CDK4/6 inhibitors: The Devil is in the Detail.

PURPOSE OF REVIEW: Update on the most recent clinical evidence on CDK4/6 inhibitors (CDK4/6i) in the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor (HER)2-negative breast cancer. RECENT FINDINGS: Over the past decade, CDK4/6i have become part of the standard of care treatment of patients with both metastatic and high-risk early HR + /HER2- breast cancers. The three available CDK4/6i (palbociclib, ribociclib and abemaciclib) have been extensively studied in combination with endocrine therapy (ET) in metastatic breast cancer (mBC) with consistent prolongation of progression free survival; however, ribociclib has emerged as the preferred first line agent in mBC given overall survival benefit over endocrine monotherapy. In early BC, abemaciclib is the only currently approved agent while ribociclib has early positive clinical trial data. Toxicities and financial burden limit the use of CDK4/6i in all patients and resource-poor settings, and optimal timing of their use in mBC remains unclear. There is considerable evidence for the use of CDK4/6i in metastatic and early HR + /HER2- breast cancer, but knowledge gaps remain, and further research is necessary to better define their optimal use.

Multiple primary melanoma in association with other personal and familial cancers.

BACKGROUND: Multiple primary melanoma (MPM) is known to be associated with familial melanoma. However, the association between MPM and other personal and familial cancers is not well documented. The objective of this study was to evaluate the association between MPM and personal history of other cancers or cancer history among first-degree relatives (FDRs). METHODS: We performed a retrospective case-control study including cases with gender-matched MPM and single primary melanoma (SPM) at a 1:2 ratio from the University of Pittsburgh Cancer Institute Melanoma Center Biological Sample and Nevus Bank. The associations between MPM and other cancers were evaluated using univariable and multivariable logistic regression models. RESULTS: In total, 378 patients (44.2% men; median age 52 years) were enrolled, including 252 with SPM and 126 with MPM. In comparison to patients with SPM, patients with MPM were more likely to have squamous cell carcinoma (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.001-3.79, p = 0.047) and prostate cancer (OR 2.72, 95% CI 1.07-7.01, p = 0.034). FDRs of patients with MPM had higher prevalence of melanoma (OR 2.37, 95% CI 1.31-4.28, p = 0.004) and prostate cancer (OR 2.92, 95% CI 1.47-6.14, p = 0.002) but not other cancers. In multivariable analysis, the association remained significant between MPM and squamous cell carcinoma (OR 2.18, 95% CI 1.08-4.39, p = 0.028), prostate cancer (OR 2.85, 95% CI 1.09-7.54, p = 0.032), FDR history of melanoma (OR 2.37, 95% CI 1.31-4.29, p = 0.004), and FDR history of prostate cancer (OR 3.26, 95% CI 1.59-6.83, p = 0.001). CONCLUSIONS: Patients with MPM have a higher prevalence of personal and FDR histories of nonmelanoma skin cancers and prostate cancer.

Negative Correlation Between Health Care Coverage and Postpartum Depression Among Hispanic Women.

Postpartum depression (PPD) affects women across all races with serious health consequences for mothers and infants. Maternal factors may increase PPD risk, but research in exclusive Hispanic populations is limited. This secondary analysis evaluated the associations between maternal sociodemographic characteristics and reliable decrease in depressive symptoms in Hispanic women between prenatal study enrollment and 2 months postpartum. Data from all women (n = 178) who completed a randomized control trial assessing the efficacy of a home-visitation program were included. Most women were from Mexico (66.9%), had incomes <$10,000/year (68.5%), had health insurance (58.4%), and intended to breastfeed (84.2%). Few women had high school education/graduate equivalency degree (19.3%) or a health care provider (2.3%). Using multivariate logistic regression and controlling for baseline Edinburgh Postnatal Depression Score, gestational age at enrollment, and group assignment, health care coverage (OR = 4.04, 95% CI 1.27, 12.76, p = 0.017) increased the likelihood of a decrease in level of depressive symptoms at 2 months postpartum. Acculturation, breastfeeding behaviors, and age were not associated with change in depressive symptoms. Results increase our understanding of variability of depressive symptoms in Hispanic women. Having access to health care coverage is critical. Findings provide guidance for culturally competent interventions and policies.

Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma.

Advanced ovarian clear cell carcinoma (OCCC) carries a very poor prognosis in large part secondary to the extremely high rate of resistance to standard platinum and taxane chemotherapy. Signal transducer and activator of transcription 3(STAT3) expression and activation has been shown to regulate tumor progression in various human cancers, though has not been well studied in OCCC. Preliminary work in our lab has demonstrated constitutive activation of STAT3 (pSTAT3Tyr705 or pSTAT3727) in OCCC cell lines as well as human OCCC tumor tissue samples. Significantly, pSTAT3 is expressed in the absence of other forms of activated STAT (pSTAT1, 2, 6). Therefore, this work was planned to investigate the role of STAT3 and examine the efficacy of a novel anti-cancer compound -HO-3867, which is an inhibitor of STAT3, using known OCCC cell lines. Results demonstrate that treatment with HO-3867 decreased expression of pSTAT3 Tyr705 as well pSTAT3 Ser727, while total STAT3 remained constant. STAT3 overexpression increased the migration capability in OVTOKO cells in vitro and led to an increased tumor size when injected in vivo. The inhibitory effect of HO-3867 on cell proliferation and cell survival was accompanied by increased apoptosis, within 24 h post treatment. Treatment with HO-3867 resulted in a decrease in Bcl-2 and increase of cleavage of caspase 3, caspase 7, and PARP, confirming induction of apoptosis after treatment with HO-3867. In addition, HO-3867 significantly inhibited formation of human umbilical vein endothelial cells capillary-like structures and invasion at both 5 and 10 µM concentrations. STAT3 expression plays an important role in the spread of OCCC in vitro as well as in vivo. Thus, we can exploit the STAT3 pathway for targeted drug therapy. Inhibition of pSTAT3 using HO-3867in OCCC cell lines appears to be a promising therapy. This is of utmost importance given the poor response of OCCC to standard chemotherapy regimens.