HER2-positive/hormone-receptor-positive breast cancer represents approximately 10% of all breast cancer cases and constitutes a distinct biological entity with unique therapeutic challenges. The complex crosstalk between HER2 and estrogen receptor signaling pathways contributes to both primary and acquired resistance to anti-HER2 therapies, and the convergence of these pathways on cell cycle regulation, particularly through the cyclin D1-CDK4/6-Rb axis, has provided a compelling rationale for combining CDK4/6 inhibitors with anti-HER2 therapy. This scoping review aimed to map preclinical and clinical evidence evaluating combinations of CDK4/6 inhibitors with HER2-targeted therapy in HER2+/HR+ disease. Eligible sources included preclinical models and clinical studies assessing CDK4/6 inhibitor-based combinations with anti-HER2 therapy, identified through searches of PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov. Data were charted and synthesized descriptively according to PRISMA-ScR guidelines. Preclinical studies have demonstrated synergistic antitumor activity when CDK4/6 inhibitors are combined with trastuzumab, pertuzumab, or newer HER2-targeted agents across multiple HER2+ breast cancer models. In the metastatic setting, phase II trials including MonarcHER and PATRICIA II have shown encouraging efficacy signals, while the phase III PATINA trial demonstrated a clinically meaningful 15.2-month progression-free survival benefit with palbociclib plus anti-HER2 therapy and endocrine therapy. In the neoadjuvant setting, trials including NA-PHER2 and MUKDEN-01 demonstrated marked Ki67 suppression and promising pathologic responses, supporting the exploration of chemotherapy de-escalation strategies. Despite these advances, key challenges remain including the identification of predictive biomarkers, optimal treatment sequencing, and the integration of emerging HER2-targeted agents such as trastuzumab deruxtecan. Novel CDK4/6 inhibitors including dalpiciclib and next-generation agents are expanding therapeutic options, while combination strategies incorporating CDK7 inhibition represent future therapeutic frontiers. The evolving landscape of HER2+/HR+ breast cancer treatment increasingly emphasizes precision medicine approaches that leverage cell cycle control mechanisms to overcome resistance and improve patient outcomes across all disease stages.

Adjuvant endocrine therapy for early breast cancer significantly reduces recurrence but increases bone fragility. Given limited data on denosumab (60 mg every 6 months) in premenopausal patients receiving endocrine therapy for early breast cancer, we conducted a retrospective real-world study at the Gemelli Hospital (September 2018–January 2025). A descriptive analysis was performed. The primary endpoint was to assess efficacy, evaluated by changes in bone mineral density via dual-energy X-ray absorptiometry and by monitoring bone turnover markers, particularly serum C-terminal telopeptide of type I collagen. Safety was evaluated based on adverse endocrine therapy events (osteoporotic fractures) and adverse denosumab events (osteonecrosis of the jaw). Sixty-nine patients were eligible for the study. Endocrine therapy included ovarian function suppression with exemestane (89.8%) or tamoxifen (10.1%). Baseline spinal osteoporosis decreased from 20.3% to 5.8%, osteopenia from 39.1% to 34.8%, with normal T-scores rising from 17.4% to 34.8%. Femoral improvements were similar. Serum C-terminal telopeptide of type I collagen levels (evaluated in 35.8%) showed stable reduction in 97%. Denosumab adherence was 89.9%. One osteonecrosis of the jaw case occurred (1.4%); no fractures were reported. Denosumab demonstrated efficacy in improving bone density and reducing bone turnover, with excellent adherence and favorable safety. Longer follow-up is needed to assess post-discontinuation effects.

Introduction: Perioperative chemoimmunotherapy improves outcomes in resectable non-small-cell lung cancer (NSCLC), but the absolute benefit-harm balance of treatment intensification, particularly postoperative immunotherapy continuation, remains uncertain.Methods: We conducted a systematic review and meta-analysis of randomized phase II-III trials evaluating perioperative chemoimmunotherapy in resectable NSCLC. PubMed, CENTRAL, Embase and major oncology congresses were consulted. Efficacy and safety outcomes were translated into number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and likelihood of being helped or harmed (LHH). Scenario analyses estimated the event-free survival (EFS) hazard ratios (HRs) required to reach predefined postoperative LHH thresholds.Results: Six trials including 3503 patients were included. Perioperative chemoimmunotherapy improved pathological complete response (pCR) (OR, 7.38; 95% CI, 4.81-11.32), corresponding to an NNTB of 4.6 (95% CI, 3.5-6.9), and EFS, with a pooled HR of 0.57 (95% CI, 0.50-0.65) and an NNTB of 5.8. Grade 3-4 treatment-related adverse events yielded a NNTH of 21.1, with favourable LHH values for pCR, major pathological response (MPR) and EFS. In the postoperative phase, grade 3-4 adverse events yielded an NNTH of 15.4. Threshold analysis showed that EFS HRs of 0.82, 0.67 and 0.53 were required to reach LHH values of 1, 2 and 3, respectively; corresponding thresholds for discontinuation were 0.84, 0.69 and 0.55.Conclusions: Perioperative chemoimmunotherapy shows a favourable benefit-harm profile in resectable NSCLC. LHH threshold analysis suggests that postoperative immunotherapy value depends on whether achievable EFS benefit offsets toxicity, supporting prospective response and risk adapted trials.