In my thoracic oncology tumor board today, we discussed a situation that comes up fairly often: a patient has a collapsed lung lobe from a tumor near the middle of the chest, with some regional lymph nodes involved, and the surgeon thinks he’s likely to need the whole lung removed because the location of the tumor is nestled in just the wrong place.  The patient has enough lung function to undergo surgery, but losing an entire lung (pneumonectomy) is a big loss, and he’s already only a debatable candidate to be able to undergo surgery safely.  So the question emerges, “Can we give pre-operative chemotherapy specifically with the intent of shrinking a cancer enough to enable a less extensive surgery than would be needed if no pre-operative therapy is done?”

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?

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One of the very common themes that emerges in the questions from the GRACE community is whether a “local therapy” such as focal radiation or surgery could be useful for advanced NSCLC.  There’s an FAQ question and answer about the general concept of why treatment directed to a specific area (i.e., a “local therapy”, as opposed to a systemic therapy that works throughout the body) isn’t typically recommended for metastatic cancer, but local therapies are still often discussed and may have a role for patients who have more advanced NSCLC.   Very often, I’m coming down against the concept of local therapy when people here ask, but there are some settings in which local therapies are very appropriate, in addition to others where we might strongly consider it. I work very closely with my radiation oncologists, my thoracic surgeons, and my interventional pulmonologist — who all provide local therapies — and we are all part of a team that share patients depending on their case needs. But I do feel that local therapies are all too often misapplied, whether because of financial motivations of the practitioners or the misguided, unclear rationale for doing it (”magical thinking“), which I see as creating a fundamental disconnect between a patient’s expectation and the reality of what such an intervention can deliver.

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.

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The idea is simple enough: we want to identify the patients with a resected early stage NSCLC that has a high risk of recurrence, so that we can give them additional therapy, usually in the form of post-operative (adjuvant) chemotherapy, while sparing this additional challenging and even potentially dangerous therapy for the people who have a more favorable prognosis.  Right now, the system we generally use to identify patients at higher vs. lower risk of recurrence is based on lung cancer staging, which is based on the size of the tumor, whether the cancer invades nearby structures, the extent of lymph node involvement, and whether there is spread to distant parts of the body.  That staging system works reasonably well, but we also know that there are many patients with early stage disease who fall below the general threshold for adjuvant chemotherapy but will still recur, while many people who receive chemotherapy were already cured from the surgery alone.  This leads us to the question, “Can we refine our prognostic ability by looking at the molecular characteristics of the cancer?”.  We keep learning that molecular features of a cancer are becoming less opaque and are very important, and we also know that some tumors of the same stage respond much more aggressively than others.

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.

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On Feb 22nd, 6:30 PM Eastern/3:30 PM Pacific, GRACE and LUNGevity Foundation will be broadcasting a live panel discussion from Santa Monica, where the International Association for the Study of Lung Cancer will be kicking off its12th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting.  Host Dr. Jack West will be joined by four great luminaries from different centers of excellence and with different perspectives on the timely issue in lung cancer of molecular testing in advanced non-small cell lung cancer:

(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

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One of the lung cancer surgeons I work closely with sent me and a couple of the radiation oncologists at my center a report that just came out from a group in Kyoto highlighting that they have a seen a notable proportion of their patients develop late recurrences, even well beyond five years, among their patients who underwent stereotactic body radiation therapy (SBRT) for node-negative early stage NSCLC many years earlier (see Dr. Loiselle’s great summary of SBRT for a review of the topic).  Many Japanese centers have been pioneers in SBRT, doing it for more than a decade, but over the past 3-5 years the strategy has become far more widely practiced, based on very encouraging local control and outcomes going out several years, which lead to the question of whether SBRT might be an effective and  alternative to surgery (hence the keen interest among thoracic surgeons about whether newer radiation techniques will lead to reduced demand for their services).  The authors of this report, who are radiation oncologists, highlight that it’s possible we’ll see late recurrences beyond the time when we’d be inclined to declare a victory for SBRT.  In general, if we see patients doing well 3-5 years after diagnosis and the start of treatment, we begin to think we’re getting out of the woods.

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%.

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A few months ago, I had a patient in my clinic who is a lifelong never-smoker with an adenocarcinoma.  I had her tumor checked for molecular markers, which revealed that she had both an activating EGFR mutation (exon 19 deletion) and a T790M mutation associated with resistance (see Dr. Pennell’s excellent summary for an introduction to EGFR mutations).   Not sure what to expect from an EGFR tyrosine kinase inhibitor like Tarceva (erlotinib), I started her on chemo first, which she responded to for a while, and then put her on a Tarceva-based trial for second line.  Though her cancer-related symptoms of cough and non-exertional chest pain improved significantly within just a few weeks, her scan actually showed a mixed response: dramatic improvement of her chest disease, but modest progression with new bone lesions.

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.

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Drs. Bob Doebele, Ross Camidge, and their colleagues at the University of Colorado just published an interesting and clinically relevant paper in Clinical Cancer Research that looked in detail at the mechanisms of resistance in ALK rearrangement positive patients to the ALK inhibitor XALKORI (crizotinib).   Evaluating 14 patients with a known ALK rearrangement who were resistant to XALKORI, either from first treatment (in the case of two patients), or after a period of response (for the other 12), they performed repeat tissue biopsies after resistance was documented, in order to determine whether the ALK rearrangement was still present, whether there were additional copies of the ALK gene, or whether there were new mutations documented that might now be an alternative mechanism of driving the cancer.

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)

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Thanks (and congratulations) to GRACE member Craig, who highlighted the just-published report that is the first to characterize the frequency and clinical features of the newly identified ROS1 rearrangement, identified in 2007, similar in structure to an ALK rearrangement, and found to also be responsive in preclinical cell lines to ALK inhibitor therapy.  Craig has a special perspective on this new target, since a ROS1 rearrangement was detected in his tumor.   Importantly, very early but quite promising work is showing that patients with a ROS1 rearrangement may respond very well to the oral ALK inhibitor XALKORI (crizotinib), Craig being one of the beneficiaries of this treatment.

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).

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Several weeks ago we did a webinar, co-sponsored with LUNGevity Foundation, with Dr. Mark Millard, pulmonologist at Baylor University in Dallas, TX, who provided a brief summary of tobacco’s uptake in the US and worldwide, then covered the controversy over its association with lung cancer.   These are the subject of the first podcast covering his webinar, and part two will cover current approaches to smoking cessation.

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

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Podcast: Play in new window | Download

Dr. Pinder previously covered the potentially clinically relevant target of HER2/neu (HER2) mutations for lung cancer.   Specifically, she noted that Herceptin (trastuzumab), an antibody against the HER2 receptor (in the same family as EGFR, which is also known as HER1), but it hasn’t been especially impressive in NSCLC thus far.  For example, an ECOG phase II study by Dr. Langer (who was a mentor of Dr. Weiss’s at the University of Pennsylvania) looked at a target population of patients with advanced NSCLC and HER2 protein expression by immunohistochemistry (IHC).  This captures a large proportion of people with NSCLC, but it may be so broad a population that it dilutes the subset whose cancer is especially driven by HER2.  Instead, mutations in the HER2 gene, similar to mutations in EGFR that are far better studied in NSCLC, appear to be present in about 3-4% of patients with NSCLC.  While this population may be far more likely to benefit greatly from HER2-targeted therapy, this is an essentially completely untested hypothesis.

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)

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