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« Απάντηση #12 στις: Νοέμβριος 16, 2011, 12:58:57 πμ » |
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Tuesday, November 01, 2011
ONLINE FIRST: Early Data Promising in SU2C Pancreatic Cancer Trial
BY RABIYA S. TUMA, PHD
SAN FRANCISCO -- Molecular profiling is feasible in advanced pancreatic cancer patients and selecting therapies based on those data may improve outcomes. That was the conclusion of researchers presenting early results from a Phase II study, reported here at AACR’s Translation of the Cancer Genome meeting.
Although the data are still preliminary and the numbers small, the researchers are hopeful that the proof-of-principle trial, funded by Stand Up To Cancer, will improve the one-year survival rate in patients with metastatic pancreatic cancer that has already progressed on at least one therapy.
“There are now two patients who have survived over a year on this trial, which is really good news,” said Michael Barrett, PhD Associate Professor and Head of the Oncogenomics Laboratory Unit at Translational Genomics Research Institute in Phoenix, who presented the interim data. “But we still have a ways to go to get all the outcomes.”
In fact, the trial, which aims to improve one-year survival by selecting therapies based on molecular tumor data, opened only in August 2010 and is still accruing patients. Of 38 patients who consented to participate, 28 have started treatment, one withdrew consent, three were too ill to proceed, and six had insufficient biopsies for the necessary tests. The team expects to have the trial fully enrolled with 35 patients by the end of this month.
3 Core Needle Biopsies
For the molecular analyses, each patient has three core needle biopsies, often taken from a liver metastasis. The biopsy samples are then sent to three laboratory sites for protein expression tests, copy number analysis, and gene expression profiling. The research team then uses all those data to select a therapy most likely to control an individual’s cancer.
Of the three tests, the protein analysis is the simplest, with immunohistochemistry staining for 18 proteins, including topoisomerase, HER2/Neu, and EGFR. Additionally, investigators use PCR to look for common KRAS mutations. Dr. Barrett noted that each of the markers have been associated with an increased or decreased benefit for certain therapies.
In the copy number analysis, the team uses first uses flow cytometry and DNA staining to separate the cells according to their overall genome copy number, 2N, 4N or aneuploid. The aneuploid fraction typically comprise 8% or less of the biopsy sample, he said. Next is a look for regions of amplification or deletion in each cell fraction using comparative genomic hybridization.
The investigators then try to interpret these data in the context of the protein results. For example, one patient had an amplification of the region on Chromosome 18 that spans thymidylate synthase and had high expression of the enzyme in the IHC tests.
Not surprisingly, this patient had progressed previously when treated with fluorouracil. In another example, a patient’s aneuploid genome showed loss of the PTEN gene region on Chromosome 10 and also had low PTEN protein expression in the IHC test.
Gene Expression with a Twist
The final assay is a “gene expression assay with a twist,” Dr. Barrett said. After the tumor expression levels are determined for approximately 20,000 genes, the expression pattern is compared with the expression pattern obtained from pancreatic xenobank tumors. By looking for a xenograft tumor that has an expression pattern similar to the patient’s tumor, the investigators can predict what drugs the patient is likely to respond to based on what drugs work best in the xenograft models.
Once the data from all three assays are collected, the team has to integrate and interpret the information – and then decide on an individual patient’s therapy. “Every week we have our ‘molecular rounds’ and go through all the data and try to inform what the decision is going to be,” Dr. Barrett said, noting that this was a fascinating part of the project.
More Patient-Specific Presentations
As the number of tumors analyzed increases, the team is seeing more patient-specific presentations. For example, one patient’s tumor harbored two distinct aneuploid cell populations. The two populations shared many, but not all, of the same aberrations, suggesting that they originated from a single cell population.
Dr. Barrett said that he was interested to follow this patient and see if the multiple populations were indicative of a fast evolving tumor. (When asked later by an audience member if the populations differed morphologically, Dr. Barrett said they did not have the ability to answer the question yet, but were working on more cell sorting techniques that might help answer such questions in the future.)
Audience Intrigued
The team’s work clearly intrigued the audience, with several individuals asking about the assays used and how predictive the assays are. For example, one audience member asked how predictive the xenobank drug sensitivity information is and whether the responses in animals accurately reflected the treatment responses of the patients’ whose tumors gave rise to the models. Dr. Barrett said that the original patient data were not available because the xenobank was established quite a while ago.
As for the assay’s predictive ability in the current trial, the analyses are ongoing. “That is an excellent question,” he said. “We are just starting to see outcomes.” More data will be available at the AACR annual meeting next spring.
In the meantime, Dr. Barrett thinks the team’s effort is paying off: “I think we have shown that molecular profiling, even in these advanced tumors, is feasible. And, in fact, these are very target-rich tumors, and we need to be very aggressive with this advanced disease.”
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