This study evaluates whether serum phospholipids fatty acids (PL-FAs) and markers of their endogenous metabolism are associated with breast cancer (BC) subtypes. EpiGEICAM is a Spanish multicenter matched case-control study. A lifestyle and food frequency questionnaire was completed by 1017 BC cases and healthy women pairs. Serum PL-FA percentages were measured by gas chromatography-mass spectrometry. Conditional and multinomial logistic regression models were used to quantify the association of PL-FA tertiles with BC risk, overall and by pathological subtype (luminal, HER2+ and triple negative). Stratified analyses by body mass index and menopausal status were also performed. Serum PL-FAs were measured in 795 (78%) pairs. Women with high serum levels of stearic acid (odds ratio (OR)_T3vsT1 = 0.44; 95% confidence interval (CI) = 0.30–0.66), linoleic acid (OR_T3vsT1 = 0.66; 95% CI = 0.49–0.90) and arachidonic to dihomo-γ-linolenic acid ratio (OR _T3vsT1 = 0.64; 95% CI = 0.48–0.84) presented lower BC risk. Participants with high concentrations of palmitoleic acid (OR_T3vsT1 = 1.65; 95% CI = 1.20–2.26), trans-ruminant palmitelaidic acid (OR_T3vsT1 = 1.51; 95% CI = 1.12–2.02), trans-industrial elaidic acid (OR_T3vsT1 = 1.52; 95% CI = 1.14–2.03), and high oleic to stearic acid ratio (OR_T3vsT1 = 2.04; 95% CI = 1.45–2.87) showed higher risk. These associations were similar in all BC pathological subtypes. Our results emphasize the importance of analyzing fatty acids individually, as well as the desaturase activity indices.

Breast cancer (BC) survivors are advised to follow the WCRF/AICR cancer prevention recommendations, given their high risk of developing a second tumour. We aimed to explore compliance with these recommendations in BC survivors and to identify potentially associated clinical and sociodemographic factors. A total of 420 BC survivors, aged 31–80, was recruited from 16 Spanish hospitals. Epidemiological, dietary and physical activity information was collected through questionnaires. A 7-item score to measure compliance with the recommendations was built according to the 2018 WCRF/AICR scoring criteria. Standardized prevalences and standardized prevalence ratios of moderate and high compliance across participant characteristics were estimated using multinomial and binary logistic regression models. The mean score was 3.9 (SD: 1.0) out of 7 points. Recommendations with the worst adherence were those of limiting consumption of red/processed meats (12% of compliance, 95% CI: 8.2–15.0) and high fibre intake (22% of compliance, 95% CI: 17.6–27.0), while the best compliance was observed for the consumption of fruits and vegetables (73% of compliance, 95% CI: 69.2–77.7). Overall, adherence was worse in women with university education and in those with first-degree relatives with BC. This information may be of interest to design and implement personalized preventive measures adapted to the characteristics of these patients.

Despite the initial clinical success of CDK4/6 inhibitors in combination with endocrine therapy, the development of resistance (intrinsic and acquired) remains a significant challenge in the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). Recent advances have shed light on resistance mechanisms that primarily affect the cell cycle machinery, including loss of Rb function, cyclin E1 overexpression leading to CDK2 activation, and CDK6 or CDK4 upregulation. These alterations disrupt the G1/S checkpoint and drive proliferation independently of CDK4/6 inhibition. In contrast, non-cell cycle-related pathways, such as PI3K/AKT/mTOR and FGFR signaling, may also contribute but appear less central in many resistant tumors. These findings have highlighted the need for next-generation therapeutic approaches aimed at overcoming resistance. Selective inhibition of CDK2 and/or CDK4 is among the most promising strategies, potentially offering a more favorable therapeutic index while maintaining anti-proliferative efficacy. Early-phase trials of selective CDK2/CDK4 inhibitors, alone or combined, have shown encouraging activity, particularly in tumors resistant to prior CDK4/6 inhibition. However, most available data are limited to small, selected cohorts, underscoring the need for larger, randomized studies. Another emerging approach targets lysine acetyltransferases (KAT), key epigenetic regulators of transcription and cancer progression. KAT inhibition has shown potential to modulate oncogenic signaling and sensitize tumor cells to existing therapies, offering a complementary avenue for overcoming resistance. This review focuses on emerging cell cycle-centric mechanisms of resistance to CDK4/6 inhibitors and highlights innovative therapeutic strategies aimed at improving outcomes in HR+/HER2- mBC.