CDK4/6 inhibitors as adjuvant treatment for hormone receptor-positive, HER2-negative early breast cancer: a systematic review and meta-analysis.

BACKGROUND: The combination of cyclin-dependent kinases 4/6 inhibitors (CDK4/6is) and endocrine therapy (ET) is standard of care for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (BC). However, studies evaluating adjuvant CDK4/6is provided contradictory results thus far. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis to assess if the addition of CDK4/6is to adjuvant ET impacts on survival's outcomes and safety of patients with HR+/HER2- early BC (EBC). This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and was registered in the PROSPERO database (ID: CRD42020218597). A systematic review of PubMed, Cochrane and EMBASE databases and major conference proceedings was performed up to 15 December 2020. All randomized controlled trials including patients with HR+/HER2- EBC treated with CDK4/6is plus ET versus ET alone in the adjuvant setting were included. Pooled hazard ratios (HRs) and odds ratios (ORs) for survival and safety outcomes, respectively, were calculated with 95% confidence intervals (95% CIs) using random effect models. RESULTS: With data available from three studies (N = 12 647), the addition of CDK4/6is to adjuvant ET showed a trend for a benefit in terms of invasive disease-free survival (IDFS; HR 0.85, 95% CI 0.71-1.01; P = 0.071). No significant improvement in distant relapse-free survival was observed (HR 0.83, 95% CI 0.58-1.19; P = 0.311). The risk of all-grade toxicities and early treatment discontinuation increased significantly with the addition of CDK4/6is to ET (OR 9.36, 95% CI 3.46-25.33, P < 0.001, and OR 22.11, 95% CI 9.45-51.69, P < 0.001, respectively). CONCLUSION: The administration of adjuvant CDK4/6is to patients with HR+/HER2- EBC showed a trend for an IDFS benefit and an increase in the risk of toxicities and treatment discontinuation. The role of adjuvant CDK4/6is remains controversial and a longer follow-up of these randomized controlled trials is needed before supporting a straightforward change in clinical practice.

Beta-blockers in early-stage breast cancer: a systematic review and meta-analysis.

BACKGROUND: Preclinical and retrospective studies suggest that beta-blockers are active against breast cancer. We carried out a systematic review and meta-analysis to assess the impact of beta-blockers on the outcomes of patients with early-stage breast cancer. METHODS: A systematic literature search was performed to identify studies comparing outcomes of patients with early-stage breast cancer according to beta-blocker use (yes versus no). The primary endpoint was recurrence-free survival (RFS), defined as the occurrence of breast cancer recurrence or death. Secondary objectives were pathologic complete response (pCR), breast cancer recurrence, breast cancer-specific mortality and overall survival (OS). Hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were extracted from each study and a pooled analysis with the random-effect model was conducted. The Higgins' I-squared test was used to quantify heterogeneity. Egger's test was applied to assess publication bias. All P values were two-sided and considered significant if ≤0.05. RESULTS: Overall, 13 studies were included as follows: RFS (6), pCR (2), breast cancer recurrence (6), breast cancer-specific mortality (7) and OS (5). The use of beta-blockers was associated with a significant RFS improvement in the overall population (N = 21 570; HR 0.73; 95% CI, 0.56-0.96; P = 0.025) and in patients with triple-negative disease (N = 1212; HR 0.53; 95% CI, 0.35-0.81; P = 0.003). No significant differences in terms of pCR (N = 1554; OR 0.77; 95% CI, 0.44-1.36; P = 0.371), breast cancer recurrence (N = 37 957; OR 0.66; 95% CI, 0.42-1.03; P = 0.065), breast cancer-specific mortality (N = 64 830; HR 0.77; 95% CI, 0.56-1.08; P = 0.130) or OS (N = 103 065; HR 1.03; 95% CI, 0.87-1.23; P = 0.692) were observed according to beta-blocker use. DISCUSSION: In this meta-analysis, beta-blocker use was associated with a longer RFS in patients with early-stage breast cancer, with a more pronounced effect observed in those with triple-negative disease. Beta-blockers arise as an interesting option to be explored in prospective studies for patients with early-stage breast cancer.

Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors.

In this review, we discuss biomarkers of response and resistance to PI3K inhibitors (PI3Ki) in estrogen receptor-positive breast cancer, both in the early and advanced settings. We analyse data regarding PIK3CA mutations, PI3K pathway activation, PTEN expression loss, Akt signalling, insulin levels, 18FFDG-PET/CT imaging, FGFR1/2 amplification, KRAS and TP53 mutations. Most of the discussed data comprise retrospective and exploratory studies, hence many results are not conclusive. Therefore, among all of these biomarkers, only PIK3CA mutations have proved to have a predictive value for treatment with the α-selective PI3Ki alpelisib (SOLAR-1 trial) and the ß-sparing PI3Ki taselisib (SANDPIPER trial) in the advanced setting. Since the accuracy of current individual biomarkers is not optimal, a composite biomarker, including DNA, RNA and protein expression data, to more precisely assess the PI3K/AKT/mTOR pathway activation status, may arise as a promising approach. Finally, we describe the rational for new combination therapies involving PI3Ki and anti-HER2 agents, chemotherapy, CDK4/6 inhibitors, mTOR inhibitors or new endocrine treatments and discuss the ongoing trials in this field.