NCCN Decision

Here is the NCCN decision on whether to add HERmark:

(Side note: HERmark is a technology developed within the past decade – as opposed to one developed in the 1950’s as is the case with IHC – and is an alternative option for medical professionals trying to give women with a new diagnosis of breast cancer the proper medication. It is the modern age of personalized medicine and the entire purpose of this blog.

NCCN decides to stick with IHC & FISH/CISH. They balk at a chance to lead the upgrade to better technology for women with breast cancer. Their explanation is “that’s what ASCO is doing”.

What that means is physicians (and families) now have fewer options when considering HER2 targeting agent, or whether to consider toxic  chemotherapy as the only current option (or clinical trial with something in the pipeline, of course).

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October Update

Just in case anyone has been waiting with baited breath for an update, here you go: the NCCN (National Comprehensive Cancer Network) breast cancer panel met in late July, 2014 to discuss updates to their breast cancer guidelines. With the help of various high-level scientists, I successfully persuaded a megalith in the US reference lab industry to submit a “change request” to NCCN.

The submission asks NCCN to consider HERmark, a fascinating technology that identifies women who are eligible for a drug called HERceptin, as an alternative to IHC and FISH/CISH – technologies currently used to identify a woman’s ability to use Herceptin and other HER2 targeting agents.

Here’s the kicker: IHC & FISH/CISH are known to be wrong at least 20% of the time yet are the standard of care all around the world for this subset of oncology testing, and current medical reimbursement standards reward physicians, hospitals, clinics and pathologists to continue running these flawed technologies.

If NCCN mentions HERmark as a possible alternative as a result of their meeting in July, even only in the off-chance of an “indeterminate” IHC/FISH call (meaning IHC and/or FISH fail to identify the patient as being eligible nor ineligible…the purgatory of HER2 decisions, crucified by terrible, outdated technologies), as many as 40,000 women every year could have an improved life expectancy by being given the proper combination of drugs.

Much weighs in the balance of the NCCN decision, and word on the street is that the update is expected sometime during the month of October.

What a coincidence, NCCN decides the fate of women with breast cancer during the same month that the NFL and countless organizations around the world make a killing by claiming they’re out to save the tatas.

Let’s hope NCCN is out to save some tatas by improving the technological options of women diagnosed with breast cancer. Help spread the news, the oncorevolution is set to begin!

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Improving Breast Cancer Diagnostics

In case this is the first time you have read this blog, I encourage you to read the very first post way back at the beginning then return here to better understand what this is all about. If you want to get angry, also read the one that describes why 1941 = Ungood.

In three weeks time the National Comprehensive Cancer Network (NCCN) will meet to discuss breast cancer guidelines. One specific subset of breast cancer testing is acknowledged as being flawed upwards of 20% of the time, and the two technologies that are approved by NCCN in this realm are also not shown to be any better than the other.

That is, a well-recognized governing body that gives guidance on how oncologists & pathologists should determine a woman’s course of cancer therapy – and thus both her life expectancy and her quality of life – blatantly admit that two approved technologies are wrong at least 20% of the time, and that neither is any better than the other.

My mission is to attempt to improve this clear inefficiency.

The purpose of these two flawed technologies is to define a woman’s eligibility for drugs that bind to specific receptors on a breast cancer tumor cell. By binding to the specific receptor, the drug controls the growth and proliferation of cancerous tumor cells.

If you have ever heard of the term “HER2-negative”, that means a woman cannot use a HER2 targeting drug like Herceptin. HER2-negative also means that a woman has much fewer treatment options. Getting a woman’s “HER2 status” correct is imperative.

Getting it wrong 20% of the time is the current standard of care.

I discovered a technology developed by a biotechnology company in San Francisco that is much more sophisticated in determining whether a woman can benefit from these HER-2 targeting agents. HER stands for Human Epidermal growth-factor Receptor, by the way, and #2 just denotes that the drugs bind to one particular receptor out of 4 possible receptors (HER1, HER2, HER3, HER4).

The more sophisticated technology that I discovered is called HERmark, and it has been available since 2008. The scientists who developed this technology have published paper after paper on the clinical implications of this technology, and yet the company that developed this assay suffered the consequences of capitalism: they don’t have a sales force because they are financially strapped. The technology never took hold in the market, and oncologists continue to rely on technologies that are wrong 20% of the time.

With over 220,000 newly diagnosed breast cancer patients every year, a 20% error rate is mind-boggling. Imagine if GM had a 20% error rate when they produced cars in their manufacturing plants (oh wait, they already do). The consequences of this rate of failure are catastrophic when we are talking about people’s lives.

About two months ago I began networking within the company that developed the HERmark assay and successfully convinced the scientific team to submit a request to NCCN to change their breast cancer diagnostic guidelines. NCCN will meet for 2 days between July 20-22nd, and at that meeting the NCCN panel will determine whether HERmark is a suitable alternative to the current standard of care for assessing whether a woman can benefit from HER2 targeting medications. Note that I say alternative, not replacement.

The pharmaceutical companies that conduct clinical trials for HER2 targeting medications continue to only use the out-of-date technologies in the trials that lead to the approval of their medications. This is the part that grinds my gears. HERmark can never supplant the current standard of care because HERmark has never been used at the beginning of a clinical trial to screen patients for HER2-targeting therapies – otherwise known as a prospective clinical trial. Retrospective analyses, or backwards looking data analysis, has shown that HERmark is significantly more accurate at predicting treatment outcomes.

This is not difficult to understand, though. If a technology is flawed 20% of the time, very often patients will be put on a medication when it should not have been given because the drug will have no benefit. The more sensitive & specific a technology is, the more beneficial the treatments become. This is the basic concept of personalized medicine – the right medication for the right patient at the right time.

We should not put the entire population on antibiotics, only those patients who have bacteria that will respond to the specific antibiotic in question. That same principle applies to HER2 targeting drugs: only patients who will respond to these drugs should be given the drugs, and accurate testing is critical if the goal is to save lives.

Help save a life. Join the OncoRevolution. Let’s see if we can help sway public opinion prior to the start of the NCCN meeting on July 20th. Or are you willing to roll the dice should you or your loved one be diagnosed with breast cancer?

Heck, 20% wrong means 80% right!

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A quick update on progress

For those who have followed this blog, I wanted to give a brief update. Through tedious networking I was able to persuade the medical teams within both Monogram Biosciences & Laboratory Corporation of America to submit a guidelines change request to the National Comprehensive Cancer Network (NCCN).

The submission will request an update to current HER2 testing guidelines – guidelines for testing that is known to be flawed upwards of 20% of the time. This guidelines-change-request will ask the NCCN advisory committee to review a new HER2 technology, known as HERmark, and ask the committee to address whether this is a valid supplemental tool for the oncology-treating community in determining a woman’s ability to use HER2-targeting agents.

This may all sound like mumbo-jumbo, but realize that with over 200,000 newly diagnosed breast cancer patients every year, getting the wrong result 20% of the time with current technologies means that over 40,000 women are either deprived access to life-saving medications or are being exposed to agents that are expensive and ineffective – every single year in the US alone. The global implications of faulty HER2 technology is breath-taking.

HERmark has the ability to improve patient quality of life, provide more accurate information to physicians and families, and potentially save a ton of money in long-term financial costs that are associated with disease progression in cancer (when improperly diagnosed and given wrong medications).

The tricky part is that the submission needs to be received at least 3 weeks prior to the July 20th NCCN meeting, and apparently the documents need to go through a team of lawyers within a ginormous, multinational corporation with the thickest of bureaucratic red tape. Let’s hope LabCorp does the right thing and expedites this request.

I’ll write an entirely new post over the coming days explaining the submissions, the bar that needs to be surpassed, and the clinical impact of a positive outcome.

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Mayday: the business of breast cancer

I think it’s interesting that the holiday that praises international workers on May 1st – one that is a loose nod to communism/socialism –  is also recognized as an international distress signal.

Mayday, mayday: breast cancer HER2-diagnostics is a racket.

This week I learned about TC/PC, otherwise known as “technical component/professional component”. This simple acronym explains why breast cancer HER2-diagnostics are presently in the dark ages.

TC/PC is laboratory-speak for “reimbursement for highly skilled services rendered”. Technical Component (TC) allows a local laboratory, Lab A on 50 Main St, to get reimbursed for preparing an IHC/FISH breast tumor sample. Professional Component (PC) enables the send-out hospital, laboratory, surgery center, or oncology clinic to get reimbursed for the interpretation of that IHC/FISH sample since someone has to look under a microscope to make a subjective determination of the patient’s course of therapy.

TC/PC is how the oncology-treating community gets reimbursed for using IHC & FISH methodologies (the ones that are stated in the guidelines as being incorrect upwards of 20% of the time) to assess a woman’s ability to use HER2-targeting monoclonal antibodies.

However, in January, 2014, the reimbursement for TC/PC was cut considerably under the Affordable Care Act, otherwise known as ObamaCare.

I visited a message board recently that was discussing this topic of reduced reimbursement for TC/PC, and the authors of the statements on that board were presumably either oncologists or pathologists. The uproar in the chat room was all about how much these TC/PC reimbursement cuts were going to affect the pocketbooks of said disgruntled authors.

Anecdotal reports describe reimbursement cuts from around $200 per IHC/FISH tumor sample down to about $50 bucks. That, my Fellow Readers, is what I would call “profiteering”.

I would also call it downright dirty money.

Why is it dirty? Because these clinics/pathologists/hospitals are choosing to run IHC/FISH through a local laboratory – a decision that everyone knows can generate incorrect values upwards of 20% of the time (a conservative estimate, I’m sure) – for the sole reason that these local laboratories enable the clinic to get reimbursed for the “Professional Component”, or PC reimbursement procedure code.

Look it up. I’m not making this up, folks. Now let’s take an even further dive into this farce:

There have been numerous studies documenting how a “Local Lab” is less efficient at getting accurate IHC/FISH results when compared to a “Central Lab” because of various degrees of quality controls. To put this in layman’s terms, a “local lab” is Lab A on 50 Main St, and a “central lab” is a well-recognized lab that is publicly traded on Wall Street (the one that sends you bills in the mail).

In honor of Mayday, this is where I will confess that I don’t see any difference between “local” & “central”. Both are capable of performing what’s called an “in-house brew” of IHC & FISH, and both local & central rely on a subjective pathologist’s retina/glasses/mental acuity to determine the outcome of IHC & FISH (and thus a patient’s course of therapy/livelihood).

That, my Fellow Reader, is exactly why IHC/FISH is only capable of achieving reproducible results 80% of the time.

My honest opinion is that the idea of “central lab is better than local lab” is just a big marketing ploy by the central lab that has sufficiently deep pockets to make that bold of a statement. However, it is accepted as fact among the oncology/pathology community that “central is better than local” when determining HER2 status with IHC/FISH (and yet these samples are still being sent to local labs, can you believe it? Why you ask? Because the central lab gets reimbursed on both TC & PC, whereas the PC reimbursement goes to the clinic/pathologist/hospital if the tumor sample is sent to a local lab. Outraged yet? Join the OncoRevolution).

So back to the point of the story, what is the business of breast cancer? An oncologist/breast surgeon/hospital/pathologist has little-to-no incentive to get a HER2 result correct – the incentive is to get reimbursement from an insurance company for the PC fee schedule.

Mayday, mayday: Welcome to crazy (or “kray-kray” for short).

So what incentive would a clinic/pathologist/hospital have to send a breast cancer tumor specimen to a specialty, high-science biotechnology company that can quantify HER2 protein expression?

There’s no incentive at all!

That high-science biotech company would perform the entire HER2 assay itself, and wouldn’t allow the clinic/pathologist/hospital/central/local lab to get reimbursed for the Technical Component nor the Professional Component.

To sum this up: first an IHC sample is sent to a local lab, and the pathologist/hospital/clinic gets reimbursement for the PC (subjective) interpretation of HER2 status (and thus a patient’s treatment options and survival outcome); then if there is some concern of accuracy, the pathologist/hospital/clinic will request that a FISH assay be performed and again, there is reimbursement for the “professional component”. Finally, regardless of these 2 outcomes, no one is ever considering that both IHC & FISH are wrong upwards of 20% of the time, and that the results of both of these assays are entirely subjective/flawed.

The ASCO/CAP guidelines explicitly describe IHC & FISH as being incorrect upwards of 20% of the time, and yet where are the guidelines that expose the fraud of breast cancer HER2-diagnostics?

In this twisted capitalistic society we live in, a patient’s livelihood and her health outcome is less important than making a buck on the treatment decision-making process.

Mayday, mayday: this business is killing us.

Meeting adjourned.

 

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National Comprehensive Cancer Network

To anyone following this story, I wanted to quickly share some great news: the NCCN meets this July 20-22 to review updates to their guidelines for all things Breast Cancer. Submissions must be made at least 21 days prior to the meeting, and below I have indicated how they score the evidence provided upon submission.

This is so exciting, given all the data out there I cannot imagine that HERmark will not at least clip the 2B mark for addition to their guidelines, but clearly a Category 1 outcome would pave the way for improved oncology diagnostics worldwide.

Mini victory for sure, now comes the tough part: convincing Monogram Biosciences to submit a guideline change request. More to follow…

“NCCN Categories of Evidence and Consensus

  • Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
  • Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
  • Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
  • Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.”

http://www.nccn.org/about/submissions.aspx

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Garbage In, Garbage Out

It was probably at some point in my 20’s that I understood the concept of “you are what you eat”. Call me slow, but I finally figured out that eating burritos/pizza purchased from a gas station and heated in a hazmat microwave – for breakfast – was a bad idea.

Next I remember walking through a museum in London (it likely was something less exotic, like St. Louis) that described improvements to the body’s overall health at each time interval after one stops smoking: after 30 days your sense of smell improves; at 90 days your taste buds function better; at 3 years your circulation returns to normal; at 10 years your risk of death or slightly less than had you never started smoking. I’m clearly making the specifics up, but Dr. Google will fill in the missing blanks for those interested.

Now think about oil spills in Alaska and in the Gulf of Mexico, and all the little fish that feed the larger fish that are then served on our dinner plates at fancy restaurants across the country. Or at Micky D’s & Kantucky’s, more likely. One nugget of wisdom I learned recently is that dates, those sweet jewels from mother earth, attach to heavy metal ions as they pass through your intestines, ridding your body of chemicals such as mercury, for instance.

The point of all these anecdotes is that everyone reading this can make the logical link between input and output. You put bad things into your mouth, your body feels bad as a consequence (hello, hangover). You put bad info into a computer algorithm, wrong information comes out the back.

The predictive value of any oncology diagnostic is only as good as the technological sophistication of the methods being used. For anyone who has read previous posts, is interested in science, and wants to change the world, let’s now explore IHC & FISH…

IHC & FISH are the two standard of care methodologies used to determine if a woman diagnosed with breast cancer is a candidate for some of the most modern drugs on the market today, known as monoclonal HER2-targeting antibodies. The result of the IHC/FISH assays also gives the physician valuable information about the patient’s prognosis, ie whether he/she is facing an aggressive form cancer.

Seems like pretty valuable technology, if it were my family member who was being treated, I would certainly be interested to learn the outcome of this IHC/FISH result (tongue-in-cheek; I would demand that my doctor use more advanced technologies).

IHC is a relatively inexpensive technology, around 200 bucks, and is most commonly ordered for breast cancer tumors. To simplify the science, IHC stains the proteins found on the tumor cell and a pathologist looks under a microscope and makes a subjective assessment of whether he/she is seeing lots of HER2 proteins, or few HER2 proteins.

If he/she is unsure, the result is “equivocal”, or “beats me”. For anyone who read my previous posts, remember that Lab A will only get the same answer as Lab B ~80% of the time – for the same patient’s tumor drawn on the same day under the exact same circumstances.

Talk about garbage in, garbage out. It gets worse though, in case you weren’t incensed enough with just that level of subjectivity.

Not only is the “reproduceability” of the IHC assay only 80%, but inherent flaws of the assay also lead to improperly stained HER2 proteins in the first place. Finally, after a pathologist looks under a microscope he/she has the inauspicious task of determining whether this woman has aggressive breast cancer, and whether he/she will be denying access to potentially life-saving treatment. Sounds like wild guesswork to me. I’ll even take it one step further and call it: Cowboy Medicine.

So the pathologist doesn’t want to go out on a limb and he gives it a 2+ IHC score, which means “I don’t know” or scientifically “equivocal”. In 99% of all scenarios, this biopsy sample will then automatically trigger a FISH analysis. Let’s now dive into FISH…

(For those reading this far, anxious to know what these acronyms stand for here you go: ImmunoHistoChemistry & Flourescent In Situ Hybridization. Now aren’t you glad I didn’t mention that previously? Don’t even worry about what they mean, from now on let’s just say IHC is Incredibly-unHolyCrap and FISH is downright FISHY.)

As to FISH, let’s expose the fraud once-and-for-all: it is a ratio, plain and simple. It is a ratio of DNA. But wait a minute, aren’t we trying to find out if a HER2-targeting agent will work, and isn’t HER2 a protein? Why is FISH looking at DNA if HER2 is a protein? I hope at least a few of my readers don’t click away at this biology sarcasm, but the point is FISH is looking at a breast tumor’s DNA, and then makes a prediction of HER2 protein expression.

Remember: garbage in, garbage out. Predictions based on flawed assessments are totally flawed at the end of the day. Back to FISH, it gets worse…

So everyone now understands that FISH is a ratio of DNA, but in any ratio you need 2 items to compare, right? Good on the two of you keeping score!

So what is the denominator, if tumor DNA of predicted HER2 expression is the numerator? Here’s where I even lose myself in the science: the denominator is what’s known as a “centromere of chromosome 17”. But don’t even worry about it, we don’t even need to know what that means, does or says for now. Just trust me on this, you’ll be able to solve this riddle without knowing DNA from proteins from centromeres from s’mores crunch bars.

After the pathologist who said “I don’t know” to an IncredibyunHolyCrap result, another pathologist is looking into yet another microscope and is ready to make YET ANOTHER subjective call. I’m shocked, join the revolution.

In this subjective call, he/she is literally counting up little specs of fluorescent dots. It’s easy though, because they’re either red or green. The pathologist is counting up the red dots, and dividing by the number of green dots – and voila! Patient prognosis and drug options at your service.

But hold on a second, does FISH find every single DNA cell in the breast tumor? Not a chance, there would just be a big glow under the microscope in that scenario. FISH is looking at a subset of maybe 1% of the tumor, and making a prediction of the entire tumor. Fascinating, no? Or is that what we humans would describe as appalling?

So now what if the FISH pathologist counts 12 reds and 12 greens? That would be HER2 negative, since the ratio is a 12:12, also known as 1 for us math wiz’s. In this case the patient will not be given the drug Herceptin, since this patient is found to not have many HER2 proteins (remember though, FISH is looking at DNA, not proteins; quite the stretch of logic, but there it is).

So what if a different pathologist looks under the same microscope for the same patient at a  lab directly across the street? Consider this scenario: he/she now counts 2000 reds and 1900 greens. “Holy canoly, that’s a lot of reds…but that’s also a lot of greens. Divide and carry the one…the ratio is 1..05”. In this scenario, the patient is also deemed to have a HER2-negative tumor, and the patient is denied access to potentially life-saving treatments.

Now I’m no math genius, but 2000 looks to be a lot more than 12 in my mind, so how can these two results provide the exact same clinical outcome? Could it be a function of garbage in, garbage out? For anyone keeping up, the red dots are DNA that are thought to code for HER2 expression. Lots of red dots tells me there is a lot of coding going on, so simply taking a ratio of DNA could lead to totally arbitrary results.

And what are those results? Apparently only 50% of patients respond to Herceptin, and the entire scientific/pharmaceutical community is wondering why and desperately trying to find bigger and better drugs to give those 50% of patients who don’t respond to Herceptin.

When I ask the question, why is the medical community still using IHC & FISH, the response is: that’s all there was available since we began treating with Herceptin, it’s all these docs know from their time at medical school; also, the pathology/laboratory/hospital community makes money from the interpretation of IHC/FISH results so there’s a reluctance to cutoff that revenue-stream; and for the most part, Herceptin seems to work; finally, for those patients for whom Herceptin doesn’t work, there’s another drug on the market called XYZ.

For those that are firmly aboard the OncoRevolution train, you’ll remember that the other drug available to HER2-positive tumors is a drug that crosses the blood-brain-barrier, whereas Herceptin does not.

Brain metastasis occurs much more frequently for patients on Herceptin vs. patients not on Herceptin – but don’t confuse cause and effect here. Herceptin doesn’t cause brain metastasis, it simply does not cross the blood-brain-barrier and thus has no ability to mitigate tumor development within the central nervous system.

That other drug does cross the blood-brain-barrier. If I was a doc, I would want to know if my patient has a ton of HER2 expression, or relatively low levels. The max score of IHC is 3+, and IHC is looking directly at HER2 protein expression. FISH is looking at DNA, and it’s just a ratio of DNA, not HER2 expression.

Come on folks, someone has to be keeping up with all this. Let’s change the world. Check that, let’s improve the way our families and neighbors are being treated by oncologists, pathologists, and the entire pharmaceutical industry. IHC is even being used in ongoing clinical trials for colorectal cancer, nonsmall cell lung cancer, ovarian cancer, etc. I promise there are better solutions out there than IncrediblyunHolyCrap.

Is it time for me to research what the heck a hashtag is? Help make this info go viral, join the OncoRevolution.

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