Purpose Local transdermal therapy to the breast may achieve effective target-organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in-situ (DCIS). Methods 27pre and postmenopausal women were randomized to 4-OHT (4mg/day) or oral-T (20mg/day) for 6-10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography-tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGF-1), sex hormone-binding globulin (SHBG), and coagulation protein concentrations were determined. Results Post-therapy Ki-67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (p < 0.03 in both, between-group p=0. 99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (p=0.0003), while mean breast adipose tissue concentrations of 4-OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (p=0.88). There were significant increases in plasma SHBG, Factor VIII and von Willebrand factor and a significant decrease in plasma IGF-1 with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups. Conclusions The anti-proliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention.

The purpose of this study is to evaluate the efficacy and safety of neoadjuvant treatment with carboplatin and eribulin in patients with early-stage triple negative breast cancer (TNBC), and to explore biomarkers based on DNA and protein expression profiles as predictors of response. Patients with histologically confirmed early-stage TNBC received carboplatin AUC 6 iv every 21 days, and eribulin 1.4 mg/m(2) day 1 and day 8 every 21 days for four cycles. The primary endpoint of the study was pathologic complete response (pCR), with secondary endpoints including clinical response and safety of the combination. Exploratory studies assessed DNA-based biomarkers [homologous recombination deficiency (HRD) score, and HR deficiency status (HRD score + BRCA1/BRCA2 mutation status)], protein-based biomarkers (Ki67, TP53, androgen receptor, Cyclin E, CDK2, Cyclin D, CDK4, Pin1 and Smad3), and clinical pretreatment factors as predictors of pCR. 13/30 (43.3 %) patients enrolled in the study achieved pCR. 24 (80.0 %) had a clinical complete or partial response. The combination was safe with mostly grade 1 and 2 toxicities. HRD score (P = 0.0024) and HR deficiency status (P = 0.0012) significantly predicted pCR. Pretreatment cytoplasmic CDK2 was also associated with pCR (P = 0.021). Significant differences in pre- versus post-treatment expression levels of nuclear Cyclin D (P = 0.020), nuclear CDK4 (P = 0.0030), and nuclear Smad3 (P = 0.015) were detected. The combination of carboplatin and eribulin is safe and efficacious in the treatment of early-stage TNBC. HRD score, HR deficiency status, and cytoplasmic CDK2 predicted pCR in this patient population.

Rationale Fibrosis is an important structural contributor to formation of atrial fibrillation (AF) substrate in heart failure (HF). TGF-β signaling is thought to be intricately involved in creation of atrial fibrosis. Objective We hypothesized that gene-based expression of dominant-negative type II TGF-β receptor (TGF-β-RII-DN) in the posterior left atrium (PLA) in a canine HF model will sufficiently attenuate fibrosis induced changes in atrial conduction and/or restitution to decrease AF. Since AF electrograms (EGMs) are thought to reflect AF substrate, we further hypothesized that TGF-β-RII-DN would lead to increased fractionation and decreased organization of AF EGMs. Methods and Results 21 dogs underwent injection + electroporation in the PLA of plasmid expressing a dominant negative TGF-β type II receptor (pUBc-TGFβ-DN-RII) (N=9) or control vector (pUBc-LacZ) (N=12), followed by 3–4 weeks of right ventricular tachypacing (VTP) (240 bpm). Compared to controls, dogs treated with pUBC-TGFβ-DN-RII demonstrated an attenuated increase in conduction inhomogeneity (CI), flattening of restitution slope and decreased duration of induced AF, with AF EGMs being more fractionated and less organized in pUBc-TGFβ-DN-RII versus pUBc-LacZ dogs. Tissue analysis revealed a significant decrease in replacement/interstitial fibrosis, pSMAD2/3 and pERK1/2. Conclusions Targeted, gene-based reduction of TGF-β signaling in the PLA – with resulting decrease in replacement fibrosis – led to beneficial remodeling of both conduction and restitution characteristics of the PLA, translating into a decrease in AF and increased complexity of AF EGMs. In addition to providing mechanistic insights, this data may have important diagnostic and therapeutic implications for AF.

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