Addressing physician barriers to administering cyclin-dependent kinases 4 and 6 inhibitors in first-line treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer

Reshma L Mahtani, Charles L Vogel Sylvester Comprehensive Cancer Center, University of Miami Health System, Deerfield Beach, FL, USA Abstract: Combination therapy with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and an aromatase inhibitor (AI) for first-line treatment of postmenopausal women with advanced breast cancer (ABC) has demonstrated improvement in progression-free survival (PFS) over AI monotherapy without adding substantial toxicity. However, CDK4/6 inhibitor plus AI therapy is not uniformly used as first-line therapy for ABC, indicating that barriers to CDK4/6 inhibitor use exist. Such barriers may include the following perceptions: patients with bone-only metastases, with a long disease-free interval, or who are older may respond to AI monotherapy and may not benefit from a CDK4/6 inhibitor; tumor response rates may be lower and delayed with CDK4/6 inhibitor plus AI therapy than chemotherapy; the increased incidence of adverse events with CDK4/6 inhibitor plus AI therapy outweighs benefits; and the cost of CDK4/6 inhibitors may be prohibitive. Some of these barriers are addressed with data from follow-up analyses of CDK4/6 inhibitor trials, which have shown a PFS benefit of combination therapy in all subgroups assessed, including older patients, those with bone-only metastatic disease, and those with a long disease-free interval. Tumor response rates with CDK4/6 inhibitor plus AI therapy are comparable to those with first-line cytotoxic chemotherapy. Finally, adverse events associated with CDK4/6 inhibitor plus AI therapy are manageable and occur with decreasing severity during treatment, with similar reports of quality of life to those with AI monotherapy. These data support CDK4/6 inhibitor plus AI therapy as the standard of care in first-line treatment of ABC. Keywords: aromatase inhibitor, ribociclib, palbociclib, abemacicli

Comparative effectiveness of early-line nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer: a US community-based real-world analysis

Reshma L Mahtani,1 Monika Parisi,2 Stefan Glück,3 Quanhong Ni,2 Siyeon Park,4 Corey Pelletier,2 Claudio Faria,2 Fadi Braiteh5,6 1Division of Hematology/Oncology, University of Miami, Miami, FL, 2Health Economics and Outcomes Research, Celgene Corporation, Summit, NJ, 3Global Medical Affairs, Celgene Corporation, Summit, NJ, 4School of Pharmacy, The Ohio State University, Columbus, OH, 5Department of Hematology/Oncology, University of Nevada School of Medicine, Las Vegas, NV, 6Department of Hematology/Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA Background: Real-world analyses of treatments for patients with metastatic breast cancer are limited. We evaluated the comparative effectiveness of nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer using data from an electronic medical record database from community practices across the USA.Methods: We performed a retrospective cohort study using fully de-identified data from an independent US electronic medical record platform of patients with metastatic breast cancer initiating single-agent nab-paclitaxel or paclitaxel as a first- or second-line treatment from December 1, 2010 to October 6, 2014. The clinical efficacy objectives were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Subgroup analyses were performed in patients with 2 types of metastatic breast cancer as follows: 1) hormone receptor-positive and human epidermal growth factor receptor 2 negative, and 2) triple-negative disease. Results: This analysis included 925 patients. Patients receiving nab-paclitaxel vs. paclitaxel had significantly longer TTD (median 4.2 vs. 2.8 months, P<0.0001) and TTNT (median 6.0 vs. 4.2 months, P<0.0001); similar outcomes were observed for patients with hormone receptor-positive/human epidermal growth factor receptor 2 negative disease. Compared with paclitaxel, nab-paclitaxel was associated with significantly longer TTD in patients with triple-negative disease. nab-Paclitaxel was associated with significantly less all-grade neuropathy, anemia, pain, and diarrhea than paclitaxel. Antiemetic and antihistamine use were significantly less frequent with nab-paclitaxel vs. paclitaxel, whereas use of granulocyte colony-stimulating factor, hydrating agents, and bone-directed therapy to decrease skeletal-related events were more frequent. Conclusion: nab-Paclitaxel demonstrated improved clinical effectiveness compared with paclitaxel when examining TTD and TTNT in patients with metastatic breast cancer in a real-world setting. Keywords: metastatic breast cancer, nab-paclitaxel, paclitaxel, hormone receptor positive, triple negativ

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes

MAPK-activated protein kinase 2-deficiency causes hyperacute tumor necrosis factor-induced inflammatory shock

Background: MAPK-activated protein kinase 2 (MK2) plays a pivotal role in the cell response to (inflammatory) stress. Among others, MK2 is known to be involved in the regulation of cytokine mRNA metabolism and regulation of actin cytoskeleton dynamics. Previously, MK2-deficient mice were shown to be highly resistant to LPS/D-Galactosamine-induced hepatitis. Additionally, research in various disease models has indicated the kinase as an interesting inhibitory drug target for various acute or chronic inflammatory diseases. Results: We show that in striking contrast to the known resistance of MK2-deficient mice to a challenge with LPS/D-Gal, a low dose of tumor necrosis factor (TNF) causes hyperacute mortality via an oxidative stress driven mechanism. We identified in vivo defects in the stress fiber response in endothelial cells, which could have resulted in reduced resistance of the endothelial barrier to deal with exposure to oxidative stress. In addition, MK2-deficient mice were found to be more sensitive to cecal ligation and puncture-induced sepsis. Conclusions: The capacity of the endothelial barrier to deal with inflammatory and oxidative stress is imperative to allow a regulated immune response and maintain endothelial barrier integrity. Our results indicate that, considering the central role of TNF in pro-inflammatory signaling, therapeutic strategies examining pharmacological inhibition of MK2 should take potentially dangerous side effects at the level of endothelial barrier integrity into account.Research was supported by the agency for Innovation by Science and Technology (IWT); Research Foundation Flanders (FWO); and Ghent University: Concerted Research Actions (GOA