Personalized Medicine Interface Tool: Choosing the Correct Dose
Clinical trials demonstrate the effectiveness of Personalized Medicine Interface Tool (PerMIT) software in coagulation treatment
American researchers at PGXL Laboratories (KY, USA) in collaboration with ARUP Laboratories (UT, USA), have published the first data from a clinical trial on their pharmacogenomic dosage assessment software – Personalized Medicine Interface Tool (PerMIT). The results from the trial were published in the Journal of Thrombosis and Haemostasis and showed that patients who were treated with a PerMIT-recommended warfarin dose took less time to reach a steady coagulation response than the control patients.
PerMIT was developed at the University of Louisville (KY, USA) and uses an algorithm model to calculate the optimum dose for each patient based on their genetics. Twenty six patients were treated in a recent PerMIT/warfarin study, of which 13 were randomly selected to be genotyped for two genes; CYP2C9 and VKORC1.
The genotypes were analyzed by the web-based software, which then calculated an optimum dose for each individual patient. All participants were then monitored until they reached a constant therapeutic range. On average, PerMIT/warfarin treated patients took 3.6 days less to reach a stable International Normalized Ratio (INR), a measure of blood coagulation, compared with the control subjects who were treated conventionally.
When speaking to Pharmacogenomics, the coinventor of PerMIT and one of the founders of PGXL Laboratories, Mark Linder, said, “early attempts at using genotyping for warfarin therapy did not sufficiently focus on an actionable protocol and failed to take into consideration how ongoing INR monitoring would need to be modified to accommodate the functional pharmacological differences between patients that are identified through genotyping”. However, he went on to explain, “a tool such as PerMIT, that enables a longitudinal perspective of therapy, is an essential element for the ongoing accommodation of standard practices to the alternate pharmacologic characteristic of individual patients. The PerMIT approach is not to suggest or recommend specific dosages, buet to create a context for the treating physician to make informed decisions.”
Despite being a small study, the findings are encouraging and displays that PerMIT has efficiency in advising doctors on individual patients. Linder concluded by explaining the importance potential of the software, “PerMIT will empower all physicians regardless of their knowledge of genetics, with the information they need to make informed therapeutic choices for their patients”.
– Written by Theo Bond
Sources: Borgman MP, Pendleton RC, McMillin GA et al. Prospective pilot trial of PerMIT versus standard anticoagulation service management of patients initiating oral anticoagulation. Thromb. Haemost. 108(3), 561–569 (2012); PGXL Laboratories press release: www.pgxlab.com/permit-works-the-age-of-companion-informatics-begins
Specific Genetic Causes of Colon Cancer Could Lead to Potential Personalized Treatment
A paper published in the August issue of Nature by researchers at the University of Minnesota Masonic Cancer Center (MN, USA) and Genentech, Inc. (CA, USA) identified new genetic markers in colon cancer tumors, including a number of gene fusions in the R-spondin family. By understanding the biogenetic basis of particular colon cancers, researchers hope to develop personalized therapies to treat these tumors.
The study examined 70 pairs of colon tumors with next-generation sequencing to analyze the cancer‘s genetics. They identified various protein-altering mutations that could induce specific types of colon cancer. In addition to insertion, deletion and amplifying mutations, the research teams also discovered 36 genetic rearrangements, which caused gene fusions. A total of 10% of the tumors analyzed contained these gene-fusion mutations, which involved two genes from the R-spondin family, RSPO2 and RSPO3. The R-spondin family is involved in activating and regulating the Wnt signaling pathway during development. The fusions in these genes causes them to reactivate, which in turn trigger the Wnt pathway leading to proliferation of colon cells, and eventually cancer.
The findings of this research suggests that R-spondin gene fusions are responsible for inducing certain colon tumors, although additional studies will have to be carried out to back this up. However, the identification of the potential genetic cause of particular colon cancers could lead to personalized treatment of colon tumors. As the R-spondin family act on colon cancers indirectly, via Wnt signaling, there are a large number of possible therapeutic targets to treat R-spondin-fusion positive tumors.
David Largaespada, one of the study authors from the University of Minnesota, said, “these results suggest there is a potential for personalized therapies based on knowing a tumor‘s specific genetics. And because these R-spondins are related to embryonic growth, and seem to not have major roles in the adult, targeting them would likely be low in side effects.”
Although promising, the discovery of R-spondin-positive tumors will require additional studies to verify these findings. Nevertheless, the University of Minnesota has already started work on finding an inhibiting agent for the R-spondin fusions as a potential treatment.
– Written by Theo Bond
Sources: Seshagiri S, Stawiski EW, Durinck S et al. Recurrent R-spondin fusions in colon cancer. Nature 488, 660–664 (2012); University of Minnesota press release: www.health.umn.edu/media/releases/colon-cancer/index.htm
Encouraging Results from Oncotype DX® Studies
At the 2012 Breast Cancer Symposium, in San Francisco (CA, USA), Genomic Health, Inc. (CA, USA) presented their latest findings from two large studies that followed breast cancer patients whose genetic makeup had been analyzed by the Oncotype DX® test. The data suggest that the genetic test gives an accurate prognosis and has a significant impact for additional therapies.
The Oncotype DX breast cancer assay has become an important analysis tool for physicians in treating node-positive breast cancer. The 21 genes screened by the Oncotype DX panel produce a recurrence score (RS); this predicts the likely benefits from chemotherapy as well as the probability of invasive breast cancer returning with the next 10 years. Since its development by Genomic Health in 2004, over 100,000 physicians have ordered more than 295,000 Oncotype DX tests in 65 countries.
The first study presented was an initial NSABP B-28 trial that was carried out on 1065 breast cancer patients, who were all being treated with anthracycline-containing chemotheraphy. Each patient underwent an Oncotype DX test producing a personal RS between 1–100. The data from this study were presented by Eleftherios Mamounas (Aultman Hospital Cancer Center, OH, USA) and showed that the Oncotype DX gives an accurate prognosis, with 90% of women with a low RS score surviving. A total of 75% of patients with a low RS survived disease free, compared with the 48% of patients with a high RS who stayed in remission.
The chief medical officer for Genomic Health, Steven Shak, praised the study, saying “These results add to a large body of evidence, now totaling more than 2000 patients, demonstrating that the RS provides independent distant recurrence risk information that provides value beyond clinical and pathologic factors in node-positive disease. Across multiple studies, we observe consistent support for the use of Oncotype DX as a useful tool to guide treatment decisions for early-stage breast cancer patients, including those with node-positive disease.”
An additional study was also presented at the symposium by Genomic Health. The study described the findings from 100 ductual carcinoma in situ breast cancer patients who had an Oncotype DX ductal carcinoma in situ score generated. This gives physicians additional information regarding the patient‘s tumor and allows a more personal treatment plan to be developed.
The positive data produced from these studies have reinforced the value of the Oncotype DX test and the prognostic advantages of a personalized RS.
– Written by Theo Bond
Sources: Mamounas EP. Prognostic impact of the 21-gene recurrence score (RS) on disease-free and overall survival of node-positive, ER-positive breast cancer patients (pts) treated with adjuvant chemotherapy: results from NSABP B-28. J. Clin. Oncol. 30(27), Abstract 1 (2012); Genomic Health press release: http://investor.genomichealth.com/releasedetail.cfm?releaseid=706766; Oncotype DX: www.oncotypedx.com
Launch of the SureGene Test for Antipsychotic and Antidepressant Response: a Pharmacogenetic Test for Antipsychotic and Antidepressant Drugs
The launch of the SureGene Test for Antipsychotic and Antidepressant Response (STA2R) has recently been announced as a joint venture by two companies, SureGene (KY, USA) and PGXL Laboratories (KY, USA). The simple swab test identifies each patient‘s allele variants, providing their physicians with the ability to make an informed decision when deciding on a course of treatment.
STA2R is a combination of genetic tests used to identify various markers in patients who are being prescribed antipsychotic and antidepressant drugs. Composed of a panel that screens a number of genes, this DNA analysis tool provides prescribers with more information about their patient‘s genetic make up before selecting a treatment. As well as covering adverse effects, the data from this test will also provide information about the patient‘s clinical response and drug metabolism to the most commonly prescribed antipsychotic and antidepressant drugs.
The president of SureGene, Bill W Massey, announced “STA2R represents a revolutionary change to the treatment of schizophrenia and bipolar disorder. For the first time, physicians will have a test that can help them prioritize the treatment choices for their patients.”
The test screens a number of genes including SULT4A1, a gene discovered by SureGene, which can be found in a positive- and negative-haplotype form in patients. SULT4A1-1-positive patients are found to respond better than negative patients to the antipsychotic drug olanzapine, which is used to treat schizophrenia and bipolar disorder.
Another gene that is analyzed in the STA2R test is SLC6A4, which codes for a serotonin transporter and has a number of allele variants. Different alleles cause various levels of this transporter to be expressed, affecting a patient‘s response to selective serotonin reuptake inhibitors. STA2R classifies patients into three groups (poor, normal or intermediate responder) depending on their SLC6A4 allele; this corresponds to their response to selective serotonin reuptake inhibitors drugs.
STA2R has the potential to allow personalized medication selection of antidepressant and antipsychotic drugs when treating sufferers of psychotic symptoms and depression, reducing the number of adverse reactions and improving treatment outcome.
– Written by Theo Bond
Source: PGXL Laboratories press release: www.pgxlab.com/wp-content/uploads/2012/08/pgxl-suregene-approved.pdf