Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer.

Individual trials of abemaciclib, palbociclib, and ribociclib show a similar impact on progression-free survival yet differing statistical significance for overall survival (OS). A robust comparative evaluation of OS, safety, and tolerability of the three drugs is warranted. A systematic literature search identified phase 3 randomized clinical trials reporting OS of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy in ER-positive/HER2-negative advanced breast cancer. Trial-level data on OS and common and serious adverse events (AE) were extracted for each drug. In the absence of direct comparisons, a network meta-analysis was performed to evaluate pairwise comparative efficacy, safety, and tolerability of each of the CDK4/6i. Seven studies comprising of 4415 patients met the inclusion criteria. Median follow-up was 73.3 months (range: 48.7-97.2 months). There were no statistically significant differences in OS between any of the CDK4/6i. Compared to palbociclib, ribociclib and abemaciclib both showed significantly higher GI toxicity (grade 1-2 vomiting OR 1.87 [95% CI 1.37-2.56] and OR 2.27 [95% CI 1.59-3.23] respectively). Compared to palbociclib, abemaciclib was associated with more grade 3-4 diarrhea OR 118.06 [95% CI 7.28-1915.32]. In contrast, palbociclib was associated with significantly more neutropenia than ribociclib and abemaciclib but significantly lower risk of grade 3-4 infections. Abemaciclib had significantly less grade 3-4 transaminitis and grade 3-4 neutropenia than ribociclib. Treatment discontinuation and death due to AE were significantly higher with abemaciclib than palbociclib and ribociclib. There is no statistically significant difference in OS between CDK4/6i despite differing statistical significance levels of individual trials. Real-world data analyses may help to identify if there is a meaningful inter-drug difference in efficacy. Significant differences between CDK4/6i are observed for safety and tolerability outcomes.

Modifiable risk factors for prostate cancer in low- and lower-middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Most of the epidemiological data on prostate cancer risk factors come from high-income countries (HIC). Reducing exposure to prostate cancer modifiable risk factors may significantly lower PCa morbidity and mortality in LIC and MIC. The objective of this study was to summarize the evidence on modifiable risk factors (RFs) for PCa in LIC and lower-middle-income countries (LMIC). METHODS: We conducted a systematic search on MEDLINE, EMBASE, and Global Health databases. We selected case-control and cohort studies from 2010 onwards that studied modifiable RFs for PCa in LIC and LMIC with a population of 30 million or more, as defined by the World Bank in January 2021. Risk of bias was assessed by the Ottawa-Newcastle tool. Individual study estimates were pooled when estimates were available for at least two studies. RESULTS: 5740 studies were initially identified; 16 studies met inclusion criteria. All were case-control studies except one retrospective cohort study. Higher fat intake was associated with a higher risk of PCa incidence with an odds ratio (OR) of 3.13 (95% CI 1.33-7.33). Higher vegetable intake (OR 0.48, 95% CI 0.24-0.97) and tea consumption (OR 0.51, 95% CI 0.32-0.83) were associated with a lower risk for PCa. There was no association between fruits, fish, and chicken consumption and risk of PCa. Alcohol consumption, smoking, red meat intake, and a BMI ≥ 25-30 kg/m2 showed a trend towards an increased risk, although these were not statistically significant. CONCLUSIONS: In LIC and LMIC, high fat intake was associated with higher risk of PCa while a diet rich in vegetables and tea intake was associated with a lower risk. Future prospective studies will be important to elucidate whether other modifiable risk factors for PCa specific to LIC and LMIC can be identified to inform impactful and cost-effective preventive strategies in these countries.

Cardiac Monitoring and Heart Failure in Advanced Breast Cancer Patients Treated With Trastuzumab in Ontario, Canada.

Background: Trastuzumab has improved patient outcomes in HER2 + breast cancer (BC) but carries a risk of cardiotoxicity. Routine cardiac imaging is recommended for advanced breast cancer (aBC) patients during trastuzumab treatment despite a lack of evidence that this improves patient outcomes. This study was conducted to understand predictive factors for cardiac events and determine the impact of cardiovascular monitoring in aBC. Methods: This retrospective population-based cohort study included aBC patients treated with trastuzumab (all lines), in Ontario, Canada from 2007 to 2017. The overall cohort was divided into two groups; those who developed a cardiac event (CE) vs. those who did not. Patients with pre-existing heart disease were excluded. Logistic regression was performed to identify patient characteristics associated with an increased risk of CE. Results: Of 2,284 patients with HER2 + aBC treated with trastuzumab, 167 (7.3%) developed a CE. Median age at first dose of trastuzumab was 57 (IQR 49-66); 61 (IQR 51-70) for patients with a CE. Median number of cycles was 16 (IQR 7-32); 21 (IQR 8-45) for patients with a CE (p < 0.01). Twelve (0.5%) patients died of cardiac causes; all had a prior CE. Increased risk of CEs was associated with age > 60 (OR 5.21, 95% CI 1.83-14.84, p = 0.05) and higher number cycles of trastuzumab (OR 1.01; 95% CI 1-101, p = 0.028). Conclusion: This is the first population-based study to report on CEs and cardiac monitoring in HER2 + aBC patients during trastuzumab-based therapy. Older age and longer treatment with trastuzumab were associated with an increased risk of a CE.

Pursuing Connectivity in Cardio-Oncology Care-The Future of Telemedicine and Artificial Intelligence in Providing Equity and Access to Rural Communities.

The aim of this review is to discuss the current health disparities in rural communities and to explore the potential role of telehealth and artificial intelligence in providing cardio-oncology care to underserviced communities. With advancements in early detection and cancer treatment, survivorship has increased. The interplay between cancer and cardiovascular disease, which are the leading causes of morbidity and mortality in this population, has been increasingly recognized. Worldwide, cardio-oncology clinics (COCs) have emerged to deliver a multidisciplinary approach to the care of patients with cancer to mitigate cardiovascular risks while minimizing interruptions in cancer treatment. Despite the value of COCs, the accessibility gap between urban and rural communities in both oncology and cardio-oncology contributes to health care disparities and may be an underrecognized determinant of health globally. Telehealth and artificial intelligence offer opportunities to provide timely care irrespective of rurality. We therefore explore current developments within this sphere and propose a novel model of care to address the disparity in urban vs. rural cardio-oncology using the experience in Canada, a geographically large country with many rural communities.

Comprehensive genomic profiling of treatment resistant metastatic castrate sensitive prostate cancer reveals high frequency of potential therapeutic targets.

INTRODUCTION: While comprehensive genomic profiling (CGP) data is becoming increasingly important in the management of prostate cancer, it remains under-utilized in the setting of metastatic castrate sensitive prostate cancer (mCSPC). We aimed to explore the feasibility and potential utility of CGP in mCSPC. PATIENTS AND METHODS: Patients with mCSPC were prospectively recruited at the Princess Margaret Cancer Centre to the OCTANE trial (NCT02906943). The objective was to assess the feasibility of profiling archival standard diagnostic tumor tissue using next generation sequencing with a custom hybridization capture DNA-based or a targeted DNA/RNA amplicon-based panel. Clinical data were extracted from electronic health records. RESULTS: Among 39 mCSPC patients enrolled, 21 (54%) had sufficient archival tissue for CGP. Most had high volume (71%) or de novo (71%) mCSPC, with the majority being androgen deprivation therapy (ADT) naïve. In total, 62% of patients had a pathogenic and/or a likely pathogenic variant, many of which involved DNA damage repair (DDR, 19%), cell cycle (24%), and Androgen Receptor (AR, 10%) pathways. After median follow-up of 32.1 months, 18 of 21 patients progressed, with median time to mCRPC of 14.3 months (95% CI 10.2-21.0). Patients with AR and DDR variants seemed to have shorter median time to mCRPC; 10.2 (95% CI 9.50-NR) and 10.3 months (95% CI 6.6-14.3) respectively. CONCLUSION: In this cohort of highly treatment resistant mCSPC, most of which were ADT-naïve, CGP using archival tumor tissue was feasible for over half of patients, and 62% of patients profiled had a pathogenic and/or a likely pathogenic variant. The presence of de novo variants provides biological basis for evaluating intensification strategies of systemic therapy. This highlights the potential role of routine CGP in biomarker development and clinical trial design in the setting of mCSPC.

ALK inhibitor-induced bradycardia: A systematic-review and meta-analysis.

INTRODUCTION: Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC. MATERIALS AND METHODS: We conducted a systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, National clinical trial registry, and Web of Science Core Collection. We included all randomized controlled trials in which an ALK-inhibitor was compared with another ALK-inhibitor or standard chemotherapy. Meta-analyses were conducted to evaluate the pooled incidence rates of bradycardia and dizziness using fixed effect models. RESULTS: The pooled incidence of bradycardia among 1737 individuals prescribed ALK inhibitors was 8% during a mean follow-up of 1.26 years. Crizotinib led to more bradycardia than standard chemotherapy (relative risk, RR 24.68, 95% CI 7.11-85.), while no difference was seen between crizotinib and alectinib (RR 1.12, 95% CI 0.79-1.59). The next-generation ALK inhibitors alectinib, brigatinib and lorlatinib combined resulted in a similar rate of bradycardia when compared to crizotinib (RR 0.77, 95% CI 0.57-1.04). All ALK inhibitors (as an aggregate) caused more dizziness (as a potential symptom of bradycardia) than standard chemotherapy (RR 1.88, 95% CI 1.44-2.44). CONCLUSION: Crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors.

A survey of Canadian breast health professionals' recommendations for high-risk benign breast disease

Summary: The management of high-risk benign breast disease (BBD) is changing because of improvements in radiological and pathological analysis. We sought to determine the current practice recommendations of breast health professionals in managing patients with high-risk BBD. We surveyed members of the Canadian Society of Surgical Oncology, Canadian Association of General Surgeons and Canadian Association of Radiologists. The survey contained demographic and case-based questions concerning management of high-risk benign breast lesions. Participants were asked for their recommendations and opinions regarding future risk of breast cancer as well as the role of chemoprevention. There was no consistency among the 41 respondents in the treatment recommendations for any of the high-risk benign conditions, and the lifetime risk associated with classic lobular carcinoma in situ was vastly underestimated. Education and evidenced-based guidelines are urgently needed to ensure more uniform practice nationally.