The Cancer Genetics blog has a post on the approval of Veridex's new RT-PCR test for breast cancer spread.
What was emphasized in the Globe article which is striking is that this test can potentially be performed while the patient is still on the operating table, avoiding a delay between screening test & initiating follow-up testing. If this holds true, then this is an example of molecular diagnostics really having a big impact in a major health problem. As with any diagnostic test, the key question is specificity & sensitivity aka false positives and false negatives. The key study had 300ish patients in it, which is just a small puddle compared to the ocean of breast cancer patients.
Veridex, which is owned by J&J, has some other cool technologies cooking, including some to sift tiny numbers of cancer cells from the bloodstream, cells which have escaped from the primary tumor or metastases. Since getting clinical samples can be a serious challenge, this technology is pretty amazing.
Showing posts with label clinical samples. Show all posts
Showing posts with label clinical samples. Show all posts
Tuesday, July 17, 2007
Monday, December 18, 2006
Breast Cancer Genomics
This month's Cancer Cell has a pair of papers (from the same group), plus a minireview, on breast cancer genomics.
One paper focuses on comparing 51 breast cancer cell lines to 145 breast cancer samples, using a combination of array CGH and mRNA profiling. The general notion is to identify which cell lines resemble which subsets of the actual breast cancer world. Cell lines long propagated in vitro are likely (almost assured) to have undergone evolution in the lab; this means they are not the perfect proxies for studying the disease. Array CGH is a technique for examining DNA copy number changes, which are rampant in many cancers. Its use has exploded over the last few years, with a number of interesting discoveries. It is also a useful way to fingerprint cell lines; at least one cell line was described recently as an imposter (wrong tissue type), but I can't find the paper because of the huge flood of papers a query for 'array CGH' brings up.
The second paper looks at a set of clinical samples from early breast cancer, and again uses both transcriptional profiling and aCGH. I need to really dig into this paper, but the abstract has some interesting tidbits (CNAs=copy number abberations) -- emphasis my own
One paper focuses on comparing 51 breast cancer cell lines to 145 breast cancer samples, using a combination of array CGH and mRNA profiling. The general notion is to identify which cell lines resemble which subsets of the actual breast cancer world. Cell lines long propagated in vitro are likely (almost assured) to have undergone evolution in the lab; this means they are not the perfect proxies for studying the disease. Array CGH is a technique for examining DNA copy number changes, which are rampant in many cancers. Its use has exploded over the last few years, with a number of interesting discoveries. It is also a useful way to fingerprint cell lines; at least one cell line was described recently as an imposter (wrong tissue type), but I can't find the paper because of the huge flood of papers a query for 'array CGH' brings up.
The second paper looks at a set of clinical samples from early breast cancer, and again uses both transcriptional profiling and aCGH. I need to really dig into this paper, but the abstract has some interesting tidbits (CNAs=copy number abberations) -- emphasis my own
The mini-review does highlight a key point: as impressive as this study is, no study can ever hope to be the final word. As new omics tools are developed, new studies will be desirable. Two obvious examples here: running intensive proteomics and looking in depth at alternative transcripts.
It shows that the recurrent CNAs differ between tumor subtypes defined by expression pattern and that stratification of patients according to outcome can be improved by measuring both expression and copy number, especially high-level amplification. Sixty-six genes deregulated by the high-level amplifications are potential therapeutic targets.
Monday, October 30, 2006
You can't always get what (samples) you want.
A key problem in omics research in medical research is getting the samples you need.
When I was an undergraduate, I had a fuzzy notion of a scheme for personalized medicine. Some analyzer would take a sample of what ailed you, look at it, and then generate a vial of customized antisense medicine that your doc would inject into you. I drove the pre-med in the lab nuts with my enthusiasm for it.
In graduate school, the analyzer became more clear: expression profiling. Look at the mRNA profile, figure out the disease, and voila, you are cured.
Fast forward to the latter part of my Millennium tenure. Rude surprise: you can rarely get the samples you want.
Most of my later work at Millennium was around cancer, originally because that is the research area I gravitated to & later because that was the one research area left (corporate evolution can be brutal!). Getting cancer samples turns out to be decidedly non-trivial.
If you are working in leukemia or related diseases (such as myeloproliferative syndromes), then things aren't bad. Your target tissue is floating around in the bloodstream & can be gotten with an ordinary blood draw. Patients in our society have been conditioned to expect lots of needle sticks, so this isn't hard.
For multiple myeloma and some lymphomas, you can go into the bone marrow. I'm a needlephobe, so the idea of a needle that crunches on the way in is decidedly unpleasant & sounds painful, and apparently is. Patients will do this infrequently, but not daily.
For a lot of solid tumors and other lymphomas, good luck -- particularly with recurrent disease. The tumors are hidden away (which is why they are often deadly) and quite small (if detected early). In many cases, getting a biopsy is surgical, painful, and perhaps significantly dangerous. You might get one sample; repeat visits are generally out of the question. Melanomas are one possible exception, but only for the primary lesion and not the metastases hiding everywhere.
This has significant implications. For a lot of studies, you would like to watch things over time. For example, what does the expression profile look like before and after drug treatment? How long does it take a pharmacodynamic protein marker to come up and what does its decay look like? Without multiple samples, these studies just can't happen.
Worse, what comes out may not be any good. Surgeons are in the business of saving lives, not going prospecting. Traditional practice is to cut first, then put away the samples after the patient is in recovery. But RNA & protein translational states are fragile, so if you don't pop the sample in liquid nitrogen immediately your sample may go downhill in a hurry. Multiple papers have reported finding expression signatures relating more to time-on-benchtop then any pathological state. It often takes dedicated personnel to perform this -- personnel the surgeons would rather not have 'in their way' (I've heard this first-hand from someone who used to be the sample grabber). A dirty not-so-secret in the business is that fresh frozen tissue just isn't practical for routine practice; you have to go with something else.
That is going to mean you go with several less palatable, but more available, options. One is to develop techniques to look at paraffin-embedded sections, which are the standard way of storing pathology samples. There are gazillions of such blocks sitting in hospitals, tempting the researchers. But, most of those sat on benchtops for uncontrolled time periods, so there may be some significant noise. Another is to try to fish the tiny number of tumor cells (or DNA) out of the bloodstream or perhaps an accessible fluid from the correct site (mucous from the lung; nipple aspirate for breast cancer). Or, you try to find markers in the blood or skin -- not where you are trying to treat, but easy to get to.
Whether these will work depends on what you are really looking for. For a predictive marker, it seems plausible that shed DNA or an old block might work. On the other hand, for a pharmacodynamic marker these are useless. A good PD marker allows you to measure whether your drug is hitting the target in vivo and at the correct site, and only by getting the real deal is that going to truly work. By necessity some studies use accessible non-tumor tissue, such as a skin punch or peripheral white blood cells, to at least see if the target is being hit somewhere. But that doesn't answer the question of whether the drug is getting to the tumor, a critical question. And many studies still use the traditional oncology PD marker of whether you are starting to destroy the patient's blood forming system.
At ASCO this summer, one speaker in a glioma section exhorted that a central repository for glioma samples must be imposed on the community, with a central authority determining who could do what experiments on which samples. That sort of extreme rationing shows how precious these samples are.
The scarcity of such samples also underlines why sensitive approaches, such as the nanowestern, are so critical. With small sample requirements, you might be able to go with fine needle biopsys rather than surgical biopsies, or be able to take lots of looks at the same sample (for different analytes).
Of course, things could be worse. What if you go to the trouble of getting a good sample, but then you look in the wrong place in that sample? Well, that's a post for another day.
A key problem in omics research in medical research is getting the samples you need.
When I was an undergraduate, I had a fuzzy notion of a scheme for personalized medicine. Some analyzer would take a sample of what ailed you, look at it, and then generate a vial of customized antisense medicine that your doc would inject into you. I drove the pre-med in the lab nuts with my enthusiasm for it.
In graduate school, the analyzer became more clear: expression profiling. Look at the mRNA profile, figure out the disease, and voila, you are cured.
Fast forward to the latter part of my Millennium tenure. Rude surprise: you can rarely get the samples you want.
Most of my later work at Millennium was around cancer, originally because that is the research area I gravitated to & later because that was the one research area left (corporate evolution can be brutal!). Getting cancer samples turns out to be decidedly non-trivial.
If you are working in leukemia or related diseases (such as myeloproliferative syndromes), then things aren't bad. Your target tissue is floating around in the bloodstream & can be gotten with an ordinary blood draw. Patients in our society have been conditioned to expect lots of needle sticks, so this isn't hard.
For multiple myeloma and some lymphomas, you can go into the bone marrow. I'm a needlephobe, so the idea of a needle that crunches on the way in is decidedly unpleasant & sounds painful, and apparently is. Patients will do this infrequently, but not daily.
For a lot of solid tumors and other lymphomas, good luck -- particularly with recurrent disease. The tumors are hidden away (which is why they are often deadly) and quite small (if detected early). In many cases, getting a biopsy is surgical, painful, and perhaps significantly dangerous. You might get one sample; repeat visits are generally out of the question. Melanomas are one possible exception, but only for the primary lesion and not the metastases hiding everywhere.
This has significant implications. For a lot of studies, you would like to watch things over time. For example, what does the expression profile look like before and after drug treatment? How long does it take a pharmacodynamic protein marker to come up and what does its decay look like? Without multiple samples, these studies just can't happen.
Worse, what comes out may not be any good. Surgeons are in the business of saving lives, not going prospecting. Traditional practice is to cut first, then put away the samples after the patient is in recovery. But RNA & protein translational states are fragile, so if you don't pop the sample in liquid nitrogen immediately your sample may go downhill in a hurry. Multiple papers have reported finding expression signatures relating more to time-on-benchtop then any pathological state. It often takes dedicated personnel to perform this -- personnel the surgeons would rather not have 'in their way' (I've heard this first-hand from someone who used to be the sample grabber). A dirty not-so-secret in the business is that fresh frozen tissue just isn't practical for routine practice; you have to go with something else.
That is going to mean you go with several less palatable, but more available, options. One is to develop techniques to look at paraffin-embedded sections, which are the standard way of storing pathology samples. There are gazillions of such blocks sitting in hospitals, tempting the researchers. But, most of those sat on benchtops for uncontrolled time periods, so there may be some significant noise. Another is to try to fish the tiny number of tumor cells (or DNA) out of the bloodstream or perhaps an accessible fluid from the correct site (mucous from the lung; nipple aspirate for breast cancer). Or, you try to find markers in the blood or skin -- not where you are trying to treat, but easy to get to.
Whether these will work depends on what you are really looking for. For a predictive marker, it seems plausible that shed DNA or an old block might work. On the other hand, for a pharmacodynamic marker these are useless. A good PD marker allows you to measure whether your drug is hitting the target in vivo and at the correct site, and only by getting the real deal is that going to truly work. By necessity some studies use accessible non-tumor tissue, such as a skin punch or peripheral white blood cells, to at least see if the target is being hit somewhere. But that doesn't answer the question of whether the drug is getting to the tumor, a critical question. And many studies still use the traditional oncology PD marker of whether you are starting to destroy the patient's blood forming system.
At ASCO this summer, one speaker in a glioma section exhorted that a central repository for glioma samples must be imposed on the community, with a central authority determining who could do what experiments on which samples. That sort of extreme rationing shows how precious these samples are.
The scarcity of such samples also underlines why sensitive approaches, such as the nanowestern, are so critical. With small sample requirements, you might be able to go with fine needle biopsys rather than surgical biopsies, or be able to take lots of looks at the same sample (for different analytes).
Of course, things could be worse. What if you go to the trouble of getting a good sample, but then you look in the wrong place in that sample? Well, that's a post for another day.
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