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Exploratory Study Provides Early Evidence for PGx Chemo Response Predictor in Osteosarcoma

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NEW YORK (GenomeWeb) – A team led by researchers from Radboud University in The Netherlands has published an early-stage study suggesting that a set of SNPs may be able to predict the outcomes of patients with osteosarcoma after standard chemotherapy treatment.

In the study, published last month in Clinical Cancer Research, the team identified five variants that were significantly associated with osteosarcoma patients' five-year progression-free survival. Individuals that carried zero or only one risk allele had a 100 percent five-year PFS compared to those with more than five alleles who had only a 42 percent rate of survival without advancement of their disease.

Melanie Hagleitner, the study's first author, told GenomeWeb in an email this week that she and her colleagues were interested in developing a way to better predict the outcomes of chemo-treated osteosarcoma patients after observing how little the standard treatment strategies for the disease have improved over the last few decades.

"Whereas in other forms of cancer clear progress has been made … either by the use of new drugs or by … risk stratification and subsequent treatment adjustments, in patients with osteosarcoma no substantial improvement in survival has been achieved," she wrote.

Overall, survival for patients with osteosarcoma — the most common primary malignant bone tumor in children and young adults — is only about 60 percent, the study authors wrote. Poor response to chemotherapy is understood to be the dominant contributor to this statistic.

In light of this, the Radboud group decided to pursue a candidate gene approach focused on chemotherapy response genes, initially genotyping 126 patients with osteosarcoma using the Illumina BeadArray platform to profile 381 SNPs in 54 genes known to be involved in the metabolism of the chemotherapy drugs cisplatin and doxorubicin, which are the mainstays of osteosarcoma first-line treatment.

Among this first sample set the researchers were able to successfully genotype 120 patients, and overall, they identified 23 SNPs with a statistically significant association with five-year PFS.

The team then set out to replicate or validate these variants in another 64 patients, 57 of which were successfully genotyped.

Nine of the initial 23 variants showed low call rates in the replication cohort, and so the group excluded them. That left 14 SNPs for analysis, five of which demonstrated an "improved association signal," the team wrote.

The researchers then took these five SNPs and created a genetic risk score dividing patients into four groups based on the number of risk alleles present — either zero to one allele, two to three, four to five, of more than five alleles.

PFS varied dramatically between the lowest and highest risk allele groups, with a five-year survival rate of 100 percent in patients with no alleles or one allele, and then dropped for each subsequent risk category down to about 42 percent in subjects with six or more alleles.

The researchers also looked at how the genetic risk score related to the presence of absence of metastasis, currently the most important conventional risk factor in the disease. The team concluded that the genetic risk information significantly improved the ability to predict PFS over the presence or absence of metastasis alone.

Interestingly, the investigators did not find any link between the five SNPs they identified as being significantly linked to five-year PFS and patients' histological therapy response, which supports other research that has found that histological response may be of limited value in assessing treatment effectiveness in terms of long-term survival.

The team also looked for the presence of SNPs significantly associated with histological response, but none showed an improved signal in the analysis of both the initial and replication cohorts.

The authors acknowledged that though promising in opening a new door for more accurate prediction of outcomes and response to chemotherapy in osteosarcoma, the results raise many new questions about their ultimate clinical implications.

Importantly, it's unclear how patients who are predicted to be less responsive to cisplatin and doxorubicin should be treated. The authors wrote that both drugs have dose-limiting toxicities, so higher doses may not be a possibility for higher-risk patients. And if not with more chemo, it's still unclear how else high-risk patients should be treated or otherwise managed, although clinical trials are being conducted of targeted and other alternative therapies in osteosarcoma patients.

Hagleitner wrote that her team is now joining several other osteosarcoma study groups to more comprehensively investigate the influence of genetic polymorphisms on the course of the disease.

Before the team's initial results could become useful for clinical risk stratification, she said it will be important that the findings be replicated in additional cohorts, preferably in the context of a prospective clinical study.

She also stressed that because the Radboud group took a candidate gene approach, additional, more extensive studies with a more agnostic approach to variant discovery could help improve the predictive power of the team's initial five-SNP score, and would also be a logical next step.

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