The following is laden with personal opinion as much as actual evidence. Feel free to take it or leave it.

In my last post, I introduced the key questions we're facing in my own institution, and many other oncologists and their own hospitals are doing the same thing: which patients do we now routinely test for molecular markers in their lung cancer tumors, and what markers do we request? Here's an outline of the questions where there's still back and forth, and why:

1) Which histologies? As I mentioned in yesterday's post, the NCCN guidelines divide patients into squamous and non-squamous and say that everyone with a non-squamous NSCLC should have their tumor tissue tested for an EGFR mutation. In general, I think that's reasonable, though the incidence of an EGFR mutation is greater for patients with an adenocarcinoma than for patients with a large cell NSCLC or someone with a NSCLC tumor so poorly differentiated that the pathologist can't tell what histology it is (NSCLC not otherwise specified, or NOS). There is no evidence I know of (I don't think there is any good evidence at all) to suggest that the probability of someone with a non-adenocarcinoma of any particular subtype, such as large cell or "NSCLC NOS" has anything higher than squamous cell carcinoma, which is in the low single digits in terms of percentages. Moreover, since Tarceva (erlotinib) is still an FDA approved and medically appropriate treatment for second or third line treatment in patients with previously treated advanced NSCLC, there isn't any good evidence that patients who get an EGFR tyrosine kinase inhibitor (TKI) like Tarceva have a less impressive survival if they receive this agent as a second line therapy vs. first line, even if they have an EGFR mutation.

This brings us to the next question.

2) If a patient has enough tissue for making a diagnosis but not enough for molecular marker testing, do we feel that there is a mandate to do additional biopsies to get more tissue? I think there should be a different threshold for sending molecular marker tests on those who have tissue available and taking the time, slightly increased risk, and expense of doing another biopsy for those who don't have adequate tissue available. You can have a pretty broad definition of who to test if people have plenty of tissue available, but I think that in a longtime and current smoker with a very poorly differentiated NSCLC tumor, the probability of that person having an EGFR mutation or ALK rearrangement is somewhere in the range just barely calculable, even if it's greater than zero. Should we do 1000 additional biopsies and spend literally half a million dollars or more to find one person in this category who has an EGFR mutation, especially if they can still just get Tarceva as a second line therapy and do just as well? Bear in mind that some of the people who undergo this additional biopsy will suffer a pneumothorax (collapsed lung) that requires a hospitalization and chest tube, and every other person who gets a biopsy and testing without having a mutation will have experienced a delay in treatment for 2-3 weeks while this additional workup is being done.

Therefore, I think that there is reason to apply some common sense in estimating the pre-test probability that someone will test positive before becoming "so open-minded that our brains fall out" with regard to testing everyone. The people who don't test positive can be harmed by the risk of re-biopsy and the delay in treatment, and I don't think this is justified in cases where the probability of a positive result is remarkably scant.

The fact that the NCCN guidelines don't offer this kind of nuance doesn't dissuade me here. Nearly all of the people who contribute to the NCCN guidelines see relatively few patients, and by definition they all work in places very different from those where the vast majority of people get their cancer care. Many if not most are making their careers on highlighting molecular marker work, and they very often have to go to the least effort of anyone in oncology to get molecular marker studies, since their own centers have a lab to do this testing, and there is often someone else to take care of all of the difficult details of getting biopsies completed. I personally feel that it's a Marie Antoinette "let them eat cake" attitude from the people who don't actually work in real world cancer clinics to just effortlessly issue an edict that everyone should get tested for everything all the time (again, my editorializing).

3) These guidelines and nearly all of the data address metastatic NSCLC. Do we test tumors in patients with earlier stages of NSCLC as well? This was one of the most debated issues in our discussion, and one that we haven't resolved yet. We can agree that the biology may well be different and that molecular marker testing of someone's resected tumor can save us time if the cancer recurs, but if that recurrence is 2-3 years later, we'd probably want to get a new biopsy anyway to both confirm the diagnosis of a new lesion and to get the most current reflection of the biology of the cancer (I don't think we'd rely on results from a cancer 3 years ago accurately reflecting the biology of recurrent disease today). Right now, we also have no good evidence that supports treating people with stage I-III NSCLC and an EGFR mutation or ALK rearrangement differently from patients who don't. Having this information could tempt us to make non-evidence based decisions based on presumptions that could backfire, such as the strong trend toward an especially harmful effect of EGFR TKI therapy Iressa (gefitinib) as maintenance/adjuvant therapy in patients with a resected NSCLC early stage NSCLC tumor and an EGFR mutation. Though all of us in our group agree that this information is likely to provide insights into the biology of NSCLC and help us in the future, we can't say that there is a medical indication to sending these tests today. And if insurers refuse to pay, as is very easy to imagine, is it fair to saddle patients with a >$1000 charge for a test we decide to do routinely that doesn't have evidence will help our treatment recommendations for them?

4) The NCCN guidelines specify EGFR, but should we broaden that recommendation to other markers? I actually feel that testing for an ALK rearrangement is arguably more compelling than testing for an EGFR mutation, because anyone can get an EGFR inhibitor regardless of the result of testing (and appears to do comparably well if they have a mutation and get it later than first line), while only people with an ALK rearrangement have an opportunity to receive the ALK inhibitor crizotinib. Because ALK rearrangements are seen in the same patient populations as an EGFR mutation (but almost never in the same patient), I think it makes sense to include ALK testing in just about all patients who you're going to be sending out tissue for EGFR mutation testing anyway.

While we don't have lots of evidence for a clear role of testing for KRAS mutation in shaping clinical decisions (and the evidence indicates that it's an error when oncologists misinterpret the data on EGFR inhibitors to say that people with a KRAS mutation shouldn't get Tarceva at all), I have favored KRAS testing along with EGFR and ALK because it is another nearly mutually exclusive marker that could help us assess probabilities of response and benefit with other agent, because it's being incorporated into more and more eligibility questions for clinical trials with targeted agents, and because I suspect it will be integrated more and more into refining predictions and prognosis in NSCLC. Finally, a practical aspect is that it will usually be covered if done along with EGFR and/or ALK testing. That said, none of these arguments is extremely strong, and I might feel differently about this if patients were getting charged $400 for KRAS testing because insurers said that there isn't sufficient evidence to use this variable in routine clinical management.

Our own institution's view is that predictive markers like ERCC-1, RRM-1, and thymidylate synthase (TS), which are purported to be helpful in shaping recommendations for chemo, are not really well validated enough to use these to alter treatments indicated to be the standard of care otherwise (such as deciding not to use an otherwise clearly indicated platinum-based doublet chemotherapy backbone for advanced NSCLC based on a tumor's high ERCC-1 expression). We also feel that EGFR immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are too inconsistent in their association with outcomes from EGFR TKI therapy to recommend testing any of these as a standard "reflex" testing battery.

5) Will insurers pay? Though I do have issues with some of the NCCN's guidelines not being as evidence-based as the NCCN might imply, I think they can serve a helpful purpose, and one is to define what insurers should be expected to cover. However, this cuts both ways. While inclusion of EGFR mutation testing for patients with advanced NSCLC of a non-squamous histology means that it should be far easier to get this test covered for these patients, it could also mean that insurers are not inclined to cover testing in patients with squamous tumors, earlier stage NSCLC, or to pay for different markers that aren't specified in the guidelines. Some of my own preferences are based on what it seems insurers for my patients will readily cover vs. not, and I suspect that my experience is different from that of oncologists in different areas and/or with a very different payer mix.

Again, I'll highlight that these guidelines are meant to reflect a broad institutional policy, but individual doctors managing individual patients will still have the latitude at our institution to order marker studies outside of these parameters; they just won't be tested automatically.

I also envision these specifics of our own guidelines, however we finalize them at my institution in the coming days, will change rapidly over time, especially as we get more information from new trials. We may well revise them on an annual basis, or even more frequently than that.

As always, I welcome your thoughts, questions, objections, etc.