It’s a question that doesn’t have a clear answer.  The concept of “downstaging” a cancer with neoadjuvant (pre-operative) chemotherapy or chemo/radiation is an appealing potential appeal of the strategy, but there isn’t clear evidence that it really works.  In the ChEST trial that has been recently published that compared pre-operative cisplatin/gemcitabine chemotherapy followed by surgery to surgery alone, the recipients of neoadjuvant therapy were less likely to have undergone a pneumonectomy (17% vs. 25%) and more likely to have received a lobectomy (70% vs. 60%) .  On the other hand, the SouthWest Oncology Group (SWOG) ran a similar neoadjuvant chemotherapy trial and found that there were no differences in the pneumonectomy rates with or without pre-op chemo — 17% in both arms.  What gives?

Part of the challenge is that surgeons have different styles: some have come to believe that a cancer is like a balloon, and if it appears to shrink, you presume that the new borders of the cancer don’t have any additional cancer around them.  Therefore, it’s OK to do a smaller surgery than you would have originally done.  On the other hand, some surgeons see a cancer as a puddle drying up, so that even though the main borders are smaller on repeat scans, and maybe even when directly visualized by the surgeon, you can’t be confident that there aren’t little satellite areas of cancer outside of the main borders.  Therefore, they feel that if someone needed a pneumonectomy originally, you can’t do a smaller surgery after pre-operative therapy, even if it looks as if the cancer is now small enough to enable a more limited surgery.

So the question of which patients receive a larger or smaller surgery depend only in part on what their tumor requires, and in part on the philosophy of the medical team (but usually especially the surgeon, who tends to get more votes in such matters).   We can’t rely on the rates of pneumonectomy vs. lobectomy to tell us whether all of the pneumonectomies were clearly needed or not.  What would be most helpful would be to determine if the patients who were deemed to require a pneumonectomy that was then converted to a lobectomy do just as well as the patients who were anticipated to require a lobectomy from the beginning.  But to my knowledge, we don’t have any such data.

In the end, let me give you a sense of how variable these styles are. I work with four board-certfied, excellent thoracic surgeons who get along amazingly well, even if they don’t all do things the same way. Two of them favor revising the surgery after pre-operative therapy, and two favor doing the original surgery that would have been required.  And the one who presented the case today? He favored pre-operative therapy for a patient we shared a few months ago (but who ended up requiring a pneumonectomy after neoadjuvant chemo/radiation anyway), but for this particular patient, he favored up front surgery with a pneumonectomy.  In the more recent case, he wasn’t at all optimistic that the operative options would be better after chemo or chemo/radiation.  It just goes to show how individualized patients and their cancers can be, with no “right way” for everyone, even with the same surgeon and team.

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The clearest role for local treatments in metastatic lung cancer is to improve QOL and reduce symptoms. Indeed, that’s exactly the place where they have a clear role. Radiation, for instance, is appropriate in metastatic disease in four basic circumstances:

1) brain metastases, which cause symptoms from local growth and swelling, or usually will very soon after detection, if not treated effectively
2) hemoptysis (coughing up blood), where radiation can treat local bleeding from erosion of the cancer into adjacent blood vessels quite effectively
3) local pain, such as from a bone or soft tissue lesion, in which case radiation-induced shrinkage can reduce that and improve pain effectively
4) airway compression, in which case radiation-induced response can lead to better air movement

Radiation isn’t the only form of local therapy. Mechanical ones like surgery (removing a single brain metastasis, treating a collapsed vertebra with kyphoplasty) or interventional pulmonology techniques (removing tumor from within an airway or placing a stent in an airway compressed from outside of it), may also be helpful in many cases.  Other common local therapies are a pleurodesis or placement of a PleuRx catheter to control shortness of breath and the cough that can accompany a recurrent large pleural effusion.  These interventions are all extremely appropriate and offer quality of life benefits/symptomatic benefits first and foremost, though they may also improve survival.

The problem that I see is that local therapies are often recommended far beyond these settings, such as for asymptomatic and multifocal metastatic disease, where multiply-directed stereotactic radiation is pursued as a presumably curative technique.   While this might sometimes work for people with a single focus of metastatic spread (see my post about when, in my opinion, breaking the general rules and treating oligometastatic lung cancer with curative intent makes sense), focusing on local therapy with curative intent when the cancer isn’t “oligometastic” veers into the realm of magical thinking. Too often, patients and physicians pursue local therapy because they really just want to “treat the scan” to make themselves feel like they’re just doing something, shrinking or removing the cancer by brute force, but if the cancer is active in multiple sites, it can spread and cause new problems before the patient recovers from side effects of local therapy.  And even if the treatment has very little risk, doing a pricey treatment that has no realistic probability of benefit just because it’s possible doesn’t make a lot of sense.

I recognize that it’s not only hopeful patients are pressing for these treatments when they don’t necessarily make good sense. Many physicians make these kinds of futile recommendations and referrals every day, as I see this in the practice patterns all around me. But I believe the true motivation  for these doctors is that it is easier for them to sidestep the emotional and time-consuming challenge of discussing the realistic limitations of our standard therapies, especially after a few lines of treatment, than to just glad hand and send a patient out of your office for an intervention that truly just going through the motions. There are also some doctors who are misinformed enough about the biology of metastatic cancer, or just subject to so much wishful thinking on behalf of their patients, that it’s easy to slip into a collective delusion of what a local therapy can provide.

Highlighting that certain treatments are a poor option for many patients is far less fun that describing a wonderful new therapy for patients.  But local therapies still have a clear role for many patients with advanced lung cancer.  Not only can they be a critical component in maximizing quality of life and minimizing side effects, they may also offer a realistic possibility of an extraordinarily good outcome for well selected patients.  They just aren’t broadly helpful when used indiscriminately as a solution for most people with advanced cancer.

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We’ve looked at molecular markers (one or a few distinct variables that may be particularly important) and genetic signatures (an overall pattern of the genetic activity level of an often complex collection of genes) for a few years.  For instance, ERCC-1 is an enzyme that was shown in a retrospective analysis of a single trial was prognostic for survival and predictive of the benefit or lack of benefit from adjuvant cisplatin based chemo, and an analysis of a different adjuvant chemotherapy trial demonstrated that a molecular signature was also prognostic of better or worse survival and predictive of which patients benefit from chemotherapy.  But these methods have had limitations and detractors.  Markers that are called positive or negative, high or low by immunohistochemistry (IHC), which is essentially the intensity and frequency of a protein on the surface of cancer cells, is a subjective interpretation.  And work on molecular signatures has generally required “snap frozen” tissue, which requires special preparation right at the time of the surgery, and this is a technical challenge that is not widely feasible.

It is in this setting that the results of a study by Kratz and colleagues, now published online in the prestigious journal the Lancet, is novel and interesting.  This work was done at the University of California - San Francisco (UCSF) in collaboration with the company Pinpoint Genomics (conflict of interest: though I have no financial interest in these entities,  I have been friends for several years with both Dr. David Jablons, surgeon at UCSF who directed much of this work, and Mr. David Berryman, who is CEO of Pinpoint Genomics, though I knew him mostly from his time working at Genentech several years ago).  They set out to develop a “gene expression assay”, a predictive pattern from multiple genes expressed by tumors, that could be run from formalin-fixed paraffin-embedded (FFPE, the basic way that tumor tissue is routinely stored after surgery everywhere), developing this from the pairing of gene expression patterns with the outcomes of 361 patients with stage I non-squamous NSCLC who had undergone surgery at UCSF and whose outcomes in the years after surgery were known.   They were able to develop a 14-gene assay that could separate patients into low, intermediate, or high risk groups (of approproximate 1/3 of the overall population each) with a 5 year overall survival (OS) of 71.4%, 58.3%, and 49.2%, respectively.

They then tested this multi-gene assay that was developed with the data from UCSF patients against two other groups.  One was pretty much next door, as they reviewed the prognostic utility of the assay on 433 patients with stage I non-squamous NSCLC from Kaiser Permanente Division of Research, centered in California; the second was a group of 1006 patients with stage I to III non-squamous NSCLC from a research group called the China Clinical Trials Consortium (CCTC).  For the Chinese patients, the same assay was done in a lab based in China, in order to test whether it would also work if the molecular assay is done in a different lab and on a cohort of patients with a very different genetic composition compared with the California-based populations.

The Pinpoint Genomics assay worked just as well at providing a helpful division of prognosis into low, intermediate, and high risk groups in the Kaiser (5-year OS: 71.4%, 58.3%, and 49.2%, respectively) and CCTC (5-year OS 74.1%, 57.4%, and 44.6%, respectively) cohorts.  They also compared how helpful the molecular assay is compared with other factors like age, sex, smoking status, histologic subtype (though squamous NSCLC was excluded, adenocarcinoma, large cell, mixed subtype, and NSCLC “not otherwise specified” were all included), and tumor size greater than 4 cm or not; this analysis revealed that being in the intermediate or especially high risk group was among the most predictive factors.  It was also more predictive than some a combination of factors that are advocated by the National Comprehensive Cancer Network (NCCN) guidelines as being of some utility in raising the concern for recurrence and consideration of chemotherapy in patients with smaller node-negative cancers: poorly differentiated tumor, vascular invasion, history of a wedge resection rather than lobectomy or bigger surgery, visceral pleural (the lining around the lung) involvement, and unknown lymph node status (not assessed properly).

Suffice it to say that this assay appears potentially valuable in helping guide us in our decision-making about who is at higher risk of recurrence and dying from their early stage cancer.  What are the limitations? First, this work is all retrospective.  We can identify who did poorly, but we don’t know that we can identify patients prospectively and then enable them to do better because of an intervention.  We want to presume that if we can identify patients with stage I NSCLC who have a high risk profile, we can say that the anticipated benefit from adjuvant chemotherapy in reducing that risk of recurrence clearly outweighs the risk of serious problems from more treatment.  However, we don’t know that: it could be that this test only identifies that patients will do less well but that we can’t reduce that risk of recurrence by giving more treatment.  A trial is being conducted that is prospectively assigning stage I patients identified as high risk by this assay to either additional chemotherapy or observation, but it will literally be many years, and even likely a decade or more, before we have the results of this study (studies of early stage patients take many years to see whether the intervention made a difference 3-5 years later).  And this assay doesn’t apply to the 20-25% of patients with a squamous NSCLC, who were presumably excluded because of the finding that the pattern of genetic derangements is too different from non-squamous NSCLC to pool these groups together and expect to see the same trends with the same gene collection.

In the meantime, the authors highlight several advances from this work.  This work represents a test that is more objective than an interpretation of IHC results, and they were able to show the assay’s prognostic utility from different labs in different parts of the world, and looking at very large populations that were very different from one another.  In light of the growing work showing the differences in molecular features of tumors from Asian and North American or European populations, demonstrating that the same multi-gene assay produces very similar results in North American and Chinese patients is a meaningful accomplishment.

The authors note that the prospective research is underway but will take many years to complete and report.  In the meantime, they note that the NCCN advocates incorporating “soft” variables like tumor grade, pleural or blood vessel invasion, and adequacy of the surgery in the decision of whether to recommend adjuvant chemotherapy, and it’s fair to highlight that this test is better studied and has more evidence behind it than the loose clinical considerations that the NCCN favors incorporating based on faith and presumptions alone.  However, saying that inadequate evidence is better than poor evidence is damning with faint praise.  (The NCCN guidelines are implied to be evidence-based, but that’s only selective: they are a product of human effort that involves a combination of evidence and the biases of real people who still promote faith-based edicts.)

In the end, though, it’s also fair to say that we are left facing decisions that often don’t have perfect evidence to guide them.  The circumstances for individual patients and whether we would strongly recommend adjuvant chemotherapy are often fuzzy: many patients do have cancers that fall along the border of sufficient risk of recurrence to justify chemo, and other patients may have a cancer that merits chemotherapy by a pathologic staging-based system but may be riskier candidates for chemotherapy or just very wary about accepting it after a big lung surgery.  Having this additional information from a commercially available test could certainly serve as a useful additional piece of information for some patients and their doctors as they struggle to get the best sense of their probability of doing well and whether to accept the additional challenge of more treatment after resection.

I imagine that many/most patients would be very interested in having one more piece of prognostic information at their disposal. Would you favor having your tissue tested with this assay and getting a result back of low, intermediate, or high risk? Would you participate on a randomized trial that demonstrates that your stage I tumor is high risk but that then randomly assigns you to either chemotherapy or observation?

I’m very interested in your thoughts.

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(click on image to enlarge)

Over the course of an approximately 90 minute program, we’ll alternate between group discussions on a wide range of controversial questions in molecular testing and brief presentations by the panelists on key elements of this complex topic.  The presentations planned are as follows:

Dr. Alice Shaw: Prevalence of mutations by histology, race, and smoking status
Dr. Charlie Rudin: Finding a druggable target: The Lung Cancer Mutation Consortium splintering lung cancer into small subsets
Dr. David Spigel: Integration of molecular markers into multicenter clinical trials: Benefits and Challenges
Dr. Glen Goss: The feasibility of integrating molecular markers across a comprehensive health care system: the intersection of benefit with cost and other practical factors

We’ll also have the opportunity to integrate questions from our live webinar audience.

As always, this program will be made into a series of free podcasts in audio and video format.  But you still won’t want to miss the live program, with so many great guests engaged in a lively discussion of what is probably the most pressing topic in advanced lung cancer today, and one upon which the entire field of molecularly-based therapies depends.

So register for this free program here! We hope to have you join us, and I’m sorry we’ll be broadcasting from indoors (and subterranean), so we won’t be able to gloat while doing a program outside…

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The longer-term outcomes for a total of 66 patients who had undergone SBRT for node negative NSCLC between 1999 and 2005 were reviewed, though the median follow-up was only three years.  Given the fact that these treatments were done 6-12 years ago, this median reflects that many people were lost to follow-up or died in the first few years.  As is typical for retrospective reviews of patients who underwent radiation for potentially resectable NSCLC, many of the patients who died (14 of 39) had other significant medical problems had no evidence of active cancer at the time of their death.  Sixteen patients remained alive and without evidence of disease beyond five years from the time of SBRT, and the authors noted that four of them (25%) had recurrences beyond that point — in fact, three of the four had recurrences more than eight years after treatment.  In three of the four cases, the recurrences were local (one patient had both local and distant recurrence in another part of the body).   Past history with surgery for early stage NSCLC has generally shown that the risk of recurrence beyond 5 years is in the range of 5-7%.

This isn’t a large series of patients, and it’s the experience from just a single (well experienced) center.  They also note that the dose used (48 Gray (Gy) over 4 treatments is less than the 60 Gy over three fractions that is often used in some places now, so results could be different with these different techniques.  Of course, no local treatment — neither excellent surgery nor the best radiation therapy — will cure disease that is destined to recur distantly from micrometastatic disease outside of the local area visible on scans.  But the promise of SBRT, of providing comparable long-term local disease control and perhaps working as effectively as the historical gold standard of surgery, still awaits a test of time to really clarify whether it looks very favorable beyond the first few years.

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We now have a little more information to help guide our expectations in this setting. A new publication in the Journal of Clinical Oncology from Su and colleagues from Taiwan provides several valuable new insights on T790M, the mutation that has been identified as the most common cause of acquired resistance to an EGFR tyrosine kinase inhibitor (TKI) after an initial good response in patients with an EGFR activating mutation The investigators looked for both activating mutations and T790M mutations in Taiwanese patients, predominantly (about 75%) never-smokers and >90% with an adenocarcinoma, both before (107 patients) and after EGFR TKI therapy (87 patients) using three different methods: typical DNA sequencing, MALDI-TOF, and next generation sequencing.  For those who are really curious, extremely scientifically gifted, or very bored, this last link provides a good explanation of sequencing techniques, but this is really getting outside of the scope of what we need to know here; basically, direct gene sequencing is the usual mutation detection technique, MALDI-TOF is a less commonly used novel approach, and next generation sequencing is the “gold standard” that really clarifies who has what.

What they found was that MALDI-TOF was far more sensitive at picking up mutations than direct sequencing, with the former correlating very well with next generation sequencing.  While this was true for activating mutations in the EGFR TKI-naive patients (mutations detected in 37% vs. 44% of patients with direct sequencing vs. MALDI-TOF, respectively), this was especially true for T790M, detected in 3% vs. 25% of patients by direct sequencing vs. MALDI-TOF, respectively.  In the EGFR TKI treated population (who may have been selected for high probability of having a response to an EGFR TKI, or have been enriched for being already known to have a mutation before going on an EGFR TKI), EGFR activating mutation frequency before they started EGFR TKI therapy was 55% with direct sequencing and 77% with MALDI-TOF; T790M was detected in 3% and 32% of these patients with these two techniques.  Finally, in the 12 patients who had tissue testing for EGFR activating and T790M resistance mutation after they completed EGFR TKI therapy, direct sequencing detected activating mutations in 9 patients (75%) and a T790M mutation in 4 patients (33%), while MALDI-TOF detected an EGFR activating mutation in all 12 patients (100%) and a T90M mutation in 10 patients (83%).

As you would expect, these molecular markers were correlated with outcomes on an EGFR TKI (shown for MALDI-TOF as the more sensitive technique).  Specifically, those who had an activating EGFR mutation and no resistance mutation had the longest progression-free survival (PFS), followed by those who had both an activating EGFR mutation but also a T790M resistance mutation, and then patients with no activating or resistance mutation having the least impressive PFS:

(click on image to enlarge)

In contrast, there were no differences in outcomes by overall survival, nor were there differences in the response rate based on initial T790M status.

Where do these results leave us? We’re limited by the fact that the MALDI-TOF technique of mutation detection is not readily available (I don’t know of any commercial lab that uses it), but the findings indicate that the particular technique matters greatly in detecting both activating mutations and T790M mutations associated with resistance, presumably because a fraction of patients will have a smaller proportion of cancer cells with the mutation in question, and the techniques vary in their sensitivity at small numbers of copies of the mutated genes.  These results demonstrate that patients T790M mutations are not rare prior to the start of EGFR TKI therapy (though they may be difficult to detect with the more commonly available techniques) and are associated with a shorter PFS than we see in patients with an activating EGFR mutation and no T790M mutation; in the small numbers reported here, the clear majority have a T790M mutation after having received EGFR TKI therapy for a while.

It’s also important to note, however, that this work was done on a relatively small Taiwanese population with a low incidence of smoking, almost entirely looking at adenocarcinomas, and an overall group in which the general majority of patients have an EGFR activating mutation.  For this reason, I think we need to be cautious in presuming that everything we learn here is likely to follow the same patterns in North America or Europe.

Still, the results provide some new information and indicate that patients with an initial T790M mutation can still respond to an EGFR TKI, but that we might expect that they won’t respond for long.   In my patient’s case, I presume that the cancer in her chest has more activating mutation than T790M, the bone involvement is resistant because of the prevalence of T790M in the cancer cells of her progressing skeletal metastases.  A short response, to be sure, but understandable. One more piece of the puzzle.

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Of the 11 patients who had sufficient tumor tissue for analysis, they found a wide range of apparent mechanisms of progression.  Four of the 11 (36%) developed new mutations in the ALK gene that conferred resistance, and in two cases this was associated with a particular mutation(known as G1269A) that has been associated with resistance to crizotinib in lab-based work.  Two patients (18%), including one who had an ALK resistance mutation, were now found to have developed additional copies of the ALK gene in their cancer cells, which could overcome the inhibitory effect of crizotinib. Three patients (27%) no longer had the ALK rearrangement present in their tumor tissue, of whom one had developed a new EGFR mutation, one had developed a KRAS mutation, and one had developed an unknown mutation (they tested for a limited panel of known high yield ones). Another patient (9%, in case you haven’t figured out the pattern) developed a KRAS mutation but continued to have an ALK rearrangement detectable.  The final two continued to have an ALK rearrangement present and no detectable mutation or other changes that could explain the development of resistance.  The summary of mechanisms of recurrence is as shown on the left in the figure below:

(click on image to enlarge)

Part B, on the right side of the figure, illustrates two potential mechanisms for acquired resistance.  The first is the emergence of a second cancer driver that is present and coexistent in the cancer cell with the mutation in question (left side of figure B), like the development of c-MET over-expression in EGFR mutation positive cancer cells. This occurs under evolutionary pressure of a treatment with an EGFR tyrosine kinase inhibitor (TKI) to produce a population of cancer cells that still have the driver mutation (EGFR, in this example) but have now developed a competing and overriding feature that confers resistance.

In this paper, even though the numbers are small, the authors demonstrate that it’s also possible for the evolutionary selection pressure of effective treatment to lead to the prevalence of a new and separate oncogenic (cancer-facilitating) driver mutation (right side of part B in the figure above).  Here, the idea is that there are different subsets of cancer cells.  For example, prior to treatment with a targeted therapy the cancer may be comprised of predominantly ALK rearrangement positive cancer cells with a small minority having a KRAS mutation, but that after ALK inhibitor therapy, those ALK positive cells die and leave a cancer growing that is comprised of a predominantly KRAS mutation positive cancer.

There are many potential implications of this work, although none is proven yet.  One is that there is a real value in repeat biopsies, at least in patients who have had great responses to targeted agents and/or identified mutations, to help shape subsequent treatment decisions.  Though rare, it’s possible for a person to have a new EGFR mutation that could lead to effective treatment with an EGFR TKI.  The finding that some of these cancer cells no longer have an ALK rearrangement suggests that these patients aren’t likely to benefit from a new ALK inhibitor or treatment with a heat shock protein inhibitor (which has appeared very promising for ALK positive patients).

We’ve seen examples of situations in which the cancer, or at least some areas of the cancer, have morphed into a new version, sometimes a different subtype of lung cancer entirely; in some cases, that may occur from induced fundamental changes in the cancer cells (model 1, above), and in other cases, that might occur because different cells become predominant (model 2, above).  Even looking at the small number of cases here, we can see a complex array of possibilities.  Our knowledge of what’s possible is growing on a case by case basis, but it is helping direct us to literally individualized recommendations for patterns that are becoming cancer and patient-specific.

NEXT: New insights on T790M and EGFR TKI resistance.

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He’s one of a very limited number who we’re only beginning to learn about.    The article looked at the molecular features of 1073 tumors from patients mostly from Massachusetts General Hospital and Vanderbilt University, reporting that 18 (1.7%) had a ROS1 rearrangement and 31 (2.9%) had an ALK rearrangement.  Both groups share the same clinical features, specifically skewing toward a much younger median age than the broader NSCLC population (around 50 in both ROS1- and ALK-positive patients, compared with 62 in the larger NSCLC population), being seen predominantly in never-smokers (in whom a ROS1 rearrangement was seen in 6% of the group), and being seen predominantly in patients with an adenocarcinoma (in fact, all 18 patients with a ROS1 rearrangement had an adenocarcinoma).  The adenocarcinomas included many different subtypes and tended towards being more poorly differentiated and higher grade (correlated with a more aggressive appearance).

Work on a cell line with a ROS1 rearrangement showed that it responded to an experimental ALK inhibitor (TAE684), then that XALKORI could also inhibit these cells.  This led to a patient with a ROS1 rearrangement receiving XALKORI as a component of a clinical trial.  As we’ve come to sometimes see with XALKORI given to patients with an ALK rearrangement, the response was dramatic, with near complete resolution of his advanced bronchioloalveolar carcinoma (BAC), as dramatically illustrated in the images below:

While the published experience of XALKORI for ROS1-positive NSCLC is limited to one patient, there are about a dozen patients out there right now with a ROS1 rearrangement who have started XALKORI, and like Craig, most are doing very well on it.  Dr. Shaw relayed to me that she’s seen particularly impressive responses in the patients with BAC who have a ROS1 rearrangement and have received XALKORI (though this observation is based on just a few patients).

Others with a ROS1 rearrangement are waiting in the wings, generally because they’re doing well on their current therapy. I met one such patient in my own clinic this week; she has done remarkably well on Alimta (pemetrexed), which has also been reported to be unusually effective for patients with an ALK rearrangement, with a plan to start XALKORI on clinical trial when a new treatment is needed.

Obviously, we’ll need to get a larger experience with XALKORI in ROS1-positive patients, but there’s plenty of reason to be very optimistic when the clear majority of the first dozen patients experience a dramatic response.  This leads to a discussion of the limited number of patients with a ROS1 rearrangement, which will probably amount to about 2000-3000 patients per year in the US.  That’s not a lot, but if we can see dramatic and long-lasting responses (the latter is still too early to speak to right now) in the clear majority of these patients, it raises the incentive greatly for testing.  Right now, that’s available at just a few centers (I believe only MGH and University of Colorado, but others may be coming on line soon).  In the future, though, with more and more patients getting adequate amounts of tissue for molecular testing, and now a growing collection of markers important to test for, we’ll likely soon see new testing platforms developed that will test for a panel of multiple relevant markers all from one sample.

Though these smaller and geographically dispersed patient populations engender new challenges for research and routine clinical practice, the finding of more and more of these targets in small subgroups that receive big benefits from the right targeted therapy just raises the value proposition of crossing the chasm into the world of molecular oncology.  We’re only going to continue to identify more subgroups that will be appropriate candidates for individualized treatments.

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Here’s the audio and video versions of the podcast, as well as the transcript and figures:

millard-on-tobacco-and-lung-cancer-audio-podcast

millard-on-tobacco-and-lung-cancer-transcript

millard-on-tobacco-and-lung-cancer-figures

We’ll follow with the second part of his talk, which focused on cultural, behavioral, and pharmaceutical/medical interventions to help with smoking cessation in the next couple of weeks.

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An article by Li and colleagues out of Shanghai was just published in the Journal of Thoracic Oncology evaluates and attempts to better characterize this population of patients with a HER2 mutation a little more.  They reviewed tissue from the cancers of 224 consecutive patients with a lung adenocarcinoma in their tumor registry, looking for EGFR, KRAS, and HER2 mutations.  It should be noted that this population, which is evenly split between men and women but is 62% never-smokers, only 5% stage IV, and entirely Chinese, is clearly a clinically distinct population from the more heterogeneous NSCLC populations seen in Europe or North America, but it’s interesting that they saw a HER2 mutation in 3.6% of patients.  This is in contrast with a 64.4% prevalence of an EGFR mutation (wow!) and a 4.5% prevalence of a KRAS mutation — and these were all mutually exclusive of each other: (click on image to enlarge)

Interestingly, all of these HER2 mutations were in female never-smokers (Dr. Pinder had also noted that these are known associations with HER mutations in NSCLC). If you looked only at the lung adenocarcinoma patients who don’t have an EGFR mutation or KRAS mutation, the prevalence was 11%.

Another relevant point is that while there hasn’t been a completed study of HER2-inhibiting targeted therapy for NSCLC patients with a HER2 mutation, there is an interesting report in the New England Journal of Medicine by my Italian friend Federico Cappuzzo and colleagues that describes their favorable experience treating a heavily pre-treated patient with a HER2 mutated advanced NSCLC with a combination of Taxol (paclitaxel) and Herceptin that led to a very impressive result (and he also mentions the likely error of using Herceptin in too broad a population of patients with HER2 protein expression, rather than the much smaller population with a HER2 mutation).

We’re definitely learning that the lung cancer populations in different locations vary in genetics along with their prevalence of smoking history, distribution of NSCLC histologic subtypes, and sex balance, so we can’t generalize from Shanghai to the rest of the world.  But there is an emerging theme that HER2 may well be a clinically relevant population who are present in sufficient numbers to do meaningful trials. Moreover, as testing for EGFR, KRAS, and ALK becomes more commonplace and we have tissue more readily available, it may be far more feasible to identify patients who could be very well served by being treated with HER2-targeted therapy that is already commercially available.

About 10 years ago, when Dr. Langer was first summarizing his experience in treating lung cancer patients with Herceptin, he identified that there could be a small population who did especially well with it but noted that the proportion of patients appeared to be so small that we would need to do an “intergalactic” trial to identify sufficient numbers to test this approach meaningfully. Today, broad testing for molecular markers is far more common, and we’ve just seen the FDA approval of a drug (XALKORI, also known as crizotinib) that is known to be very effective for a population that amounts to around 4% of the NSCLC population. The world of “molecular oncology” sees these 2-5% populations as a challenge but very worthy of study. It may require patients going to where the trials are, rather than having the ideal trial for them available in the same city, but I hope and expect that we’ll see HER2-mutated lung cancer studied far more in the next few years, and hopefully we’ll find another limited population for whom we can identify a very effective therapy. And this work may lead to advances in treatment of the much broader NSCLC population as well.

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