e15030 Background: Interstitial lung disease (ILD) is a clinically relevant adverse event associated with trastuzumab-deruxtecan (T-DXd). Reported ILD incidence often does not account for competing clinical events, potentially leading to risk overestimation. In parallel, real-world data on patient- and treatment-related risk factors remain limited. We aimed to estimate the cumulative incidence of T-DXd–related ILD using a competing-risk approach and to identify clinical and inflammatory factors associated with increased risk. Methods: We retrospectively collected data from 406 patients with metastatic breast cancer (223 HER2-positive, 162 HER2-low; 21 missing data) treated with T-DXd between October 2024 and January 2026 in 16 Italian Institutions. Competing events included death without ILD and treatment discontinuation due to disease progression or other non-ILD causes. Cumulative incidence functions (CIF) were estimated for each event. For risk factor analysis, 74 candidate variables were evaluated, including 10 clinical characteristics, 20 prior treatment variables, 24 concomitant diseases and drugs, and 20 baseline inflammatory biomarkers. Gray’s test was used for univariable screening, followed by multivariable Fine–Gray regression. Results: Seventy-four patients (18.3%) developed T-DXd–related ILD, with a median time to onset of 5.5 months and a mean of 8.4 months. The CIF of first ILD was 14.5% at 10 months and 16.8% at 20 months, plateauing at 18.8% at 50 months. No significant differences in ILD incidence were observed between HER2-positive and HER2-low disease (Gray test p = 0.83). Disease progression was the most frequent competing event, affecting 47.3% of patients at 10 months and 73.3% at 50 months. In univariate analysis, higher continuous neutrophil-to-lymphocyte ratio (NLR), impaired renal clearance (CLcr), prior lung radiotherapy (RT), smoking, and visceral disease were associated with increased ILD risk, while prior Trastuzumab exposure was protective. No correlation was seen for concomitant disease and drugs. In multivariable analysis, reduced creatinine clearance (sHR 3.53, 95% CI 1.64–7.58; p = 0.001), prior lung radiotherapy (sHR 2.40, 95% CI 1.08–5.33; p = 0.032), and higher baseline neutrophil-to-lymphocyte ratio (sHR 1.14, 95% CI 1.05–1.24; p = 0.002) remained independently associated with increased ILD risk. Conclusions: In this multicenter real-world cohort, the cumulative incidence of T-DXd–related ILD was approximately 19%, accounting for competing risks. The high frequency of competing events underscores the importance of competing-risk methodology for accurate toxicity estimation. Baseline renal impairment, prior lung radiotherapy, and systemic inflammatory status identified patients at increased risk and may support risk-adapted monitoring and earlier clinical intervention during T-DXd treatment.

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 .

Background Older patients with Hormone Receptor–positive, HER2-negative advanced breast cancer (HR+/HER2− aBC) are often frailer than younger patients. Endocrine therapy (ET) plus CDK4/6 inhibitors (CDK4/6i) is the standard first-line treatment regardless of age; however, CDK4/6i real-world effectiveness in older patients is unknown. Patients and Methods PALMARES-2 (NCT06805812) is a large real-world study investigating first-line ET plus CDK4/6i effectiveness in HR+/HER2− aBC patients. We compared real-world progression-free survival (rwPFS) between older (>75 years) and younger (≤75 years) patients in the whole study cohort, as well as in palbociclib, ribociclib, or abemaciclib sub-cohorts. Cox regression models and inverse probability of treatment weighting (IPTW) were used to adjust for prognostic covariates. Results Older patients accounted for 302 (15.2%) of the PALMARES-2 study cohort (n=1982). Compared with younger patients, older patients were less likely to have ECOG PS 0 or bone-only disease, and more likely to receive palbociclib. At multivariable analysis, older patients had better rwPFS when compared to younger patients (aHR 0.77; 95% CI 0.67–0.90, p=0.001). In younger patients, ribociclib and abemaciclib were more effective than palbociclib, whereas in older patients palbociclib showed similar effectiveness to abemaciclib and superior effectiveness to ribociclib (p for interaction <0.001). Among patients treated with palbociclib, older patients had improved rwPFS compared with younger patients (aHR 0.69; 95% CI 0.57–0.84, p<0.001). Conclusion First-line ET plus CDK4/6i is highly effective in older patients with HR+/HER2− aBC. Based on effectiveness and clinical manageability, palbociclib represents a particularly suitable option in this population.

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.

Importance Young BRCA carriers may undergo breast-conserving surgery (BCS) or mastectomy with or without contralateral risk-reducing mastectomy at the time of an index breast cancer diagnosis. A variety of factors may influence surgical decision-making. Objective To explore surgical patterns of care and factors associated with uptake of bilateral mastectomy among affected BRCA1 or BRCA2 ( BRCA1/2 ) carriers diagnosed with early-onset breast cancer. Design, Setting, and Participants The BRCA BCY Collaboration is an international, hospital-based retrospective cohort study conducted at 109 centers across 5 continents. Women aged 40 years or younger with germline pathogenic or likely pathogenic variants in BRCA1/2 who were diagnosed between January 1, 2000, and December 31, 2020, with invasive stage I to III breast cancer were included. Data were collected between January 2022 and June 2024, and analyses were performed between May 21 and 28, 2025. Main Outcome and Measures The main outcome was the evaluation of surgical management as primary treatment for a first diagnosis of invasive breast cancer, defined as BCS, unilateral mastectomy, or bilateral mastectomy. Results Of 5660 eligible BRCA1/2 carriers, 4715 women (median [IQR] age, 35 [31-38] years) had unilateral stage I to III breast cancer with surgical treatment details available. In the cohort, 1805 patients (38.3%) underwent BCS, 1752 (37.2%) underwent unilateral mastectomy, and 1158 (24.6%) underwent bilateral mastectomy. The proportion of BRCA1/2 carriers undergoing BCS decreased over the study period (55.7% [49 of 88] in 2000 vs 27.0% [82 of 304] in 2020), whereas the use of bilateral mastectomy significantly increased (8.0% [7 of 88] in 2000 vs 44.4% [135 of 304] in 2020). Bilateral mastectomy was more common in women who had genetic testing performed before (248 of 435 [57.0%]) or within 6 months (729 of 1892 [38.5%]) of a breast cancer diagnosis compared with those tested after diagnosis (111 of 2167 [5.1%]). On multivariable analysis, compared with those tested after diagnosis, earlier genetic testing was the factor most strongly associated with bilateral mastectomy receipt (testing prior to diagnosis: adjusted odds ratio, 20.72 [95% CI, 15.27-28.13]; testing at diagnosis: adjusted odds ratio, 6.83 [95% CI, 5.39-8.66]). In subgroup analyses, including 2327 patients who had genetic testing performed before or within 6 months of diagnosis, 977 (42.0%) underwent bilateral mastectomy, with the lowest rates reported in Asia and Africa (130 of 499 [26.1%]) and the highest rates reported in North America (233 of 351 [66.4%]). Conclusions and Relevance The findings of this cohort study of young BRCA1/2 carriers suggest that geographic region and timing of genetic testing were the factors most strongly associated with surgical management.

BACKGROUND:Evidence to guide (neo)adjuvant chemotherapy choices in carriers of germline BRCA1/BRCA2 pathogenic variants (BRCA carriers) with early breast cancer (BC) is limited. We evaluated the association of different chemotherapy regimens with survival outcomes in this population. METHODS:The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, retrospective cohort study of BRCA carriers diagnosed with stage I-III BC at age ≤ 40 years, between 2000 and 2020. Disease-free survival (DFS) and overall survival (OS) were assessed among patients with HER2-negative disease treated with anthracycline-taxane, anthracycline-no-taxane, or non-anthracycline (neo)adjuvant chemotherapy. The association of platinum use with outcomes was evaluated in triple-negative breast cancer (TNBC). RESULTS:Among 4200 young BRCA carriers from 109 centres who received (neo)adjuvant chemotherapy for HER2-negative BC, 58.7% had TNBC. Median follow-up was 8.1 years (IQR, 4.7-12.6 years). Anthracycline-taxane, anthracycline-no-taxane, and non-anthracycline regimens were used in 74.4%, 19.3%, and 6.3% of patients, respectively. Platinum agents were administered in 19.8% of TNBC cases. After multivariable adjustment, no significant differences in DFS or OS were observed between anthracycline-no-taxane and anthracycline-taxane regimens (DFS adjusted hazard ratio [aHR] 0.88, 95% CI 0.73-1.05; OS aHR 1.20, 95% CI 0.87-1.67) or non-anthracycline regimens (DFS aHR 1.07, 95% CI 0.82-1.38; OS aHR 1.16, 95% CI 0.68-2.0). In TNBC, platinum use was not associated with improved outcomes. CONCLUSIONS:In young BRCA carriers with HER2-negative early BC, no statistically significant differences in survival outcomes were detected across different chemotherapy regimens. Our findings may inform future prospective studies evaluating chemotherapy de-escalation strategies in this genetically defined population.

Introduction Invasive lobular breast cancer (ILC) is the second most common breast cancer subtype, with distinctive biological and epidemiologic features. Although phase III trials of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive, HER2-negative advanced breast cancer (HR+/HER2- aBC) included patients with ILC, their real-world effectiveness in this population remains poorly characterized. Material and Methods In this sub-analysis of the multicenter, real-world PALMARES-2 study (NCT06805812), we assessed the predictive and prognostic value of lobular histology in HR+/HER2- aBC treated with first-line endocrine therapy (ET) plus CDK4/6i. The primary endpoint was real-world progression-free survival (rwPFS). Associations between histology and outcomes were adjusted for 15 covariates using multivariable Cox-regression and inverse probability of treatment weighting. Results Among 1982 patients, 367 (18.5%) had ILC and 1481 (74.7%) non-special type (NST). Median follow-up was 29.8 and 31.2 months, respectively. ILC was associated with shorter rwPFS versus NST (adjusted hazard ratio [aHR]: 1.24, 95%CI:1.04-1.47, P=0.017). Palbociclib efficacy was not affected by lobular histology (P for interaction=0.553) while abemaciclib was less effective in ILC (P=0.009). All three CDK4/6i achieved similar rwPFS in ILC (ribociclib vs palbociclib: aHR: 1.01, 95%CI: 0.67-1.45, P=0.949; abemaciclib vs palbociclib: aHR: 1.13, 95%CI: 0.75-1.71, P=0.551; abemaciclib vs ribociclib: aHR: 1.15, 95%CI: 0.73-1.80, P=0.549). Conclusions Tumor histology affects the real-world effectiveness of first line ET plus CDK4/6i. In ILC, all three CDK4/6i performed similarly; therefore, treatment selection should prioritize tolerability, manageability, drug-drug interactions, and patient preferences.

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:The benefit of adjuvant chemotherapy in patients with surgically-resected, stage-I TNBC remains controversial, especially when tumors are smaller than 10 mm in maximum diameter. We conducted a meta-analysis to evaluate the impact of adjuvant chemotherapy on survival outcomes in this setting, with prespecified subgroup analyses by pathological tumor size (pT1a/b/c). METHODS:This study followed PRISMA guidelines and was registered in PROSPERO. Literature search from PubMed, EMBASE, Cochrane (2000-2025) and recent conference proceedings was reviewed for studies comparing overall survival (OS) and/or breast cancer-specific survival (BCSS) in stage I TNBC patients receiving adjuvant chemotherapy versus no chemotherapy. Hazard ratios (HR) were pooled using fixed- or random-effects models according to prespecified heterogeneity criteria (Q statistic, P < 0.10 and/or I2 > 25%). Small-study effects and robustness were evaluated with Egger's test and influence diagnostics. RESULTS:Twenty-seven studies including 98,499 patients were analysed. Adjuvant chemotherapy resulted in significantly improved OS (HR 0.53, 95%CI 0.42-0.68; p < 0.001) and BCSS (HR 0.70, 95%CI 0.62-0.79; p < 0.001). In pT1a tumors, we found no benefit in terms of OS (HR 0.97, p = 0.91) or BCSS (HR 1.49, p = 0.12). In pT1b disease, chemotherapy use was associated with improved OS (HR 0.68, p < 0.0001), while no BCSS benefit was observed (HR 1.01, p = 0.94); this subgroup analysis should be interpreted cautiously. Finally, in pT1c tumors, adjuvant chemotherapy was associated with improved OS (HR 0.46, p < 0.0001) and BCSS (HR 0.68, p < 0.001). CONCLUSIONS:In surgically-resected stage I TNBC, the association between adjuvant chemotherapy and better survival appears to vary according to tumor-size, with more consistent benefit in patients with tumors > 5 mm and no significant survival advantage observed in pT1a disease. These findings support a tailored, size-based approach, although the OS results should be interpreted cautiously given the observational nature of the evidence and the substantial heterogeneity of the pooled OS analysis.

e12512 Background: Treatment of stage I HER2-positive breast cancer has shifted toward increased use of taxane-only chemotherapy (CT), which is associated with lower rates of treatment-related amenorrhea and other long-term toxicities. In hormone receptor–positive disease, this evolution may influence outcomes through preserved ovarian function and subsequent adjuvant endocrine therapy (ET) selection. Data focusing on ET type in young premenopausal women are limited. Methods: We identified patients with Stage I breast cancer from a retrospective international multicenter registry of premenopausal women (≤45 years) with HR+/HER2+ early breast cancer treated between 2013-2020 with (neo)adjuvant CT and ET. CT was categorized as multiagent or taxane-only. ET was categorized as tamoxifen alone, tamoxifen with ovarian function suppression (OFS), or aromatase inhibitor with OFS (AI+OFS). The primary endpoint was invasive disease-free survival (IDFS) from ET initiation. Kaplan–Meier estimates were reported at 80 months with log-rank testing. Results: Among 1,231 patients, 258 met inclusion criteria; 246 had complete follow-up data. Median age at diagnosis was 39 years (range 23-45), and median follow-up was 65.2 months (IQR 45.7-86.0). Multiagent CT (92.9% anthracycline-containing) was administered to 168/258 patients (65.1%), taxane-only regimens to 69/258 (26.7%) and CT data were unavailable for 21/258 (8.1%) patients. ET included tamoxifen alone in 117/258 (45.3%), tamoxifen+OFS in 78/258 (30.2%), and AI+OFS in 51/258 (19.8%). Over time, taxane-only CT use increased from 9% (≤2015) to 53% (≥2020), while AI+OFS use increased from 9.3% to 51.4%. Patients treated with taxane-only CT more often received trastuzumab without additional anti-HER2 therapy (100.0% vs 83.3%, p=0.001) and were more likely to receive tamoxifen alone as adjuvant ET (55.1% vs 39.9%, p=0.039). Fourteen IDFS events occurred (14/246, 5.7%); distant recurrences were uncommon (4/246,1.6%). At 80 months, IDFS was 95.0% with multiagent CT and 94.1% with taxane-only CT (p=0.21). By ET type, 80-month IDFS was 91.0% with tamoxifen alone, 97.3% with tamoxifen+OFS, and 100% with AI+OFS (p=0.18). Eighty patients (31.0%) were aged <35 years; neither treatment patterns nor 80-month IDFS differed significantly compared with older patients (91.8% vs 93.7%, p=0.17). Conclusions: In this international real-world cohort of premenopausal women with stage I HR+/HER2+ breast cancer, IDFS at 80 months was high across CT, ET, and age subgroups. As de-escalated taxane-only regimens become more common and ET strategies evolve, these data provide clinically relevant context for systemic therapy selection in young women with excellent-prognosis disease.

BACKGROUND:Higher body mass index (BMI) is a risk factor for breast cancer (BC) development, but the relationship with BC subtypes in pre- and post-menopausal women remains unclear. METHODS:We performed a systematic search from PubMed, Embase and Cochrane databases until 09/24 (CRD42020206108) for cohort and case-control studies assessing the association between BMI and BC subtypes and/or menopausal status. BC risk in overweight (BMI 25-29.9 kg/m2) or obese (BMI≥30 kg/m2) subjects was compared to risk in under/normal weight (BMI<25 kg/m2). BC subtypes were classified as i) ER-positive (regardless HER2-status) ii) ER-negative (regardless HER2-status) iii) HER2-positive (regardless ER-status); iv) triple-negative BC (TNBC). RESULTS:Out of 2841 records screened, 33 studies (9 cohort and 24 case-control) including 2,103,181 women were eligible. Obesity was associated with a modestly increased risk of ER-positive BC (pOR 1.13; 95 % CI 1.03-1.24). In postmenopausal women, obesity was associated with a moderate higher risk of ER-positive BC (pOR 1.29; 95 % CI 1.18-1.41), while overweight was associated with an increased risk of ER-positive (pOR 1.14; 95 % CI 1.06-1.22) and HER2-positive BC (pOR 1.13; 95 % CI 1.05-1.22). In premenopausal women, overweight was linked with reduced risk of ER-positive (pOR 0.80 95 % CI 0.71-0.91) but increased risk of ER-negative BC (pOR 1.15 95 % CI 1.05-1.26) and TNBC (pOR 1.30; 95 % CI 1.15-1.47). CONCLUSIONS:Obesity was associated with a modestly higher risk of ER-positive BC, driven by postmenopausal status. Considering potential confounders, in premenopausal women, higher BMI was associated with lower risk of ER-positive BC, and an increased risk of ER-negative BC.

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 oncological safety of breast-conserving surgery followed by radiation therapy (BCS + RT) in young women carrying pathogenic or likely pathogenic BRCA1/2 variants remains debated, with mastectomy (MS) often favoured despite limited comparative real-world evidence. We evaluated survival and recurrence outcomes associated with different loco-regional strategies in a large international cohort of young BRCA carriers. METHODS:The BRCA BCY Collaboration (NCT03673306) is a retrospective, multicentre cohort including women aged ≤ 40 years with invasive breast cancer and confirmed germline BRCA1/2 variants treated between 2000 and 2020. Outcomes were compared between patients treated with BCS + RT, MS alone, or MS plus RT (MS + RT). Endpoints were overall survival (OS), breast cancer-free interval (BCFI), and second primary breast cancer events, defined as ipsilateral breast recurrence (IBR) or contralateral breast cancer (CBC). Multivariable Cox models were used for OS and BCFI. Competing-risks models were used for IBR/CBC. Models were adjusted for prespecified prognostic factors, and subgroup analyses were conducted by BRCA gene, stage, and tumour grade. RESULTS:Among 4,837 patients, 1,704 (35.2%) received BCS + RT, 1,488 (30.8%) MS alone, and 1,645 (34.0%) MS + RT. After a median follow-up of 8.2 years (IQR 4.8-12.7), OS did not differ between BCS + RT and MS alone (adjusted hazard ratio [aHR] 1.02, 95% CI 0.78-1.34). BCFI was comparable across groups. BCS + RT was associated with a higher risk of second primary breast cancer events compared with MS alone (aHR 1.33, 95% CI 1.07-1.66), particularly in patients with BRCA1 variants and stage III disease. CONCLUSION:In young BRCA1/2 carriers, BCS + RT was not associated with worse OS compared with MS alone, despite a higher risk of second primary breast events. Differences in second primary breast cancer events should be interpreted cautiously given differences in BRCA testing timing and treatment era across groups. These data support individualised loco-regional management within a multidisciplinary framework.

Abstract Introduction: Cyclic fasting and fasting-mimicking diets (FMDs) showed broad antitumor activity in mice with breast cancer (BC), with promising results in patients (pts) enrolled in conpleted or ongoing clinical trials (NCT03340935; NCT03454282; NCT04248998; NCT05763992). However, with the exception of glucose and growth factor modulation, the mechanistic determinants of fasting/FMD antitumor activity are poorly understood. Methods: We combined in vitro and in vivo experiments in BC models with ex vivo analyses of blood and tumor samples collected from BC pts undergoing FMD in the context of clinical trials (NCT03454282; NCT04248998) to investigate the role of lipid metabolism modulation in mediating fasting/FMD antitumor effects. In in vitro experiments, we used six murine and human BC cell lines to study the role of polyunsaturated fatty acids (PUFAs) in affecting cell proliferation (IncucyteS3), survival (propidium iodide), apoptosis (cleaved PARP/caspase 3), lipid peroxidation (malondialdehyde, MDA) and ferroptosis during nutrient starvation. In in vivo experiments, orthotopic mouse BC models (4T1-bearing BALB/c mice, E0771-bearing C57BL/6J mice and MDA-MB-231-bearing NOD-scid IL2rgnull (NSG) mice) were randomized to control conditions (ad libitum diet), intermittent fasting (IF), oral administration of the PUFAs arachidonic acid (AA) or docosaexahenoic acid (DHA), or a combination of IF and PUFAs, with or without carboplatin. We assessed primary tumor growth, lung metastasis formation (through IVIS) and animal survival. Mass Spectrometry analysis was used to quantify plasma and intratumor free fatty acids (FAs), as well as FAs in lipid fractions, in mice and in patients. Results: In both mice and pts (n=112) with BC, fasting/FMD-induced reduction of blood glucose and insulin activated lipolysis in fat tissue, followed by an increase of blood and intratumor AA and DHA. Inhibiting lipolysis through BAY 59-9435 reversed the in vivo antitumor effects of fasting in mice, thus revealing a crucial role of blood FA increase in nutrient starvation antitumor activity. Among several FAs modulated by fasting, AA and DHA accumulate in mitochondrial phospholipids, where they promote radical oxygen species (ROS) formation, lipid peroxidation and ferroptosis. Combining cyclic fasting with AA/DHA administration resulted in cooperative delay of in vivo tumor progression, reduced metastasis formation and prolonged animal survival via ferroptosis activation. These effects were enhanced when chemotherapy was combined with IF plus AA/DHA. Conversely, vitamin E reversed the antitumor effects of nutrient starvation plus AA/DHA. Conclusions: Ferroptosis emerges as a novel determinant of fasting/FMD anticancer activity via PUFA accumulation. Cyclic fasting/FMD plus AA/DHA supplementation is a new, safe and effective antitumor metabolic combination that deserves investigation in phase I/II clinical trials. Citation Format: Claudio Vernieri, Giovanni Fucà, Francesca Ligorio, Laura Tronci, Paola A. Corsetto, Giulia Salvadori, Arta Ajazi, Antonino Belfiore, Andrea Vingiani, Beatrice Cantarelli, Mattia Pavani, Keagile Bati, Lorenzo Drufuca, Saverio Minucci, Pagani Massimiliano, Filippo de Braud, Pruneri Giancarlo, Angela Bachi, Marzia Santamaria. Fasting induces ferroptosis by modulating lipid metabolism in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2008.

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.

Pathologic complete response after neoadjuvant treatment is considered a surrogate of cure in triple-negative breast cancer, yet around 10% of patients still relapse. Whether baseline stromal tumor-infiltrating lymphocytes can stratify this residual risk is unknown. Here, we report on GAMBIT, a multicentric real-world retrospective study of 2457 patients with triple-negative breast cancer or estrogen receptor-low disease, HER2-negative, of whom 1192 obtained a pathological complete response and 690 have evaluable tumor infiltrating lymphocytes. Among patients with pathological complete response, clinical nodal status and tumor infiltrating lymphocytes are independently prognostic and patients with clinical node-positive/low-tumor infiltrating lymphocytes tumors experience substantially worse outcomes, with five-year distant relapse-free survival of 83.4% and overall survival of 85.8%. In this high-risk subgroup, five-year cumulative incidence of central nervous system reaches 7.5%, including 6.9% presenting as isolated central nervous system relapse. In this work, we identify a high-risk subgroup despite pathologic complete response and provide a framework supporting risk-adapted trial design incorporating central nervous system-directed strategies.

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.