RESUMEN
Although the use of (neo-)adjuvant chemotherapy in breast cancer patients has resulted in improved outcome, not all patients benefit equally. We have evaluated the utility of an in vitro chemosensitivity assay in predicting response to neoadjuvant chemotherapy. Pre-therapeutic biopsies were obtained from 30 breast cancer patients assigned to neoadjuvant epirubicin 75 mg/m2 and docetaxel 75 mg/m2 (Epi/Doc) in a prospectively randomized clinical trial. Biopsies were subjected to a standardized ATP-based Epi/Doc chemosensitivity assay, and to gene expression profiling. Patients then received 3 cycles of chemotherapy, and response was evaluated by changes in tumor diameter and Ki67 expression. The efficacy of Epi/Doc in vitro was correlated with differential changes in tumor cell proliferation in response to Epi/Doc in vivo (pâ=â0.0011; râ=â0.73670, Spearmans rho), but did not predict for changes in tumor size. While a pre-therapeutic gene expression signature identified tumors with a clinical response to Epi/Doc, no such signature could be found for tumors that responded to Epi/Doc in vitro, or tumors in which Epi/Doc exerted an antiproliferative effect in vivo. This is the first prospective clinical trial to demonstrate the utility of a standardized in vitro chemosensitivity assay in predicting the individual biological response to chemotherapy in breast cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Perfilación de la Expresión Génica , Biopsia , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Docetaxel , Ensayos de Selección de Medicamentos Antitumorales , Epirrubicina/administración & dosificación , Femenino , Humanos , Técnicas In Vitro , Antígeno Ki-67/metabolismo , Terapia Neoadyuvante , Estudios Prospectivos , Taxoides/administración & dosificaciónRESUMEN
BACKGROUND: Tuberin, the protein product of tuberous sclerosis gene 2 (TSC2), is the functional component of the TSC1/TSC2 complex and regulates cell cycle through activation of the cyclin-dependent kinase inhibitor p27. The transcriptional regulation of p27 is, however, also linked to a functional BRCA protein, since in BRCA1 mutant breast cancer cells, which lack the ability to repair DNA damages by homologous recombination, p27 is down-regulated. We have therefore investigated the expression of both tuberin and p27 in normal breast tissue, and in malignant epithelium from women with and without a BRCA mutation. MATERIALS AND METHODS: immunohistochemistry was used to compare p27 and tuberin protein expression in 26 BRCA1 and 2 mutation carriers, in 53 matched breast cancer patients without a family history, and in 74 benign breast tissues in a case-control study. RESULTS: Tuberin and p27 protein expression were significantly more common in benign when compared to malignant breast tissue (p = 0.01 and p = 0.03), but no difference was observed when sporadic and BRCA-mutated breast cancer specimen were compared. Tuberin and p27 were positively correlated with each other (p = 0.0017, r = 0.2527). Furthermore, p27 expression was positively correlated with ER and PR, and negatively correlated with tumor size. The expression of tuberin and p27 in breast cancer was not correlated with clinical outcome. CONCLUSION: Our results suggest that tuberin and p27 are aberrantly expressed in malignant tissue, but their expression does not appear to be dependent on the BRCA mutation state of a breast cancer patient.