HR+乳腺癌转移后逐年OS数据

Background Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. Patients and methods We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2−; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). Results The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2– MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2– and TNBC cohorts, respectively, whatever YOD. Conclusion OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed.

Data on real-world effectiveness of cyclin-dependent kinase 4/6 inhibitor combination therapy versus endocrine therapy alone are limited. The Flatiron Health Analytic Database was used to assess overall survival (OS) in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) metastatic breast cancer (MBC) treated with first-line palbociclib plus an aromatase inhibitor (AI) versus an AI alone in routine US clinical practice. In total, 2888 patients initiated treatment during February 3, 2015–March 31, 2020, with a potential ≥6-month follow-up (cutoff date, September 30, 2020). After stabilized inverse probability treatment weighting, median OS (95% CI) is significantly longer among palbociclib versus AI recipients (49.1 [45.2–57.7] versus 43.2 [37.6–48.0] months; hazard ratio, 0.76 [95% CI, 0.65–0.87]; P  < 0.0001). Progression-free survival (95% CI) is 19.3 (17.5–20.7) versus 13.9 (12.5–15.2) months, respectively (hazard ratio, 0.70 [95% CI, 0.62–0.78]; P  < 0.0001). These data support first-line palbociclib plus an AI treatment for HR+/HER2− MBC. (Trial number NCT05361655).

This article aimed to assess the clinical effectiveness of non-hormonal targeted therapies (TTs) in terms of increase of median progression-free survival (PFS) and overall survival (OS) in receptor-positive metastatic breast cancer (MBC) patients by performing a systematic review and meta-analysis. We systematically searched relevant randomized controlled trials and extracted data about number of patients on targeted and comparator therapy, receptor status, line of treatment, median PFS and OS, p values, hazard ratios (HRs) and 95% confidence intervals (CI). Inverse variance was used to estimate pooled HRs, chi-square test for heterogeneity and Jadad scale for quality were applied. Thirty-eight studies (n=17,192 patients) were eligible for inclusion. TTs added 3.3months to the median PFS [0.7-9.6; HRs 0.74, 95% CI 0.71-0.77] of receptor-positive MBC patients and prolonged their median OS with 3.5months [0-4.7; HRs 0.90, 95% CI 0.82-0.98]. The highest increase in median PFS of 3.6months was found in HER2-/hormone receptor(HR)+ patients, while the highest increase in median OS of 7.2months was observed in HER2+/HRmixed status patients. First-line TTs were most effective in increasing the median PFS in the HR+/HER2- group with 2.0months, and in the HER2+/HRmixed group by adding 4.7months to the median OS. Second-line TTs were most effective for HER2-/HR+ patients by adding 2.6months to their PFS, and for HER2+/HRmixed patients by adding 3.1months to their median OS. Albeit small, the gain in months of median PFS and median OS was significant. Importantly, the results reported show large variation, and thus routinely applying a personalized approach seems warranted.

This study examined biomarker alteration prevalence, treatment patterns, and clinical outcomes among patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) metastatic breast cancer to investigate racial differences. Analysis of 2,384 patients from the Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB) (2017-2022) assessed PIK3CA, AKT1, PTEN, ESR1, and BRCA1/2 alterations via NGS testing. Treatment patterns and overall survival were evaluated. In the study population (13% Black, 87% White), Black patients had lower PIK3CA mutation rates (34% vs. 42%, p = 0.03). In first-line treatment, Black patients were less likely to receive CDK4/6 inhibitors (53% vs. 66%, p < 0.01) and more likely to receive chemotherapy (27% vs. 17%, p < 0.01). After adjustment, Black patients had 38% lower odds of receiving first-line CDK4/6 inhibitors and experienced significantly shorter median overall survival (34.1 vs. 42.1 months, p < 0.01). Significant differences exist in biomarker prevalence, treatment access, and survival outcomes in HR+/HER2− metastatic breast cancer by race, highlighting unmet medical needs.

Cyclin‐dependent kinase 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy are the preferred choice for first‐line treatment of patients with HR+/HER2− locally advanced/metastatic breast cancer (aBC). The CDK4/6i ribociclib in combination with an aromatase inhibitor (AI) or fulvestrant (FUL) has demonstrated significant progression‐free survival (PFS) and overall survival (OS) benefits for pre‐ and postmenopausal aBC patients who were enrolled in the three pivotal MONALEESA trials. Following the initial approval of ribociclib in 2017, the non‐interventional RIBANNA study was initiated to evaluate the effectiveness and safety of ribociclib plus AI/FUL therapy among patients with aBC in a real‐world setting. Two additional treatment cohorts (endocrine monotherapy [ET] and chemotherapy [CT]) were included to extend the knowledge about current aBC treatments. A total of 2567 patients were enrolled in 279 study centers, of whom 1852 were treated with ribociclib+AI/FUL, 183 were treated with ET, and 139 were treated with CT, who were available for effectiveness analyses. Median PFS (mPFS) and median OS (mOS) on first‐line treatment with ribociclib+AI/FUL were 35.0 and 76.0 months, respectively. Adjustment for differences in demographic and baseline characteristics resulted in a longer mPFS on ribociclib+AI/FUL (34.7 months) compared to ET (26.4 months) or CT (19.2 months). Adverse events (AEs) on ribociclib were consistent with those seen in the pivotal trials, and no new safety signals were observed. The RIBANNA study confirmed the PFS and OS benefit seen in the MONALEESA trials. Together with the safety data, this large real‐world dataset supports the favorable risk/benefit profile of ribociclib in large scale patient populations.

To evaluate the efficacy and safety of first-line therapy with palbociclib in a Spanish cohort treated after palbociclib approval. PALBOSPAIN is an observational, retrospective, multicenter study evaluating real-world patterns and outcomes with 1 L palbociclib in men and women (any menopausal status) with advanced HR+/HER2– BC diagnosed between November 2017 and November 2019. The primary endpoint was real-world progression-free survival (rw-PFS). Secondary endpoints included overall survival (OS), the real-world response rate (rw-RR), the clinical benefit rate, palbociclib dose reduction, and safety. A total of 762 patients were included. The median rw-PFS and OS were 24 months (95% CI 21–27) and 42 months (40-not estimable [NE]) in the whole population, respectively. By cohort, the median rw-PFS and OS were as follows: 28 (95% CI 23–39) and 44 (95% CI 38-NE) months in patients with de novo metastatic disease, 13 (95% CI 11–17) and 36 months (95% CI 31–41) in patients who experienced relapse < 12 months after the end of ET, and 31 months (95% CI 26–37) and not reached (NR) in patients who experienced relapse > 12 months after the end of ET. rw-PFS and OS were longer in patients with oligometastasis and only one metastatic site and those with non-visceral disease. The most frequent hematologic toxicity was neutropenia (72%; grade ≥ 3: 52.5%), and the most common non-hematologic adverse event was asthenia (38%). These findings, consistent with those from clinical trials, support use of palbociclib plus ET as 1 L for advanced BC in the real-world setting, including pre-menopausal women and men. NCT04874025 (PALBOSPAIN). Date of registration: 04/30/2021 retrospectively registered.

… the methodological approaches used in key RW studies that compared overall survival with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in metastatic breast cancer (mBC). …

Sacituzumab govitecan (TRODELVY®) is a first-in-class trophoblast cell-surface antigen 2 (Trop-2)–directed antibody and topoisomerase I inhibitor conjugate that is approved globally as monotherapy for the treatment of adults with unresectable locally advanced or metastatic, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−; defined as immunohistochemistry 0, 1+ or 2+ and in situ hybridization-negative) breast cancer who have received endocrine-based therapy and ≥ 2 additional systemic therapies in the advanced setting. In the phase III TROPiCS-02 trial, intravenous sacituzumab govitecan demonstrated statistically significant and clinically meaningful improvements in progression-free survival and overall survival compared with physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine or vinorelbine) in adults with metastatic HR+/HER2− breast cancer. Sacituzumab govitecan had a generally manageable tolerability profile in these patients; the most common treatment-related grade ≥ 3 adverse events included neutropenia, diarrhoea, leukopenia, anaemia, fatigue and febrile neutropenia. Sacituzumab govitecan carries regulatory warnings for severe neutropenia and severe diarrhoea. Sacituzumab govitecan demonstrated an overall benefit in terms of health-related quality of life. Current evidence indicates that sacituzumab govitecan is an effective treatment option, with a generally manageable tolerability profile, for patients with pre-treated, unresectable locally advanced or metastatic HR+/HER2− breast cancer. The most common type of breast cancer is hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−), and management of metastatic (spread to areas near the breast or to other areas) HR+/HER2− breast cancer eventually requires chemotherapy or surgery if resistance develops. Intravenous sacituzumab govitecan (TRODELVY®) is approved globally for adults with inoperable or metastatic HR+/HER2− breast cancer who have previously received endocrine therapy and ≥ 2 additional systemic therapies for advanced disease. In a clinical trial, sacituzumab govitecan therapy significantly improved the duration adults with metastatic HR+/HER2− breast cancer survived without their disease progressing, along with overall survival time, versus standard chemotherapy. The tolerability profile of sacituzumab govitecan was generally manageable; the most common side effects were decreased neutrophil count, diarrhoea and decreased white blood cell count. Sacituzumab govitecan can severely reduce neutrophil count and cause severe diarrhoea. Sacituzumab govitecan demonstrated an overall benefit in terms of health-related quality of life. Current evidence indicates that sacituzumab govitecan is an effective treatment option, with a generally manageable tolerability profile, for patients with pre-treated, inoperable or metastatic HR+/HER2− breast cancer.

Abstract Background The phase III MONALEESA-3 trial (NCT02422615; N = 726) investigated RIB, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, + FUL as first-line (1L) or second-line (2L) treatment for postmenopausal pts with HR+/HER2− ABC. Here we report OS and 1L progression-free survival (PFS) results. Methods Postmenopausal pts with HR+/HER2− ABC were randomized 2:1 to receive RIB + FUL or PBO + FUL in 1L and 2L settings. This is the 2nd of 3 protocol-specified OS analyses. Results At the data cutoff (3 Jun 2019), 153 pts were still on treatment (RIB, n = 121 [25.0%]; PBO, n = 32 [13.2%]); OS was evaluated after 275 deaths (RIB, 167 [34.5%]; PBO, 108 [44.6%]). Median follow-up was 39.4 mo. RIB + FUL demonstrated a statistically significant OS prolongation over PBO + FUL (median, NR vs 40.0 mo; HR, 0.724, 95% CI, 0.568-0.924, P = 0.00455). The result crossed the prespecified Lan DeMets (O’Brien Fleming) stopping boundary (P = 0.01129) for superior efficacy. Per protocol, these OS results will be considered final. OS benefit with RIB vs PBO was consistent across all subgroups, including the 1L subgroup (median, NR vs 45.1 mo; HR, 0.700 [95% CI, 0.479-1.021]) and the early-relapse/2L subgroup (median, 40.2 vs 32.5 mo; HR, 0.730 [95% CI, 0.530-1.004]). In pts receiving 1L treatment, the median PFS (descriptive analysis) with RIB + FUL vs PBO + FUL was 33.6 vs 19.2 mo (HR, 0.546 [95% CI, 0.415-0.718]). Time to progression on next-line therapy or death (PFS2) was also longer with RIB vs PBO (median, 39.8 vs 29.4 mo; HR, 0.670 [95% CI, 0.542-0.830]). The safety profile was consistent with previously published analyses. Conclusions There was a statistically significant OS prolongation with RIB over PBO, which was consistent across all subgroups. The median PFS with RIB in the 1L setting is the longest reported in a phase III trial in HR+/HER2− ABC. These data, combined with results from MONALEESA-7, confirm RIB benefit with multiple combination partners in pre- and postmenopausal pts, and support RIB as a recommended CDK4/6 inhibitor as 1L and 2L treatment in pts with HR+/HER2- ABC. Clinical trial identification NCT02422615. Editorial acknowledgement Editorial assistance in the writing was provided by Tara Wabbersen, PhD, of MediTech Media, LLC, through funding by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure D.J. Slamon: Leadership role, Travel / Accommodation / Expenses: Biomarin; Research grant / Funding (self), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Eli Lilly. S. Chia: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Hoffman-La Roche; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly. P.A. Fasching: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy: Myelo Therapeutics GmbH; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Puma Biotechnology; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Teva; Research grant / Funding (institution): BioNTech AG. M. De Laurentiis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen. S. Im: Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai. K. Petrakova: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Travel / Accommodation / Expenses: BMS. F.J. Esteva: Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy: Celltrion Healthcare ; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (self): GlaxoSmithKline. M. Martin: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy: Roche-Genentech; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: Taiho Oncology ; Research grant / Funding (self): Roche. A. Nusch: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Amgen. G.S. Sonke: Honoraria (institution), Research grant / Funding (institution), institutional reimbursement for patient accrual; institutional reimbursement for education and steering committee activities: Novartis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche. J.T. Beck: Research grant / Funding (institution): Novartis . M. Sondhi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation. Y. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation. A. Chakravartty: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation. K. Rodriguez-Lorenc: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis Pharmaceuticals Corporation. G. Jerusalem: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Puma Biotechnology. All other authors have declared no conflicts of interest.

BACKGROUND This study explored the impact of multiple prognostic factors on patient overall survival (OS) and real-world progression-free survival (rwPFS) for patients with hormone receptor-positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (MBC). MATERIALS AND METHODS This retrospective study used electronic health record data of patients in the United States from community oncology practices from January 1, 2008 to April 30, 2017. Eligibility included HR+/HER2- MBC diagnosis in 2008 or later and prior systemic therapy for MBC. An index variable was created to assess the effect of multiple clinical prognostic factors collectively, including liver metastases (LM), primary endocrine resistance (PER), negative progesterone receptor (PR-) status, and high tumor grade (TG). Patients were grouped based on the number of prognostic factors present at MBC diagnosis: 0, 1, and 2+. Differences in rwPFS and OS from start of first-line therapy were evaluated by the Kaplan-Meier method and multivariable Cox proportional hazards regression. RESULTS Approximately 29.1% of the 378 eligible patient sample had 0, 36.0% had 1, and 34.9% had 2+ prognostic factors. For the patients with 1 of the prognostic factors, 24.3% had high TG, 14.7% were LM+, 39.7% had PER, and 21.3% were PR-. Univariate and multivariate results showed that rwPFS and OS were significantly (P < .05) shorter in patients with 1 and 2+ prognostic factors compared with patients with 0. CONCLUSIONS The individual prognostic factors and the prognostic factor index may enable early identification of patients with a less favorable prognosis across the HR+/HER2- MBC population and help inform treatment decisions in difficult-to-treat populations.

Resistance to endocrine therapy poses a major clinical challenge for patients with hormone receptor-positive (HR +), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC). We present the preplanned 24-month final overall survival (OS) results, alongside updated progression-free survival (PFS), and objective response rate (ORR) results. nextMONARCH is an open-label, controlled, randomized, Phase 2 study of abemaciclib alone or in combination with tamoxifen in women with endocrine-refractory HR + , HER2– MBC previously treated with chemotherapy. Patients were randomized 1:1:1 to: abemaciclib 150 mg and tamoxifen 20 mg (A + T), abemaciclib 150 mg (A-150), or abemaciclib 200 mg and prophylactic loperamide (A-200). OS was the main prespecified secondary endpoint. PFS, ORR, and safety at 24 months were compared to previously reported primary analysis results. Of the 234 patients enrolled, 12 were receiving study treatment at data cutoff (28Jun2019). Median follow-up was 27.2 months. Median OS was 24.2 months in the A + T arm, 20.8 months in A-150, and 17.0 months in A-200 (A + T versus A-200: HR 0.62; 95%CI [0.40, 0.97], P = 0.03 and A-150 versus A-200: HR 0.96; 95%CI [0.64, 1.44], P = 0.83). PFS and ORR results at 24 months were consistent with the primary analysis. The safety profile corresponded with previous reports. The addition of tamoxifen to abemaciclib demonstrated greater OS benefit than monotherapy. This study confirmed the single-agent activity of abemaciclib in heavily pretreated women with endocrine-refractory HR + , HER2– MBC, as well as the previously reported primary PFS and ORR results, with no new safety signals observed. Trial Registration ClinicalTrials.gov Identifier: NCT02747004.

Background Randomized controlled trials have shown inconsistent overall survival (OS) benefit among the three cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) as first-line (1L) treatment of patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC). Several real-world studies compared CDK4/6i effectiveness, with inconsistent findings. This study compared overall survival (OS) of patients with HR+/HER2− mBC receiving 1L palbociclib, ribociclib, or abemaciclib, in combination with an aromatase inhibitor (AI), in US clinical practice. Patients and methods This retrospective study used real-world data from the Flatiron Health electronic health record-derived deidentified longitudinal database. Patients with HR+/HER2− mBC aged ≥18 years at mBC diagnosis started 1L CDK4/6i therapy (index treatment) between February 2015 and November 2023, with a potential ≥6-month follow-up. OS was defined as months from start of index treatment to death. Stabilized inverse probability of treatment weighting (sIPTW; primary analysis) was used to balance baseline patient characteristics. Multivariable Cox proportional hazards model was carried out as a sensitivity analysis. Results Of 9146 eligible patients, 6831, 1279, and 1036 received palbociclib plus AI, ribociclib plus AI, or abemaciclib plus AI, respectively. After sIPTW, baseline characteristics were balanced between treatment groups. After sIPTW, no significant OS differences were found between treatment groups [ribociclib versus palbociclib: adjusted hazard ratio (aHR) 0.98, 95% confidence interval (CI) 0.87-1.10, P = 0.7531; abemaciclib versus palbociclib: aHR 0.95, 95% CI 0.84-1.08, P = 0.4292; abemaciclib versus ribociclib: aHR 0.97, 95% CI 0.82-1.14, P = 0.6956]. Sensitivity analysis including a subanalysis of patients who started index treatment in 2017 or later also showed no significant OS differences between treatment groups. Conclusions This large real-world study suggested that there were no significant OS differences between 1L ribociclib, abemaciclib, and palbociclib in combination with an AI for patients with HR+/HER2− mBC. These findings together with other factors such as safety and quality of life are helpful in the selection of CDK4/6i combination therapy for patients with HR+/HER2− mBC.

Background: This review aims to qualitatively summarize the published real-world evidence (RWE) for CDK4/6 inhibitors (CDK4/6i) approved for treating HR+, HER2-negative advanced/metastatic breast cancer (HR+/HER2- a/mBC). Materials & methods: A systematic literature review was conducted to identify RWE studies of CDK4/6i in HR+/HER2- a/mBC published from 2015 to 2019. Results: This review identified 114 studies, of which 85 were only presented at scientific conferences. Most RWE studies investigated palbociclib and demonstrated improved outcomes. There are limited long-term and comparative data between CDK4/6i and endocrine monotherapy, and within the CDK4/6i class. Conclusion: Available RWE suggests that CDK4/6i are associated with improved outcomes in HR+/HER2- a/mBC, although additional studies with longer follow-up periods are needed.

Purpose Advanced breast cancer is a heterogeneous disease with several well-defined subtypes, among which, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) is most prevalent. Determination of HR and HER2 status influences prognosis and, thus, disease management. Although literature on these prognostic factors exist, especially in the early breast cancer setting, it remains unclear to what extent these factors can guide clinical decision-making in the advanced disease setting. Therefore, we sought to identify the strength and consistency of evidence for prognostic factors in patients with HR+/HER2– advanced breast cancer. Methods A systematic literature review (SLR) of the major electronic databases was conducted in November 2018 for primary research studies published since 2010. Endpoints of interest were tumor response, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS). Results Seventy-nine studies were included wherein all patients were diagnosed with advanced breast cancer and ≥50% of the population were HR+/HER2–. OS was the most commonly assessed endpoint (n=67) followed by PFS (n=33), BCSS (n=5) and tumor response (n=3). The prognostic factors with strongest evidence of association with worse OS were negative progesterone receptor status, higher tumor grade, higher circulating tumor cell (CTC) count and higher Ki67 level, number of metastatic sites (eg multiple vs single) and sites of metastases (eg presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, poor performance status, prior therapy attributes in the early or metastatic setting (type of therapy, treatment line, response of prior therapy), and race (black vs white). The prognostic factors that had strongest evidence of association with PFS included CTC count, number and sites of metastases, and absence of prior therapy or higher lines of therapy in the early or metastatic setting. The directionality of association was consistent for all prognostic factors except between lymph node and OS, and de novo metastatic breast cancer and PFS. Conclusion Multiple disease, treatment, and patient-related prognostic factors impact survival, particularly OS, in patients with HR+/HER2– advanced breast cancer. Treatment outcomes can vary considerably due to these factors. Understanding poorer prognostic factors for patients can result in improved clinical decision-making.

To compare patient characteristics, treatment patterns, and survival between de novo and metachronous metastatic breast cancer (MBC) using nationwide data. A total of 2,366 MBC patients (900 de novo, 1,466 metachronous) diagnosed in 2019 were selected from the Netherlands Cancer Registry. Patient- and tumor characteristics and systemic treatment patterns were compared using chi-squared or Fisher’s exact tests. Overall survival (OS) was compared using Kaplan-Meier curves and Cox proportional hazard analyses. All analyses were stratified by clinical subtype (HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-). For patients with HR+/HER2 − tumors, a sub-analysis examined OS in de novo versus metachronous MBC, stratifying the latter by receipt of prior (neo)adjuvant systemic treatment. De novo MBC patients were younger, had more HER2-positive (22% vs. 11%) and fewer triple-negative tumors (11% vs. 16%). Patients with metachronous MBC more often had CNS metastases and metastases in other localizations than the lymph nodes, bone, visceral organs and CNS. Among HER2 + patients, chemotherapy and targeted therapy were more often administered in de novo versus metachronous MBC. Median OS was longer in de novo MBC for HR+/HER2- tumors (40.8 vs. 30.3 months, aHR 1.27, 95%CI 1.12–1.43) and HR−/HER2 + tumors (51.1 vs. 9.1 months, aHR 1.62, 95%CI 1.03–2.54). In HR+/HER2 − patients, metachronous MBC patients who received prior (neo)adjuvant systemic treatment had worse OS than de novo cases (prior chemotherapy: aHR 1.52, 95%CI 1.29–1.78); prior hormonal therapy only: aHR 1.33, 95%CI 1.10–1.61), whereas those without prior systemic treatment had similar outcomes. De novo and metachronous MBC have different tumor biology, treatment patterns, and survival. In metachronous MBC patients, prior (neo)adjuvant systemic treatment was associated with worse survival compared to de novo MBC or patients with metachronous MBC without prior (neo)adjuvant treatment.

1077 Background: In the clinical trial setting, T-DXd improves survival for patients with HER2+ and HER2-low metastatic breast cancer (MBC), and has also shown preliminary activity in HER2-0 MBC. Little real-world evidence is available on the performance of T-DXd. Methods: We conducted a retrospective observational study using the nationwide Flatiron Health electronic health record (EHR)-derived deidentified database to evaluate the real-world activity of T-DXd. We included patients with MBC who initiated T-DXd between 12/2019 and 1/2023. Tumors were categorized as HER2+ if positive at any timepoint, with HER2- cases further divided into HER2-low (IHC 1+ or 2+ not amplified) and HER2-0 (IHC 0) according to the last biopsy before T-DXd. Real world progression-free survival (rwPFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: A total of 930 patients were included: 636 with HER2+, 268 with HER2-low and 26 with HER2-0 MBC. Among HER2- patients, 241 (82.0%) were HR+ and 53 (18.0%) were HR- (i.e., triple-negative). A total of 572 (61.5%) patients were White, 101 (10.9%) Black/African American, 88 (9.4%) Hispanic/Latino, 37 (4.0%) Asian and 132 (14.2%) other or missing. Median age was 59 [range 25, 84] and patients received T-DXd in the following lines of therapy (LOT): 54 (5.8%) as 1st line, 110 (11.8%) as 2nd line, 179 (19.2%) as 3rd line, 182 (19.6%) as 4th line and 405 (43.6%) as ≥5th line. Median number of LOT for advanced disease prior to T-DXd were 3 and 4, respectively, for HER2+ and HER2- patients. In patients with HER2+ MBC, rwPFS and OS were 12.1 and 26 months after initiating T-DXd, respectively. The longest rwPFS, 14.9 months, was observed in the 1st or 2nd LOT, followed by 14.1 months in LOT 3, 12.4 months in LOT 4, and 10.8 months in LOT ≥5. In patients with HER2- MBC, median rwPFS and OS were 6.3 and 15.5 months, respectively. The longest median rwPFS of 8.1 months was observed in the 1st or 2nd LOTs, followed by 6.9 months in LOT 4, 6.2 months in LOTs ≥5, and 6.0 months in LOT 3. Outcomes with T-DXd by HER2 and HR status are provided (Table). Updated data with a larger sample size will be presented. Conclusions: In the largest dataset to date, T-DXd showed favorable real-world activity for treating MBC, although rwPFS appeared shorter than what observed in clinical trials. Encouraging rwPFS was observed in understudied groups, such as patients with triple-negative and HR+/HER2-0 MBC. [Table: see text]

1059 Background: In the era of modern dual HER2 blockade, the necessity of taxane induction for ER+/HER2+ metastatic breast cancer (MBC) remains debated. While CLEOPATRA established pertuzumab/trastuzumab plus taxane as a standard backbone, emerging de-escalation strategies suggest that endocrine therapy (ET) combined with HER2 blockade may provide durable disease control in this favorable-prognosis subgroup (SYSUCC002, PERTAIN). Robust real-world comparative data addressing the survival–toxicity trade-off between chemotherapy-free versus taxane-induction approaches are limited. Methods: The TriNetX Global Collaborative Network (168 healthcare organizations; data updated Dec 2025) was queried for adults (≥18 years) with incident HR+/HER2+ MBC treated with dual HER2 blockade (trastuzumab + pertuzumab) plus ET. Patients receiving induction taxane (paclitaxel or docetaxel) comprised the induction cohort (IND); those treated with dual blockade + ET without induction comprised the chemotherapy-free cohort (Chemo-Free). 1:1 propensity-score matching (greedy nearest-neighbor; caliper 0.10) on demographics and comorbidities yielded 137 well-balanced pairs (N=274) with all post-match standardized mean differences <0.10. The primary endpoint was 3-year overall survival (OS; 1095-day window). Secondary outcomes included neutropenia, sepsis, heart failure, emergency department (ED) visits, and ICU admission. Results: Among 957 eligible patients, 153 received Chemo-Free and 804 received IND; 137 matched pairs were analyzed. Three-year OS was similar between cohorts with no statistically significant separation of survival curves (3-year OS 89.1% Chemo-Free vs 82.0% IND; HR 0.65 [0.32–1.31]; p=0.219). Deaths within 3 years were 13/137 (9.5%) in Chemo-Free versus 19/137 (13.9%) in IND, corresponding to an absolute death risk difference of −4.4% (95% CI −12.0% to +3.2%). Omitting induction was associated with reduced neutropenia (12.4% vs 21.9%; absolute risk reduction 9.5%; OR 0.51 [0.26–0.97] and a lower time-to-neutropenia hazard (HR 0.50 [0.28–0.91]; p=0.020). Serious adverse events and acute care utilization were not increased with Chemo-Free: heart failure 16.1% vs 16.1%; sepsis 10.9% vs 13.1%; ICU admission 11.7% vs 13.9%; ED visits 40.9% vs 45.3%. Conclusions: In a propensity-matched real-world cohort receiving contemporary dual HER2 blockade plus ET, a chemotherapy-free strategy demonstrated similar 3-year OS compared with taxane induction, with a clinically meaningful reduction in neutropenia (number needed to treat ≈11 to prevent one event) and no signal for higher sepsis, heart failure, or acute care utilization. These data support the feasibility of chemotherapy de-escalation in selected HR+/HER2+ MBC patients and motivate prospective validation to refine patient selection and minimize treatment-related toxicity.

1084 Background: Oral selective estrogen receptor degraders (SERDs) are designed to overcome endocrine resistance in HR+ HER2- breast cancer due to ESR1 mutations. Several SERDs have been evaluated in recent trials. We performed a meta-analysis evaluating oral SERDs in previously treated patients with HR+ HER2- metastatic breast cancer (MBC). Methods: Randomized controlled trials comparing oral SERDs to standard endocrine therapy in previously treated HR+, HER2- MBC, reporting progression-free survival (PFS) or overall survival (OS) and adverse events (AEs), were identified via a systematic PubMed search. To incorporate the latest SERDs data, results from the recently presented giradestrant trial were included. Meta-analysis was performed for the overall intention-to-treat (ITT) population and the ESR1-mutant (ESR1m) subgroups. Leave-one-out analyses excluding giradestrant were conducted to highlight its specific impact. Rates of serious adverse events (grade ≥3) and treatment discontinuation were also analyzed. Results: A total of 2324 patients from six phase III trials were included in this analysis. Oral SERDs improved PFS compared with standard endocrine therapy in the ITT population (HR 0.734, CI 0.620-0.869, p<0.001) with greater benefit observed in the ESR1m subgroup (HR 0.538, CI 0.430-0.673, p<0.001). Excluding giradestrant data from the evERA trial led to modest reduction in PFS benefit in both the ITT (HR 0.755, CI 0.661-0.908, p<0.05) and the ESR1m (HR 0.582, CI 0.471-0.718, p<0.05) subsets, though overall PFS benefit remained. Additionally, SERDs were associated with an OS advantage in pooled analyses for the ITT population (HR 0.743, CI 0.621-0.889, p<0.05) and ESR1m population (HR 0.584, CI 0.433-0.768, p<0.001). Excluding giradestrant did not result in significant changes in OS estimates. Grade ≥3 AEs were more frequent with SERDs (OR 1.53, CI 1.20-1.95, p<0.001) while discontinuation rates were similar between groups (OR 1.53, CI 0.99-2.37, p=0.06). Conclusions: Oral SERDs significantly improve PFS in previously treated HR+ HER2- MBC with the greatest benefit in patients with ESR1 mutations. Pooled analysis suggests an OS advantage favoring SERDs. Giradestrant contributes to the observed PFS class effect without altering OS outcomes. SERDs are associated with increased toxicity. Although a trend towards higher discontinuation rates was noted, it did not reach statistical significance, and discontinuation rates remain comparable to standard endocrine therapy. These findings support the use of oral SERDs in the second- and third-line treatment of HR+ HER2- MBC, particularly in ESR1-mutant disease.

This cohort study investigates the association of hormone receptor status and first-line endocrine therapy with survival among patients with hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–positive (ERBB2+ metastatic breast cancer.

Background Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2− MBC. Methods A systematic literature review of RCTs in HR+, HER2− MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson’s product–moment correlation and Spearman’s rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]). Results Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P=0.000; Spearman =0.650, P=0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R2 of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5–6 months of incremental PFS/TTP. Conclusion We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2− MBC.

Background Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We have evaluated the clinicopathologic characteristics and genomic profiles of real-world hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) patients to examine the determinants of outcome for younger vs. older patients in a single clinical subtype undergoing treatment in the same clinic. Patients and methods This study included patients presenting at the Peking University Cancer Hospital with primary stage IV or first-line metastatic HR+/HER2- breast cancer who consented to an additional blood draw for genomic profiling prior to treatment. Plasma samples were analyzed with a targeted 152-gene NGS panel to assess somatic circulating tumor DNA (ctDNA) alterations. Genomic DNA (gDNA) extracted from peripheral blood mononuclear cells was analyzed for germline variants using a targeted 600-gene NGS panel. Kaplan-Meier survival analysis was performed to analyze disease free survival (DFS), progression free survival (PFS) and overall survival (OS) in association with clinicopathologic and genomic variables. Results Sixty-three patients presenting with HR+/HER2- MBC were enrolled in this study. Fourteen patients were < 40 years, 19 were 40-50 years, and 30 were > 50 years at the time of primary cancer diagnosis. No significant associations were observed between age and DFS, PFS or OS. Shorter OS was associated with de novo Stage IV disease (p = 0.002), Luminal B subtype (p = 0.006), high Ki67 index (p = 0.036), resistance to adjuvant endocrine therapy (p = 0.0001) and clinical stage (p = 0.015). Reduced OS was also observed in association with somatic alterations in FGFR1 (p = 0.008), CCND2 (p = 0.012), RB1 (p = 0.029) or TP53 (p = 0.029) genes, but not in association with germline variants. Conclusion In this group of real-world HR+/HER2- MBC breast cancer patients younger age was not associated with poor outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients.

1055 Background: Cyclin-dependent kinase 4/6 inhibitors (CDKI) are FDA-approved for use in combination with aromatase inhibitors (AI) for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced or metastatic breast cancer (MBC) as initial (1L) endocrine-based therapy. We have previously reported the pooled analyses of the benefit in progression-free survival of adding CDKI to AI, and here report the pooled overall survival (OS) results for adults treated with CDKI + AI for 1L HR+/HER2- MBC. Methods: We pooled individual patient data (N=2252) from 4 randomized trials (MONALEESA-2 & 7, MONARCH-3, PALOMA-2) of a CDKI (abemaciclib, palbociclib, ribociclib) or placebo + AI in adults with 1L HR+/HER2- MBC. OS was defined as time from randomization to death from any cause and was a key secondary endpoint in all 4 trials. Not all 4 trials reached OS statistical significance, but all OS hazard ratios of the individual trials were <1. The median OS was estimated using Kaplan-Meier methods, and hazard ratios with 95% confidence intervals (CI) were estimated using Cox regression models. Analyses were prespecified, with patients analyzed collectively and by various clinicopathological subgroups of interest. Results: Overall results in all patients and various clinicopathologic subgroups of interest are shown (Table). Conclusions: In this descriptive exploratory pooled analysis, the addition of a CDKI to AI suggested an association with an OS benefit for this class of drugs used as a component of 1L endocrine-based therapy for adults with HR+/HER2- MBC. Additional research is needed to determine which subgroup of patients may benefit more or less of the addition of a CDKI to AI. n # Events CDKI/n (%) # Events Placebo/n (%) HR (95% CI) All 2252 716/1320 (54) 550/932 (59) 0.81 (0.73, 0.91) PR negative 273 84/155 (54) 89/118 (75) 0.51 (0.38, 0.70) De Novo 752 233/450 (52) 173/302 (57) 0.82 (0.67, 1.00) Lobular Histology 144 72/97 (74) 34/47 (72) 0.99 (0.66, 1.50) Bone-Only 493 142/284 (50) 115/209 (55) 0.74 (0.58, 0.95) Liver/Lung Mets 1111 365/639 (57) 291/472 (62) 0.81 (0.70, 0.95) Age <40 193 40/106 (38) 44/87 (51) 0.78 (0.51, 1.21) Age >70 403 159/247 (64) 106/156 (68) 0.86 (0.67, 1.09) ECOG 1 851 305/499 (61) 239/352 (68) 0.78 (0.66, 0.93) White 1594 529/919 (58) 407/675 (60) 0.88 (0.77, 1.00) Asian 438 113/269 (42) 89/169 (53) 0.59 (0.45, 0.78) Black or African American 43 14/25 (56) 11/18 (61) 0.80 (0.36, 1.76) Additional clinicopathologic subgroup analyses conducted with results not shown.

Objective. To compare the real-world effectiveness of everolimus-based therapy and chemotherapy in postmenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor-2-negative (HR+/HER2−) metastatic breast cancer (mBC). Methods. This retrospective chart review examined a nationwide sample of postmenopausal HR+/HER2− mBC women in community-based oncology practices. Patients received everolimus-based therapy or chemotherapy for mBC between 07/01/2012 and 04/15/2013, after failure of a non-steroidal aromatase inhibitor. Overall survival (OS), progression-free survival (PFS), and time on treatment (TOT) were compared using Kaplan-Meier analysis and Cox proportional hazards models adjusting for line of therapy and baseline characteristics. Results. 234 and 137 patients received everolimus-based therapy and chemotherapy. Patients treated with everolimus-based therapy tended to have less aggressive mBC than patients treated with chemotherapy. Multivariate-adjusted Cox models showed that everolimus-based therapy was associated with significantly longer OS [hazard ratio (HR) = 0.37, 95% confidence interval (CI): 0.22–0.63], PFS (HR = 0.70, 95% CI = 0.50–0.97), and TOT (HR = 0.34, 95% CI: 0.25–0.45) than chemotherapy. Adjusted comparative effectiveness results were generally consistent across lines of therapy. Conclusion. In this retrospective chart review of postmenopausal HR+/HER2− mBC patients, treatment with everolimus-based therapy was associated with longer OS, PFS, and TOT than chemotherapy.

BackgroundHormone receptor-positive, human epidermal growth factor receptor-2-negative (HR+/HER2−) is the most common type of metastatic breast cancer (mBC). While mBC patients generally have poor prognosis with limited progression-free survival (PFS) and overall survival (OS), those with multiple metastatic sites may have even worse clinical outcomes due to multiple organ involvement. This study aimed to compare clinical outcomes including PFS, time on treatment (TOT), and OS between HR+/HER2− mBC patients with multiple metastases versus those with a single metastasis in a real-world clinical setting.MethodsThis was a retrospective chart review study of postmenopausal HR+/HER2− mBC women who had failed a non-steroidal aromatase inhibitor in the adjuvant or metastatic setting and initiated a new treatment for mBC between 07/01/2012 and 04/15/2013. Patients were classified to one of two study groups (multiple metastases or single metastasis) based on the number of non-lymph-node metastases at the initiation of the new treatment. PFS, TOT and OS were compared between the two groups using Kaplan–Meier analyses and multivariable Cox proportional hazard models adjusting for patient disease and treatment characteristics. Separate Cox models were conducted including models with an interaction term between line of therapy and study group to assess the impact of multiple metastases on clinical outcomes across different lines of therapy.ResultsA total of 699 patient charts were collected, including 291 patients with multiple metastases and 408 single metastasis patients. Worse performance status and a higher proportion of prior chemotherapy for mBC were observed among patients with multiple metastases. Overall, patients with multiple metastases had significantly shorter PFS [adjusted hazard ratio (HR) = 1.55, 95 % confidence interval (CI) 1.21–1.98], TOT (adjusted HR = 1.33, 95 % CI 1.05–1.67), and OS (adjusted HR = 1.77, 95 % CI 1.15–2.74) than single metastasis patients. Similar outcomes were observed in each line of therapy.ConclusionsAmong HR+/HER2− mBC patients, patients with multiple metastases had significantly shorter PFS, TOT, and OS than single metastasis patients, highlighting the substantial clinical burden and unmet need for more efficacious treatments for the former group of patients.

Prognostic factors are well established in early-stage breast cancer (BC), but less well-defined in advanced disease. We analyzed 323 BC patients who had distant relapse during follow…

The purpose of the present study was to analyze the clinical and pathological characteristics, treatment, and prognosis of de novo metastatic breast cancer (DnMBC). Information regarding 1,890 patients treated for advanced breast cancer at the Tianjin Medical University Cancer Hospital between January 2008 to December 2017 was collected. Clinicopathological characteristics, treatments and outcomes of these patients were compared using the chi-square test, log-rank test, and Cox regression analysis. A total of 171 patients were diagnosed with DnMBC. The median age at diagnosis was 53 years (range, 23–77). The percentage of T4 staging was higher (37.4%), 69.6% of patients were estrogen receptor (ER) positive, 59.1% were progesterone receptor positive, 29.8% had positive human epidermal growth factor receptor 2 (HER2) status, 68.4% had Ki-67 ≥20%, 55% had oligometastasis at the initial diagnosis, ~87.7% were treated with chemotherapy initially and 24% received palliative surgery for the primary tumor. After a median follow-up time of 26 months, the median progression-free survival (PFS) and overall survival (OS) among patients with DnMBC were 11 (8.7–13.3) months and 34 (27.9–40.1) months, respectively. In the multivariable model, ER status and sites of first metastasis (oligometastasis or polymetastasis) were identified to be independent predictors of PFS (P<0.05); ER status, primary tumor stage, and surgical treatment of primary tumors were identified to be independent predictors of OS (P<0.05). In conclusion, the clinicopathological characteristics of DnMBC are greater invasiveness and a higher risk of progression. Palliative surgical treatment may improve the prognosis of HR+/HER2-patients with oligometastasis. Therefore, individualized treatment as required is particularly important.

Summary Background Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) combined with endocrine therapy are the standard of care for metastatic hormone receptor–positive, HER2-negative breast cancer (HR+ MBC). However, systemic therapy options and outcomes after progression on CDK4/6is remain poorly defined. We analyzed real-world treatment patterns and outcomes in patients with advanced HR+ MBC who received systemic therapy following CDK4/6i progression. Methods We identified all patients with HR+ MBC treated at MD Anderson Cancer Center between January 1, 1997, and December 31, 2024. Kaplan–Meier and log-rank tests compared PFS and OS across post-CDK4/6i therapies, and a multivariable Cox model assessed prognostic factors. Findings Among 1826 patients (99% female; median follow-up, 32.4 months), the median age at metastatic diagnosis was 56 years, and most were White (72%),with 10% Black, 9% Hispanic, 6% Asian/Pacific Islander, and <1% Native American. Following progression on CDK4/6is, 43% received chemotherapy, 38% targeted therapy, 12% endocrine therapy alone, and 7% investigational agents. Nearly half (48%) had visceral progression. Median PFS on subsequent therapy was 4.73 months (95% CI, 4.40–4.96), with no significant difference by therapy type. CDK4/6i duration ≥12 months was independently associated with improved PFS (HR 0.86; p = 0.021). Interpretation Following CDK4/6i progression, most patients received chemotherapy, but PFS did not differ significantly across post-CDK4/6i treatment types. As CDK4/6is remain frontline therapy, further studies are needed to optimize treatment sequencing and improve post-CDK4/6i outcomes. Funding 10.13039/100000005Department of Defense grant (HT9425-24-1-0991) and the 10.13039/100000054National Cancer Institute MDACC Support Grant (P30 CA016672).

Simple Summary Hormone receptor-positive, HER2-negative metastatic breast cancer is the most common form of advanced breast cancer. Palbociclib combined with hormone therapy has shown strong benefits in clinical trials, but local real-world data from Saudi Arabia are limited. This study evaluated the effectiveness and safety of palbociclib in 169 women treated at a large cancer center in Riyadh. The results showed that many patients achieved good disease control and meaningful survival outcomes. Side effects were generally manageable, with neutropenia being the most frequent, but serious complications were uncommon. These findings confirm that palbociclib is an effective and tolerable treatment option in routine clinical practice and provide important regional evidence to support treatment decisions for women with advanced breast cancer.

Background The ABC 6/7 guidelines recommend megestrol acetate (MA) as a later-line hormonal option for HR+/HER2− metastatic breast cancer (MBC) when targeted therapies are unavailable, though current evidence on its efficacy and safety remains limited. Materials and methods This retrospective study assessed the effectiveness and tolerability of MA (200–400 mg) in HR+/HER2− MBC patients treated at the reference Cancer Center in Poland (January 2020–December 2024). Patients on other systemic therapies or with active malignancies were excluded. Median progression-free survival (mPFS) and overall survival (mOS) were assessed using Kaplan–Meier estimates and Cox proportional hazards models. Statistical significance was defined as p < 0.05. Results The study included 20 patients (median age: 70.2 years; range: 49.5–92.4) with a median follow-up of 4.5 months [interquartile range (IQR): 0.34–9.99]. Patients had received a median of 2.5 prior systemic therapies (IQR: 1–5) and 2 prior hormonal therapy lines (IQR: 0–4). Eleven patients (55.0%) had exhausted hormonal options, and eleven (55.0%) were ineligible for chemotherapy, including eight (40.0%) with no other systemic treatment options. mPFS was 2.6 months [95% confidence interval (CI): 1.37–4.32], and mOS, 4.1 months (95% CI: 1.5–10.8). Performance status 2–4 was associated with higher risk of progression or death [hazard ratio (HR) = 2.75] and death (HR = 9.42) vs. PS 1. One grade 2 thromboembolic event occurred. Conclusions Despite the small sample size, the observed outcomes support the continued inclusion of MA in ABC guidelines for the treatment of HR+/HER2− MBC, further substantiated by the comprehensive review of clinical evidence and recommendations presented in this article.

… Survival outcomes were estimated using the Kaplan— Meier method and compared using Cox regression. Analyses … Methods: We retrospectively analyzed HR+/HER2 MBC pts …

Abstract Background Real-world data are limited for patients with brain metastases secondary to metastatic breast cancer (MBC) and treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). This study describes real-world outcomes in patients with hormone receptor-positive, human epidermal growth factor 2-negative (HR+/HER2−) MBC with brain metastases diagnosis before abemaciclib initiation. Patients and Methods A nationwide electronic health record-derived de-identified MBC database (January 2011-December 2021) was assessed retrospectively. Patients with HR+/HER2− MBC who were treated with abemaciclib (monotherapy or in combination) following diagnosis of brain metastases were included. Real-world best response reflected clinician-documented response assessment of the brain imaging (intracranial) and change in disease burden following radiographic imaging (extracranial); these were reported descriptively. Time to treatment discontinuation (TTD), real-world progression-free survival (rwPFS), and overall survival (rwOS) were assessed using Kaplan-Meier methods from abemaciclib initiation (index date). Results Among 82 included patients (mean age 57.0 years; 98.8% female), 22.0% and 19.5% received CDK4/6i and chemotherapy before abemaciclib initiation, respectively, and the majority (80.5%) received radiation/local surgery to the brain before abemaciclib initiation. Patients mostly received abemaciclib as monotherapy (n = 6) or in combination with endocrine therapy (n = 68). Median TTD was 7.1 (95% CI 4.6-11.3) months, rwPFS was 9.2 (95% CI 6.0-11.6) months, and rwOS was 20.8 (95% CI 13.9-26.0) months. Intracranial and extracranial objective response rates, as determined by treating physicians, were 45.1% (n = 23/51) and 56.7% (n = 34/60), respectively. Intracranial and extracranial clinical benefit rates were 62.7% (n = 32/51) and 70.0% (n = 42/60), respectively. Conclusion In this real-world study of patients diagnosed with brain metastases and initiating abemaciclib, most patients received radiation/local surgery to the brain before abemaciclib initiation. Although the outcomes in this real-world study are encouraging, it is unclear if the benefit was due to local therapy, abemaciclib, or the combination, and causality cannot be inferred. Further prospective clinical studies are needed to confirm the clinical benefit of this approach.

Objectives: To analyze differences in overall survival (OS) between male breast cancer (MBC) and female breast cancer (FBC) according to tumor subtype compared with other factors. Materials and Methods: We evaluated men and women with breast cancer between 2010 and 2013 with known hormone receptor (HR) status and human epidermal growth factor receptor 2 (HER2) status reported to the National Cancer Institute’s Surveillance, Epidemiology, and End Results program. Patient characteristics were compared between groups. Univariate and multivariate analyses were performed to determine the effect of each variable on OS. Breast cancer–specific survival was a secondary endpoint. Results: We included 1187 MBC and 166,054 FBC. Median follow-up was 21 months (range, 1 to 48) for both groups. OS at 3 years for MBC and FBC was 85.6% and 90.4%, respectively (P=0.0002). MBC were more ductal, had higher grade, presented with more advanced stage and were often HR+/HER2− (each P<0.0001). MBC had worse OS than FBC in HR+/HER2− (Hazard ratio [HaR], 1.5; P=0.0005), HR+/HER2+ (HaR, 2.8; P<0.0001) and triple negative (HaR, 4.3; P<0.0001) (Pinteraction<0.02). MBC had significantly worse OS than FBC in stages I and II, but similar OS in stages III and IV (Pinteraction<0.01). In multivariate analysis, HR+/HER2+ was the only subtype with significant differences in OS between MBC and FBC (HaR, 2.0; P=0.002). Conclusions: OS was significantly different in both groups. Men had worse OS in early stages while similar OS in stages III and IV. There were significant differences in OS according to tumor subtype; compared with women, men with HR+/HER2+ tumors had twice the risk of death.

Background: Palbociclib (PAL), the first CDK4/6i, in combination with endocrine therapy (ET) was approved for HR+/HER2- advanced/metastatic breast cancer (MBC) in 2015. Two additional CDK4/6is, Ribociclib (RIB) and Abemaciclib (ABE), were approved in 2017. CDK4/6i combination therapy has become standard of care for 1st line HR+/HER2- MBC. Randomized clinical trials (RCT) demonstrated that the 3 CDK4/6is plus ET vs ET plus placebo all significantly prolonged patients’ progression free survival (PFS, primary endpoint). However, the 3 CDK4/6is have inconsistent 1st line RCT overall survival findings (OS, secondary endpoint). In the absence of head-to-head RCTs, real-world data (RWD) is an important complementary source of evidence. Several small RWD studies have evaluated the relative effectiveness between CDK4/6is, and their findings are inconsistent. Large RWD studies are needed to understand the effectiveness of the 3 CDK4/6is. This study compared OS of 1st line PAL vs RIB and ABE plus AI for HR+/HER2- MBC in routine US clinical practice. Methods: We conducted a retrospective comparative effectiveness study of CDK4/6is plus AI in HR+/HER2-MBC using the US nationwide Flatiron Health electronic health record (EHR)-derived deidentified Panoramic database, comprised of >650k patients with breast cancer. Patients included had HR+/HER2- MBC, were ≥18 years, started index treatment (PAL+AI, RIB+AI, or ABE+AI) as 1st line therapy within 90 days of MBC diagnosis between February 2015 and September 2023 (index period), and did not participate in clinical trials. Patients were assessed from start of index treatment to March 2024, death, or last medical activity, whichever came first. OS was defined as months from start of index treatment to death. Patients were balanced via exact 1:1 matching on age, gender, race and ethnicity, practice type, disease stage at initial diagnosis, ECOG, time from initial to MBC diagnosis, visceral disease, bone-only disease, and number of metastatic sites. Kaplan-Meier method and Cox proportional hazard regression model were used to analyze OS. Results: Of 9770 patients eligible for the analysis, 7563, 1130, and 1077 patients received PAL+AI, RIB+AI, and ABE+AI, respectively. Median follow-up was 32.9 months for PAL+AI, 16.5 months for RIB+AI, and 21.3 months for ABE+AI treated patients. Compared with RIB and ABE groups, PAL group was 1-2 years older and had a lower proportion of patients with ECOG=0. After 1:1 matching, baseline demographics and clinical characteristics were well balanced between PAL vs RIB pairs (n=942) and PAL vs ABE pairs (n=857). In PAL-RIB pairs, 2- and 3-year OS rates were 81.3% and 67.6% for PAL group vs 79.8% and 69.7% for RIB group. In PAL-ABE pairs, 2- and 3-year OS rates were 76.8% and 63.0% for PAL group vs 75.7% and 67.4% for ABE group. Compared with PAL+AI, RIB+AI was not significantly associated with prolonged OS (unadjusted HR=0.90, 95%CI=0.80-1.02, p=0.097; matched HR=0.98, 95%CI=0.84-1.15, p=0.823). Similarly, ABE+AI vs PAL+AI was not significantly associated with prolonged OS (unadjusted HR=0.95, 95%CI=0.84-1.07, p=0.376; matched HR=0.90, 95%CI=0.77-1.06, p=0.212). Further analyses with additional follow-up, treatment duration, subsequent therapies, and time to chemotherapy will be reported. Conclusions: Our findings suggest that there is no significant OS superiority of first-line RIB+AI and ABE +AI compared to PAL+AI for HR+/HER2- MBC patients in routine clinical practice in the US. Although the sample size precludes a formal non-inferiority analysis and short follow up may limit interpretation, this study represents the largest real-world comparative analysis of OS between the CDK 4/6is in combination with AI conducted to date. Citation Format: Hope S. Rugo, Rachel M. Layman, Filipa Lynce, Xianchen Liu, Benjamin Li, Lynn McRoy, Aaron B. Cohen, Melissa Estevez, Giuseppe Curigliano, Adam Brufsky.Comparative overall survival of CDK4/6is plus an aromatase inhibitor (AI) in HR+/HER2- MBC in the US real-world setting [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS2-03.

AIM Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort. METHODS ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts. RESULTS Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P < .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively). CONCLUSIONS The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.

Summary Background This study aims to evaluate whether changes in therapeutic strategies have improved survival of patients diagnosed with hormone receptor positive (HR+), HER2 negative (HER2−) advanced breast cancer (ABC) in real-world. Methods All 1950 patients systemically treated for HR+/HER2− ABC and diagnosed between 2008 and 2019 in eight hospitals were retrieved from the SONABRE Registry (NCT-03577197). Patients were categorized per three-year cohorts based on year of ABC diagnosis. Tests for trend were used to examine differences in baseline characteristics, Kaplan–Meier methods and Cox proportional hazards for survival analyses, and competing-risk methods for 3-year use of systemic therapy. Findings Over time, patients were older (≥70 years, 37%, n = 169/456 in 2008–2010, 47%, n = 233/493 in 2017–2019, p = 0.004) and more often had multiple metastatic sites at ABC diagnosis (48%, n = 220/456 in 2008–2010, 56%, n = 275/493 in 2017–2019, p = 0.002). Among patients with metachronous metastases the prior exposure to (neo-) adjuvant therapies increased over time (chemotherapy, 38%, n = 138/362 in 2008–2010, 48%, n = 181/376 in 2017–2019, p = <0.001; endocrine therapy, 64%, n = 231/362 in 2008–2010, 72%, n = 271/376 in 2017–2019, p = <0.001). Overall survival significantly improved from median 31.1 months (95% CI:28.2–34.3) for patients diagnosed in 2008–2010 to 38.4 months (95% CI:34.0–41.1) in 2017–2019 (adjusted hazard ratio = 0.76, 95% CI:0.64–0.90; p = 0.001). Three-year use of CDK4/6 inhibitors increased from 0% for patients diagnosed in 2008–2010 to 54% for diagnosis in 2017–2019. Conversely, three-year use of chemotherapy was 50% versus 36%, respectively. Interpretation Over time, patients diagnosed with HR+/HER2− ABC presented with less favourable patient characteristics. Nevertheless, we observed that overall survival of ABC increased between 2008 and 2019, with increased use of endocrine/targeted therapies. Funding The SONABRE Registry is supported by the Netherlands Organization for Health Research and Development (ZonMw: 80-82500-98-8003); 10.13039/100004336Novartis BV; 10.13039/100004337Roche; 10.13039/100004319Pfizer; and 10.13039/100004312Eli Lilly & Co. Funding sources had no role in the writing of the manuscript.

Background: Everolimus was the first orally targeted therapy for certain cancers. It was introduced before CDK4/6 inhibitors and is widely used to treat advanced hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. This study presents comprehensive findings including updated data and long-term survival analyses focusing on patients with HR+/HER2− metastatic breast cancer who received everolimus-based treatment. The objectives were to assess the impact of everolimus on overall survival (OS) and progression-free survival (PFS) by treatment line, and to evaluate its role in therapeutic strategies in a real-world setting. Methods: We included 299 women aged over 20 years with histologically confirmed HR+/HER2− breast cancer who received everolimus-based treatment from multiple medical centers in Taiwan. Survival curves were generated using the Kaplan-Meier method, with the log-rank test for comparisons. Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. Adverse effects were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Results: The median PFS was 5.6 months, and the median OS was 60.1 months. Patients receiving everolimus treatment in three or more lines and those who underwent chemotherapy before everolimus-based treatment had a significantly shorter PFS but longer OS. Patients with liver and central nervous system metastases had significantly shorter PFS and OS. The disease control rate was 51.5%, and the overall response rate was 8.0%. Conclusion: These findings support current guidelines and advocate for the inclusion of everolimus in treatment plans for patients with metastatic HR+/HER2− breast cancer, particularly in late-line treatment, with careful consideration of the benefit-risk profile for each patient.

Background Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification). Methods We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan–Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman’s correlation coefficient. Analyses were conducted by tumor subtype. Results 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8–6.2) for HR-/HER2 − subtype to 13.3 months (36% CI 12.7–14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR − /HER2 − mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies. Conclusions Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates.

Background Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2−) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody–drug conjugates. Patients and methods This retrospective, observational study included adults with HR+/HER2− mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment. Results Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had de novo mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment. Conclusions This real-world study demonstrates that for patients with HR+/HER2− mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options.

De novo metastatic breast cancer (dnMBC) accounts for ~6–10% of all breast cancers and for ~30% of MBC with increasing incidence over time. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) tumours are the most frequent subtype with a similar incidence to that observed amongst recurrent MBC (rMBC). Higher frequency of PI3KCA and ARID2 mutations and a lower frequency of ESR1 mutations and of genes involved in DNA damage, as compared with rMBC, have been reported in HR+/HER2− dnMBC; however, these are not correlating with prognosis, whilst tumour mutational burden is inversely correlated with outcome. Bone represents the most frequent metastatic site, being the single site in up to 60% of patients with dnMBC. HR+/HER2− dnMBC has been generally reported to have better outcomes than rMBC, with a median overall survival ranging from 26 months to nearly 5 years in patients with favourable features such as age <40 years and bone-only disease, but not when compared with patients with late recurring disease (≥2–5 years). Analyses of the de novo cohorts within randomized clinical trials and large real-world series report a better outcome after treatment with CDK4/6 inhibitors and endocrine agents as compared to rMBC. Despite the limitations of retrospective studies and controversial results of the randomized trials, locoregional treatment of the primary tumour after response to systemic therapy appears to confer a survival benefit, particularly in patients with favourable prognostic factors. Altogether genomic, biological and clinical findings highlight HR+/HER2− dnMBC as a peculiar entity as compared with rMBC and deserve a dedicated treatment algorithm. This article is part of the Tackling clinical complexity in breast cancer Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/

Metastatic breast cancer (MBC) is the leading cause of cancer-related morbidity and mortality among women worldwide. Endocrine therapy is the standard of care for the most common subtype of MBC, hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) disease. Advances in treating this type of MBC have focused on improving the efficacy of endocrine therapy by adding agents that target specific molecular pathways of breast cancer cell growth and survival. The combination of the aromatase inhibitor exemestane and the mammalian target of rapamycin inhibitor, everolimus, more than doubled median progression-free survival compared with exemestane alone (7.8 vs 3.2 months, respectively; hazard ratio 0.45 [95% confidence interval 0.38-0.54]; log rank P < 0.0001) in the BOLERO-2 study in postmenopausal women with HR+, HER2- locally advanced or metastatic breast cancer that had recurred or progressed on prior non-steroidal aromatase inhibitor therapy. In addition, everolimus plus exemestane was associated with a manageable safety profile. The results of BOLERO-2 led to regulatory approval of everolimus plus exemestane. Additional everolimus-based combinations have been or are under investigation in the HR+, HER2- MBC setting, including combinations with letrozole, fulvestrant, ribociclib, tamoxifen, and chemotherapy. This review summarizes key data on everolimus-based combinations focusing on efficacy, safety, biomarkers, quality of life, and health economic outcomes. These data are discussed in the context of the changing MBC treatment algorithm to provide insights into the clinical relevance of everolimus-based combinations.

Objective To describe patient profiles and clinical outcomes associated with first-line endocrine monotherapy (ET) and chemotherapy (CT) for postmenopausal HR+/HER2– metastatic breast cancer (mBC) patients. Methods This is a retrospective chart review of 139 postmenopausal HR+/HER2– mBC patients initiating first-line ET monotherapy or CT. Overall survival (OS) was described using Kaplan–Meier curves. Exploratory comparative proportional hazards regression was conducted. Results Patients on first-line CT had significantly more frequent liver metastases than patients on first-line ET monotherapy at baseline. The median OS was 35.5 months [95% confidence interval (CI), 22.7–41.2 months] for patients on first-line ET monotherapy and 22.2 months (95% CI, 13.6–25.9 months) for those on first-line CT (P = 0.021). Adjusting for baseline characteristics, the OS between first-line ET monotherapy and CT was not significantly different. Conclusions Patients who were prescribed CT as first-line treatment had evidence of more advanced disease at baseline and shorter OS than those who received ET monotherapy as first-line treatment, suggesting a need for additional safe and effective treatment options for these patients.

According to international guidelines, endocrine therapy (ET) is the preferred option for hormone receptor-positive (HR+) HER2-negative (HER2−) metastatic breast cancer. In spite of clear recommendations, these are not strictly followed in daily practice. The objectives of this study were to investigate the effect of the first anti-metastatic treatment therapy choice on progression-free survival (PFS) and overall survival (OS). In this population-based study, we included patients with HR+/HER2− metastatic breast cancer recorded in the Côte d’Or Breast Cancer Registry. Differences in PFS and OS between patients initially treated with chemotherapy (CT) or ET were analysed in Cox proportional hazards models. In a sensitivity analysis, we used a propensity score (PS) to limit the indication bias. Altogether, 557 cases were included, 280 received initial ET and 277 received initial CT. PFS and OS in patients initially treated with ET was improved significantly when compared to patients with initial CT (respectively, HR = 0.83 (95% CI 0.69–0.99) and HR = 0.71 (95% CI 0.58–0.86)). The results of the sensitivity analysis supported these findings. This study shows that treating patients with HR+/HER2− metastatic breast cancer with initial ET could provide a survival advantage in comparison with initial CT.

Patients with HR+/HER2- metastatic breast cancer (MBC) whose cancers have progressed despite conventional therapies represent an unmet clinical need. Trop-2, a transmembrane calcium signal transducer, is highly expressed in MBC and plays a role in tumor growth and progression. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate comprising an Trop-2 antibody coupled to SN-38, the active metabolite of irinotecan, via a unique hydrolyzable linker. SG has demonstrated promising activity in a Phase I/II IMMU-132-01 basket study in heavily pretreated solid tumors, including HR+/HER2- MBC. We describe the registrational Phase III TROPiCS-02 study (NCT03901339), evaluating SG versus treatment of physician's choice in HR+/HER2- MBC. Trial registration number: NCT03901339.

Background: HER2-ultralow is an emerging subgroup of metastatic breast cancer (mBC). However, despite an increasing interest, limited data exist on its prevalence and outcomes, especially among patients receiving standard first-line chemotherapy. Objectives: This study assessed the prevalence and outcomes of HER2-ultralow mBC in a real-world cohort of hormone receptor-positive (HR+)/HER2-negative patients receiving first-line standard-of-care (SOC) chemotherapy. Design: A retrospective, single-center cohort study. Methods: We included HR+/HER2-negative mBC patients treated with SOC between January 2016 and February 2023. Patient data were reviewed from electronic health records. HER2-zero tumors (immunohistochemistry 0) were rescored by expert pathologists using the American Society of Clinical Oncology/College of American Pathologists guidelines to distinguish HER2-ultralow from HER2-null cases. Real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were estimated using Kaplan–Meier and multivariable Cox regression models. Results: Among 320 patients (median age, 62.4 years), 72.8% had visceral metastases, and 17.5% had bone-only disease. Previous CDK4/6 inhibitor treatment was reported in 43.4%. Rescoring identified 15.6% with HER2-ultralow, 61.9% with HER2-low, and 22.5% with HER2-null tumors. The median follow-up was 39.4 months (95% confidence interval (CI), 37.1–47.6). Median rwPFS was 7.9 months (95% CI, 4.6–19.0), 7.3 months (95% CI, 6.4–9.1), and 6.2 months (95% CI, 4.6–8.9) for HER2-ultralow, HER2-low, and HER2-null groups, respectively. Median rwOS was 19.5 months (95% CI, 10.7–33.4), 21.5 months (95% CI, 19.0–25.8), and 16.6 months (95% CI, 11.9–23.6). In patients previously treated with CDK4/6 inhibitors, median rwPFS was 4.6 months (95% CI, 2.7–21.4), 6.1 months (95% CI, 5.5–7.3), and 5.6 months (95% CI, 3.8–8.7). Conclusion: HER2-ultralow accounts for 15.6% of HR+/HER2-negative mBC cases and demonstrates outcomes comparable to HER2-low with SOC chemotherapy.

Estrogen receptor (ER)-positive breast cancer (BC) is the most common BC subtype. Endocrine therapy (ET) targeting ER signaling still remains the mainstay treatment option for hormone receptor (HR)-positive BC either in the early or in advanced setting, including different strategies, such as the suppression of estrogen production or directly blocking the ER pathway through SERMs—selective estrogen receptor modulators—or SERDs—selective estrogen receptor degraders. Nevertheless, the development of de novo or acquired endocrine resistance still remains challenging for oncologists. The use of novel ET combined with targeted drugs, such as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, has significantly improved long-term outcome rates, thus changing the therapeutic algorithm for metastatic BC (MBC) and recently the therapeutic strategy in the adjuvant setting for early high-risk BC. Eluding the resistance to CDK4/6 inhibitors combined with ET is currently an unmet medical need, and there is disagreement concerning the best course of action for patients who continue to progress after this combination approach. Genetic changes in the tumor along its growth uncovered by genomic profiling of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict the response or resistance to specific agents, suggesting the best therapeutic strategy for each patient by targeting the altered ER-dependent pathway (novel oral SERDs and a new generation of anti-estrogen agents) or alternative ER-independent signaling pathways such as PI3K/AKT/mTOR or tyrosine kinase receptors (HER2 mutations or HER2 low status) or by inhibiting pathways weakened through germline BRCA1/2 mutations. These agents are being investigated as single molecules and in combination with other target therapies, offering promising weapons to overcome or avoid treatment failure and propose increasingly more personalized treatment approaches. This review presents novel insights into ET and other targeted therapies for managing metastatic HR+/HER2− BC by exploring potential strategies based on clinical evidence and genomic profiling following the failure of the CDK4/6i and ET combination.

Abstract Advanced breast cancer is associated with the development of brain metastases in 20%–40% of patients. Differential post‐radiotherapy recurrence patterns depending on hormone receptor (HR) and human epidermal growth receptor 2 (HER2) status have been reported. We investigated recurrence patterns after microsurgical resection stratified for HR and HER2 expression. The institutional database was screened for patients who had undergone tumor resection for breast cancer brain metastases between 2013 and 2023. Patient and imaging data were analyzed. Response Assessment in Neuro‐Oncology (RANO) guidelines were applied. Sixty‐seven patients were identified. Nineteen patients (28%) were diagnosed with HR+/HER2−, 31 patients (46%) with HER2+, and 17 patients (25%) with triple‐negative (TN) brain metastases. Local, i.e., in or adjacent to the resection cavity, or distant brain‐specific progression‐free survival (PFS) was shortest in patients with TN status, followed by patients with HER2+ and HR+/HER2− brain metastases (median: 170 vs. 419 vs. 1152 days; p < .01). Patients with HER2+ brain metastases showed earlier local progression than patients with HR+/HER2− status (HR 0.25; 95% CI 0.08–0.75; p = .01). The receptor status of the brain metastases diverged from the primary tumor in 13 patients (21%). In five patients (8%), a newly gained HR or HER2 expression was detected. Post‐surgery recurrence patterns of breast cancer brain metastases are associated with the tumor biology. TN brain metastases show earliest local and distant recurrence, confirming the pressing need for better local and systemic treatments. As HER2+ brain metastases tend to recur locally, refinement of local strategies might be warranted.

The latest and newest discoveries for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer are the three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in association with endocrine therapy (ET). However, even if this treatment revolutionized the world and continued to be the first-line treatment choice for these patients, it also has its limitations, caused by de novo or acquired drug resistance which leads to inevitable progression after some time. Thus, an understanding of the overview of the targeted therapy which represents the gold therapy for this subtype of cancer is essential. The full potential of CDK4/6i is yet to be known, with many trials ongoing to expand their utility to other breast cancer subtypes, such as early breast cancer, and even to other cancers. Our research establishes the important idea that resistance to combined therapy (CDK4/6i + ET) can be due to resistance to endocrine therapy, to treatment with CDK4/6i, or to both. Individuals’ responses to treatment are based mostly on genetic features and molecular markers, as well as the tumor’s hallmarks; therefore, a future perspective is represented by personalized treatment based on the development of new biomarkers, and strategies to overcome drug resistance to combinations of ET and CDK4/6 inhibitors. The aim of our study was to centralize the mechanisms of resistance, and we believe that our work will have utility for everyone in the medical field who wants to deepen their knowledge about ET + CDK4/6 inhibitors resistance.

Combinations of endocrine therapy (ET) and targeted therapy (CDK4/6 or mTOR inhibitors) are standard of care for HR+/HER2− metastatic breast cancer (MBC). When ET is not effective, chemotherapy is commonly used. However, clinical outcomes of chemotherapy in the endocrine-resistant setting are limited. The purpose of this study was to identify predictive factors and the compare efficacies of chemotherapy agents in endocrine-resistant MBC. We conducted a retrospective study of patients with HR+/HER2− MBC who received chemotherapy after progression on ET with or without targeted therapy at MD Anderson Cancer Center from 1999 to 2017. We collected baseline clinicopathological and all treatment data. Primary endpoint was time to treatment failure (TTF) of first-line chemotherapy for MBC. For the 1258 patients analyzed, mean age was 55.3 years (range 21–91). Previous treatment with targeted therapy was recorded for 390 patients (31%): 264 with CDK4/6 inhibitor, 205 with mTOR inhibitor, and 79 treated with both. The most frequent chemotherapy agents were capecitabine (48.9%) and taxanes (28.6%). After adjustment for all factors in a multivariate model, previous treatment with a CDK4/6 inhibitor had the strongest negative effect on TTF regardless of ET duration (hazard ratio [HR] 1.84; 95%CI 1.49–2.27; p < 0.001). Conversely, capecitabine had significantly longer median TTF than taxanes regardless of whether patients had prior exposure to taxanes in primary setting (6.1 vs 4.9 months; HR 0.64; 95%CI 0.55–0.75; p < 0.001). Previous exposure to CDK4/6 inhibitor had a negative predictive effect for the efficacy of chemotherapy. Capecitabine had the best efficacy against endocrine-resistant breast cancer.

INTRODUCTION: Breast cancer spine metastases are a devastating and pervasive clinical problem. Discoveries in tumor biology and the pathophysiology of metastatic disease have expanded systemic treatment options for metastatic breast cancer. The implications of evolving treatment strategies should inform the surgical treatment of spine metastases and the predicted prognosis to guide personalized approaches. METHODS: This is a multi-institutional, retrospective, observational cohort study of patients who underwent spine surgery for symptomatic breast cancer spine metastases from 2008-2020. We studied overall survival, stratified by breast cancer molecular subtype and calculated hazard ratios adjusting for demographics, tumor characteristics, treatments, and laboratory values. We tested the performance of established models (Tokuhashi, Bauer, SORG, NESMS) to predict and compare all-cause mortalities using time-dependent performance metrics. RESULTS: A total of 98 patients surgically treated for breast cancer spine metastases were identified. The 1-year probabilities of survival for HR+, HR+/HER2+, HER2+, and TNBC were 63%, 83%, 0%, and 12% (P <0.001). Postoperative chemotherapy and endocrine therapy were associated with prolonged survival. The SORG prognostic model had the highest discrimination. The performance of all prognostic scores improved when preoperative molecular data was considered in addition to postoperative systemic treatment data. CONCLUSIONS: Advanced HR+, HR+/HER2+ breast cancer portended significantly longer overall survival compared with HER2+ and TNBC tumors after surgery for symptomatic spine metastases. Hormone receptor status and postoperative systemic therapy should be considered in prediction models for a more accurate assessment of prognosis.

1058 Background: Some recommend curative treatment for oligometastatic breast cancer (OMBC). To date, no randomized clinical trial has demonstrated the benefits of such a strategy. We present the largest retrospective series of patients treated consecutively for ER and/or PR positive (HR+) OMBC in a single institution. The objective was to describe the clinical and biological characteristics and prognostic factors of HR+ OMBC. Methods: We retrospectively reviewed all patients treated consecutively from 2014 to 2018 at our institution for synchronous or metachronous metastatic breast cancer (MBC). HR+ OMBC was defined as MBC with up to five metastases at diagnosis, positive hormone receptor status, and no other inclusion criteria. Clinical and biological characteristics, treatment modalities - intent-to-cure vs palliative - and outcomes were recorded. Progression-free survival (PFS) and overall survival (OS) were calculated. Log rank test and Cox regression models were used for survival analyses including time-dependent variable. Results: Of 998 patients treated for MBC within our institution between 2014 and 2018, 11.3% (N=113/998) met inclusion criteria. 62.5% of them had SBR grade I/II HR+ OMBC and 80.5% had HR+/HER2- OMBC. 89.3% patients had only one organ involved. None had more than two; 89.3% patients had 1-3 metastases at diagnosis. Among these 113 patients, 63.7% had bone metastases, 54.9% had bone only metastases, 19.5% had visceral metastases, 17.7% had lymph node metastases, 7.1% had brain metastases, and 3.5% had other metastases. Forty-one patients (36.3%) were treated in a curative intent with systemic treatment plus ablative focal treatment of primary tumor – or local relapse – and all distant metastases. Median follow up was 67.2 months (95%CI= [63.1-75.4]). For the entire series, five-year PFS and OS were respectively 35.2% (95%CI= [25.6-44.6]) and 67.0% (95%CI= [56.7-75.3]) respectively. In univariable analysis, liver metastases was associated with worse OS (HR=3.13, 95%CI=[1.43-6.87], p=0.003). In multivariable analysis, HER2 positive status (HR=0.43, 95%CI= [0.21-0.90], p=0.024), bone only metastases (HR=0.46, 95%CI= [0.27-0.78], p=0.004), and intent-to-cure treatment (HR=0.53, 95%CI= [0.30-0.93], p=0.027) were significantly associated with longer PFS. In multivariate analysis, only intent-to-cure strategy was associated with better OS (HR=0.24, 95%CI= [0.09-0.60], p=0.002). Conclusions: This is the largest retrospective series of patients treated consecutively for HR+ OMBC to date. 71.5 % of OMBC and 11.3 % of all MBC are HR+ OMBC. Most had only one invaded organ and 1-3 metastases. Among our cohort, intent-to-cure treatment improve drastically HR+ OMBC PFS and OS. A multimodal intent-to-cure strategy should be routinely discussed for patients with HR+ metastatic breast cancer with one to five metastases at diagnosis.

CDK4/6 inhibitors have transformed treatment for HR + HER2 − advanced breast cancer (aBC). However, adverse events (AEs) often lead to dose adjustments or discontinuation, potentially impacting outcomes. This study assessed AE incidence and its effect on survival in patients receiving abemaciclib (AB), ribociclib (RB), or palbociclib (PB). A retrospective study of 162 h + HER2 − aBC patients treated with CDK4/6 inhibitors as first-line therapy (July 2017–September 2024) was conducted. AE incidence, progression-free survival (PFS), and overall survival (OS) were analyzed. Most patients (91.4%) were postmenopausal, with a median follow-up of 24.6 months. AEs occurred in 87% of patients, with grade 3–4 neutropenia most common in PB (79.3%) and RB (80%), while AB caused more diarrhea (66.7%). Dose reductions due to AEs were linked to significantly longer PFS (38.5 vs. 16.3 months, p < 0.001) and OS (NR vs. 32.4 months, p = 0.024). Treatment discontinuation was highest for PB (19.6%), followed by RB (16.9%) and AB (14.9%). CDK4/6 inhibitors have distinct toxicity profiles. Effective AE management and dose adjustments are crucial for maintaining efficacy, emphasizing the need for AE prediction models to optimize CDK4/6i use in HR + HER2 − aBC.

Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59–1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659. A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates

Endocrine therapy (ET) + cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care first-line (1L) treatment for hormone receptor-positive (HR+)/HER2-negative (HER2−) metastatic breast cancer (mBC). Given that outcomes tend to worsen following progression to next-line therapy, understanding the relationship between the duration of 1L treatment and subsequent outcomes may be an important factor for clinical decision-making. This real-world, retrospective, observational cohort study investigated the relationship between time to discontinuation (TTD) of 1L therapy and overall survival (OS) in patients with HR+/HER2− mBC. Adults with HR+/HER2− mBC were identified from electronic health records in the US Flatiron Health Database. Included patients had started 1L ET + CDK4/6i between March 1, 2018, and March 31, 2024, and had ≥2 clinical activities on different days after 1L initiation. Patients were followed until September 30, 2024. Descriptive statistics were used to summarize demographics, baseline characteristics, and treatment patterns. 1L TTD was defined as time from 1L initiation to final administration of 1L therapy (whichever component was administered last) or death. TTD and OS were assessed using Kaplan-Meier methodology. The relationship between 1L TTD and OS was assessed using rank correlation and a multivariate, covariate-adjusted, time-dependent Cox regression model. A total of 2910 patients were included, with a mean age of 63.2 years. Most were White (66.2%) and postmenopausal (71.4%), with Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 (63.2%), and estrogen receptor (ER) expression >70% (82.0%); 49% had recurrent disease (4.7% unknown), and few had liver metastases (16.1%). With a median (interquartile range) follow-up of 24.8 (14.0-41.0) months, median 1L TTD was 20.6 (95% CI: 19.4-22.0) months, and median OS was not reached. OS rate was 92.1% at 12 months and 83.8% at 24 months. There was a strong positive correlation between TTD and OS (r = 0.74 [95% CI: 0.70-0.78]). For each additional month on 1L treatment, the adjusted hazard ratio for OS was 0.95 (95% CI: 0.94-0.96; p<0.001). In real-world terms, this means that an additional 2, 4, 6, 8, and 10 months on 1L treatment would result in cumulative hazard ratios (calculated as 0.95^number of months) of 0.90, 0.81, 0.74, 0.66, and 0.60, respectively, and a 10%, 19%, 26%, 34%, and 40% lower risk of death, respectively. Lower ECOG PS, de novo disease, and ER expression >70% were also associated with better survival outcomes. Age, region, menopausal status, and practice type were not associated with survival outcomes. In this real-world dataset, a longer duration of 1L treatment prior to clinical progression was highly positively correlated with longer OS, suggesting a clinical benefit to extending 1L treatment in HR+/HER2− mBC. It is therefore critical to identify ways to increase the duration of 1L therapy to improve patient outcomes. E. Mayer, K. A. Betts, R. Ramasubramanian, X. Nie, T. Pham, C. Chen. Correlating time to treatment discontinuation with overall survival: real-world data on outcomes for first-line endocrine therapy + CDK4/6 inhibitor in metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-05.

Hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) breast cancer comprises approximately 70% of all breast cancer cases. In early-stage breast cancer, adjuvant endocrine therapy (ET) reduces recurrence and mortality, while in advanced/metastatic breast cancer (MBC), ET prolongs survival and delays the use of chemotherapy. However, there remains a need for agents that further improve outcomes across the spectrum of breast cancer presentations. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, such as abemaciclib, ribociclib, and palbociclib, are used in combination with ET as a standard of care first-line option in HR+, HER2- advanced disease to improve survival outcomes. Moreover, the addition of abemaciclib and ribociclib to adjuvant ET reduces risk of cancer recurrence, with abemaciclib also improving overall survival. Here, we provide a comprehensive analysis of the clinical trials that have demonstrated the efficacy of abemaciclib across the HR+, HER2- breast cancer continuum, improving outcomes in both high-risk, node-positive early breast cancer as well as in advanced disease. Abemaciclib has also been shown to be effective when combined with a variety of ET options, including aromatase inhibitors, tamoxifen, fulvestrant, imlunestrant, or as monotherapy, and has shown efficacy regardless of prior CDK4/6 inhibitor exposure, ESR1 or PI3K pathway mutational status, menopausal status, and in both endocrine-sensitive and endocrine-resistant breast cancer. Importantly, the safety profile of abemaciclib has been consistent across trials and allows the administration of the drug over long periods of time when needed, particularly if dose-reduction strategies are employed. Together, the data summarized in this publication help inform clinical decision making regarding the role of abemaciclib in the treatment of patients with both early and metastatic HR+, HER2- breast cancer.

CDK4/6 inhibitors (CDK4/6i), used in combination with endocrine therapy (ET), are standard of care for advanced and higher risk early stage hormone receptor-positive (HR+), HER2 negative (HER2-) breast cancer. PALLAS investigated the addition of 2 years (y) of palbociclib to adjuvant ET (ET/P) compared to ET alone in patients (pts) with stage II-III HR+/HER2- breast cancer. We now present overall survival (OS) with 7-y outcomes and impact of post-recurrence therapy. This global phase III trial randomized pts to ET for at least 5 y with or without 2 y of P. Primary endpoint was iDFS; distant recurrence-free survival (DRFS) and OS were preplanned endpoints. Kaplan Meier estimates and hazard ratios (HR) from Cox and Fine & Gray models were performed. Post-recurrence OS was analyzed as time from first distant recurrence (DR) until death. The post-recurrence OS model adjusted for both clin/path factors (including DR-free y, DR site) and time-dependent post-DR therapy (chemo, CDK4/6i). 5,796 pts enrolled at 406 centers in 21 countries worldwide over 3 y. In the intent-to-treat (ITT) population, with a median follow-up of 82.7 months (mo), 7-y outcomes for iDFS, DRFS and OS are shown in the table. DR occurred in 781 pts (377 ET/P, 404 ET alone) with balanced pt/disease characteristics between arms. ET/P had more visceral (46% vs. 36%) and fewer non-visceral (61% vs. 68%) DR compared to ET alone (p=0.03). Unadjusted post-recurrence OS was significantly worse for ET/P vs. ET (median 22.6 vs. 27.9 mo, HR 1.21 (95% CI 1.01-1.46, p=0.04). However, receipt of any post-recurrence CDK4/6i was significantly higher on ET vs. ET/P arms (41% vs. 66%) and time to post-progression CDK4/6i initiation was significantly shorter for those in the ET vs. ET/P arms (HR 0.50, 95% CI 0.41-0.61, p<0.001) adjusting for region, bone/visceral DR type, DR-free time and age. Conversely, time to post-progression chemotherapy initiation was significantly longer for ET alone vs. ET/P arms (HR 1.31, 95% CI 1.07-1.61, p=0.01). However, after adjustment for clinical factors and post-DR treatment, the OS difference was no longer seen (HR 1.05, 95% CI 0.85-1.28, p=0.65). 3-mo landmark analysis showed similar effect on OS after adjusting for CDK4/6i initiation within 3 mo from DR (unadjusted HR 1.24, p=0.03 vs. adjusted HR 1.15, p=0.22). The PALLAS trial revealed significant differences in treatment post-DR that impact OS. Reduced/delayed use of metastatic CDK4/6i after adjuvant P was associated with significantly poorer OS, suggesting that patients who relapse after adjuvant CDK4/6i may still benefit from metastatic CDK4/6i. This has implications for optimal treatment in those who relapse after adjuvant CDK4/6i and warrants further study to determine if this is therapy-specific or an overarching biological effect. AFT, ABCSG, NRG, PrECOG; Pfizer A. DeMichele, A. Dueck, M. Gnant, D. Hlauschek, M. Martin, A. Wolff, G. Rubovsky, F. Henao, O. Hahn, A. Chan, A. Brusky, P. Morris, H. Burstein, G. Huber, D. Anderson, L. Garcia-Estevez, G. Pfeiler, H. Rugo, N. Zdenkowski, S. Gampenrieder, N. Wolmark, D. Sabanathan, K. Miller, D. Cameron, E. Winer, C. Brunner, E. Gauthier, P. O’Brien, C. Fesl, E. Mayer. Adjuvant Palbociclib for ER+ Breast Cancer in the PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): Post-Recurrence Treatment and Overall Survival [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF7-07.

Objective: To review the pharmacology, efficacy, and safety of capivasertib for the treatment of adults with hormone receptor-positive, HER2-negative (HR+/HER2–) locally advanced or metastatic breast cancer with 1 or more PIK3CA/AKT1/PTEN alterations. Data sources: A literature search was conducted using PubMed and MEDLINE databases, published abstracts, and studies from ClinicalTrials.gov between 2003 and February 2024. Keywords included capivasertib, AZD5363, PI3K/AKT/mTOR pathway, and breast cancer. Data extraction: All applicable publications, package inserts, meeting abstracts, and clinical trials with capivasertib were reviewed. Data synthesis: Capivasertib is a first-in-class inhibitor of 3 isoforms of AKT (AKT-1, AKT-2, and AKT-3) which is an essential component in the PI3K/AKT/mTOR signaling pathway involved in oncogenesis. In the phase III CAPItello-291 trial, capivasertib in combination with fulvestrant (C+F) demonstrated improved progression-free survival (PFS) (7.3 vs 3.1 months) compared with placebo-fulvestrant (P+F) cohort in AKT-altered pathway patients who had progressed through prior aromatase inhibitor. The most common adverse reactions of any grade reported in the C+F group were diarrhea, cutaneous skin reactions, nausea, fatigue, and vomiting. Relevance to patient care and clinical practice in comparison with existing drugs: HR+/HER2– advanced breast cancer patients experience progression following endocrine therapies and cyclin-dependent kinase (CDK) 4/6 inhibitors. Capivasertib is a viable treatment option for patients with PIK3CA/AKT1/PTEN activating mutations following progression on endocrine-based regimens in the metastatic setting or recurrence within 12 months of completing adjuvant therapy. Conclusion: Integration of capivasertib into clinical practice is ongoing; intermittent dosing and favorable toxicity are attractive for future novel combination prospective trials.

To date, no prospective randomized trials have been published to validate a curative-intent strategy combining standard-of-care systemic therapy (SOC ST) with local ablative treatment (LAT) in patients with oligometastatic breast cancer (OMBC). Available evidence derives solely from retrospective series. These series can sometimes be criticized for their short follow-up periods, the biological and anatomical heterogeneity of the patients’ tumors, the use of suboptimal or insufficiently detailed imaging modalities, and the non-consecutive nature of their recruitment. Our objective was to identify prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with HR+/HER2- OMBC. We specifically evaluated the impact of modern versus standard imaging techniques and the contribution of LAT. To minimize selection bias, we enrolled all eligible patients consecutively, and to ensure biological homogeneity we therefore restricted inclusion to the HR+/HER2- phenotype. We retrospectively reviewed all patients consecutively diagnosed and treated from 2012 to 2020 at our institution for HR+/HER2-negative OMBC. OMBC was defined as breast cancer with 1 to 5 distant metastases. Cases were categorized as de novo or metachronous. Surrogate intrinsic subtype - Luminal A-like (Lum-A) and Luminal B-like (Lum-B) were defined according to St Gallen consensus criteria. Imaging were classified as modern imaging methods (MIMs: PET-CT or whole-body MRI) versus standard imaging methods (SIMs: bone scintigraphy or thoraco-abdomino-pelvic (TAP) CT). Number and location of metastases, treatments - SOC ST vs SOC ST plus LAT (surgery or SBRT) were collected. Survival analyses were performed using the Kaplan-Meier method, the Logrank test, and the Cox model including time-dependent variable. The use of time-dependent models allowed adjustment for the timing of LAT and helped mitigate immortal time bias. Median age was 57.0 years [29.0; 90.0]; 23% patients had Lum-A and 77% had Lum-B tumors. OMBC was de novo in 34%, and metachronous in 65%. One organ was involved in 94% and 1 to 3 metastases in 88% cases. Metastatic sites included bone in 98 (68%), lymph node in 20 (14%), liver in 18 (12%), lung in 10 (7%), and brain in 7(5%) cases. MIMs were applied for staging in 54% of patients. No patients with four or five metastases received LAT (surgery or SBRT). Unfortunately, by lake of data, systemic treatment could not be analyzed. The median follow-up was 82.8 months. 73% relapsed and 51% died. Median OS was 81.1 months (95%CI [60.0-94.1]). Median PFS was 26.5 months (95% CI [21.0-33.8]). In univariable analysis, worse OS was associated with 4-5 metastases, liver metastases, Lum-B and SIMs (HR=2.56, 95% CI [1.58-4.13], p<0.0001). LAT was associated with improved PFS (HR=0.34, 95% CI [0.20-0.58], p<0.0001) and OS (HR=0.32, 95% CI [0.16-0.63], p=0.0009). In multivariable analysis: worse OS was associated with Lum-B, liver metastases and SIMs (HR=1.64, 95% CI [1.12-3.16], p=0.017). LAT improved PFS (HR=0.52, 95% CI [0.29-0.91], p=0.0233), showed a non-significant trend toward better OS (HR=0.52, 95% CI [0.25-1.08], p=0.078). In the subgroup staged with MIMs, in univariable analysis, LAT was significantly associated with improved PFS (HR=0.40, 95% CI [0.21-0.77], p=0.0064) and OS (HR = 0.29, 95% CI [0.12-0.73], p= 0.008). This retrospective study reports prognostic data from a biologically homogeneous and unselected cohort of HR+/HER2- OMBC patients, with extended follow-up. In this study, LAT significantly improved PFS and showed a strong trend toward improved OS. In patients staged with MIMs, LAT was significantly associated with both PFS and OS, underscoring the importance of advanced imaging in selecting candidates for curative-intent strategies. J. Lacaze, F. Dalenc, E. De Maio, B. Cabarrou, T. Cassou Mounat, C. Massabeau, V. Nicolai, G. Selmes, E. Jouve, M. Ung, C. Korenbaum. Impact of modern imaging on survival in a retrospective and consecutive cohort of 145 HR+/HER2 negative oligometastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-15.

Background Denovo metastatic young breast cancer (dnmYBC), defined as age <40 years, is a challenging entity, with a significant burden and sparse data from low and middle-income countries. Method We analysed the prospectively collected data of dnmYBC women from 2015 to 2016. Results There were 188 dnmYBC with a median age of 35.5 years. Of these, hormone receptor positive (HR+) were 72 (38.3) %, triple-negatives (TNBC) were 45 (23.9) %, Human Epidermal Growth Factor Positive (HER2+) were 42 (22.4) % and triple positives were 29 (15.4) %. TNBC women predominantly had visceral 40 (88.9%) metastasis, HR+ had nodal 51 (70.8%) and skeletal 10 (13.8%), while HER2+ women had higher brain metastasis (BM) 16 (38.1%). At a median follow-up of 39.8 [Interquartile range (IQR): 24–55.5] months, the median event-free survival (EFS) was 9.3 (95% CI; 8.1–10.4) months for the entire cohort and 1-year, 2-year and 3-year predicted EFS were 47.8%, 13.4% and 3%, respectively. The median EFS was superior in HR+ women. [15.7 months, hormone receptor (HR)−0.53;95% CI-9.8–21.7; p-0.013] versus (11.4 months, 95 %CI-5.9–16.8) in TNBC versus (7.7 months, 95% CI-6.0–9.5) in HER-2 + women and without BM at baseline [9.3 versus 3.0 months (with BM), HR-5.65; CI-1.72–17.9; p-0.001]. Median EFS was superior in the treatment-naïve (155, 82.4%) versus prior-treated (33, 17.5%) women, 35.5 (95% CI:12.24–58.72) versus 12.4 (95% CI:11.45–13.51) months; p-0.000]. The HER2+ women who received targeted therapy in the first line had a significantly superior median EFS of 13.0 versus 7.7 months (HR -0.465:CI 0.22–0.57: p-0.038). Conclusion Denovo mYBC is associated with an aggressive course, poor prognosticators include HR negative disease, brain metastasis, inadvertent prior treatment and inadequate access to targeted therapies. Early diagnosis, prompt treatment and expanding accessibility are warranted to improve care.

Survival after metastatic breast cancer (MBC) has improved in high-income countries, yet international differences in outcomes and access to optimal care, particularly for recurrent disease remain unclear. We compared survival after recurrent MBC across four high-income countries, examining tumour subtype, treatment patterns and guideline adherence. Individual-level data were obtained from population-based cancer registries in Canada (British Columbia), Ireland, the Netherlands and the United States (Connecticut) for women who were diagnosed with stage I-III invasive breast cancer between 2005 and 2008 and developed distant metastatic recurrence between 2008 and 2010. Follow-up was from first recurrence until death, loss to follow-up or December 31, 2015. Kaplan-Meier methods were used to estimate overall survival, and age-standardised net survival (ASNS) at 1, 3 and 5 years after recurrence was estimated by registry and subtype. Among 2735 women with recurrent MBC, treatment at initial diagnosis varied across registries. Median survival after recurrence ranged from 12 months in Ireland to 18 months in the United States (p = 0.015). One-year ASNS ranged from 51.3% in Ireland to 63.6% in the United States and the Netherlands. Across countries, ASNS was highest for HR+/HER2− tumours and lowest for HR−/HER2− tumours. The Netherlands consistently showed the highest subtype-specific survival, while survival for HER2+ disease in Canada was closer to HR−/HER2− than HR+/HER2− disease. Differences narrowed over longer follow-up and in sensitivity analyses. Survival after recurrent MBC differed across these high-income countries. Improved harmonisation of recurrence data and timely implementation of evidence-based therapies may help reduce persistent international disparities.

… The 1-year survival did not differ between LAC and OC … The 5-year survival was significantly better in the LAC (vs. OC… member health plan over a 3-year horizon. Estimates of plan …

BACKGROUND: The use of Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors has profoundly changed the challenge of endocrine therapy (ET) resistance in hormone receptor-positive (HR+)/HER2-negative (HER2-) breast cancer. However, there is currently no comprehensive evaluation of the evidence for the efficacy of CDK4/6 inhibitors. We conducted an umbrella review to explore the impact of CDK4/6 inhibitor combined with ET on breast cancer by summarizing and assessing the meta-analysis (MA) and systematic review (SR) evidence. METHODS: Cochrane, PubMed, Embase, and Web of Science databases were searched from inception to August 1st, 2022. Eligible studies were assessed for methodological quality, report quality, and evidence quality using the AMSTAR-2 scale, PRISMA 2020, and GRADE grading systems, respectively. We summarized all efficacy outcomes of CDK4/6 inhibitors for breast cancer and reported them in narrative form. RESULTS: Our study included 24 MAs and SRs. The strongest evidence demonstrated that CDK4/6 inhibitor combined with ET significantly improved progression-free survival (PFS), overall survival (OS) in advanced breast cancer (ABC). A large body of moderate to high evidence showed a significant association between combination therapy and objective response rate (ORR), and clinical benefit response (CBR) benefit in ABC. Low evidence suggested some degree of benefit from combination therapy in second progression-free survival (PFS2) and time to subsequent chemotherapy (TTC) outcomes in ABC and invasive disease-free survival (IDFS) outcomes in early breast cancer. CONCLUSIONS: Based on current evidence, CDK4/6 inhibitors combined with ET have great confidence in improving PFS, OS, ORR, and CBR outcomes in patients with ABC, which provides more rational and valid evidence-based medicine for CDK4/6 inhibitor promotion and clinical decision support.

Breast cancer represents the most frequently diagnosed malignancy in women, with the hormone receptor-positive/HER2-negative (HR+/HER2-) subtype being the most prevalent. For advanced HR+/HER2- breast cancer, the combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy has become the established first-line standard, significantly prolonging both median progression-free survival (mPFS) and overall survival (OS). Nevertheless, the majority of patients eventually develop resistance, leading to disease progression. The underlying mechanisms of resistance are multifactorial, involving dysregulated cell cycle control, reprogramming of signaling pathways, and remodeling of the tumor microenvironment (TME). At present, there is no standardized treatment strategy for overcoming CDK4/6i resistance. This article systematically reviews current post-CDK4/6i therapeutic strategies, including next-generation endocrine therapies (e.g., oral SERDs), targeted agents directed at the PI3K/AKT/mTOR axis, AKT inhibitors, and antibody–drug conjugates (ADCs), and discusses potential future therapeutic directions.

… -sensitive or endocrine-resistant population in metastatic HR+/HER2− breast cancer. … /CDK4–6/Rb pathway is associated with the development of endocrine resistance in breast cancer […

Simple Summary Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become a cornerstone for the treatment of hormone receptor-positive, HER2-negative breast cancer, yet their role differs between early-stage and metastatic disease. In this meta-analysis of 22 phase III trials, we found that in early-stage breast cancer, CDK4/6 inhibitors improved invasive disease-free survival but did not demonstrate a clear overall survival benefit and were associated with increased hematologic and non-hematologic toxicities, leading to higher treatment discontinuation and dose reductions. These findings highlight the importance of individualized risk–benefit assessment and the need for longer follow-up to determine survival impact in early-stage disease. In contrast, in metastatic disease, CDK4/6 inhibitors significantly improved overall survival, progression-free survival, and response rates, supporting their established role as standard first-line therapy. These results reinforce stage-specific treatment considerations in clinical practice.

Objective To evaluate the clinical efficacy and security of CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) in patients with hormone receptor-positive (HR⁺), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer. Methods We selected 145 patients with HR+HER2− advanced breast cancer from the hospital’s electronic medical record system and divided them into an observation group of 83 cases (CDK4/6i combined with ET treatment) and a comparison group of 62 cases (ET treatment) according to the treatment plan. Analyze and compare the efficacy and security of patients receiving different treatment regimens. Results The ORR was significantly higher in the observation group (CDK4/6i + ET) compared to the comparison group (ET alone) (45.8% vs. 22.6%, p=0.005). The DCR was also superior in the observation group (84.3% vs. 67.7%, p=0.018). The median PFS was 15.0 months (95% CI: 12.5–17.5) in the observation group versus 9.0 months (95% CI: 7.5–10.5) in the comparison group (p<0.001). The median OS was 20.5 months (95% CI: 18.0–23.0) and 9.5 months (95% CI: 8.0–11.0), respectively (p=0.002). COX multivariate analysis identified ER level as an independent protective factor (HR=0.559, 95% CI: 0.352–0.888, p<0.05), while liver metastasis was an independent risk factor for PFS. Conclusion CDK4/6 inhibitors combined with ET demonstrates favorable clinical efficacy in patients with HR⁺HER2− advanced breast cancer, with manageable adverse reactions and a good security profile. The ER level may be an independent protective factor affecting the PFS of the overall population, while liver metastasis may be an independent risk factor affecting the PFS of patients.

Purpose This study aimed to evaluate the real-world outcomes and treatment patterns of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with endocrine therapy (ET) for hormone receptor-positive, HER2-negative (HR+/HER2−) advanced breast cancer (ABC), as well as the use and effectiveness of later-line therapies, in a single tertiary center in Poland. Patients and Methods This retrospective, single-center study included 661 patients who initiated CDK4/6 inhibitor-based therapy between September 2019 and December 2023. Data were extracted from medical records to assess progression-free survival (PFS), chemotherapy-free survival, and treatment trajectories. Statistical analyses included Kaplan–Meier estimates and Log rank tests for survival outcomes. Results The majority of patients (80%) received CDK4/6 inhibitors as first-line therapy, predominantly combined with aromatase inhibitors. Median PFS was 25.8 months overall, with superior outcomes observed in the first-line setting (29.0 months vs 13.8 months in second-line; p < 0.0001). AI-based combinations outperformed fulvestrant in the first line (38.9 vs 16.8 months; p < 0.0001). Chemotherapy-free survival of patients treated in the first line with CDK4/6 inhibitors reached 39.1 months. After progression on first-line CDK4/6 inhibitors, 71% received second-line treatment (49% chemotherapy, 35% ET); median PFS was 4.2 vs 5.3 months, respectively. Only 31% received third-line treatment (median PFS: 3.1 vs 2.6 months). Conclusion CDK4/6 inhibitors continue to provide substantial clinical benefit in routine practice, with evolving treatment strategies reflecting growing emphasis on individualized, less toxic approaches. A notable shift from chemotherapy towards targeted and endocrine therapies in later lines underscores the changing landscape of ABC management. However, the outcomes in the later lines of therapy are still unsatisfactory. Enhancing biomarker testing is critical for advancing precision oncology in this setting.

Background: The clinical impact of HER2‐low status on the efficacy of cyclin‐dependent kinase 4/6 inhibitor (CDK4/6i). Therapy in patients with hormone receptor‐positive (HR+), HER2‐negative metastatic breast cancer (MBC) remains unclear.

Abstract 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.