番茄社区

CHICAGO – Genomic testing of tumor samples indicated that more than half had variants amenable to drug therapy, but only a small fraction of the patients were actually treated with appropriately targeted drugs, according to a French study reported here.

Among 1,944 patients with advanced cancer undergoing routine genomic testing, 52% were found to have these actionable alterations, but only 676 of the patients were recommended by a molecular tumor board to be treated – and just 143 patients were actually treated with some agent, said , of the Centre Léon Bérard in Lyon, France.

In his presentation at the annual meeting of the American Society of Clinical Oncology, Tredan said that when patients who did receive drugs that attacked the actionable mutations, their 5-year survival rate was 34.8% compared with 28.1% among patients recommended for treatment with these targeted agents but who did not receive them.

"This study confirms that comprehensive genomic profiling can be performed in routine practice to select patients for targeted cancer therapies," said Tredan. "The technology is widely available and requires only a small amount of DNA. Theoretically, we could do this testing for every patient in France."

In the so-called ProfiLER trial, genomic profiling of tumors was used to guide treatment decisions for patients with advanced cancer. DNA from tumor samples was analyzed by next-generation sequencing of cancer-related genes and whole-genome-comparative genomic hybridization. Both technologies are widely available in the world, according to the authors.

A multidisciplinary board of experts met weekly to review genomic testing results and, if actionable mutations were found, provided recommendations for molecularly targeted therapies. "We recommended molecularly targeted therapies to patients who had mutations in pathways that could be targeted with either commercially available drugs or those tested in early clinical trials," said Dr. Tredan.

To date, 2,676 patients have enrolled in the study, and 1,944 tumors were analyzed, including colorectal, gynecologic, breast, brain, and head and neck cancer, as well as sarcoma. Among the 1,004 found to have actionable mutations, 609 patients had only one and 394 had two or more (up to six) such mutations. The most common actionable pathway was the PI3K/mTOR pathway. The molecular tumor board recommended molecularly targeted treatments to 676 patients based on availability of drugs hitting either the target protein or the pathway activated by the target.

Of those, 143 received the recommended treatment, most through enrollment in a clinical trial. The other 533 patients were not able to receive the recommended treatment because of poor health/rapid progression of the cancer, not meeting eligibility criteria for a clinical trial, or difficulty obtaining off-label commercial medicines.

The researchers are planning a new, randomized clinical trial, ProfiLER 02, which will compare the 70-gene test used in the current study to a commercial 315-gene test. That trial should reveal whether screening a larger number of genes leads to more recommendations for targeted therapy.

"This study gives more validation for the use of genomics in clinical practice and shows it could very well guide treatment for patients with advanced cancer," said , of City of Hope in Duarte, Calif., and an ASCO expert commenter for this study.

Liquid Biopsy ID's Treatable Tumors

In a second study, so-called liquid biopsy helped find a genetic abnormality that may be a treatment target in 89% of patients, a different group reported.

"Our findings show that high-intensity circulating tumor DNA sequencing is possible and may provide invaluable information for clinical decision-making, potentially without any need for tumor tissue samples," said, of Memorial Sloan Kettering Cancer Center in New York. "This study is also an important step in the process of developing blood tests for early detection of cancer."

The researchers prospectively collected blood and tissue samples from 161 patients with metastatic breast cancer, non-small cell lung cancer or castration-resistant prostate cancer. Thirty-seven patients were excluded due to unavailability of the results of the genetic analysis of the tumor or cell-free DNA samples. For 124 evaluable patients for concordance analysis, researchers compared genetic changes in the tumors to those in circulating tumor DNA from the blood samples.

Tumor tissues were analyzed using MSK-IMPACT, a 410-gene diagnostic test that provides detailed genetic information about a patient's cancer. In each blood sample, plasma was separated from the blood cells. Cell-free DNA was analyzed in the plasma and, separately, 508 genes within white blood cell genomes were sequenced.

"Finding tumor DNA in the blood is like looking for a needle in a haystack. For every 100 DNA fragments, only one may come from the tumor, and the rest may come from normal cells, mainly bone marrow cells," said Razavi. "Our combined analysis of cell-free DNA and white blood cell DNA allows for identification of tumor DNA with much higher sensitivity, and deep sequencing also helps us find those rare tumor DNA fragments."

of Fox Chase Cancer Center, Philadelphia, commented to 番茄社区 that blood-based DNA analysis is a promising technology, because it is relatively non-invasive and results can be returned quickly.

"These include the amount of circulating mutated tumor DNA that can serve as a tumor marker, the presence of specific mutations such as KRAS that may steer patients with colorectal away from anti-EGFR targeted therapies, or the presence of kinase activating EGFR mutations in lung cancer that may direct therapy towards small molecule EGFR inhibitors. Much more can be learned from liquid biopsies including emerging drug resistance mechanisms over time, insight into intra-tumoral heterogeneity both for treatment-naïve tumors as well as those following treatment where resistance develops."

El-Deiry said it remains unclear whether a 508-gene panel that was used in the Memorial Sloan Kettering project is superior to panels of 70 genes. He said the study authors's assertion that DNA sequencing tests may help with early cancer detection is more of a distant goal than a current reality.

"However, in selected populations at high risk whether they are patients with strong family history or those who already had cancer but went into remission, this technology is very promising," he said.