TRF2 as novel marker of tumor response to taxane-based therapy: from mechanistic insight to clinical implication.

BACKGROUND: Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) - the most aggressive BC form - is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients' response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy. METHODS: Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy. RESULTS: This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention. CONCLUSIONS: Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles' heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy.

Real-world ANASTASE study of atezolizumab+nab-paclitaxel as first-line treatment of PD-L1-positive metastatic triple-negative breast cancer.

The combination of atezolizumab and nab-paclitaxel is recommended in the EU as first-line treatment for PD-L1-positive metastatic triple-negative breast cancer (mTNBC), based on the results of phase III IMpassion130 trial. However, 'real-world' data on this combination are limited. The ANASTASE study (NCT05609903) collected data on atezolizumab plus nab-paclitaxel in PD-L1-positive mTNBC patients enrolled in the Italian Compassionate Use Program. A retrospective analysis was conducted in 29 Italian oncology centers among patients who completed at least one cycle of treatment. Data from 52 patients were gathered. Among them, 21.1% presented de novo stage IV; 78.8% previously received (neo)adjuvant treatment; 55.8% patients had only one site of metastasis; median number of treatment cycles was five (IQR: 3-8); objective response rate was 42.3% (95% CI: 28.9-55.7%). The median time-to-treatment discontinuation was 5 months (95% CI: 2.8-7.1); clinical benefit at 12 months was 45.8%. The median duration of response was 12.7 months (95% CI: 4.1-21.4). At a median follow-up of 20 months, the median progression-free survival was 6.3 months (95% CI: 3.9-8.7) and the median time to next treatment or death was 8.1 months (95% CI: 5.5-10.7). At 12 months and 24 months, the overall survival rates were 66.3% and 49.1%, respectively. The most common immune-related adverse events included rash (23.1%), hepatitis (11.5%), thyroiditis (11.5%) and pneumonia (9.6%). Within the ANASTASE study, patients with PD-L1-positive mTNBC treated with first-line atezolizumab plus nab-paclitaxel achieved PFS and ORR similar to those reported in the IMpassion130 study, with no unexpected adverse events.

Prospective Study Investigating the Efficacy and Safety of a Scalp Cooling Device for the Prevention of Alopecia in Women Undergoing (Neo)Adjuvant Chemotherapy for Breast Cancer.

The prevention of chemotherapy-induced alopecia still represents an urgent need for every day clinical practice. In this regard, this prospective single-center study included breast cancer (BC) patients who underwent a scalp cooling device (Dignicap®) during (neo)adjuvant chemotherapy with the aim to evaluate the efficacy and safety of this device in preventing alopecia. One hundred and seventy-eight patients (median age 43 years) were enrolled. The chemotherapy regimen included anthracycline and taxane-based chemotherapy (68.1%), docetaxel and cyclophosphamide (25.8%), anthracycline and taxane-based plus carboplatin (3.9%), and paclitaxel alone (2.2%). In 25.3% of cases, a dose dense schedule was used. Overall, the success rate was 68.0%: 100% in paclitaxel alone, 87.0% in docetaxel-cyclophosphamide, 59.5% in anthracycline and taxane, and 71.4% in the sequential regimen plus carboplatin group (anthracycline and taxane-based chemotherapy versus taxane-based chemotherapy, p ≤ 001. No difference in terms of hair preservation between dose-dense or standard schedule was found (p = 0.557). Early discontinuation of the scalp cooling was observed in 50 patients (28.1%). Although 138 patients (77.5%) experienced adverse events, 70.2% of patients were satisfied with this device. In conclusion, this large prospective study confirmed the helpful effect of the scalp cooling system in preventing alopecia in BC patients also undergoing sequential anthracyclines and taxane-based chemotherapy.

BRCA Mutation Status in Triple-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy: A Pivotal Role for Treatment Decision-Making.

Triple-negative breast cancer (TNBC) is characterized by earlier recurrence and shorter survival compared with other types of breast cancer. Moreover, approximately 15 to 25% of all TNBC patients harbor germline BRCA (gBRCA) 1/2 mutations, which confer a more aggressive phenotype. However, TNBC seems to be particularly sensitive to chemotherapy, the so-called 'triple negative paradox'. Therefore, Neoadjuvant chemotherapy (NACT) is currently considered the preferred approach for early-stage TNBC. BRCA status has also been studied as a predictive biomarker of response to platinum compounds. Although several randomized trials investigated the addition of carboplatin to standard NACT in early-stage TNBC, the role of BRCA status remains unclear. In this retrospective analysis, we evaluated data from 136 consecutive patients with Stage I-III TNBC who received standard NACT with or without the addition of carboplatin, in order to define clinical features and outcomes in BRCA 1/2 mutation carriers and non-carrier controls. Between January 2013 and February 2021, 67 (51.3%) out of 136 patients received a standard anthracyclines/taxane regimen and 69 (50.7%) patients received a platinum-containing chemotherapy regimen. Deleterious germline BRCA1 or BRCA2 mutations were identified in 39 (28.7%) patients. Overall, patients with deleterious gBRCA1/2 mutation have significantly higher pCR rate than non-carrier patients (23 [59%] of 39 vs. 33 [34%] of 97; p = 0.008). The benefit of harboring a gBRCA mutation was confirmed only in the subset of patients who received a platinum-based NACT (17 [65.4%] of 26 vs. 13 [30.2%] of 43; p = 0.005) while no differences were found in the platinum-free subgroup. Patients who achieved pCR after NACT had significantly better EFS (OR 4.5; 95% CI 1.9-10.7; p = 0.001) and OS (OR 3.3; 95% CI 1.3-8.9; p = 0.01) than patients who did not, regardless of BRCA1/2 mutation status and type of NACT received. Our results based on real-world evidence show that TNBC patients with the gBRCA1/2 mutation who received platinum-based NACT have a higher pCR rate than non-carrier patients, supporting the use of this chemotherapy regimen in this patient population. Long-term follow-up analyses are needed to further define the role of gBRCA mutation status on clinical outcomes in patients with early-TNBC.

PI3K Inhibitors in Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives.

Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial need. Recently, several clinical trials were performed to find innovative predictive biomarkers and to improve the outcome of metastatic breast cancer through innovative therapeutic algorithms. In the pathogenesis of breast cancer, the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) axis is a key regulator of cell proliferation, growth, survival, metabolism, and motility, making it an interest and therapeutic target. Nevertheless, the PI3K/AKT/mTOR cascade includes a complex network of biological events, needing more sophisticated approaches for their use in cancer treatment. In this review, we described the rationale for targeting the PI3K pathway, the development of PI3K inhibitors and the future treatment directions of different breast cancer subtypes in the metastatic setting.

Let-7a-5p, miR-100-5p, miR-101-3p, and miR-199a-3p Hyperexpression as Potential Predictive Biomarkers in Early Breast Cancer Patients.

BACKGROUND: The aim of this study is to identify miRNAs able to predict the outcomes in breast cancer patients after neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: We retrospectively analyzed 24 patients receiving NAC and not reaching pathologic complete response (pCR). miRNAs were analyzed using an Illumina Next-Generation-Sequencing (NGS) system. RESULTS: Event-free survival (EFS) and overall survival (OS) were significantly higher in patients with up-regulation of let-7a-5p (EFS p = 0.006; OS p = 0.0001), mirR-100-5p (EFS s p = 0.01; OS p = 0.03), miR-101-3p (EFS p = 0.05; OS p = 0.01), and miR-199a-3p (EFS p = 0.02; OS p = 0.01) in post-NAC samples, independently from breast cancer subtypes. At multivariate analysis, only let-7a-5p was significantly associated with EFS (p = 0.009) and OS (p = 0.0008). CONCLUSION: Up-regulation of the above miRNAs could represent biomarkers in breast cancer.

Contrast-enhanced ultrasonography in chronic glomerulonephritides: correlation with histological parameters of disease activity.

PURPOSE: To compare contrast-enhanced ultrasonography (CEUS)-derived time-intensity (TI) curves with histological findings in kidneys of patients affected by chronic glomerulonephritides (GN) in the early stage of disease. METHODS: Research ethics committee approval and patient written informed consent were obtained. Thirty-one patients who showed clinical and laboratory signs of GN, with preserved renal function, were consecutively enrolled. They underwent kidney CEUS, from which TI curves were obtained, and kidney biopsy. TI curves were compared with clinical data, ultrasound (US) Doppler, and histological parameters. RESULTS: The persistence of contrast agent signal during the wash-out phase was found to be correlated with the degree of disease activity (p = 0.016) and in particular with the presence of mesangial hyperplasia (p = 0.008). No correlation was observed between TI curves and clinical or Doppler US-derived parameters. CONCLUSIONS: The persistence of contrast agent signal in the wash-out phase of CEUS appears to reflect a disturbance of perfusion in glomerular capillaries in the early stages of GN. We found that the histological element directly correlated with the prolonged wash-out was mesangial hyperplasia.

Neoadjuvant chemotherapy in triple-negative breast cancer: A multicentric retrospective observational study in real-life setting.

We aimed to assess the efficacy of neoadjuvant chemotherapy (NACT) in a cohort of 213 triple-negative breast cancer (TNBC) patients treated in real-world practice at eight Italian cancer centers. We computed descriptive statistics for all the variable of interest. Factors testing significant in univariate analysis were included in multivariate models. Survival data were compared by Kaplan-Meier curves and log-rank test. The median follow-up was 45 months. We observed 60 (28.2%) pathological complete response (pCR). The sequential anthracyclines-taxanes-based regimens produced the highest rate of pCR (42.6%), followed by concomitant anthracycline-taxane (24.2%), and other regimens (15.6%) (p = 0.008). When analyzing the role of baseline Ki-67, a 50% cut-off was the optimal threshold value for pCR prediction (p = 0.0005). The 5-year disease-free survival (DFS) was 57.3% and the 5-year overall survival (OS) was 70.8%. In patients not achieving pCR, the optimal Ki-67 variation between biopsy and surgical specimen with prognostic relevance on long-term outcomes was 13% (p = 0.04). Patients with a Ki-67 reduction (rKi-67)<13% had worse outcomes compared to those who experienced pCR or a rKi-67≥13%. The number of NACT cycles also affected long-term outcomes (5-year DFS 65.7% vs 51.6% in patients having received >6 cycles compared with their counterparts, p = 0.02). In multivariate analysis, node status, grading, and bio-pathological treatment response (including pCR and rKi-67) impacted DFS and OS. Our results confirmed the advantage conferred by more than 6 cycles of a sequential antracycline-taxane-based NACT. Higher baseline Ki-67 values shows greater predictive significance on pathogical response, while the rKi-67 plays a prognostic role on long-term outcomes.