Abstract Background In Canada, there are wide variations in services for patients at risk for hereditary breast and ovarian cancer (HBOC), and clinical interventions and recommendations differ ...between regions and/or provinces. National strategies for the clinical management of HBOC exist in the United Kingdom, France, and Australia, and clinical programs in Canada would benefit from similar national recommendations and a consistent approach to clinical management. The National Hereditary Cancer Task Force developed recommendations to address the clinical management of patients at high risk of HBOC and related cancers. These recommendations are based on current practice in high-risk cancer clinics that provide care for individuals with known BRCA1 or BRCA2 mutations. Methods Canadian consensus recommendations were generated by the National Hereditary Cancer Task Force and compared mainly with two recently published guidance documents on the clinical management of women with increased risk of HBOC, one from the United Kingdom and the other from France. After review of these documents and the associated supporting scientific evidence, the Canadian consensus recommendations were modified and rated using predefined criteria. Conclusions These recommendations pertain to (1) surveillance options including breast self-examination, clinical breast examination, breast surveillance by imaging, ovarian cancer surveillance, and surveillance for men; (2) risk-reduction strategies including prophylactic mastectomy, prophylactic salpingo-oophorectomy, and pharmacoprevention; and (3) the use of exogenous hormones. Regular updates should occur as new evidence becomes available.
Background: Lenalidomide improves survival for patients with relapsed or refractory multiple myeloma (MM). However, the benefit of this treatment in patients with highrisk cytogenetic abnormalities ...is not well studied. We have previously reported in an initial sub-analysis of a large, open-label study (MM016 study) the effects of the most common unfavorable cytogenetic abnormalities on outcomes in MM patients treated with lenalidomide plus dexamethasone. Since then we have performed an update of this sub-analysis within a larger cohort of patients and a longer median follow-up time of 19.6 months.
Methods: The MM016 is a multicenter single arm open label expanded access program for Lenalidomide in relapsed and refractory MM. Patients received dexamethasone orally (40mg, days 1–4; 9–12 and 17–20 for 4 cycles, then days 1–4 beginning with cycle 5) and Lenalidomide 25mg orally on days 1–21 of a 28 days cycle. Using fluorescence in situ hybridization, we examined the influence of three most common and recurrent cytogenetic abnormalities del(13q), t(4;14), and del(17p13) in 130 patients with FISH results available for the three genomic aberrations. Blade criteria were used to define RR. TTP and OS were defined according to the international uniform response criteria.
Results: The median age was 61 yrs (31–84), 55.4% had ISS stage II or III, median beta2-microglobulin was 3.125 mg/L (1.1–16.75), median number of prior treatments was 2 (1–6) with 53.8% previously treated with thalidomide, 45.9% with bortezomib and 73.3% with SCT. Del(13q), t(4;14) and del(17p13) were detected in 54 (41.5%), 28(21.5%) and 12 (9.2%) of patients, respectively. The overall response RR (CR+PR) to len-dex was 83.1% (13.1% CR and nCR) and 76.4% for the del13q, 78.6% for t(4;14) and 58.3% for del17p patients. In univariate analysis the time-to-progression (TTP) hazard ratio (HR) for del(13q) and for t(4;14) were 1.563 (P = .0479) and 1.680 (P = .0470) respectively. However in multivariate analysis, neither the presence of either del(13q) nor t(4;14) did adversely affect TTP. Similarly neither of these genomic aberrations did affect overall survival (OS) hazard ratio with HR= 1.472 (P= .1507) for del(13q) and HR=1.091 (P = .788) for t(4;14). TTP (HR 2.626, P = .0032) and OS (HR 3.213, P =0.0016) were significantly worse with del(17p13) in univariate and multivariate analysis. Among the other variables studied prior thalidomide exposure did result in a shorter TTP (HR= 2.330; P = .0004) but not OS (HR= 1.690; P = .0612).
Conclusion: Lenalidomide plus dexamethasone can overcome the negative prognostic effect of high-risk cytogenetic abnormalities conferred by the presence of del(13q) and t(4;14), and represents a good treatment option for relapsed or refractory MM patients with these adverse cytogenetic profiles. (Clinicaltrials.gov number, NCT00179647.)
Abstract 139
Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) constitute 70% of all non-Hodgkin lymphomas (NHL). Both malignancies derive from germinal center (GC) B-cells and are ...characterized by clinical and genomic heterogeneity. Chromosomal alterations that deregulate oncogenes as well as mutations in genes involved in cell proliferation and apoptosis have been described in DLBCL. This disease can also be divided into distinct molecular subtypes by gene expression profiling. Differences observed between the activated B-cell (ABC) and germinal center B cell (GCB) subtypes result in part from distinct genomic alterations (Lenz, PNAS 2008) . For example, recent targeted re-sequencing efforts have revealed mutations in various genes in the NFkB signaling pathway, which likely contribute mainly to the ABC subtype (Compagno, Nature 2009). Thus far, few GCB-specific mutations other than t(14;18) have been identified.
Targeted re-sequencing studies are only able to reveal mutations in pre-selected candidate genes and so much of the genome has not yet been investigated in lymphomas. To obtain a more global view of the mutational landscape of NHL, we applied Illumina massively parallel second-generation sequencing to sequence the genomic DNA of a FL tumor sample. In parallel, we sequenced the transcriptomes (i.e. mRNA) of 31 DLBCL tumor samples using the same technology.
Genomic sequencing revealed a mutation altering tyrosine 641 (Y641) in the polycomb group oncogene Enhancer of Zeste Homolog 2 (EZH2), a gene responsible for trimethylating lysine 27 on histone H3 (H3K27). Mutations affecting the same codon were also observed in 4 DLBCL samples. These mutations were confirmed to be somatic in nature by Sanger sequencing exon 15 in tumor DNA and germline DNA derived from peripheral blood in these 5 patients. Sanger sequencing all coding exons in EZH2 from an additional 25 FL samples revealed that mutations were restricted to codon 641. These mutations could change the tyrosine residue to Asparagine, Serine, Phenylalanine or Histidine. The frequency of EZH2 Y641 mutations in GCB-derived lymphomas was determined by Sanger sequencing exon 15 in a total of 479 lymphoma samples. EZH2 (Y641) mutations occurred predominantly in lymphomas of the GCB type: 18/80 (22%) GCB-type de novo DLBCL, 6/52 (11.5)% of “transformed” DLBCL derived from FL and 16/225 (7.1%) of pre-treatment FL samples. No EZH2 mutations were found in 42 DLBCL of the ABC subype, 25 mantle cell lymphomas, 30 small lymphocytic lymphomas or 25 T cell lymphomas or 23 reactive tonsils. Introducing each of the four Y641 mutations into wild-type EZH2 resulted in 15-fold reduction in the ability to trimethylate lysine 27 on H3 peptides in-vitro.
Over-expression of EZH2 is thought to drive malignancy in a variety of solid tumors but mutations in this gene have never been described. The trimethylated H3K27 epigenetic mark is used to silence the transcription of genes involved in differentiation and hematopoiesis. In Drosophila, the phenotypic consequence of mutating the orthologous tyrosine residue in the E(z)(“Enhancer of Zeste”) gene indicates an apparent gain-of-function (Jones, Genetics 1990). Taken together, our mutation frequency and biochemical data are compatible with the notion that alteration of the ability of germinal center B-cells to trimethylate H3K27 may promote the development of FL and the GCB subtype of DLBCL.
Zhu:BPS Biosciences: Employment. Kimbara:BPS Biosciences: Employment. Shashkin:BPS Biosciences: Employment. Charlot:BPS Biosciences: Employment. Tcherpakov:BPS Biosciences: Employment.
