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JoAnnDK
Posts: 276
Joined: Jun 2011

Detailed Genetic Tests Reveal Cancer's Complexity

Cancer gene mutation more complex than previously thought

Read articles:

http://www.npr.org/blogs/health/2012/03/08/148224862/detailed-genetic-tests-reveal-cancers-complexity

http://www.foxnews.com/health/2012/03/08/cancer-gene-mutation-more-complex-than-previously-thought/

CONCLUSIONS
Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection.

snowbird_11's picture
snowbird_11
Posts: 160
Joined: Oct 2011

Yes, Joanne, this is sobering news indeed. I read about this in my local paper this morning but wondered if should post, but we do need to keep up on all the news. I had just been discussing this as the direction of cancer treatment in the future with my gyn-onc earlier this week. This is now going to throw some big bumps in that road. Although, I have often questioned the assumed homogeneity of any tumor when I had biopsies particularly knowing my original cancer though predominantly UPSC also contained clear cell and endometroid components. Add in the continual mutations that can occur and the treatment options/decisions are getting quite complex.

Thanks for posting these links.
Annie

JoAnnDK
Posts: 276
Joined: Jun 2011

Your common sense when you said "I have often questioned the assumed homogeneity of any tumor when I had biopsies particularly knowing my original cancer" is something I see sadly lacking in many of the articles I see online.

Is it only me or does a red flag go up when the website is howcurecancer.com or glutasource.com or natural cure.com or freethoughtnation.com?

JoAnn

daisy366's picture
daisy366
Posts: 1493
Joined: Mar 2009

When a cancer patient sees a website with "Cure cancer" who wouldn't be looking for that magic bullet? Common sense and education has to be in the equation or we could easily fall victim to the various potions and snake oils out there.

JoAnnDK
Posts: 276
Joined: Jun 2011

"When a cancer patient sees a website with "Cure cancer" who wouldn't be looking for that magic bullet?"

And that is what so many charlatans are counting on! Makes me sick.

JOANN

RoseyR
Posts: 464
Joined: Feb 2011

It seems pretty obvious that who is presuming the homogeneity of a tumor based on a biopsy is the medical establishment--not some alternative med scam such as "howcurecancer.com

Red flags should be summoned not merely by commercial sites trying to sell a product with no bonafide evidence to back it up; we should see red flags when ONCOLOGISTS give chemo without prior checks of our blood levels of B-12 which, to minimize neuropathy, should be at least five to six hundred. Red flags should go up when after treatment, our ferritin levels are not carefully monitored. Red flags should go up when oncological nurses give us three different depictions of the protocols we should follow for pelvic radiation. Red flags should go up when one's oncologist and radiological oncologist, supposedly working in tandem, are at odds in their depiction of our upcoming treatment.

When we're not blinded by bias or in thrall to "official medicine," red flags are elicited as often by the methodologies of traditional treatment as by the shoddier spin-offs of alternative practice.

carolenk's picture
carolenk
Posts: 909
Joined: Feb 2011

Thanks for sharing this information. I haven't been in the cancer world very long but tumor heterogeneity is hardly news to me or the many oncologists I have consulted with. Cancer is a moving target. Which is why the focus of cancer treatment is turning towards targeted therapies.

The other hope lies in changing the "micro environment" --that's where diet, lifestyle & immune system correction come into play.

snowbird_11's picture
snowbird_11
Posts: 160
Joined: Oct 2011

The problem is this is a blow to the newer targeted therapies and explains why the newest gene-based/personalized treatments fail.

New England Journal of Medicine report on this issue...

http://www.nejm.org/doi/full/10.1056/NEJMoa1113205

carolenk's picture
carolenk
Posts: 909
Joined: Feb 2011

Fascinating! Both "good & poor prognosis" indicators in the same tumor. Let's hope someone figures out how to influence the genotype towards the good prognosis indicators. Maybe that's where the mind-body connection plays a role.

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

This "intratumor heterogeneity" issue is not a new revelation to cell function assaysts. As you can see, searching for these genetic predispositions, it is like searching for a needle in a haystack. One can chase all the mutations they want, because if you miss just one, it may be the one that gets through. Or you can look for the drugs that are "sensitive" to killing all of your cancer cells, not theoretical candidates.

Contrary to anlayte-based genomic and proteomic methodologies that yield static measures of gene or protein expression, functional profiling provides a window on the complexity of cellular biology in real-time, gauging tumor cell response to chemotherapies in a laboratory platform. By examining drug induced cell death, functional analyses measure the cumulative result of all of a cell's mechanisms of resistance and response acting in concert. Thus, functional profiling most closely approximates the cancer phenotype.

Testing of one sample of the tumor may well not render an accurate environment, unless you are recognizing the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. The human tumor primary culture microspheroid contains all of these elements. Studying cancer response to drugs within this microenvironment would provide clinically relevant predictions to cancer patients. It is the capacity to study human tumor microenvironments that distinguishes it from other platforms in the field.

They have observed some degree of "genetic drift" where mets tend to be somewhat more resistant to drugs than primaries. Over the years, they have often encouraged physicians to provide nodal, pleural or distant site biopsies to give the "best shot" at the "most defended" of the tumor elements when metastatic disease is found.

The tumor of origin (as in the NEJM study as well) and the associated mets tend to retain consanguinity. That is, the carcinogenic processes that underlie the two populations are related. This is the reason they do not see "mixed responses" (one place in the body getting better and another place in the body getting worse), but instead, generally see response or non-responses.

Heterogeneity likely underlies the recurrences that are seen in almost all patients. This is why they try to re-biopsy and re-evaluate when recurrences are observed. Heterogeneity remains a theoretical issue no matter what platform one uses. Why complicate this fact by using a less biologically relevant method like genomics that only scratches the surface of the tumor biology?

http://robertanagourney.wordpress.com/2012/03/12/the-unfulfilled-promise-of-genomic-analysis/

RoseyR
Posts: 464
Joined: Feb 2011

Thanks for your analysis.

Without pretending to possess much knowledge of the intricate dynamics innate to the genesis of cancer, I have two questions.

First: I thought that "genomics" concerned itself less with tumor biology than the "terrain" that is hospitable, or inhospitable, to cancer genesis and progression; that is, the function or malfunction of certain genes that, when all is well, protect us against certain cancers.

Secondly: It makes sense that the tumor of origin (even when heterogeneous) and its associated mets "tend to retain consanginity." But if a "recurrence" is often more resistant to chemotherapy, might that not be because the cells of the original tumor adapted and outsmarted the chemo, so that the cells that survived were the strongest? (This possibility is one that Blaylock, among others, finds so persuasive that he warns in "Natural Strategies for Cancer Patients" how many cancers he has seen made more aggressive by chemo; if the first round of chemo doesn't zap the original tumor, he warns, the recurrence will be harder to knock out with chemo.

Analogously, perhaps, a more Eastern approach to tumors, as depicted by Michael Lerner, is--unless they are directly impinging on a vital organ--to leave them alone. Left alone, the belief is, they become less aggressive; dramatically attacked, they scatter in panic and search for a new home--what for us becomes a new site of recurrence.

Would appreciate any thoughts on these ruminations.

carolenk's picture
carolenk
Posts: 909
Joined: Feb 2011

I agree with Rosey about paying attention to the terrain or micro environment of the cancer. I know Greg posted something about tumors & mets tending to behave the same--yet, that was not my experience. Twice, my scans have shown changes where some tumors went away, some tumors shrunk, some tumors grew and new spots appeared. I have no doubt that it's possible to have tumor heterogeneity.

I've heard/read the stem cell theory. Cancer stem cells are not killed by chemo--only their "daughter cells" die off. The cancer stem cells create different daughter cells each time they are exposed to chemo. This is where mutations show up. But not everyone's cancer arises from cancerous stem cells. Some people can be cured or enjoy long remissions.

Contrary to what Dr. Blaylock has written, my recurrence was not more aggressive than the primary tumors were. The "second time around stuff" seemed like a different cancer--not as scary because it was just smoldering (as opposed to the first-time where the cancer was carrying on like a house on fire). I think it is true that the faster growing cancers respond faster to chemo & the slower growing cancers respond slower to chemo.

I think Greg has posted that taxol is known to work in such a way as to cause the malignant cells to scatter & metastasize. I wonder if the thinking behind using taxol as a maintenance therapy is to "clean up" after taxol blasts the tumor all over the place.

As far as ascites goes, I had a lot of ascites both pre- and post-op with the initial tumors. Ascites is secondary to angiogenesis; the new blood vessels are leaky. I don't know what kept the ascites/angiogenesis away (bindweed? IV ascorbic acid? diet?) but I'm grateful not to be dealing with ascites again.

My oncologist seems pleased with my progress and the obvious level of health that I possess. I think taking low-dose naltrexone (LDN) at bedtime must be helping somehow. If nothing else, I think the LDN therapy helps me stay optimistic.

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

Carolenk

Your recurrence was not more aggressive than the primary tumors were. Yes, not every primary to met will act aggressively. My wife's primary took 24 years before ever recurring. And everyone thought because it recurred, the met would be aggressive, even Dr. Renzo Canetta of Bristol-Myers Squibb. When he read more about my wife's history, he thought differently. He even stated to me that she should have been treated post-operatively for her recurrence with single-agent Carboplatin, not Taxol + Carboplatin. Single-agent Carboplatin has the same mechanism that affects tumor cells, like Chlorambucil (Leukeran), the drug she received for her original stage IV ovarian cancer. They both are alkylating agents.

She turned out to be Taxol-resistant, the type of chemotherapy (dose-intense) subsequently given to just about every Mary, Jane and Stella with metastatic carcinoma of the ovary. The anti-angiogenic effects of this therapy is masked and marginalized by the way it is administered. Big doses, with long breaks of several weeks between drug administration, to allow the body to try to recover from the harmful side effects of treatment. When administering conventional cytotoxic drugs, the endothelial cells (involved in angiogenesis) are the first in the tumor to undergo cell death (apoptosis). However, this anti-angiogenic effect does not translate into significant therapeutic benefit because the damage to the vasculature of the tumor can be largely repaired during the long rest and recovery periods between successive cycles of therapy.

Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply. Most cancer patients have the drug bounce off their tumors, doing little if any good. Cautious clinical judgement should be used when considering the use of platinum and paclitaxel in patients with symptomatic platinum-sensitive cancer recurrence after a treatment-free interval of 6-12 months (in her case, 24 years).

RoseyR

Genomics (genotype analyses) looks for DNA indicators. The particular sequence of DNA that an organism possesses (genotype) does not determine what bodily or behavioral form (phenotype) the organism will finally display. The genotype of an organism is the inherited instructions it carries within its genetic code. Not all organisms with the same genotype look or act the same way because appearance and behavior are modified by environmental and developmental conditions. Similarily, not all organisms that look alike necessarily have the same genotype.

Phenotype analyses measure biological signals. A phenotype is an organism's observable characteristics or traits: such as it's morphology, development, biochemical or physiological properties, behavior and products of behavior (such as a bird's nest). Phenotypes result from the expression of an organism's genes as well as the influence of environmental factors and the interactions between the two.

The tumor of origin (as in the British study) and the associated mets tend to retain consanquinity. That is, the carcinogenic processes that underlie the two populations are related. This is the reason, in functional profiling analyses, they do not see "mixed responses" (one place in the body getting better and another place in the body getting worse), but instead, generally see response or non-responses. Heterogeneity likely underlies the recurrences that are seen in almost all patients. This is why they try to re-biopsy and re-evaluate when recurrences are observed. Heterogeneity remains a theoretical issue no matter what platform one uses. Why complicate this fact by using a less biologically relevant method like genomics that only scratches the surface of the tumor biology?

Anyway, the molecular profiling (as in this British study) uses fine needle aspiration and core biopsies which provide small samples. Sampling errors increase the smaller the sample size studied. Thus, there is a deep concern that the studies conducted upon these very small biopsies are not reflective of the tumor as a whole, because if you miss just one mutation, it may be the one that gets through. The British study had to do with "mutations." A tumor's "genetic" identity is not all revealed by a single biopsy. As stated, "sampling errors increase the smaller the sample size studied."

Greg

gdpawel's picture
gdpawel
Posts: 549
Joined: May 2001

It's a theoretical but overrated problem. The same problem applies to ER, Her2, EGFR mutations, KRAS, OncotypeDx. Even worse for trying to do studies on individual cells, e.g. as from circulating tumor cells. Less of a problem for cell function analysis, since they are sampling a much bigger mass of cells and are homogenizing the mass (actually homogenizing the distribution of microclusters).

It's analogous to the Gallup poll. You are projecting the behavior of a national electorate, based on a sample of 1,500 voters, who may or may not be representative of the whole. Rasmussen and Gallup have the same sized sample, but select different people for their polling ("likely voters" vs "all voters"), so their projections often disagree.

It is one of the reasons why (1) "resistance" predictions tend to be more accurate than "sensitive" predictions (of the cancer is resistant anywhere, it pretty much doesn't matter), if you use the "resistant" drug, the patient will have progressive disease and (2) the tests are more analogous to using the barometric pressure to predict for rain than they are analogous to a serum sodium level; i.e. the predictions are useful (assay "sensitive" drugs being seven times more likely to work than assay "resistant" drugs), but they aren't perfect (i.e. 100%), no diagnostic test in medicine is.

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