Chiara Foroni

Increased pathological complete response rate after a long-term neoadjuvant letrozole treatment in postmenopausal oestrogen and/or progesterone receptor-positive breast cancer

Background:The objective of this study was to determine the optimal scheduling of 2.5 mg daily letrozole in neoadjuvant breast cancer patients to obtain pathological complete response (pathCR) and assess Ki-67 expression as an early predictor of response.Patients and methods:This single institution study comprised 120 oestrogen receptor (ER)-positive postmenopausal women with primary breast cancer (clinical stage ⩾T2, N0–1), from three sequential cohorts (cohort A of 40, cohort B of 40 and cohort C of 40 patients, respectively) based on different duration of the neoadjuvant letrozole. Biological markers such as ER, progesterone receptor, HER2 and Ki-67 expression were tested at diagnosis and at definitive surgery.Results:A total of 89 patients (75.4%) achieved an objective response with 44 (37.3%) clinical CRs and 45 (38.1%) partial responses. The clinical CRs were significantly observed in cohort C (23 out of 40 patients, 57.5%) and B (16 out of 38 patients, 42.1%) compared with cohort A (5 out of 40 patients, 12.5%) (P-value for trend <0.001). Letrozole induced a similar significant reduction in Ki-67 index after treatment in all cohorts. The pathCR rate was significantly more frequent in cohort C (7 out of 40 patients, 17.5%) than in cohort A (1 out of 40 patients, 2.5%) and B (2 out of 40 patients, 5.0%) (P-value for trend <0.04).Conclusion:One-year neoadjuvant letrozole therapy leads to a higher pathCR rate and may be the optimal length of drug exposure.

Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer.

Purpose:To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC).Methods:Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers.Results:Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by 18FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).Conclusions:The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.

Molecular Oncology and the Neoadjuvant Setting: the Perfect Blend for Treatment Personalization and Clinical Trial Design

Breast cancer is a heterogeneous disease. Predictive molecular markers are crucial in patient management, but the only recommended predictive biomarkers are estrogen and progesterone receptors and HER2. There are many new targeted therapies, and although the target pathway expression is readily analyzed on conventional pathology, the dynamic response cannot be assessed and pathway expression is no guarantee it has a major driver role, even if mutated. Selecting therapies requires considering the patient, the molecular characteristics of the tumor, and the microenvironment of the tumor. Thus, the integration of molecular pathology, imaging, and early tumor biological response to therapy may provide evidence of drug activity and allow more rapid changes of therapy. The adaptive response of the tumor is a key resistance mechanism that can be assessed readily in the neoadjuvant setting. Although there are no markers that meet all surrogacy criteria, their use could provide crucial information on mechanisms of drug sensitivity/resistance. Validation of such markers requires a major emphasis on neoadjuvant trials to relate early-biomarker response to outcome.

Serum Vitamin D and Prostate Cancer Prognosis: The Story Continues

data that hypovitaminosis D is a reliable prognostic parameter or that the outcome of patients with PC might be improved by vitamin D supplementation. Several drawbacks hamper the clinical interpretation of serum vitamin D levels in cancer: the hormonal activity of vitamin D is mediated by its binding to vitamin D receptor (VDR) within the cell nuclei, and both VDR expression and VDR polymorphisms reflect the individual susceptibility to vitamin D action 3 ; and hypovitaminosis D is associated with secondary hyperparathyroidism, which could have contributed tothe negative prognostic features observed. Parathyroid hormone (PTH), in fact, is similar to PT-related peptide, which is a potent growth factor, and both PTH and PT-related peptide interact with the same receptor that is expressed by PC cells. 4 In the study by Nyame et al, 1 neither tissue VDR and its relevant polymorphisms nor serum PTH were measured; therefore, information on the interaction between vitamin D status and these important biologic parameters is lacking. Moreover, the assays to determine serum vitamin D levels are not standardized, and a significant variability among methods and laboratories was reported. 5 This further complicates the application of the results of the Nyame et al 1 study to clinical practice. In their discussion, Nyame et al 1 stated that patients with PC with intermediate risk may benefit, in terms of disease outcome, from the normalization of vitamin D levels. In principle, we agree with the authors that future studies are warranted to assess the efficacyofvitaminD supplementationin terms ofPC aggressiveness. However, caution should be taken in administering vitamin D to patients with PC outside a clinical trial. In fact, the results of a prospective phase III clinical trial testing the efficacy of high-dose calcitriol plus docetaxel versus single-agent docetaxel in men with castrate-resistant metastatic PC showed a shorter survival in the vitamin D arm compared with the control arm. 6

Abstract A11: Phase II trial of letrozole (L), cyclophosphamide (C) and sorafenib (S) as neoadjuvant therapy in breast cancer patients (BC): Pharmacokinetic (PK) and pharmacodinamic (PD) analysis

Introduction: This trial assessed the PK and PD of letrozole-cyclophosphamide-sorafenib combination as neoadjuvant setting in patients (pts) with operable breast cancer (BC). Methods: 13 estrogen receptor-positive postmenopausal BC pts with T2-4 N0-1 were enrolled to receive oral letrozole (L) 2.5 mg daily, 50 mg daily metronomic cyclophosphamide (C) and 400 mg twice daily sorafenib (S). S was introduced after 6 days of LC therapy. For PK analysis blood samples were collected on day 5 of cycle 1 and on day 1 of cycle 2 (day 29). At basal time and after 14 days, tumour size evaluation, Ki67 expression and MRI were performed. Results: A significant reduction in Ki67 expression was observed in all the 13 patients after 14 days only (median 20.7% (range 3-36%) and 9.75% (range 0-20%) at 15th respectively, p Conclusions: These toxicity and PK results indicated that the combination feasible but sorafenib interpheres in non significant manner with the bioavailability of C. Moreover, the PD data indicated that the association of the already tested LC combination (Bottini at al, JCO 2006) with S is promising. A randomised study of LC vs LCS is ongoing. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A11