March 31, 2006 Clinical oncology's failure: Why we need cancer cell profiling to match treatment to patient and why we are dropping the ball (continued):

 6. Meanwhile, back on the DNA and RNA and protein ranch, what is new?

Funny thing.

The next great things in cancer treatment are so-called "targeted" therapies, the most prominent of which now are tyrosine kinase inhibitors (e.g. gefitinib, erlotinib, sunitinib, sorafenib).  These drugs are very expensive and only work in a minority of cases (occasionally dramatically; more often modestly).  Investigators at the Dana-Farber Cancer Center (an internationally-renowned, Harvard-affiliated institution) developed a predictive test, based on DNA content.

"We are eager for this technology to be widely available to physicians and their lung cancer patients, as it can help identify those who are likely to dramatically respond and survive for extended periods of time with a relatively benign treatment," said [one Dana-Farber oncologist; from a press release].

"We are entering an exciting new era in cancer therapy," [another Dana-Farber oncologist, from the same press release] said. "We are now beginning to be able to use molecular profiling to provide personalized treatment that offers hope of improved survival and less toxicity from therapy. And the ability to provide this molecular diagnostic test on a worldwide basis with rapid turnaround will be critical for further clinical research and application in the clinic."

Dana-Farber licensed the test to Genzyme, a large US cancer laboratory.  Genzyme is actively marketing the test as a non-investigational service to cancer patients, at a cost of about $1,000 (to predict for the activity of a single drug).

The Director of Thoracic Oncology at Dana Farber has been quoted as saying that 50% of all non-small cell lung cancer patients at Dana Farber are now receiving the Genzyme test to obtain information to guide their treatment.

Now, what were the data supporting the use of this test at the time of the above quotations? 

Prospective, randomized trials showing improved treatment outcomes in patients so tested? Nope. Prospective trials, showing survival advantages in patients with "positive" test results (as exist to validate cell culture drug resistance testing)? Nope.
Prospective trials, showing response advantages in patients with "positive" test results (as exist to validate cell culture drug resistance testing)? Nope. Retrospective trials, showing both response and survival advantages in patients with "positive" test results, in thousands of patients, from multiple laboratories (as exist to validate cell culture drug resistance testing)? Nope. Two entirely retrospective studies, from two Harvard-affiliated hospitals, showing response, but not survival, advantages with a grand total of 26 assay/treatment correlations?  Yes.

A subsequent study from another laboratory did not show correlations between gene mutations and patient survival.

Now, in January, 2006, I submitted an abstract to ASCO describing correlations between cell culture assay results (cell death in response to gefitinib exposure) and survival of 31 patients with non-small cell lung cancer who had received extensive prior chemotherapy.  These correlations were based on the actual assay results which had been reported, in real time, prospectively to the doctors who had ordered our laboratory tests.  There were striking correlations between test results and patient survival, yet the ASCO reviewers did not even select this work for poster presentation. (They will publish the abstract in this year's ASCO Proceedings, which is why I'm not posting it at this time).

Now, I can't begin to understand the thinking which goes into reviews like this (and like the other similar reviews detailed elsewhere on this website).  Can the reader begin to appreciate that I may be correct in my charges that there is a certain closed-mindedness which has been rampant now for two decades relating to cell culture assays? 

What do the EGFR gene mutations code for?  Anti-apoptotic pathways. So we inhibit anti-apoptosis with gefitinib or erlotinib, and the cells undergo apoptosis and die.  And we detect that at the whole cell level with our cell culture assays and report out -- prospectively -- that this correlates strikingly with patient survival, and ASCO determines that it's not even worthy of a look?  If I'm right, then not only will we have a very important predictive test, but we'll have a unique tool for identifying newer, better drugs, testing drug combinations, serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity, and so on.

And these same close-minded ASCO reviewers condemn the use of the whole cell function assays until they've been shown to improve patient treatment outcomes in prospective, randomized trials.  While enthusiastically endorsing the clinical application of DNA content assays which have been shown to correlate only with response and not survival, and only in a handful of patients, and only in entirely retrospective studies.

What is going on here?  It's the same mentality which wouldn't even agree to look at data indicating a near doubling in the survival of patients with platinum resistant ovarian cancer (see below).  And wouldn't agree to consider data showing striking correlations between platinum activity and patient survival in previously-untreated ovarian cancer (see below).  And wouldn't agree to publish a comprehensive meta-analysis of scores of studies reporting response and survival correlations in thousands of patients (see below).

While turning a blind eye to the corrosive practice of selecting drug regimens based on the profit motive.

In the coming weeks, I'll take a closer look at "molecular" assays vis a vis cell culture assays.