Applying Whole-Genome Analysis to Treatment Decisions in Daily Practice

January 2013, Vol 4, No 1

Vienna, Austria—Several studies presented at the 2012 European Society for Medical Oncology Congress offered a look into what many believe will lead to the application of genome-based biomarker information into clinical use based on the concept of personalized medicine, although not all of the results were unconditionally encouraging.

Jean-Yves Pierga, MD, PhD, Pro­fessor of Medical Oncology and Senior Medical Oncologist, Department of Medical Oncology, Institut Curie, Paris, France, presented the first results of the phase 3 REMAGUS04 trial using whole-genome DNA arrays to select the neoadjuvant treatment of breast cancer that is matched to the genetic profile of the tumor.

“There is a need to determine robust and high throughput biotechnologies for biomarker determination for clinical use. DNA arrays allow quantifying gene expression at the whole-genome level and could improve prediction of the benefit from specific treatment,” Dr Pierga said.

The Diagonal Linear Discriminant Analysis-30 (DLDA30) probe was de­­veloped to predict resistance to neoadjuvant chemotherapy. Expression of the gene encoding topoisomerase 2-alpha (TOP2A), which is correlated with treatment response to anthracyclines, was also included in the model.

The REMAGUS04 trial evaluated the use of this probe in guiding drug selection to enhance the likelihood of pathologic complete response ([pCR], ie, complete disappearance of the tumor) over standard chemotherapy. After biopsy, 142 patients were randomized to a standard treatment arm or to the “genomic-driven” arm, where treatment selection was based on their DLDA30/TOP2A expression.

Although no differences were seen in pCR rates between the genomic- driven arm (22%) and the standard chemotherapy arm (21%), the predictive value of the DLDA30 score was validated: a positive score was associated with 36% odds of achieving a pCR versus 3% for a negative score.

“We identified a group of patients with a very low rate of response, who need specific strategies,” Dr Pierga said. The success rate for the genomic analysis and for applying the results clinically was 61%.

“This is the first prospective trial showing that whole-genome array is feasible in the context of daily practice within 15 days,” Dr Pierga said. “Gene expression arrays could be a solution in the future, for promising an all-in-one assay for personalized medicine.”

Whole-Genome Testing in the Metastatic Setting

In the metastatic breast cancer setting, French investigators performed whole-genome analysis on 251 of 393 patients, of whom 172 (69%) had genetic alterations. The majority of these patients had an alteration that was considered “targetable” by an anticancer drug, and approximately 20% actually had rare, and sometimes unexpected, alterations. Patients with targetable alterations were matched with specific targeted treatments.

The SAFIR01 trial is the first large-scale study to prospectively test the entire genome from a biopsy of a meta­­static lesion to help guide treatment. Most genetic testing looks for specific genetic alterations and analyzes only a limited number of genes.

That 20% of patients had low-frequency alterations “highlights the need for whole-genome approaches,” said Fabrice André, MD, PhD, Associate Professor, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France, who led the trial.

The study used a whole-genome array (ie, a comparative genomic hybridization array) to look at genetic copy numbers, and identified “hot-spot” mutations, specifically PIK3CA and AKT mutations, which are common in patients with breast cancer. Patients do not receive mutation-guided targeted drugs, however, until they demonstrate progressive disease.

To date, only 26 patients have progressed and have been matched with treatments. This has included 13 different targeted therapy regimens. Evidence of some response for at least 4 months has been noted in 8 patients.

“This study suggests that it is time to bring personalized medicine to the field of cancer research,” Dr André concluded.

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