Sunday, January 6, 2013

p53 matters in DLBCL too.

I've written about 17p deletion in CLL previously.  You may recall that this is the chromosomal home of TP53 - the gene which encodes the p53 protein- one of the most important determinants of chemotherapy success.  P53 is mutated with lower frequency in many of the lymphoid cancers than it is in solid tumors (such as pancreatic, esophageal, etc) which may partially explain the success we enjoy in treating diseases like DLBCL.

A recent paper has evaluated the impact of p53 mutations on survival of patients with DLBCL treated with R-CHOP chemotherapy.  They found a mutation in about 1/5 patients.  It was important!  Those without a mutation survived about twice as long as those in whom it was not mutated.

I've attached a link to an editorial / summary I wrote on behalf of Clinical Oncology News for the interested reader:  p53 Is a biomarker in patients with DLBCL on R-CHOP.  Below is a copy of the text.  It is written for an audience of oncologists so the writing might be a little more technical than what I usually put here in the blog.  Hopefully it is still worth the read.

Personalized medicine is the goal of detecting unique characteristics of an individual’s cancer and appropriately modifying therapeutic interventions to maximize efficacy and minimize side effects. A growing number of molecular diagnostics offer multiplex analysis of many oncologic targets bundled within one commercial assay. With the explosive progress in genome sequencing technology, a thorough understanding of molecular biomarkers is imperative if the goal of personalized medicine is to be reached.

p53 is one of the most important molecular markers in cancer. Known as the “guardian of the genome,” p53 determines cell fate in response to a variety of cellular stresses by regulating transcription of important proteins resulting in cell cycle arrest or activation of pro-apoptotic machinery. Loss of p53 activity is therefore a common mechanism by which cancer cells avoid cell death in response to chemotherapy.

The article by Xu-Monette et al highlights the importance and complexity of p53 analysis in patients with DLBCL. Despite histopathologic similarities, patients with DLBCL can be clustered into distinct subgroups based on gene expression profiling. Beyond RNA expression differences, DNA mutational analysis adds further insight into the prognosis of these patients.

This study evaluates a large multi-institutional cohort of patients with de novo DLBCL (excluding patients with transformed disease), treated in uniform manner according to p53 status, using a variety of molecular techniques including sequencing, expression profiling, fluorescence in situ hybridization and immunohistochemistry.

p53 mutation is shown to be an adverse molecular finding in the 21.9% of patients with abnormalities. Overall survival in patients with wild-type p53 was nearly twice as great as it was for those patients with mutated p53, with similar effect on PFS. This effect was independent of germinal center (GC) or activated B-cell subtype, which differs from the prior analysis of DLBCL patients treated with CHOP alone (pre-rituximab) where the effect was limited to patients with GC subtype DLBCL. This highlights the importance of re-evaluation of prognostic markers as standards of care change.

One concern is the incredible complexity of p53 alterations. This study highlights the multitude of ways p53 can be altered in gene sequencing. Although there are hotspots for recurring abnormalities, not all mutations are created equally. Some mutations may not affect amino acid sequence, whereas others cause an amino acid substitution or premature termination of the coding sequence.

It is tempting to consider p53 changes in a binary “yes/no” manner but that probably oversimplifies the biology. As personalized diagnostics emerge, the interpretation of such abnormalities may be as important as the detection of the change in the first place.

Identification of a high-risk cohort may enable therapeutic intensification, but such trials are difficult to design and execute. As the molecular taxonomy of cancer advances more quickly than our ability to know what to do with the data, clinical research remains a vital link in advancing the care of these patients.