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Background: Survival outcomes in metastatic breast cancer (MBC) have improved due to novel agents such as CDK4/6 inhibitors (CDK4/6i). Nevertheless, Black patients and patients with lower socioeconomic status (SES) continue to bear a disproportionate mortality burden., Methods: We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database (FHD). A dataset was constructed to include Black/African-American (Black/AA) and White patients with hormone receptor (HR)-positive, HER2-negative MBC. Outcomes included CDK4/6i use (overall and first-line), and rates of leukopenia, dose reduction, and time on treatment for first-line CDK4/6i. Multivariable logistic regression was used to evaluate factors associated with use and outcomes., Results: A total of 6802 patients with MBC were included, of which 5187 (76.3%) received CDK4/6i. Of those, 3186 (61.4%) received CDK4/6i first-line. Overall, 86.7% of patients were categorized as White and 13.3% as Black/AA; 22.4% were > 75 years old; 12.6% were treated at an academic site; 3.3% had Medicaid insurance. In addition to advanced age and poorer performance status, lower use of CDK4/6i was associated with Black/AA vs White race (72.9% vs 76.8%; OR 0.83, 95% CI 0.70-0.99, p = 0.04) and Medicaid vs commercial insurance (69.6% vs 77.4%; OR: 0.68, 95% CI 0.49-0.95, p = 0.02). Odds of CDK4/6i use were twofold higher for patients treated at an academic center (p < 0.001). Rates of CDK4/6i-induced leukopenia and dose reductions did not differ significantly by race, insurance type, or treatment site. Time on CDK4/6i was significantly lower among Medicaid patients (395 days) than patients with commercial insurance (558 days) or Medicare (643 days) (p = 0.03)., Conclusion: This analysis of real-world data suggests that Black race and lower SES are associated with decreased CDK4/6i use. However, among patients treated with CDK4/6i, subsequent toxicity outcomes are similar. Efforts to ensure access to these life-prolonging medications are warranted., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Delaying chemotherapy remains a vital goal in therapeutic management of HR+/HER2- metastatic breast cancer (MBC). However, recent reports continue to highlight substantially high chemotherapy utilization in earlier therapy lines. In this study, we explored the impact of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy class, introduced in 2015, on early chemotherapy utilization in an older population of patients with HR+/HER2- MBC in the United States (US)., Methods: Using an interrupted time series design, patients with a confirmed diagnosis of MBC aged ≥ 65 years initiating systemic therapy during 2010-2019 were selected from the SEER-Medicare database. The proportion of chemotherapy use was summarized quarterly based on the date of treatment initiation separately in the first, second, and third lines. Segmented regression models adjusted for autocorrelation over time were fitted to estimate trends before and after the availability of CDK4/6 inhibitors in the first quarter of 2015., Results: Of the 3244 eligible women (median age at diagnosis: 74 years), all initiated first-line therapy; 47.9% (n = 1581) initiated second-line therapy, and 50.1% (n = 792) initiated third-line therapy. Overall utilization of chemotherapy (alone or in combination) during the study period was 15.7% for the first line, 19.6% for the second line, and 24.8% for the third line. Chemotherapy utilization in the period immediately after introduction of CDK4/6 inhibitor therapy decline by estimated 2.5% in the first line (P = 0.408), 15.5% in the second line (P = 0.005), and 16.3% in the third line (P = 0.003)., Conclusions: This population-based study illustrates that chemotherapy utilization in earlier therapy lines for HR+/HER2- MBC declined steadily between 2010 and 2019. These declines were significantly accelerated by the introduction of CDK4/6 therapy class in 2015, notably in the second- and third-line settings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To examine the real-world incidence and management of select adverse events (AEs) among female patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), receiving a cyclin-dependent kinase 4 and 6 (CDK4 and 6) inhibitor (palbociclib, abemaciclib, or ribociclib)., Methods: This retrospective study analyzed data from the US Oncology Network iKnowMed electronic health record database for 396 patients with an initial MBC diagnosis on/after 1 January 2014 and receipt of first CDK4 and 6 regimen between 1 January 2017 and 31 December 2018. In this descriptive study, the proportion of patients who experienced select AEs and associated dose modifications or discontinuations were reported. The occurrence of select healthcare resource utilization categories was also reported., Results: Median follow-up time was 451, 262, and 355 days for patients in the palbociclib, abemaciclib, and ribociclib cohorts, respectively. The most common AEs were neutropenia (palbociclib, 44.8%; abemaciclib, 10.6%; ribociclib, 36.3%), diarrhea (palbociclib, 8.0%; abemaciclib, 43.0%; ribociclib, 8.8%), and fatigue (palbociclib, 12.9%; abemaciclib, 17.6%; ribociclib, 16.5%). AEs resulted in a treatment hold among 91 (23.0%), a dose reduction among 86 (21.7%), and permanent discontinuation among 48 (12.1%) patients overall., Conclusions: This real-world study provides insight into the occurrence of AEs which varied by CDK4 and 6 inhibitor. Compared to clinical trials, frequencies of AEs were numerically lower but dose reductions due to AEs were numerically higher. It is possible these differences reflect proactive management of AEs on the part of clinicians to help patients remain on therapy.

More than two-thirds of patients with breast cancer present with hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative disease at their initial diagnosis. HR-positive breast cancer's growth depends on Cyclin D1, a direct transcriptional target of estrogen receptors (ER). The recent introduction of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors (palbociclib, ribociclib, and abemaciclib) has revolutionized the treatment of metastatic HR-positive, HER2-negative breast cancer in both endocrine-sensitive and endocrine-resistant settings and in both pre-and post-menopausal women. Multiple large randomized clinical trials had demonstrated improvement in progression-free survival (PFS) and, more recently, in overall survival (OS). Adjuvant endocrine therapy (ET) significantly reduces the risk of recurrence and death among patients with HR-positive early-stage breast cancer (EBC). However, up to 20% of these patients will experience local, regional or distal recurrences in the first ten years. Such resistance to ET motivated researchers to try CDK4/6 inhibitors in EBC, both in adjuvant and neoadjuvant settings. While many clinical trials are still ongoing, at least one study and two meta-analyses had shown beneficial results, based on which the US Food and Drug Administration had recently approved the use of one of these agents, abemaciclib, in combination with ET for the adjuvant therapy of patients with high-risk EBC. In this paper, we review the recently published and ongoing landmark clinical trials attempting to expand the use of CDK4/6 inhibitors, in combination with ET, in the adjuvant setting of EBC., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Abdel-Razeq and Sharaf.)

Background: Skin cancer screening is routinely performed for members of melanoma-prone families, but longitudinal studies evaluating the efficacy of surveillance in this high-risk population are lacking., Methods: We evaluated thickness for first primary melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) enrolled in NCT00040352 (NCI familial melanoma study) from 1976 through 2014; enrolled patients received routine skin cancer screening and education about skin self-exams. We used linear and ordinal logistic regression models adjusted for gender and age with a generalized estimating equations approach to report changes in thickness and tumor (T) stage over time, comparing outcomes for NCI cases diagnosed before (pre-study) versus after study participation (prospective) and for NCI cases versus nonfamilial cases [Surveillance, Epidemiology, and End Results (SEER) 9 registries]., Results: Tumor thickness was evaluated for 293 NCI (pre-study = 246; prospective = 47) patients. Compared with NCI pre-study cases, NCI prospective melanomas were thinner (0.6 vs. 1.1 mm; P < 0.001) and more likely to be T1 stage [39/47 (83%) vs. 98/246 (40%); P < 0.001]. Similar findings ( P < 0.05) were observed for familial cases with and without germline CDKN2A and CDK4 mutations. Peters-Belson modeling suggested that calendar period effects of decreasing thickness in the general population (SEER 9) did not fully explain thickness trends in NCI families., Conclusions: Participation in a longitudinal surveillance program providing skin cancer screening and education about skin self-exams was associated with thinner melanomas for members of melanoma-prone families., Impact: The study findings support the clinical benefit of screening (physician and self) for this high-risk population., (©2021 American Association for Cancer Research.)

Melanoma incidence rates are rising rapidly, particularly in older men. Older men are also more likely to have thick melanomas, which confer high mortality and morbidity. The reasons for the rate of increase are not known; increasing sun and UV exposure, however, is the major hypothesized explanation. In the past several years, two major susceptibility genes for melanoma, CDKN2A and CDK4, have been identified, but the two genes together account for a minority of familial melanoma. Other high-risk susceptibility genes are being sought actively. Genetic epidemiologic studies suggest that penetrance of each of the two identified genes is altered by other factors, either genetic or environmental. Epidemiologic studies have also identified other major host factors important in the development of melanoma. In European, North American, and Australian populations, the presence of clinically identified dysplastic nevi confers greatly increased risk of melanoma. A new measure of sun exposure, based on individual residential history, confers substantially increased risk of melanoma. Recent surveys of sun behavior in the US reveal extensive sunburning and use of tanning beds in adolescents and adults. Sun protective behaviors are not as prevalent as in Australia, where population rates of melanoma are stabilizing.

Colorectal cancer is the second leading cause of death from cancer in the United States. Continuous use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the risk of colorectal cancer in humans by 40-50%. Patients with familial adenomatous polyposis who take NSAIDs, such as sulindac, undergo a regression of intestinal adenomas. Rodents exposed to carcinogens that cause colon cancer have a 50-60% reduction in the size and number of colonic tumors when treated continuously with NSAIDs. One common target for these drugs is prostaglandin endoperoxide synthase, also referred to as cyclooxygenase (COX). We and others have shown recently that COX-2 levels are increased dramatically in 85-90% of human colorectal adenocarcinomas and in 40-50% of colonic adenomas. We prepared intestinal epithelial cells that express the COX-2 gene permanently and found that they have altered adhesion properties and resist undergoing apoptosis. We report here that these cells also have a 3-fold increase in the duration of G1, lower levels of cyclin D1 protein, and a marked decrease in retinoblastoma kinase activity associated with cyclin-dependent kinase 4. The delay in G1 transit may relate to the resistance of these cells to undergo programmed cell death, which could affect their tumorigenic potential.