The previous CMS administrator for Medicare in Southern California (NHIC) spent almost the entire 2006 doing a extensive, transparent tech assessment of chemoresponse assays and made the decision that the assays were a perfectly appropriate medical service, worthy of coverage on a “non-investigational” basis.

What was of particular significance this time (as compared to approval for the resistance part of the testing in 2000) was that they abandoned the artificial distinction between “resistance” testing and “sensitivity” testing and provided coverage for the whole FDA-approved kit.

Why it was a local coverage decision (LCD) and not a national coverage decision (NCD)? Medicare has only about 20 doctors and 40 total clinicians working in its coverage office.

Also, Medicare doesn’t have a single oncologist on staff, yet since the year 2000, they issued 165 restrictions and directives on the use of cancer drugs and diagnostic tools. Private insurers (like NHIC), on the other hand, employ thousands of doctors and nurses to do this.

Medicare wants to put off-lable drug decision making (which some 60% of cancer drugs are) in the hands of compendia writers in the private sector, many of whom are on the payrolls of the companies that make the drugs. I am just wondering if this had anything to do with what Palmetto GBA is doing?

It amazes me that they don’t emphatically mandate this testing as a requirement for obtaining chemotherapy reimbursement against ill-directed treatments. Evidence in support of these tests is more than sufficient to justify them, particularly in light of the Duke University impact study of chemoresponse assays on the treatment costs for recurrent ovarian cancer.

Impact of a chemoresponse assay on treatment costs for recurrent ovarian cancer.

Havrilesky LJ, Krivak TC, Mucenski JW, Myers ER. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC.

Objective

We sought to estimate mean costs of chemotherapy treatment for recurrent ovarian cancer with or without use of a chemoresponse assay.

Study design

We estimated mean costs for 3 groups: (1) assay assisted: 75 women who received oncologist’s choice of chemotherapy following chemoresponse testing (65% adherence to test results), (2) assay adherent: modeled group assuming 100% adherence to assay results, and (3) empiric: modeled from market share data on most frequently utilized chemotherapy regimens. Cost estimates were based on commercial claims database reimbursements.

Results

The most common chemotherapy regimens used were topotecan, doxorubicin, and carboplatin/paclitaxel. Mean chemotherapy costs for 6 cycles were $48,758 (empiric), $33,187 (assay assisted), and $23,986 (assay adherent). The cost savings related to the assay were associated with a shift from higher- to lower-cost chemotherapy regimens and lower use of supportive drugs such as hematopoiesis-stimulating agents.

Conclusion

Assay-assisted chemotherapy for recurrent ovarian cancer may result in reduced costs compared to empiric therapy.

PMID: 20417480

I always like to search on UTube for videos on tamoxifen and breast cancer, you can learn a lot about tamoxifen and breast cancer although like blogs you have to filter out the dross. This was a better article than most. Thanks….

http://www.biofocus.de/data/biofo/en/data/Link_1273_download.pdf

The study looked at whether the presence of specific mutations in people who had breast and colon cancer and chronic myeloid leukemia determined if patients would respond to expensive new drugs commonly used to fight the diseases. Only in colon cancer did the mutation matter and in that case, while it ruled out the effectiveness of drug therapy, the relevant mutation only appears in a small percentage of cases.

In the finding most likely to cause controversy, the AHRQ report found there was “no consistent associations” between breast cancer patients with the relevant CYP2D6 polymorphism and the outcome of tamoxifen therapy, whether as primary treatment or in as post-operative adjuvant therapy. Estimates vary, but anywhere from 10 to 40 percent of women have the gene variant of CYP2D6 that is believed to slow the metabolism of tamoxifen and make it less effective. A number of companies sell a $300 test that can show if women have the allegedly telltale CYP2D6 polymorphism.

As is often the case, the 13 studies identified by the systematic review didn’t contain enough data to draw definitive conclusions. “Most studies were relatively small and thus underpowered to detect what would be a plausible effect size for the modification of response to tamoxifen by a single polymorphism,” the report noted.

Numerous studies in recent years have noted that colon cancer patients with the KRAS mutation do not respond to epidermal growth factor receptor inhibitors like cetuximab (Imclone Systems/Bristol Myers Squibb’s Erbitux) and panitumumab (Amgen’s Vectibix). The Food and Drug Administration, the European Medicines Agency and the American Society of Clinical Oncology have issued guidelines suggesting patients with the mutation shouldn’t be given the drugs.

The AHRQ-sponsored review confirmed that finding. “Patients with KRAS mutations were less likely to experience treatment benefit, compared to patients whose tumors were wild-type for KRAS mutations,” the report said. About 20 percent of patients have KRAS mutations, which generally signal a more virulent form of the disease.

Chronic myeloid leukemia is one of the great success stories for targeted chemotherapy drugs and imatinib (Novartis’ Gleevec) has been a godsend for patients with CML since it came on the market a decade ago. But resistance is growing, and at least two similar drugs are now on the market, dasatinib (Bristol-Myers’ Sprycel) and nilotinib (Novartis’ Tasigna).

Some mutations of the BCR-ABL1 gene make the cancer resistant to imatinib (Gleevec), which is designed to block the action of the hyperactive tyrosine kinase receptors in people with CML. But don’t look to any tests currently on the market to determine what they are. The review of 31 studies found that “the presence of any BCR-ABL1 mutation does not appear to predict differential response to treatment in CML patients treated with imatinib-, dasatinib- (Sprycel), or nilotinib- (Nilotinib) based regimens.”

Indeed, the report said there is “no evidence that presence of any BCR-ABL1 mutation can differentiate response to tyrosine kinase inhibitor therapies.”

“It is possible that pharmacogenetic (how our inherited genes affect the way we respond to drugs) testing and the subsequent use of targeted therapies will add cost without producing clinically meaningful improvements in patient outcomes,” the report said.

http://www.ahrq.gov/clinic/ta/pharmgentest.pdf

Source: Gooznews on Health

Over the last couple of years, there has only been mounting interest in treating NSCLC in a new, more intelligent way by using molecular testing to tailor our therapy. In fact, I’ve been among the people hailing the wondrous promise of a new age in which we can deliver response rates of more than 50% by identifying a targeted population for a targeted therapy. From where I’m standing, though, the reality hasn’t measured up that well.

For starters, getting tissue has been a pain, at least for me. A large number of my patients come from outside institutions, so getting tissue from another hospital sent for EGFR mutation testing adds a major layer of obstruction and delays, and that’s even presuming that there’s enough tissue. I’ve come to the conclusion that it can be easier to get tissue at my own institution, which is I believe what Memorial Sloan-Kettering, MD Anderson, and other places have concluded as well. It’s a little troubling that we need to submit patients to an additional invasive procedure, but it can be a delay of weeks otherwise, and sometimes it just seem like pathology departments can’t handle the simple task of sending slides elsewhere.

On the other hand, I can’t say that my own institution has done a much better job. Three weeks ago, I saw a woman with a rapidly recurring effusion and thought it would be easier to get the effusion drained at my own place and have the cell block sent for mutation testing. Great, and within 2 days that had been performed, but my center’s pathology department is part of a national mega-group that contracts with a lab in North Carolina for their mutation testing and didn’t want to send it to Response Genetics, which is about the only place I’ve found that makes any real effort to get EGFR mutation testing done within a week. I agreed to let them try, but now I’m still waiting and told I won’t get the result until more than three weeks after the test went out. I’ve had to use words like substandard to convey that this is unacceptable from a clinical standpoint. But I think this kind of runaround is probably pretty common right now.

Finally, my center is one of the earliest places activated for the EML4-ALK mutation testing as part of the trials with the agent PF-02341066. The agent is only available for people who have the mutation, and the test isn’t commercially available. Pfizer had promised up and down that they’d guarantee that they can get the test turned around in 5 days. Well, now that I’ve consent a bunch of patients who are sitting by the phone waiting to find out if they have the mutation, Pfizer calls to say that the guy who runs their lab isn’t going to be able to do it for another two weeks at least. I have patients on hold waiting for this, and this kind of crap undermines my relationship with them. Even if they know it’s not my fault, it’s frustrating for all involved, and it just underscores how Pfizer has already bungled this process terribly, with just two sites active in the country. How will they manage when they get another 20 sites activated?

Sorry to rant, but the truth is that our system doesn’t have the infrastructure to deal with a roll-out of molecularly-defined treatment of lung cancer yet. The idea is great, but I don’t think we can execute this yet in a way that makes it broadly clinically applicable. And it’s pretty disappointing to know the data but not be able to act on it.

The question should be, “Why was nothing presented at the ASCO meeting with regard to drug selection through the use of molecular profiling?” Sad to say, there has not been any progress with it. Is molecular profiling ready for prime-time use in clinical decision making?

http://theoncologist.alphamedpress.org/cgi/content/full/12/3/301

One of the things that lead to the closure of Bath Cancer Research was the refereeing of a grant application of mine by a leading UK Oncologist who said something along the lines of:
“This is old hat. We are now going to select drugs by molecular profiling.”

I do not agree with one thing you said:
These data show that obtaining a pCR is *everything*. Get a pCR, and the survival is excellent. Don’t get a pCR and the survival, especially for TNBC patients, is very poor.

There is a subtle difference between this and:
Those who got a pCR did better than those who did not.

Those who did not get a pCR, even if had been given drugs that gave them a pCR, might have done just as badly. Although what you say may be true, these data do not *necessarily* show that obtaining a pCR is everything.

Excellent summary slide at the end. And what *is* the answer to your question:
Why is there absolutely no interest in cell culture tests?

Andrew Bosanquet

The validation standard that private insurance companies is accepting from molecular profiling tests is accuracy and not efficacy. The “bar” has been instantly lowered. No longer will it be essential to prove that the use of a diagnostic test improves clinical outcomes, all they have to do for these molecular profiling tests is prove that the test has a useful degree of accuracy. However, when it comes to the validation standard they want for cell-based profiling tests, it is efficacy.

The cell-based profiling tests have the same entitlement to be judged by the same validation standard as molecular profiling tests. The combination of measuring morphologic (structural) effects and metabolic (cell metabolism) effects constitutes measuring the “profile” at the whole cell level.

However, profit, as we have seen, is a powerful motivating force. Among the private payors, at least, the profit motive is entirely consistent with the goal of the test, which is to identify efficacious therapies irrespective of drug mark-up rates.

The evidence in support of these assays is more than sufficient to justify the funding of comparative effectiveness research (CER) – validation trials, if any are truly needed, as claimed – speciously and self-servingly – by the medical establishment.

Everyone is scared to death – and rightly so – at what is going to happen to the healthcare economic system with the introduction of increasingly expensive new drugs that benefit only a small percentage of patients who receive them, hence the headlong rush to develop tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient.

Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

The FDA could benefit too, as they find themselves under increasing pressure to allow new drugs into marketplace while at the same time protecting the safety of potential recipients of those drugs as well as the financial interests of those who will have to pay for them.

It explains the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies. The pressure, in fact, is so great that the companion diagnostics they’ve approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

I think that in both of these areas – private insurance carriers and the FDA – there is a very real opportunity to make a substantial impact and contribution, an interest in saving the healthcare system perhaps billions of dollars a year (and thereby the healthcare system itself) by ensuring that expensive treatments are used appropriately.

Committee chairpersons, committee members and persons in congress who may have personal interests not only in discovering new cancer treatments – everybody wants that – but also, in the “here and now,” using currently-available cell-based assay technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.

The whole concept of proper genetic markers is not to put patients in the position of having to receive toxic cancer drugs if they’re not going to do any good. However, genomics is far too limited in scope to encompass the vagaries and complexities of human cancer biology.

The situation with Erbitux and Vectibix for colon cancer, Iressa and Tarceva for lung cancer, and Herceptin for breast cancer is that all the mutation or amplication studies can tell us is whether or not the cancer cells are potentially susceptible to this mechanism of attack.

They don’t tell you if one drug or the other is worse or better than some other drug which may target this. The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions.

No genetic profile can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can it identify situations in which it is advantageous to combine a targeted drug with other types of conventional cancer drugs.

“Targeted” drugs are poorly-predicted by measuring the ostansible “target,” but can be well-predicted by measuring the effect of a drug on the function of live cells, the net effect of all processes, not just the individual molecular targets.

The benefits of newer targeted therapies are marginal. These targeted therapies may impart a clinical benefit by stabilizing tumors, rather than shrinking them (substituting shrinkage for stabilization).

I would not want to be denied treatment with any targeted therapy because of a gene mutation or amplication. Genetic testing is not a clear predictor of a lack of benefit.