SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials.

PURPOSE: In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. EXPERIMENTAL DESIGN: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. RESULTS: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04-2.94)], rs749292 [sHR 2.11, (1.12-3.94)], and rs727479 [sHR 2.62, (1.17-5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026). CONCLUSIONS: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.

Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.

BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving. METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation. RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R. CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.

PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer.

To identify a group of patients who might benefit from the addition of weekly paclitaxel to conventional anthracycline-containing chemotherapy as adjuvant therapy of node-positive operable breast cancer. The predictive value of PAM50 subtypes and the 11-gene proliferation score contained within the PAM50 assay were evaluated in 820 patients from the GEICAM/9906 randomized phase III trial comparing adjuvant FEC to FEC followed by weekly paclitaxel (FEC-P). Multivariable Cox regression analyses of the secondary endpoint of overall survival (OS) were performed to determine the significance of the interaction between treatment and the (1) PAM50 subtypes, (2) PAM50 proliferation score, and (3) clinical and pathological variables. Similar OS analyses were performed in 222 patients treated with weekly paclitaxel versus paclitaxel every 3 weeks in the CALGB/9342 and 9840 metastatic clinical trials. In GEICAM/9906, with a median follow up of 8.7 years, OS of the FEC-P arm was significantly superior compared to the FEC arm (unadjusted HR = 0.693, p = 0.013). A benefit from paclitaxel was only observed in the group of patients with a low PAM50 proliferation score (unadjusted HR = 0.23, p < 0.001; and interaction test, p = 0.006). No significant interactions between treatment and the PAM50 subtypes or the various clinical-pathological variables, including Ki-67 and histologic grade, were identified. Finally, similar OS results were obtained in the CALGB data set, although the interaction test did not reach statistical significance (p = 0.109). The PAM50 proliferation score identifies a subset of patients with a low proliferation status that may derive a larger benefit from weekly paclitaxel.

[Biologic therapy: current and future applications in oncology]. / Bioterapia: aplicaciones actuales y futuras en oncología.

Nowadays, cancer is the first cause of death in the developed world, accounting for 94,000 yearly deaths in Spain. In recent years, advances in the field of molecular cancer biology and cancer therapy have identified a number of potential target molecules that play a critical role in the complex malignant cell transformation process. Since the approval of the first molecularly targeted drug imatinib in 2001, hundreds of novel agents are being investigated as monotherapy or in combination with chemotherapy and/or radiotherapy for the treatment of cancer of the breast, colon and rectum, lung, kidney, and head and neck, among others. Interestingly, molecularly targeted agents are becoming the new standard of care in some malignances such as renal-cell carcinoma and chronic myeloid leukemia. Future research on molecularly targeted therapies will focus on the identification of new drugs and drug targets, improved selection of tumors sensitive to these drugs, and the rational design and optimization of combination therapies.

Bioterapia: aplicaciones actuales y futuras en oncología / Biologic therapy: current and future applications in oncology

El cáncer representa hoy día la primera causa de mortalidad en el mundo desarrollado, con más de 94.000 fallecimientos anuales en Es paña. En los últimos años, los avances que han acontecido en el campo de la biología molecular del cáncer han permitido identificar toda una serie de moléculas susceptibles de ser dianas terapéuticas, dado su papel esencial en el proceso de transformación celular maligna. Desde la aprobación en 2001 del imatinib, el primer tratamiento mo lecular dirigido, hay cientos de componentes en desarrollo y algunos de ellos se han aprobado recientemente para el tratamiento del cáncer de mama, colorrectal, pulmón, renal y de cabeza y cuello, bien en monoterapia o combinados con quimioterapia y/o radioterapia. En algunos casos, como en el cáncer de células renales y en la leucemia mieloide crónica, la bioterapia ha sustituido al tratamiento estándar habitual. Ahora bien, la falta de biomarcadores y de modelos preclínicos óptimos dificulta el desarrollo de estos agentes. La investigación futura de los tratamientos moleculares deberá centrarse en la identificación de nuevos fármacos y dianas terapéuticas, en el perfeccionamiento de técnicas de selección de tumores sensibles a estos agentes y en el diseño racional y la optimización del tratamiento combinado

Nowadays, cancer is the first cause of death in the developed world, accounting for 94,000 yearly deaths in Spain. In recent years, advances in the field of molecular cancer biology and cancer therapy have identified a number of potential target molecules that play a critical role in the complex malignant cell transformation process. Since the approval of the first molecularly targeted drug imatinib in 2001, hundreds of novel agents are being investigated as monotherapy or in combination with chemotherapy and/or radiotherapy for the treatment of cancer of the breast, colon and rectum, lung, kidney, and head and neck, among others. Interestingly, molecularly targeted agents are becoming the new standard of care in some malignances such as renal-cell carcinoma and chronic myeloid leukemia. Future research on molecularly targeted therapies will focus on the identification of new drugs and drug targets, improved selection of tumors sensitive to these drugs, and the rational design and optimization of combination therapies