HR positive + HER-2 negative

With this technology, we developed trastuzumab deruxtecan, the first DXd-ADC directed toward HER2. Additionally, Dato-DXd showed TROP2-dependent antitumor activity in multiple human cancer cell line-derived and patient-derived xenograft mouse models. Clinically, the global phase III trial targeting hormone receptor-positive, HER2-negative, unresectable or recurrent breast cancer led to its first approval in Japan in December 2024, followed by the approvals in the US and Europe later.

Rhabdomyolysis due to CDK4/6 inhibitor-statin interactions is a rare but potentially life-threatening complication. Vigilant monitoring, timely intervention, and tailored treatment strategies are essential for preventing complications and improving patient outcomes.

In the context of contemporary adjuvant treatment, with patients diagnosed within three years postpartum more likely to receive chemotherapy, ovarian function suppression, and CDK4/6 inhibitors, differences in IDFS associated with time since last childbirth did not result in significantly worse IDFS within the follow-up period (89.0% in patients with PPBC up to 3 years vs. 93.7% in all other patients p = 0.39). These findings indicate that tumors diagnosed within the first year postpartum have significantly elevated RS, and that the period of most aggressive PPBC, as reflected by gene expression profiles, may arise in the more recently postpartum period, in the first 0-3 years postpartum.

Younger patients with breast cancer exhibited a higher frequency of high-grade tumors, although no differences were observed in RFS and DRFS. However, locoregional recurrence was more common among younger patients, especially HR-positive/HER2-negative breast cancer.

HRD represents a reliable independent prognostic biomarker in HR+/HER2- breast cancer in this cohort, with an inverse association with TILs suggesting immune evasion. Its potential impact on prognosis and treatment requires further validation in prospective clinical trials.

Tucatinib-based combinations and trastuzumab deruxtecan have demonstrated substantial intracranial activity in prospective trials, shifting the treatment paradigm by supporting systemic therapy even in the presence of active brain metastases. A major limitation remains the underrepresentation of patients with brain metastases in clinical trials. This review summarizes current evidence on systemic therapies for BCBM across subtypes and highlights the need for CNS-inclusive trials and the development of effective CNS-active treatments.

Treatment paradigms have advanced from non-targeted options, such as fulvestrant monotherapy or everolimus-based combinations, to precision medicine strategies, including inhibitors of the PI3K/AKT pathway, oral selective estrogen receptor degraders (SERDs), and novel ER-modulating agents, often guided by biomarkers and molecular surveillance... Early second-line standards, including fulvestrant and alpelisib for PIK3CA-mutated tumors, established the basis for biomarker-guided treatment in hormone receptor-positive, HER2-negative metastatic breast cancer...Elacestrant improved progression-free survival in ESR1-mutated disease in the EMERALD trial, capivasertib plus fulvestrant demonstrated significant benefit in tumors harboring AKT/PIK3CA/PTEN pathway alterations in CAPItello-291, and inavolisib plus palbociclib and fulvestrant achieved both progression-free and overall survival improvement in PIK3CA-mutated patients with early relapse in INAVO120... Post-CDK4/6i management increasingly relies on NGS-guided precision approaches, integrating pathway-specific therapies and ctDNA surveillance to tailor sequencing based on resistance profiles, prior ET response, and tumor heterogeneity. Future investigations into novel ER degraders and multi-targeted combinations hold potential to further optimize algorithms, extend non-chemotherapy options, and enhance survival in HR+/HER2- mBC.

P3, N=950, Recruiting, Tokyo Women's Medical University

P3, N=61, Terminated, SOLTI Breast Cancer Research Group | N=456 --> 61 | Trial completion date: Mar 2027 --> Mar 2026 | Active, not recruiting --> Terminated; The study was prematurely halted because enrollment was significantly delayed compared with the original projections due to the evolving therapeutic landscape.

Among 121 patients, 30 (24.8%) had BRCA1, 88 (72.7%) had BRCA2, and three (2.5%) had dual mutations; 66.9% received first-line therapy, with ribociclib in 69.4% and palbociclib in 29.8%. In multivariable analysis, ECOG ≥ 1 (HR 1.85; p = 0.010) and fulvestrant-based therapy (HR 1.74; p = 0.041) predicted shorter PFS; fulvestrant also predicted worse OS (HR 2.39; p = 0.008). CDK4/6 inhibitor-based therapy shows meaningful activity in gBRCAm HR+/HER2- MBC; the numerically poorer outcomes observed in BRCA2 carriers are hypothesis-generating and warrant validation in larger cohorts.

A review of the literature reveals that studies on the efficacy and tolerability of CDK 4/6 inhibitors have primarily focused on a limited number of patients aged 70 years or older. The results of these studies, similar to our study, generally indicate that efficacy and survival are similar to those in younger patients, and that dose reductions do not significantly impact survival. Furthermore, there are no studies in the literature yet that examine the relationship between the Charlson comorbidity index and survival in elderly patients with multiple comorbidities who are receiving CDK 4/6 inhibitors.

The combination of palbociclib and tamoxifen delayed deterioration in patients' QoL while they experienced reduced risk for disease progression.