Pessoa, Beatriz

160 Background: In the United States, racial/ethnic disparities in adoption of breast cancer evidence-based practices (EBPs) persist along the cancer care continuum. This scoping review applied an implementation science lens to describe the current evidence base for interventions to reduce disparities, synthesizing evidence on effective interventions while highlighting gaps in the literature. Methods: A formalized search strategy identified USA-based interventional studies aiming to improve adoption of an EBP along the breast cancer care continuum among racially/ethnically minoritized patients. Relevant articles from 1/2010 - 8/2022 (Medline, Embase, Cochrane, and Scopus) were included. For each article, two reviewers screened and extracted data, with a third resolving discrepancies. The PRISMA-ScR checklist and JBO Manual for Evidence Synthesis framework were followed. Results: Our search strategy yielded 45,215 articles. After applying inclusion/exclusion criteria, 59 articles were retained, targeting screening (85%, 50 of 59), treatment (12%, 7 of 59), and survivorship (5%, 3 of 59) (2 targeted multiple areas). No articles targeted end-of-life care. Of these, 49% (29 of 59) were randomized controlled trials (RCTs). Among 24 screening RCTs, the most common interventions—and fraction with statistically significant improved screening uptake—were patient navigation (100%, 11 of 11) and patient education (80%, 4 of 5). Among 4 treatment RCTs, 3 targeted adjuvant chemotherapy uptake. Of these, 1 had significant improvements and used patient navigation. The 2 studies without significant improvements used a patient tracking tool/alert system or patient education. Among 2 survivorship RCTs, one used email interventions, resulting in significantly improved physical activity and dietary health. A second used a nurse-facilitated internet support group, resulting in significantly improved physical/psychological symptoms. Early to mid-stage implementation outcomes (acceptability, adoption, appropriateness, feasibility, or fidelity) were commonly measured (81%, 48 of 59). No study measured later stage implementation outcomes (sustainability or costs). Conclusions: In multiple studies, patient navigation and education improved breast cancer screening among racially/ethnically minoritized populations. In one study, patient navigation improved completion of adjuvant treatment. Despite these studies, patient navigation is not reimbursed for cancer screening, and adoption has not been widespread. Future studies should focus on evaluating and improving later stage implementation outcomes (sustainability and costs). Based on these results, insurance reimbursement mechanisms for screening-related navigation may be warranted. Future breast cancer care delivery disparities research should also be expanded to include treatment, survivorship, and end-of-life care.

Abstract Background Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2− breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. Methods We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. Results We included 14 RCTs comprising 16 196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). Conclusion Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.

Abstract Introduction: CDK4/6 inhibitors (CDK4/6i), such as abemaciclib, ribociclib, and palbociclib, have significantly improved outcomes for patients with ER+/HER2− breast cancer. Nevertheless, they differ among each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. Ribociclib causes concentration-dependent increases in the QTc interval, particularly in combination with tamoxifen. However, the pathogenesis of ribociclib-induced QTc prolongation remains unclear. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. Methods: We performed a systematic review and meta-analysis of randomized clinical trials (RCTs) to compare QTc prolongation in patients using CDK4/6i in combination with hormonal agents to patients that did not use CDK4/6i, including neoadjuvant, adjuvant, or metastatic scenarios in breast cancer. We searched Embase, PubMed and Cochrane Library databases from inception to June 2023. The outcomes evaluated were QTc prolongation of all grades. Statistical analysis was performed with R software version 2023.03.0+386. Results: We included 14 RCTs comprising 16,013 patients in the quantitative analysis, of whom 8,585 underwent therapy with CDK4/6i, and one more paper was included only in the qualitative analysis due to not reporting the exact number of events of QTc prolongation. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR 2.32; 95% CI 1.67–3.23; p=0.000001; I²=46%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a risk ratio of 3.07 (RR 3.07; 95% CI 2.17-4.36; p< 0.000001; I² = 21%) while the palbociclib subgroup had a risk ratio of 1.52 (RR 1.51; 95% CI 1.05-2.16; p=0.025, I²=0%). Conclusion: Our findings suggest that QTc prolongation may be a common adverse effect of CDK4/6i, with ribociclib carrying greater risk. These results are important for guiding clinical decision-making, and further investigation is warranted to better understand the mechanisms and clinical implications of CDK4/6 i-induced QTc prolongation. Citation Format: Bruno Carvalho, Pedro Cotta Abrahão Reis, Alice Marinho, Ana Carolina Comini, Debora Xavier, Beatriz Mella S. Pessoa, Felipe Batalini. QTc prolongation as Adverse Effect of CDK4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-12-08.

Abstract Importance: The poly-adenosine diphosphate–ribose polymerase (PARP) enzymes are important for DNA single-strand break repair and PARP inhibitors (PARPi) cause an accumulation of unresolved DNA damage in tumors with BRCA1/2 mutations, resulting in cell death. However, because platinum salts also ultimately cause double-strand DNA breaks and may have overlapping mechanisms of resistance with PARPi, the efficacy of PARPi in patients with prior platinum therapy is unknown. Objective We sought to evaluate the efficacy of PARPi in patients with BRCA1/2-related breast cancer and previous platinum exposure. Data Sources: PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for papers up to June 26, 2022. Study Selection: We performed a systematic review and meta-analysis of studies that evaluated the efficacy of PARPi in patients with advanced or metastatic breast cancer and germline BRCA1/2 mutations. Two independent investigators identified double-blind, randomized controlled trials (RCTs) that included the subgroup of previous exposure to platinum. Data Extraction and Synthesis: Data extraction from published reports and quality assessment were performed under Cochrane recommendations. The software Review Manager 5.3 was selected for conducting the statistical analyses. Main Outcome(s) and Measure(s): The primary endpoint of interest was progression-free survival (PFS). Hazard ratios (HRs) with a 95% confidence interval (CI) were pooled, and a p-value of < 0.05 was considered statistically significant. Results From 2,069 database results (487 on PubMed; 1,376 on Embase; and 206 on Cochrane), 42 studies were fully reviewed, and 4 RCTs (total of 249 patients) were included in the final investigation. The PARPi included were Olaparib, Talazoparib, Niraparib, and Veliparib. Pooled analysis showed that PARPi improved PFS in breast cancer patients with prior treatment with platinum-based therapy compared to the control group [HR = 0.72; 95% CI, 0.53–0.97; p = 0.03]. For comparison, the population without previous platinum exposure had a similar magnitude of benefit from PARPi [HR = 0.68; 95% CI, 0.52–0.89; p = 0.005]. Conclusions and Relevance: Despite the concerns about cross-resistance between PARPi and platinum agents, patients with advanced breast cancer and previous exposure to platinum therapy have a longer PFS with PARPi when compared to standard chemotherapy.

Abstract Background: Approximately 5% of breast cancer patients carry a deleterious germline BRCA1/2 mutation, which leads malignant cells to be deficient in the repair of DNA double-strand breaks via homologous recombination. The poly(adenosine diphosphate–ribose) polymerase (PARP) enzymes are important on DNA single-strand break repair and PARP inhibitors (PARPi) cause an accumulation of unresolved DNA damage in tumors with BRCA1/2 mutations, resulting in cell death. However, because platinum salts also ultimately cause double-strand DNA breaks and may have overlapping mechanisms of resistance with PARPi, the efficacy of PARPi in patients with prior platinum therapy is unknown. We sought to evaluate the efficacy of PARPi in patients with BRCA1/2-related breast cancer and previous platinum exposure. Methods: We performed a systematic review and meta-analysis of studies that evaluated the efficacy of PARPi in patients with advanced or metastatic breast cancer and germline BRCA1/2 mutations. Two independent investigators identified double-blind, randomized controlled trials (RCTs) that included the subgroup of previous exposure to platinum. PubMed, Embase, and Cochrane databases were searched for papers up to June 26, 2022. Data extraction from published reports and quality assessment were performed under Cochrane recommendations. Hazard ratios (HRs) with a 95% confidence interval (CI) were pooled, and a p-value of &lt; 0.05 was considered statistically significant. The software Review Manager 5.3 was selected for conducting the statistical analysis. The primary endpoint of interest was progression-free survival (PFS). Results: Out of 2069 database results (487 on PubMed; 1376 on Embase; and 206 on Cochrane), 42 studies were selected for full review, and 4 RCTs, with a total of 249 patients, were included in the final investigation. The PARPi included were Olaparib, Talazoparib, Niraparib, and Veliparib. Pooled analysis showed that PARPi improved PFS in breast cancer patients with prior treatment with platinum-based therapy compared to the control group [HR = 0.72; 95% CI, 0.53-0.97; p = 0.03]. In comparison, the population without previous platinum exposure had a similar but slightly greater benefit from PARPi [HR = 0.68; 95% CI, 0.52-0.89; p = 0.005]. A subgroup analysis containing only the three randomized trials with PARPi monotherapy confirmed the central tendency favoring PARPi over physicians’ choice of single-agent chemotherapy in patients with prior platinum-therapy; however, because of small numbers and wide confidence interval it was not statistically significant [HR = 0.72; 95% CI, 0.51-1.01; p = 0.06]. Conclusions: Our findings suggest that PARPi are associated with longer PFS in patients with advanced breast cancer and previous exposure to platinum therapy, decreasing the concerns about cross-resistance between the drug classes. Nonetheless, more extensive studies are still necessary to investigate the efficacy of PARPi in patients with prior platinum exposure and truly platinum-resistant disease. Progression-free survival of included studies Citation Format: Alice D. Marinho, Beatriz Mella S. Pessoa, Gabriela R. Brandao, Caroliny H. Da Silva, Pedro A. Reis, Ana Carolina M. Comini, Felipe Batalini. Efficacy of PARP Inhibitors in Patients With BRCA1/2-related Breast Cancer with Prior Platinum Exposure: A Systematic Review and Meta-Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-08.