ABSTRACT
BACKGROUND: The role of serum alpha-fetoprotein (AFP) as a marker for treatment response in patients with hepatocellular carcinoma (HCC) receiving systemic therapy is poorly defined. METHODS: A retrospective study was performed on patients with advanced HCC enrolled in five phase II clinical trials. Serum AFP was prospectively collected at baseline and at different time points through treatment in parallel with radiologic response and clinical outcome. Patients were separated into three groups based on a 50% change in serum AFP from baseline. Overall survival (OS), progression-free survival (PFS), and radiologic responses were compared between groups using log-rank and Wilcoxon tests. RESULTS: Of 144 patients, 107 met the eligibility criteria. Eighteen patients experienced a >50% AFP decline, 57 patients had a >50% AFP increase, and 32 patients had a <50% change in serum AFP in either direction. Compared with patients with a <50% change in serum AFP (median PFS, 5.6 months), patients with a >50% AFP decrease had a longer PFS time (median, 16.9 months; p = .029), whereas those with a >50% increase had a shorter PFS time (median, 2.3 months; p = .038). Patients with a >50% rise in AFP had a shorter OS time than those with a <50% change (median, 6.3 months versus 11.1 months, respectively; p = .004), whereas a >50% AFP decrease was not associated with a significant difference in OS (median, 13.0 months; p = .87). AFP changes were significantly associated with radiologic response. CONCLUSIONS: Our study suggests that serum AFP change during treatment may serve as a useful surrogate marker for clinical outcome in patients with advanced HCC receiving systemic therapy.
Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/drug therapy , Liver Neoplasms/blood , Liver Neoplasms/drug therapy , alpha-Fetoproteins/analysis , Adult , Aged , Aged, 80 and over , Clinical Trials as Topic/methods , Disease-Free Survival , Humans , Male , Middle Aged , Multivariate Analysis , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs frequently in breast cancer. However, clinical results of single-agent PI3K inhibitors have been modest to date. A combinatorial drug screen on multiple PIK3CA mutant cancers with decreased sensitivity to PI3K inhibitors revealed that combined CDK 4/6-PI3K inhibition synergistically reduces cell viability. Laboratory studies revealed that sensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but cancers with reduced sensitivity fail to do so. Similarly, patients' tumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB, while nonresponding tumors showed sustained or increased levels of pRB. Importantly, the combination of PI3K and CDK 4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions in PIK3CA mutant xenografts.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Mutation , Phosphoinositide-3 Kinase Inhibitors , Animals , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Cell Survival/drug effects , Class I Phosphatidylinositol 3-Kinases , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/genetics , Cyclin-Dependent Kinase 6/metabolism , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Drug Synergism , Female , Genetic Predisposition to Disease , Humans , MCF-7 Cells , Mice , Mice, Nude , Mice, SCID , Molecular Targeted Therapy , Phenotype , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol Phosphates/metabolism , Phosphorylation , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Retinoblastoma Protein/metabolism , Signal Transduction/drug effects , Time Factors , Transfection , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Activating mutations of the PIK3CA gene occur frequently in breast cancer, and inhibitors that are specific for phosphatidylinositol 3-kinase (PI3K) p110α, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110α inhibition among PIK3CA-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORC1 signaling, although Akt phosphorylation was inhibited. Similarly, in patients, pS6 (residues 240/4) expression (a marker of mTORC1 signaling) was associated with tumor response to BYL719, and mTORC1 was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3CA-mutant cancer cell lines with persistent mTORC1 signaling despite PI3K p110α blockade (that is, resistance), the addition of the allosteric mTORC1 inhibitor RAD001 to the cells along with BYL719 resulted in reversal of resistance in vitro and in vivo. Finally, we found that growth factors such as insulin-like growth factor 1 and neuregulin 1 can activate mammalian target of rapamycin (mTOR) and mediate resistance to BYL719. Our findings suggest that simultaneous administration of mTORC1 inhibitors may enhance the clinical activity of p110α-targeted drugs and delay the appearance of resistance.
Subject(s)
Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Multiprotein Complexes/antagonists & inhibitors , Mutation/genetics , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Animals , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Class I Phosphatidylinositol 3-Kinases , Drug Resistance, Neoplasm/drug effects , Everolimus , Female , Humans , Inhibitory Concentration 50 , Insulin-Like Growth Factor I/pharmacology , Mechanistic Target of Rapamycin Complex 1 , Mice , Middle Aged , Multiprotein Complexes/metabolism , Neuregulin-1/pharmacology , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Ribosomal Protein S6/metabolism , Sirolimus/analogs & derivatives , Sirolimus/pharmacology , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/metabolism , Treatment OutcomeABSTRACT
In keeping with a long-standing tradition, Yale Medical and Physician Associate students gather at a ceremony each year after the completion of the anatomy course. The ceremony is a chance to reflect and to give thanks. It gives students the opportunity to articulate their gratitude to the selfless individuals who donated their bodies for the benefit of education. Many family members of the donors attend the ceremony. By reading poetry, performing musical pieces, and presenting works of art, the students and their teachers express some of the emotions and thoughts that the anatomy course has evoked. The following are some of the contributions presented at this year's ceremony.