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Revisiting KRAS Mutations in Lung Cancer
More than a year ago, I wrote an introductory post about mutations in KRAS, one of the genes that contributes significantly to cancer cell growth and signalling, at least in many cancers. It’s seen in around 20% of lung cancers, almost always in adenocarcinomas and not squamous NSCLC, and it’s been implicated as being associated with a low likelihood of response to EGFR inhibitors.
A Role for Non-Platinum Doublets in Treating NSCLC?
Someone recently asked a question about a recommendation she had received about being treated with a first-line combination of gemzar (gemcitabine) and navelbine (vinorelbine), because we have focused so much on doublets of either cisplatin or carboplatin with a newer drug like taxol (paclitaxel), taxotere (docetaxel), gemzar, navelbine, or most recently possibly alimta (pemetrexed). Why don’t we pair the partners of the platinums and perhaps do even better?
In the early 2000s, that was a timely question, as we wondered whether the platinum drugs might be more of a “legacy” component of the combinations we used — perhaps these newer drugs could combine to form their own doublets like taxol/gemzar, taxotere/gemzar, and gemzar/navelbine. One early trial completed in Greece (abstract here) randomized previously untreated advanced NSCLC patients to receive either taxotere/cisplatin or taxotere/gemzar. It looked at response rates as the primary objective, showed remarkably similar results overall, and a significantly higher response rate with taxotere/cis for patients with non-adenocarcinoma tumors and taxotere/gem for patients with an adenocarcinoma:
Circulating Tumor Cells from Lung Cancer as a Window into the Tumor: Important Proofs of Principle Published in NEJM
In a recent issue of the New England Journal of Medicine, a research group from Massachusetts General Hospital in Boston published some very promising results from their work showing that they can now detect circulating tumor cells (CTCs) from most patients with lung cancer and even detect EGFR mutations and other molecular findings from these cells collected just from patient blood samples (abstract here).
This new approach is based on microfluidic technology, which fortunately isn’t necessary for you to understand but basically involves having blood flow through a closed, monitored space that detects proteins on the surface of tumor cells that aren’t present on other blood cells. These proteins are called EpCAMs, for Epithelial Cell Adhesion Molecules, and with this technique, tumor cells can be detected in varying quantities from patients with blood of patients with cancer, but these cells aren’t identified in the blood of patients without cancer (abstract here). But not only can these cells be detected and the numbers monitored, but the DNA within these cells can be assessed for DNA mutations such as activating mutations that predict response to EGFR tyrosine kinase inhibitors, and even other mutations that predict resistance to EGFR inhibitors, using some novel techniques of assessing DNA from individual cells and even “free DNA” floating in the plasma.
These investigators collected blood from a few dozen patients with advanced NSCLC, many with known EGFR mutations and some with the non-mutated (“wild-type”) EGFR gene. Some had received no prior therapy, while others had received prior chemo and/or EGFR inhibitors like tarceva (erlotinib) or iressa (gefitinib). They also assessed the correlation of numbers of CTCs in a patient’s blood with the tumor burden as measured by CT scan estimates. They found that they were able to detect CTCs in every cancer patient, but that the levels didn’t correlate well with the tumor burden on imaging. They mentioned that other factors might well be important, such as the invasiveness and the vascularity (density of blood vessels) of the cancer.
Although the numbers are small, the clear majority of patients with known EGFR activating mutations from samples of their tumor also were able to the same mutation detected from CTCs (11 of 12, 92%), which worked far better than detecting the mutation in free DNA of plasma (only 4 of 12, 33%). Detection of the marker of EGFR resistance, the so-called T790M mutation, was seen in several patients who had received and progressed on EGFR inhibitors (the presence of the T790M mutation is felt to be about 50% of the patients with resistance to EGFR inhibitors – so it’s not the only mechanism of resistance). Among patients who hadn’t received a prior EGFR inhibitor but had had a T790M mutation detected (which we’d predict would be associated with no benefit from subsequent EGFR inhibitor therapy), their survival was significantly lower than that seen in the patients who didn’t have a T790M mutation:
Interestingly, some of these patients actually had a response to EGFR therapy, but they were short-lived, so they tended to have disappointing results from EGFR inhibitors even when they did respond.
A few patients were able to have their blood drawn and have the CTC levels measured over time. In contrast with the lack of correlation between tumor burden and CTC numbers in an individual patient, changing CTC levels within the same patient over time were very well correlated with responses and progression on CT imaging. And by looking at EGFR mutations over time with new techniques, the investigators saw some new mutations developing over time, not just the T790M mutation but new activating mutations sometimes as time progressed.
All of this work has been done on just a few dozen patients at a single center, so this is far from routinely available standard practice. But it’s a remarkably important demonstration for what is possible. Specifically, it’s now possible to detect and get genetic information from cancer cells collected from blood samples, and that changing numbers of these cells over time may give us information about how a patient is responding to treatment, in between or in addition to imaging results. This is particularly important because, as I had just noted in my response to nlrohde about collecting tissue from lung cancer patients, the lack of accessibility of tumor tissue from lung cancer patients is a limitation in our understanding of lung cancer, compared to the greater ability to study cancer cells from patients with leukemia, melanoma, or even breast cancer, for whom getting tissue may be an invasive procedure but doesn’t usually involve going into the chest cavity. I believe that being able to access cancer cells with a blood draw, and potentially to use these cells to monitor the status of the cancer over time, is likely to be a true breakthrough.
Gene Signature Work: The Polish Experience
Continuing on the subject from my last post of gene signatures to predict clinical behavior, another ASCO presentation came from Poland (abstract here), with the goal of validating a couple of different kinds of gene signatures that have been presented before. One, from a group in Taiwan, was with just 5 genes and had been published in the New England Journal of Medicine (abstract here), while another with just 3 genes had been reported at a prior ASCO meeting (abstract here) by the same Polish group that was presenting this year. They had snap frozen tissue available from 142 patients in Poland, ranging in stage from IA to IV, although most were from earlier stage patients. They pooled results across all of the stages, though, which isn’t a very pure way to interpret the data.
The first thing that they showed was that the three gene signature was able to discriminate a group with better vs. worse prognosis when both adenocarcinoma and squamous cell NSCLC patients were pooled together, but the five-gene signature showed a more modest difference that wasn’t statistically significant:
Gene Signatures to Predict Benefit from Adjuvant Chemo
I had described earlier this week (prior post here) how the long-term follow up of one of the more important adjuvant chemotherapy trials for early stage resected NSCLC patients showed that there may be long-term adverse effects of chemotherapy. My last post also suggested that the benefit of pre-operative chemotherapy in another trial appeared to be limited to the patients with stage IIB and IIIA disease and wasn’t present for stage IB and IIA patients. It would really be ideal if we could predict which patients should receive adjuvant chemo, so we can spare the people who don’t need it or won’t benefit from it the negative effects.
One of the emerging approaches that is still investigational but is promising is the concept of molecular signatures, or gene signatures. A technology called microarray gene analysis now exists to take a tissue sample (which must be snap frozen at the time of surgery, a significant limitation for broadening the availability of this test) and then check for levels of dozens of genes all at once. The concept of the “gene signature” has emerged, which is a collection of a few to a dozen or more genes that have patterns of being expressed at higher or lower levels that are consistent with overall more aggressive or less threatening behavior. I’ve described some of this work in a prior post here.
We can add another provocative study to the mix, based on the adjuvant chemotherapy trial designated as BR.10 and led by NCI-Canada (abstract here). This trial, which included participation throughout North America by the other cancer cooperative groups, randomized stage IB and II patients to observation or chemo with cisplatin/navelbine for four cycles after surgery:
More Work with Neoadjuvant (Pre-Op) Chemotherapy: The SWOG Experience
In my last post I described the results of the ChEST trial that showed a borderline statistically significant improvement in survival of patients who received cisplatin/gemcitabine chemotherapy for stage IB to IIIA NSCLC prior to surgery. This study was very similar to another neoadjuvant chemotherapy trial, known as SWOG 9900, which also randomized patients to upfront surgery or 3 cycles of pre-operative chemotherapy followed by surgery. In the SWOG trial, run at a few hundred sites throughout the US, the chemotherapy used was the commonly used carboplatin/taxol combination, for three cycles prior to surgery, compared to surgery alone:
Also just as with the ChEST trial, SWOG 9900 was closed to accrual quite early (2004), with only 354 of 600 planned patients enrolled, because it was felt to be unethical to continue enrolling patients onto a trial on which half of the patients would not receive chemo, in the wake of multiple positive trials that had recently been presented and showed a significant benefit from the addition of chemo.
Dr. Kathy Pisters from MD Anderson Cancer Center in Houston led the trial and presented the data at ASCO 2007 (abstract here). Importantly, 2/3 of the patients had stage IB/IIA NSCLC. This was a higher percentage than comprised the European adjuvant trials. This is because North American trials separate out the patients with N2 nodes involved and treat them separately (the stage IIIA patients on SWOG 9900 had T3N1 NSCLC), while many stage IIIA, N2 European patients receive surgery and approach them the same way as stage II patients.
Surprisingly, only 77% of patients received all three cycles of carbo/taxol before surgery: this isn’t much better than the ~70% rate of successful administration in many platinum-based trials in the adjuvant setting, and it’s notably lower than the 85% rate of delivering 4 cycles of the same carbo/taxol post-operatively in another trial (CALGB 9633, described in a prior post here). It’s also lower than the 85% rate of delivery of the three cycles of neoadjuvant cisplatin/gemcitabine given in the ChEST trial. But for whatever reason, their delivery of pre-op carbo/taxol was less than we might have hoped and expected.
At the same time, the response rate was 38%, very similar to that seen in the ChEST trial of cis/gem (35%). And several patients were bothered by problematic muscle and joint aches, as well as neuropathy. Most concerning, though, were the three deaths during pre-op chemo, which is really higher than you’d expect for treating 169 early stage patients, especially with carbo/taxol. There was also no decrease in the rate of pneumonectomies on this trial with chemo (a potential benefit of neoadjuvant chemo is that you might shrink cancers that need a pneumonectomy before chemo but only require a lobectomy after chemo); that rate was 17% in both arms of the study. There were also a few more peri-operative deaths on the chemo arm – specifically, 4 of the 24 patients (17%) who had a pneumonectomy after chemo died, while none of the 25 patients who had a pneumonectomy without prior chemo died in the weeks after surgery. There’s still some debate about whether certain types of chemo increase the rate of surgical complications later, but in truth the 0% death rate after pneumonectomy on the surgery alone arm was unusually good. The mortality rate after pneumonectomy is generally in the 4-10% range.
Despite these challenges, the progression-free survival (PFS) and overall survival (OS) rates were better for recipients of chemo compared to those who received surgery alone. Neither result was quite statistically significant, but the trends were clear and convincing (to me), and they appear to be of the same magnitude as the benefits seen with adjuvant chemo. The 5 year PFS benefit was 10%, and OS benefit was 7% with addition of chemo:
A potential issue that Dr. Pisters raised in her discussion of the SWOG 9900 trial at ASCO last year is that the trial may have been more positive if a cisplatin-based doublet had been used instead of carboplatin, since there is some evidence that cisplatin is a little more effective than carboplatin for NSCLC, which may be the difference of a few percent more patients being cured, even if it’s a more challenging approach in most settings.
My overall impression is that the results of both SWOG 9900 and the ChEST trials look very similar to those of recent adjuvant chemo trials, but the numbers here are too small, since these trials both closed early. At the same time, I expect that the SWOG 9900 trial was very limited in being able to show much of a difference because 2/3 of the patients were stage IB and IIA patients who probably didn’t get much of a benefit from chemo, if this trial is similar to the ChEST trial in that respect (see prior post). We’ve never seen a breakdown of efficacy outcomes as a function of a patient’s stage, but I’d love to see this analysis done. We might well find that the chemo has striking benefits in higher risk patients and nonexistent or even harmful effects in lower risk patients.
Pre-Operative Chemotherapy as an Alternative to Post-Operative Chemo: Evidence of Stage-Dependent Survival Benefit
In contrast with post-operative chemotherapy, which has become a standard treatment approach to reduce the probability of recurrence of resected stage II and IIIA NSCLC (still pretty controversial for stage IB), pre-operative chemotherapy (also known as neoadjuvant, or induction chemotherapy) is less well studied and isn’t a typical approach. However, a recent study called ChEST, the Chemotherapy in Early Stages Trial, was presented at ASCO (abstract here) and showed a borderline positive survival benefit with neoadjuvant chemotherapy, despite the fact that the trial was stopped very early. As a trial of chemo followed by surgery vs. initial chemo followed by surgery, and post-operative chemotherapy had been shown in several trials to improve survival in this population, the Data Safety Monitoring Board felt it was unethical to continue a trial in which half the patients receive no opportunity for chemo either before or after surgery.
As shown below, the trial enrolled 270 of an initially planned 700 patients before closing early, and these patients were randomized to receive upfront surgery or three cycles of cisplatin/gemcitabine followed by surgery:
Importantly, more than half of the patients enrolled had stage IB or IIA disease. As you’d expect, this group has a better prognosis than patients who have stage IIB or IIIA resected NSCLC, and therefore potentially less to gain from chemo.
Long-Term Risk with Adjuvant Chemo
Over the past few years, the role of post-operative, also known as adjuvant, chemo has become increasingly accepted as a standard of care. Several trials have shown an improvement in survival at about 5 years that is in the 5-15% range for recipients of chemo. However, the evidence indicates that the people at higher risk receive more benefit, as you’d expect: the risks of chemo are the same no matter what stage cancer someone has, but if the chemo reduces the recurrence rate by a similar fraction for everyone, the person with a 60% risk of recurrent cancer is going to benefit far more than the person with a 25% risk of recurrence. And many of our trials have failed to show a benefit for patients with resected stage I NSCLC, at least for those with cancers smaller than about 4 cm.
I think many oncologists and patients think of adjuvant chemotherapy as either helping significantly or not helping significantly. But there is some limited evidence that demonstrates that some people really may be harmed by chemo, either during the time of chemo, or perhaps more distantly in the future. For instance, I described early work (prior post here) on a marker called ERCC-1 that is correlated with resistance to cisplatin (low expression is associated with sensitivity to cisplatin-based chemo and better outcomes after adjuvant chemo, while high expression is associated with resistance to cisplatin-based chemo and worse outcomes). In fact, that large subset analysis showed that patients who showed high ERCC-1 expression — a pattern of resistance — actually did modestly worse than patients who were observed and received no chemo. So it may not just be that we need to understand better who is going to benefit more and who will benefit less, but rather that we need to predict better because the ones we aren’t helping we may actually be harming. We can overtreat as well as undertreat.
In fact, one of the more interesting presentations at ASCO on the subject of lung cancer was a report of the eight year follow-up of patients on the International Adjuvant Lung Trial, or IALT. This was presented initially at the plenary session at ASCO 5 years ago (abstract here), where we saw the first convincing evidence of a survival benefit from post-operative chemo, and then it was published in the New England Journal of Medicine (abstract here) as a new standard of care. It enrolled 1867 patients with resected stage I to stage IIIA NSCLC to receive post-operative observation alone or any of 4 cisplatin-based chemotherapy regimens:
SCLC with Pleural Effusions: Is there Benefit to Adding Radiation?
In my earliest introductory post about SCLC, I described the typical staging breakdown used clinically, which is essentially divided into limited disease SCLC (LD-SCLC), which is typically treated with chemo and chest radiation together, with curative intent, and extensive disease SCLC (ED-SCLC), which is typically treated with chemo alone and is not considered conventionally curable. But one of the murky areas in SCLC staging is the situation of what is limited disease except for a pleural effusion on the same side as the main tumor (called an “ipsilateral” pleural effusion) . In some trials and at some centers, this situation is considered ED-SCLC, while at others, it’s considered LD-SCLC. On the diagram below, an ipsilateral pleural effusion is designated as a controversial staging question:
A recently published report from Japan (abstract here) describes the experience of 63 patients with LD-SCLC and an ipsilateral pleural effusion. This retrospective review of patients over several years who were all treated at the same center compared the outcomes of patients who initially received chemotherapy and then received chest radiation if their effusion had resolved to the experience of patients who didn’t receive radiation after their effusion resolved. They also compared the results for these groups to outcomes in the patients whose effusions didn’t resolve after chemo.
Erbitux with Radiation in More Marginal Patients with Locally Advanced NSCLC
One of the core ideas in the management of stage III, or locally advanced, NSCLC is that unresectable disease that is being treated with curative intent is most effectively treated with a combination of concurrent systemic (“whole body”) therapy and chest radiation to all of the visible cancer. The systemic therapy, which has been conventional chemotherapy, is given to both make the radiation work better and to treat potential micrometastatic disease, cancer cells in the bloodstream that can’t be reached by radiation but could potentially be killed off by a treatment that goes throughout the bloodstream.
The challenge, though, is that concurrent chemo and radiation is hard on people, with a rate of treatment-related deaths of about 5-7% of people even on clinical trials (which often select for a fitter population than are seen in the “real world” of many ineligible patients). So we reach a point where the aggressiveness of the treatment can be associated with problems that are as threatening or worse than the underlying disease. And this is a particular problem for older and/or frailer patients, which happens to cover a significant proportion of people with lung cancer.
Part of the promise of targeted therapies all along has been that they could potentially substitute for standard chemotherapy as a systemic therapy that is perhaps as effective as chemo but with fewer side effects. Most of our work with these agents has been to just add them to our current standards, but it still makes sense to consider using them as a substitute in patients for whom conventional chemo is really at the upper limits of what is tolerable. And it’s clear that doing chemo concurrent with radiation is overall more effective than doing them sequentially, but perhaps we could get the tolerability of a sequential approach with the efficacy of concurrent therapy by doing a program of targeted therapy (and no chemo) concurrent with chest radiation.
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