Rituximab in Hodgkin lymphoma: Is the target always a hit?

In 1997, the anti-CD20 monoclonal antibody (MAb) rituximab became the first MAb approved for clinical use in oncology, and ushered in a new era of rationally designed targeted agents in cancer therapeutics. It is currently approved for use in non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and rheumatoid arthritis (RA). Rituximab is non-mutagenic, associated with low treatment-related toxicity, and few, if any, long term adverse events, making it an attractive agent to be tried in off-label settings like Hodgkin lymphoma (HL). HL consists of two distinct subtypes - classic HL (cHL) and lymphocyte predominant HL (LPHL). CD20 is present in virtually all patients with LPHL, and in a significant minority of patients with cHL. In this CD20 positive sub-population, the use of rituximab is a rational intervention strategy. Rituximab has been used in patients with cHL as well as LPHL with good efficacy. In this article, we provide a clinically-oriented overview of the use of rituximab in the different sub-types of HL, and report updated results of our series of 8 LPHL patients treated with rituximab. A systematic review of the literature is also presented. © 2010 Elsevier Ltd

Genomic Aberrations and Late Recurrence in Postmenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the SOLE Trial.

PURPOSE: Women with hormone receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late-recurrence risk. EXPERIMENTAL DESIGN: In a secondary analysis of Study of Letrozole Extension trial, a case-cohort-like sampling selected 598 primary breast cancers for targeted next-generation sequencing analysis of gene mutations and copy-number gains (CNGs). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence-free intervals (BCFIs and DRFIs) were analyzed using weighted Cox models. RESULTS: Analysis of mutations and CNGs was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time, 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%), and MYC (8%). PIK3CA mutations and MYC CNGs were associated with lower (P = 0.03) and higher (P = 0.004) tumor grade, respectively; a higher Ki-67 was seen in tumor with CCND1, ERBB2, and MYC CNGs (P = 0.01, P < 0.001, and P = 0.03, respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses [17/29 patients; BCFI: HR, 3.2; 95% confidence interval (CI), 1.48-6.92; P = 0.003 and DRFI: HR, 3.5; 95% CI, 1.61-7.75; P = 0.002) and in multivariable models adjusted for clinicopathologic factors. CONCLUSIONS: Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target.status: Published onlin

Genomic aberrations and late recurrence in postmenopausal women with hormone receptor-positive early breast cancer: Results from the SOLE Trial.

peer reviewedPURPOSE: Women with hormone-receptor-positive early breast cancers have a persistent risk of relapse and biomarkers for late recurrence are needed. We sought to identify tumor genomic aberrations associated with increased late recurrence risk. EXPERIMENTAL DESIGN: In a secondary analysis of Study of Letrozole Extension (SOLE) trial, a case-cohort-like sampling selected 598 primary breast cancer for targeted next-generation sequencing (NGS) analysis of gene mutations and copy number gains (CNG). Correlations of genomic aberrations with clinicopathologic factors and breast and distant recurrence free-intervals (BCFI and DRFI) were analyzed using weighted Cox models. RESULTS: Analysis of mutations and CNG was successfully performed for 403 and 350 samples, including 148 and 134 patients with breast cancer recurrences (median follow-up time: 5.2 years), respectively. The most frequent alterations were PIK3CA mutations (42%) and CNGs of CCND1 (15%), ERBB2 (10%), FGFR1 (8%) and MYC (8%). PIK3CA mutations and MYC CNG were associated with lower (p=0.03) and higher (p=0.004) tumor grade respectively; a higher Ki67 was seen in tumor with CCND1, ERBB2 and MYC CNGs (p=0.01, <0.001 and 0.03 respectively). FGFR1 CNG was associated with an increased risk of late events in univariate analyses (17/29 patients; BCFI: HR=3.2, 95%CI: 1.48-6.92, p =0.003; DRFI: HR=3.5, 95%CI: 1.61-7.75, p=0.002) and in multivariable models adjusted for clinicopathologic factors. CONCLUSIONS: Postmenopausal women with hormone receptor-positive early breast cancer harboring FGFR1 CNG had an increased risk of late recurrence despite extended therapy. FGFR1 CNG may represent a useful prognostic biomarker for late recurrence and a therapeutic target