Tamoxifen pharmacogenetics; GI cancers aren't sexy; vascular complications of splenectomy

Tamoxifen pharmacogenetics affects clinical outcomes

There is a growing list of drugs whose metabolism (and clinical effects) have been shown to be influenced by genetic mutations. (See my posts of March 1 and March 15, 2009: http://adrounysheme-o-gram.blogspot.com/2009_03_01_archive.html).

Besides important drugs like warfarin and clopidgorel (Plavix), tamoxifen effect has also been shown to be influenced by mutations of a metabolizing enzyme, in this case, cytochrome P450 2D6 (CYP2D6) enzyme.

The Oct 7 2009 issue of JAMA (http://jama.ama-assn.org/cgi/content/full/302/13/1429) features a German-American collaboration on clinical outcomes with tamoxifen stratified according to metabolizer type. Tamoxifen has been a foundation of breast cancer treatment for the last 30 years. Its growth inhibitory effect on breast cancer is mediated by metabolites 4-hydroxytamoxifen and endoxifen. The formation of these active metabolites is catalyzed by CP2D6. One hundred variants of CYP2D6 have been identified with four distinct phenotypes of metabolism: extensive (normal activity); intermediate (reduced activity), poor (no activity) and ultrarapid (high activity). A gene-dose effect has been demonstrated.

The study included almost fourteen hundred women from Germany and the U.S. with stages I, II and III who were given tamoxifen according to standard practices and who underwent pharmacogenetic analysis. Endpoints included standard oncologic parameters, including disease free survival and overall survival. Median follow-up was over six years.

The best results were seen in the extensive (normal activity) metabolizers. The overall recurrence rate was nearly double in the poor metabolizer group (24% vs 12.5%) and the death rate was significantly higher in the poor metabolizer group (22.8% vs. 16.7%)

This study is not the first to suggest an association between CYP2D6 mutations and clinical outcomes. However, it is the first with enough statistical power to actually prove the relationship.

The use of CYP2D6 testing is not yet a clinical standard. It may well become one. I have observed that at least one insurance company has been routinely demanding testing of patients who are prescribed tamoxifen.

An Interesting Comment

“For lack of a better word, GI cancers aren’t particularly sexy, certainly not from a political standpoint, nor is it easy to attract the blandishments of corporate largesse when the victims of these diseases comprise such a nebulous consumer base. Thus…it really falls on our shoulders to inspire and lead our patients and advocacy groups in an effort to increase funding, improve clinical trial participation, or incite a bit of a ‘riot’, if that’s what it takes to shatter insouciance and ensure that GI cancers get the attention they deserve…I strongly believe we can change the outlooks of patients with these terrible diseases…Our patients deserve better than run-of-the-mill interventions and should be demanding optimum treatment.”—John L. Marshall, M.D., Chief, Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University. Quoted in Gastrointestinal Cancer Research Volume 3 Issue 4.

Splenectomy induces a hypercoagulable state

Over 20,000 splenectomies are performed annually in the U.S. Besides a higher incidence of overwhelming sepsis, there are concerns about other potential long term complications of splenectomy. A recent article in Blood http://bloodjournal.hematologylibrary.org/cgi/content/full/114/14/2861 reviews the possibility that splenectomy induces a higher incidence of vascular complications.

Spleen contains white pulp and red pulp. White pulp is largely lymphoid tissue that processes antigens and produces antibodies. Red pulp consists of the sinusoidal cords of Billroth, which filter the blood by removing aged and damaged cells and by “polishing” red cells that have developed surface imperfections. The red pulp also contains a reservoir of platelets and granulocytes.

A number of potential vascular complications have been identified in post-splenectomy patients. These include arterial events such as stoke, M.I., carotid disease and peripheral arterial disease.

Venous events, both local and systemic, have been identified. The incidence of portal vein thrombosis after splenectomy ranges from 5 to 37%. Fatal pulmonary embolism was 5 times higher in persons with previous splenectomy than in matched controls in one autopsy study.

Pulmonary arterial hypertension is another potential vascular complication.

The authors speculate that the higher incidence of vascular events has multifactorial causes, resulting from hypercoagulability, platelet activation, disturbance and activation of the endothelium and altered lipid profiles. Absence of the filtration function of the spleen may permit particulates and cell debris to activate vascular endothelium. Splenectomy increases platelet counts, cholesterol, C-reactive protein, white count and hemoglobin concentration, all of which are associated with increased risks of arterial and venous thrombosis.

The authors conclude that further study of this is warranted, particularly with respect to issues such as whether short or long term thromboprophylaxis should be offered patients who have had splenectomy.