Histologic grading of breast cancer defines morphologic subtypes informative of metastatic potential, although not without considerable interobserver disagreement and clinical heterogeneity particularly among the moderately differentiated grade 2 (G2) tumors. We posited that a gene expression signature capable of discerning tumors of grade 1 (G1) and grade 3 (G3) histology might provide a more objective measure of grade with prognostic benefit for patients with G2 disease. To this end, we studied the expression profiles of 347 primary invasive breast tumors analyzed on Affymetrix microarrays. Using class prediction algorithms, we identified 264 robust grade-associated markers, six of which could accurately classify G1 and G3 tumors, and separate G2 tumors into two highly discriminant classes (termed G2a and G2b genetic grades) with patient survival outcomes highly similar to those with G1 and G3 histology, respectively. Statistical analysis of conventional clinical variables further distinguished G2a and G2b subtypes from each other, but also from histologic G1 and G3 tumors. In multivariate analyses, genetic grade was consistently found to be an independent prognostic indicator of disease recurrence comparable with that of lymph node status and tumor size. When incorporated into the Nottingham prognostic index, genetic grade enhanced detection of patients with less harmful tumors, likely to benefit little from adjuvant therapy. Our findings show that a genetic grade signature can improve prognosis and therapeutic planning for breast cancer patients, and support the view that low-and high-grade disease, as defined genetically, reflect independent pathobiological entities rather than a continuum of cancer progression.

Key Points NK/T-cell lymphomas failing L-asparaginse, generally fatal, showed a high CR rate to PD1 blockade with pembrolizumab. Comprehensive clinical, radiologic, pathologic, and molecular assessments showed different patterns of CRs and PRs.

IntroductionApproximately 4500 new cases of chronic myelogenous leukemia (CML) occur in the United States each year. In most patients, a characteristic t(9;22) translocation juxtaposes the 5Ј end of the bcr gene with the 3Ј end of the abl gene, resulting in a unique 210-kd fusion protein, p210 bcr/abl . 1,2 This constitutively active cytoplasmic kinase is capable of not only transforming murine fibroblasts and hematopoietic cell lines, but also causing a chronic myeloproliferative disorder resembling CML on transduction into mouse marrow. 3,4 This p210 bcr/abl -induced transformation appears to involve the activation of signaling through the Ras-Raf and phosphatidylinositol-3 kinase/Akt pathways as well as transcription mediated by signal transducer and activator of transcription 5 (Stat5) and nuclear factor B (NFB). 1,5 Collectively, these events result in the up-regulation of antiapoptotic proteins, including Bcl-x L , 6 the X-linked inhibitor of apoptosis protein (XIAP), and survivin, 7 contributing to the resistance of p210 bcr/abl -expressing cells to a variety of apoptotic stimuli. 6,8,9 Until recently, treatment options for CML, which included the use of hydroxyurea, ␣-interferon with or without cytarabine, or stem cell transplantation, were less than satisfactory. 10,11 The almost universal presence of the p210 bcr/abl kinase in CML, coupled with evidence implicating this kinase in the pathogenesis of the disorder, made this fusion protein an attractive target for CMLdirected therapy. Previous efforts identified multiple p210 bcr/abl kinase inhibitors. [12][13][14][15][16] The most widely studied p210 bcr/abl inhibitor is STI571 (formerly known as CGP 57148), 17 a reversible inhibitor that occupies the adenosine triphosphate-binding pocket of p210 bcr/abl and stabilizes the kinase in an inactive conformation. 18 Preclinical studies demonstrated that STI571 also inhibits the kinase activities of c-abl, platelet-derived growth factor receptor, and the c-kit receptor. 15,19,20 Phase 1 studies suggest that STI571 has impressive activity against chronic-phase CML 21 but more limited activity against p190 bcr/abl -expressing acute lymphocytic leukemia and the blast crisis phase of CML. 22 Recent studies have demonstrated that mutation and amplification of p210 bcr/abl are observed in samples from patients who have relapsed after STI571 therapy. 23 Additional preclinical and clinical studies of STI571, alone and in combination with conventional cytotoxic agents, are ongoing. 7,24,25 An alternative approach to inhibiting protein kinases involves the use of small molecules that alter the binding of peptide substrates rather than adenosine triphosphate. A chemically diverse group of agents, generically termed tyrphostins, has been synthesized and evaluated as potential tyrosine kinase inhibitors. 26 The tyrphostin AG957 has previously been reported to inhibit p210 bcr/abl activity in immune complex kinase assays 14 and to cause decreased For personal use only. on May 10, 2018. by guest www.bloodjournal.org From p...