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Abstract: The insulin-like growth factor (IGF)-system was evaluated in 150 breast cancer patients participating in a randomised phase III trial comparing octreotide pamoate and tamoxifen with tamoxifen+placebo. Alterations in the IGF-system in the two treatment arms and individual changes with respect to outcome were compared. Serum IGF-I and -II, free IGF-I, and insulin-like growth factor binding protein 1–3 (IGFBP1-3) were measured by radioimmmunoassay (RIA)/immunoradiometric assay (IRMA) and IGFBPs by Western ligand blots (WLB) before and during treatment. Combined treatment caused a higher increase in IGFBP-1 and larger suppression of total and free IGF-I, IGF-II, and IGFBP-3 (P <0.01 for all), but less suppression of IGFBP-2 (P <0.05) compared with tamoxifen monotherapy. An increase in IGFBP-2 ⩾25% was associated with decreased progression-free survival (PFS) in the total patient population and combined treatment group. Similar response rates and time to progression in the treatment arms suggests moderate suppression of circulating IGF-I has no influence on clinical outcome. [Copyright &y& Elsevier]

Background: PD 0332991, a selective inhibitor of CDK 4/6, prevents cellular DNA synthesis by blocking cell cycle progression. Preclinical studies in a BC cell line panel identified the luminal ER subtype, elevated expression of cyclin D1 and Rb protein, and reduced p16 expression as being associated with sensitivity to PD 0332991 (Finn et al. 2009). Synergistic activity was also observed in vitro when combined with tamoxifen. After determination of the recommended phase 2 dose in combination with letrozole (letrozole 2.5 mg QD plus PD 0332991 125 mg QD on Schedule 3/1), a randomized phase 2 study comparing letrozole alone (L) to letrozole plus PD 0332991 (L+P) was initiated. Methods: The phase 2 portion of the study was designed as a two-part study; Part 1 enrolled post- menopausal women with ER+/HER2-- advanced BC; Part 2 in addition to ER+/HER2-- as eligibility criteria, screened for CCND1 amplification and/or loss of p16 by FISH. The primary endpoint is progression-free survival (PFS); secondary endpoints include response rate, overall survival, safety, and correlative biomarker studies. In both parts, post-menopausal women with ER+/HER2-- advanced BC were randomized 1:1 to receive letrozole either with or without PD 0332991. Pts continue on assigned study treatment until disease progression, unacceptable toxicity, or consent withdrawal, and are followed for tumor assessments every 2 months. Results: 66 pts were randomized in Part 1 and 99 pts in Part 2. Preliminary results from Part 1 of this study have been previously reported (IMPAKT Breast Cancer Conference, Abstract #292, Finn et al. May 2012) demonstrating a significant improvement in median PFS in the L+P vs. L arm (HR = 0.35; 95% CI, 0.17 to 0.72; p = 0.006). With the additional 99 pts randomized in Part 2 (N = 165), the statistically significant improvement in median PFS (26.2 vs. 7.5 months, respectively) continues to be observed with a HR=0.32 (95% CI, 0.19 to 0.56) with p <0.001. The response rate for the L+P arm (n = 84) was 31% vs. 26% for the L arm (n = 81) and the clinical benefit rate was 68% vs. 44%, respectively. The most commonly reported treatment-related AEs in the combination arm were neutropenia, leukopenia, anemia, and fatigue. The updated results from the combined Part 1 and Part 2 group will be presented in December 2012. Conclusions: The combination of PD 0332991 and letrozole is well tolerated and shows encouraging clinical benefit, confirming the sensitivity of ER+ BC to PD 0332991 observed in preclinical models. A phase 3 trial in this setting will commence in 2013. [ABSTRACT FROM AUTHOR]