA) in postmenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) treated with first-line ribociclib/letrozole.Experimental Design: A total of 287 patients were enrolled, with ctDNA analyzed at baseline (n = 263), day 15 of cycle 1 (C1D15; n = 238), C2D1 (n = 241), and first imaging (n = 206). The primary objective was to identify ctDNA alterations, characterize their evolution across treatment time points, and assess their association with progression-free survival (PFS).Results: Median PFS was 23.4 months (95% confidence interval, 20.8 to not estimable). At baseline, the most frequently altered genes were PIK3CA (22.1%) and TP53 (15.5%). Alterations in TP53, MYC, and HER- and cyclin-dependent kinase 4/6- pathway genes were linked to early progression. Absence of a detectable mutation at baseline (n = 150, 57%) was associated with a better prognosis [hazard ratio (HR) = 0.41]. Among patients with a detectable mutation at baseline (n = 104), early clearance (mutation undetectability) was observed in 47.1% at C1D15 and 52.4% at C2D1 and was associated with improved PFS (C1D15, HR = 0.51; C2D1, HR = 0.44). In patients without a detectable mutation at baseline, 22.7% (n = 34) developed new mutations at C1D15, C2D1, or first imaging. Patients without new mutations had a lower risk of progression (HR = 0.45).Conclusions: Pretreatment and early dynamics of ctDNA represent promising prognostic and predictive biomarkers in patients with HR+/HER2- ABC treated with ribociclib/letrozole. Early ctDNA dynamics seem to be a promising surrogate biomarker for treatment. Further studies are warranted to validate their clinical utility.

1092 Background: Endocrine sensitivity/resistance (ES/ER) is a key prognostic and predictive factor in patients (pts) with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced Breast Cancer (HR+/HER2- aBC). Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i)+Endocrine Therapy (ET) are standard 1 st line therapy for HR+/HER2- aBC pts regardless of tumor ES/ER status at diagnosis. However, the prognostic value of tumor recurrence dynamics within ES/ER groups has never been investigated. Methods: We conducted a pre-planned analysis of the multicenter, real-world, Italian study PALMARES-2 (NCT06805812) to evaluate the prognostic role of tumor recurrence dynamics, de novo aBC presentation and distant recurrence-free interval (DFRI) in pts with HR+/HER2- aBC treated with 1 st line ET+CDK4/6i between January 2016 and September 2024. DRFI was defined as the time from surgery to the detection of aBC. The primary endpoint was real-world progression-free survival (rwPFS), defined as the time between ET+CDK4/6i initiation and disease progression (PD) or patient death. Results were adjusted through Multivariable Cox regression for 16 relevant covariates. Results: Of 4,234 pts enrolled, 2,858 (67.5%) had ES and 1,376 (32.5%) had ER disease at aBC diagnosis. Median follow-up was 38.6 and 42.7 months, respectively. After adjustment, ER was associated with poorer rwPFS compared to ES (adjusted hazard ratio [aHR] 1.78, 95% CI 1.60-1.96). In the ER cohort, secondary tumor resistance with recurrence during years (y) 3-5 of adjuvant (adj) ET or <1 y from its end, and recurrence during extended adj ET or <1 y from its end, were associated with increasingly better rwPFS when compared to primary resistance (Table). In the ES cohort, pts with tumor recurrence >10 y from adj ET end had significantly longer rwPFS when compared to pts recurring <10 y from adj ET end, or pts with no prior adj ET or de novo aBC (Table). Among pts with recurrent disease (N=2,792), any additional y of DRFI resulted in 3% reduction in the risk of disease progression (aHR:0.97, 95% CI: 0.96-0.99). Conclusions: The current ES/ER classification fails to capture the whole spectrum of prognostic heterogeneity in HR+/HER2- aBC pts treated with 1 st line ET+CDK4/6i. Recurrence dynamics, including DRFI, improve prognostic classification and may inform treatment selection and personalised patient management in this clinical context. Clinical trial information: NCT06805812 . Recurrence dynamic N rwPFS (mo) aHR (95% CI) Primary resistant 334 13.4 Ref Secondary resistant-during 5 y adj ET 668 15.7 0.85 (0.72-0.99) Secondary resistant-during extended adj ET 375 19.4 0.73 (0.61-0.89) No adjuvant ET 288 30.0 0.46 (0.36-0.59) 1-5 y from adj ET end 453 29.3 0.54 (0.45-0.65) 5-10 y from adj ET end 377 32.6 0.50 (0.40-0.61) >10 y from adj ET end 275 45.2 0.30 (0.23-0.40) De novo aBC 1422 31.3 0.50 (0.42-0.59)

BACKGROUND:The introduction of CDK4/6 inhibitors (CDK4/6i) has improved outcomes in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC), including in patients with bone metastases. Assessing their comparative effectiveness in real-world settings is crucial. METHODS:This retrospective, multicenter cohort study (January 2019-December 2023; median follow-up 39 months) evaluated the real-world progression-free survival (rwPFS) of abemaciclib, ribociclib, and palbociclib combined with endocrine therapy (ET) in HR+/HER2- mBC patients with bone metastases. Overall survival (OS) was a secondary exploratory endpoint. A total of 1399 patients with ECOG PS 0-1 and at least 12 months of follow-up were included. Analyses used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to adjust for confounding. RESULTS:Palbociclib showed shorter rwPFS (22 months) compared to abemaciclib (32 months; HR = 1.47, p = 0.001) and ribociclib (35 months; HR = 1.49, p < 0.001). No significant difference was observed between abemaciclib and ribociclib. OS was also lower with palbociclib (47 months) versus abemaciclib (60 months; HR = 1.77, p < 0.001) and ribociclib (64 months; HR = 1.69, p = 0.001). Results were consistent after PSM and IPTW adjustment. CONCLUSION:Ribociclib and abemaciclib may provide superior rwPFS and OS compared to palbociclib in HR+/HER2- mBC patients with bone metastases.

Background:In the absence of head-to-head trials, optimal treatment sequencing following disease progression on a CDK4/6 inhibitor (CDK4/6i) combined with endocrine therapy (ET) in hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) remains challenging. To address this gap, we conducted a systematic review and network meta-analysis (NMA) to provide evidence-based guidance for treatment selection in this setting. Methods:We identified randomized phase II-III trials involving HR+/HER2- mBC patients whose tumors progressed on CDK4/6i-based therapy, published between January 1, 2014 and June 6, 2025 (PROSPERO n° CRD42024604417). Hazard ratios (HRs) for progression-free survival (PFS) were extracted from published data and analyzed using a frequentist random-effects model. Subgroup analyses were performed based on the duration of CDK4/6i treatment and the presence of ESR1 or PI3K/PTEN/AKT pathway alterations. Treatments were compared with conventional ET or chemotherapy and ranked using the P-score metric. Confidence in network estimates was evaluated using the CINeMA framework. Safety data, including grade ≥3 adverse events (AEs) and treatment discontinuation, were descriptively analyzed. Findings:Twenty-eight randomized trials (n = 6544) were included in the NMA. Sapanisertib plus fulvestrant provided the greatest PFS benefit (HR 0.34, 95% CI 0.14-0.82) but had a high discontinuation rate (>15%). Among the approved therapies, ribociclib plus ET (HR 0.57, 95% CI 0.39-0.84), capivasertib plus fulvestrant (HR 0.62, 95% CI 0.51-0.75), and elacestrant (HR 0.70, 95% CI 0.55-0.89) demonstrated superior efficacy. Elacestrant was most effective in patients with ESR1-mutant tumors and among patients with prolonged prior CDK4/6i exposure. Ipatasertib and alpelisib showed the greatest benefits in patients with PI3K/PTEN/AKT alterations. Antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan and sacituzumab govitecan, outperformed standard chemotherapy, albeit with higher toxicity. Interpretation:Combinations of targeted agents with ET or novel endocrine agents such as oral selective estrogen receptor degraders (SERDs) demonstrated favorable efficacy and safety profiles in biomarker-selected populations, supporting a shift toward biomarker-driven treatment algorithms. In endocrine-resistant diseases that require chemotherapy, ADCs are the most effective therapeutic option. Funding:We acknowledge financial support under the National Recovery and Resilience Plan (NRRP), Mission 4, Component 2, Investment 1.1, Call for tender No. 1409 published on 14.9.2022 by the Italian Ministry of University and Research (MUR), funded by the European Union - NextGenerationEU - Project Title: Identifying predictive/prognostic biomarkers and mechanisms underlying resistance to CDK4/6 inhibition beyond progression in hormone receptor-positive/HER2-negative metastatic breast cancer - CUP E53D23020460001 (Project code: P2022FK2J8, ERC panel: LS7, Principal Investigator: Carmine De Angelis). Grant Assignment Decree No. 1369 adopted on 01.09.2023 by the Italian Ministry of University and Research (MUR).

Importance Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) agents is the standard first-line treatment for patients with hormone receptor-positive, ERBB2 (formerly HER2 or HER2/neu)-negative metastatic breast cancer. However, optimal therapy after tumor progression to ET plus CDK4/6i remains unclear. Objective To evaluate progression-free survival (PFS) and overall survival (OS) in the clinical practice setting in patients with hormone receptor-positive, ERBB2-negative metastatic breast cancer following progression with ET plus CDK4/6i. Design, Setting, and Participants The multicenter retrospective cohort study included 506 patients diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer between April 22, 2015, and January 31, 2023, and who received ET-based or chemotherapy (CT)-based treatment following progression during ET plus CDK4/6i. Outcomes were analyzed based on treatment type, clinicopathologic features, and the duration of prior CDK4/6i therapy. Main Outcomes and Measures The primary end point was PFS in the clinical practice setting, defined as the time between the initiation of the first systemic treatment on tumor progression to ET plus CDK4/6i treatment and the detection of disease progression or patient death from any cause. The secondary end point was OS in the clinical practice setting, defined as the time interval between tumor progression during ET plus CDK4/6i treatment and patient death from any cause. ResultsIn 506 women (median age at diagnosis, 52.4 [IQR, 44.6-62.8] years) diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer progressing during ET plus CDK4/6i, independent factors associated with poorer PFS outcomes were visceral metastases (hazard ratio [HR], 1.45; 95% CI, 1.17-1.80; P = .008) and de novo metastatic disease (HR, 1.25; 95% CI, 1.01-1.54; P = .04). A longer duration of CDK4/6i therapy (OS HR, 0.55; 95% CI, 0.41-0.73; P < .001) and an older age (PFS HR, 0.99; 95% CI 0.98-1.00; P = .03) were associated with better outcomes. Compared with oral CT, both intravenous CT- and ET-based treatments were associated with shorter PFS (intravenous CT: hazard ratio [HR], 1.45; 95% CI, 1.11-1.89; P = .006; everolimus plus exemestane: HR, 1.38; 95% CI, 1.06-1.78; P = .02; ET only: HR, 1.38; 95% CI, 1.05-1.89; P = .02). A duration of CDK4/6i treatment exceeding 12 months was associated with longer OS (HR, 0.55; 95% CI, 0.41-0.73; P < .001). Among patients with visceral metastases, intravenous CT was associated with shorter OS compared with oral CT (HR, 1.52; 95% CI, 1.03-2.24; P = .04). Conclusions and RelevanceIn this cohort study, the duration of tumor control achieved with CDK4/6i-based therapy and the presence of visceral metastases emerged as key factors that may affect treatment decision. Oral CT may offer potential benefits for specific patient subgroups.

BACKGROUND:Trastuzumab combined with chemotherapy is a standard treatment for human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer in later lines. Lapatinib and trastuzumab have also demonstrated efficacy. This study assessed the efficacy, toxicity, and quality of life (QoL) of trastuzumab plus lapatinib (with endocrine therapy for hormone receptor-positive cases) versus trastuzumab with physician-selected chemotherapy in patients previously treated with at least 2 anti-HER2 regimens. METHODS:In this open-label, multicenter phase II trial, 59 patients were randomized 1:1 to receive either trastuzumab and lapatinib (arm A) or trastuzumab with chemotherapy (arm B). The primary endpoint was clinical benefit rate (CBR), defined as confirmed complete response, partial response, or stable disease for ≥24 weeks. Secondary endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), QoL, and safety. RESULTS:With a median follow-up of 57.5 months, the CBR was 20.7% in arm A and 26.7% in arm B (P = .76). The ORR was 13.8% versus 20.0% (P = .73), and median PFS was 3.6 months in arm A versus 6.1 months in arm B (HR 0.63; P = .08). Median OS was 29.9 versus 31.1 months (HR 1.07; P = .82). Adverse events occurred in 86.2% (arm A) and 66.7% (arm B) of patients, with grade 3-4 events in 24.1% and 13.3%, respectively. QoL favored arm A (P = .03). Due to early study closure and limited sample size, all results should be considered exploratory and not powered to assess definitive treatment effects. CONCLUSIONS:While efficacy differences were not significant, trastuzumab with lapatinib showed better QoL despite higher adverse event rates, suggesting it may be a viable chemotherapy-free option for pretreated HER2-positive advanced breast cancer. EUDRACT TRIAL REGISTRATION NUMBER:2013-005044-29.

Breast cancer (BC) might change its receptor status during malignant progression, resulting in challenging clinical care. The project, developed during two residential meetings by expert Italian oncologists and pathologists, was aimed at optimizing metastatic BC management. A 17-point survey was administered to healthcare workers in centers of three regions, essentially to assess the perception of metastasis biopsy on treatment choice in different BC molecular subtypes, the appropriate timing for performing tissue and liquid biopsy in metastatic BC, the selection of target genes and the use of multidisciplinary approaches in tumour management. Nineteen centers participated in the survey. The first important finding was that most centers manage more than 150 patients yearly, and 95% have a pathology department. Some questions received a substantial agreement: tissue biopsy of metastatic BC was largely considered as mandatory, generally performed at onset of metastatic disease. Liquid biopsy is not used by all centers, confirming its strict dependency on the available technologies. The answers on the therapeutic line change in case of HER2 + disease becoming triple negative confirmed an attitude consistent with clinical practice. The survey also revealed that half of the interviewed oncologists discuss with multidisciplinary team only for selected cases. The survey revealed that while a shared consensus exists on the importance of metastasis biopsy, some areas still deserve attention to achieve standardized approaches: interdisciplinary collaboration and more effective communication between specialists and patients are necessary to optimize the diagnostic and therapeutic journey of women with metastatic BC.

A comparative analysis of Denosumab (DMAB) and Zoledronic Acid (ZA) was conducted in a real-world cohort of 864 patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer with bone metastases, who were undergoing CDK4/6 inhibitors plus endocrine therapy. We evaluated the time to first skeletal-related events (SREs), progression-free survival (PFS), and overall survival (OS). To adjust for confounding variables, we utilized propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) methodologies. In the unadjusted cohort, ZA was associated with a longer time to first SRE compared to DMAB (HR = 0.77, 95 % CI: 0.61-0.98, p = 0.031). Similar results were obtained in both the PSM (HR = 0.69, 95 % CI: 0.52-0.92, p = 0.011) and IPTW cohorts (HR = 0.74, 95 % CI: 0.63-0.87, p < 0.001), with ZA-treated patients showing an extended time to first SRE compared to those treated with DMAB. No differences in PFS and OS were observed between the two cohorts.

BACKGROUND:Hormone receptor-positive (HR+)/HER2-negative (HER2-) early-stage breast cancers (EBC) are treated with adjuvant endocrine therapy (ET), with chemotherapy (CT) reserved for high-risk cases. Obesity is linked to increased recurrence risk. The Oncotype DX® assay predicts prognosis and CT benefit. The PRO BONO study evaluated Oncotype DX test's impact on treatment decisions and explored associations between genomic risk, tumor features, and patient metabolic profiles. MATERIALS AND METHODS:Patients with HR+ /HER2-EBC undergoing Oncotype DX testing were enrolled. Body mass index (BMI), tumor characteristics (ER, PR, Ki67, grading, size, nodal status), a large panel of metabolic analytes, and Oncotype DX Recurrence Score® (RS) results were collected. Treatment recommendations (ET vs CT-ET) were recorded pre- and post-Oncotype DX, and concordance was determined using Cohen's Kappa. Associations were tested using Chi-Square test and Spearman Correlation. RESULTS:Of the 248 EBC patients (2019-2021), Oncotype DX testing reduced CT use by 47.7 %. Higher RS positively correlated with serum triglycerides and inversely with GIP (all p < 0.05). No significant association was found between patient BMI and RS result. Conversely, tumor size positively correlated with BMI (p = 0.0286) and with serum levels of leptin (p = 0.0079), PAI-1 (p = 0.0083), C-peptide (p = 0.0124), GIP (p = 0.0036), GLP-1 (p = 0.0476), glucagon (p = 0.0224), and insulin (p = 0.0327). A BMI≥ 30 and higher GLP-1 levels (>148.85pg/ml) were independently associated with increased odds of having larger tumor size (>2 cm). CONCLUSIONS:Recurrence Score result significantly impacts treatment decisions in HR+ /HER2-EBC. RS result was not associated with BMI, although unfavorable metabolic profiles and obesity-related markers correlated with larger tumors. These findings highlight the need to further investigate the link between metabolic profiles and breast cancer biology.