Video Personalized Cancer Care: Are We There Yet? Play Pause Previous Next 1 of 200 slides Volume Quality 720P 540P 270P Fullscreen Captions Transcript Chapters Slides Personalized Cancer Care: Are We There Yet? Overview Dr. Catenacci discusses personalized cancer care, and where we currently stand with such treatments. DANIEL CATENACCI: So just a general overview of what we'll be talking about is this personalized cancer care and that buzz word. And we'll be seeing how we're actually doing in this disease with colon and colorectal cancer. So it's just to set the stage from a stage-four perspective. These are the tools that medical oncology has implemented over the years, and you can see the years in which they were introduced, and we'll go through each of these a bit. So each one of these you can see with best supportive care-- I'll use Euroscreen to your right to point. Best supportive care overall survivals historically are on the order of four to six months in the stage-four setting. And you can see the incremental changes as each of these agents were added. And this is about 10 years old now where they were approaching two years in median overall survival. And I'll show you in the next few slides where we're actually at today. Clearly, the first personalized approach molecularly was the discovery that patients that had KRAS wild type versus KRAS mutant tumors did not respond to anti-EGFR therapy. That was the first incidence. And so right now the standard is to test for this and with the so-called extended RAS testing, which includes now NRAS and other less common mutations in KRAS, we do this binary into two groups. And the real question now is the sequence of the chemotherapy and whether or not that matters. And I'll show you a few instances in the next few slides that I believe that that is not the case. We do have clinical trials before anti-angiogenesis and anti-EGFR therapy was available that randomized to FOLFIRI versus FOLFOX or the reverse which showed no difference. So we knew that that did not matter. The question now is whether or not in wild-type patients starting with anti-angiogenesis inhibitors or EGFR inhibitors are better. And there are other habits that the physician's choice in terms of breaks of chemotherapy and maintenance that allow for personalization throughout the course of a stage-four therapy. So this is the new topic in medical oncology that will be debated over the next few years, which are two large trials that we're doing exactly what I mentioned earlier. Randomizing to anti-angiogenesis versus anti-EGFR therapy. And they are two large discrepant trials, both updated recently at the ESMO conference in Madrid a few weeks ago. And so one trial shows that there's no difference and another trial suggests that anti-EGFR therapy has benefit to start with that first. Many of us feel that the second-line approaches are really what led to these differences, whereas in this trial they were more controlled and there were no differences. So in our view there's no difference in starting with either one, and you can personalize it to each patient. What's most important here, though, is to note that the overall survivals in stage-four cancer are approaching 30 to 36 months now with our best therapies in sequence. And more relevant to the talk today was another abstract presented at ASCO of a subset of patients within that 80405 trial, which was referring to oligometastatic disease. And that trial showed that out of the total patients, 132 actually went to curative intent resection, and their median overall survival was more than five years. So this is the first indication of having such great survival in this setting. And in these small numbers, half and half, some getting bev first, some getting cetux there was no difference between those two. But we'll see a trial in a few minutes that actually suggests otherwise. So what else do we have in that oligometastatic realm? This was a trial looking at all unresectable patients that randomized to intensification of chemotherapy. All three agents with bevacizumab versus FOLFIRI-bev, and the primary point in that case was PFS. But you can see there's an improvement in PFS. But more importantly, in those that had liver-only disease, the one question was whether or not intensification would improve resection rate, R0 resection rate, and you can see it's higher, trends to higher, but not statistically significant, in this trial. That was just a secondary endpoint. On the other hand, a prospective trial called "Olivia," looking specifically at this question and initially unresectable liver-only disease in patients that were randomized to intensified chemo versus standard chemo, you can see an increase in R0 resection rate that was statistically significant. Small numbers, but this was a report on a recent ASCO meeting, and so suggests that intensification on the right patient is beneficial for getting to R0 section. What about anti-EGFR therapy? So this was a prospective large trial looking at whether chemo or chemo with EGFR therapy would improve R0 section rates and primary endpoint of disease-free survival and recurrence-free survival. Unfortunately, at the interim analysis it was found that patients actually did worse with the cetuximab therapy, and so it was stopped, and therefore-- and this was in KRAS wild-type patients. So some people might say is it because of the mutants? No, this was selected by KRAS wild type disease. So stopped early due to ineffective therapy. And you can see the curves here with the EGFR therapy doing worse. And this is a larger sample set than say the subset analysis of 80405, which I showed you earlier, which suggested there was no difference with the bevacizumab. So what do we know then with stage four oligometastatic disease? We know that median overall survivals in patients undergoing curative resection are good. We know that by the new EPOCH trial I just showed you that anti EGFR therapy can't be recommended in this setting based on the results. And that intensification of chemotherapy in appropriately selected patients, like the Tribe and Olivia trials, can improve our R0 resection rates in disease-free survivals. So what about stage three? Stage three, what do we do and why do we do it? So this landmark trial in the '90s randomized patients to 5-FU versus observation after stage-three therapy, and you can see the less recurrence rates and improved 6 and 1/2 year survival rates. Number needed to treat with seven to improve each life. So this became a standard of care, and my medical oncology forefathers, when they had their one drug to play with, all they did was adjust doses and the amount of time that they would treat for and see which one was better. They added leucovorin in a 2 by 2 design and showed that the leucovorin for six months and 5-FU was the winner, and that establish standard of care. What about the addition of oxaliplatin, then? That was the next question. And so this was the Mosaic trial showing that in all comers, most of them were stage threes, that there was an improvement in five-year disease-free survival. And when breaking it down by subset, clearly stage-three disease was the majority of the benefit. There was some small benefit in stage two, but you can see that many people would be fine without the therapy. Many people would recur anyway. And a very small benefit in the stage-two setting. When we looked at longer-term data, This benefit in the stage-three setting persisted and the stage two really there was no clear benefit by adding the oxaliplatin therapy. A second trial in parallel by NSABP, also a large trial, confirmed these findings. The one difference was their total cumulative oxaliplatin dose. And you can see the lower dose did not affect negatively the outcome, but they had less persistent neurotoxicity. So that has led to the next question is how long do we have to treat adjuvantly? And so there are a number of cooperative groups, including the Alliance, that is leading this question of three versus six months. The first report from the Italian group came out at the recent ESMO conference with just the toxicity and safety updates. And a large accrual there showing that neurotoxicity was substantially lower, as would be expected in the three-month. So now we are waiting to see if the outcomes are not detrimental by decreasing the amount of therapy. And the alliance have accrued to about the 1,200 patients at this point. One slide showing the other tools that we have that we know are beneficial in the stage-four setting, but all these trials listed here negative in the adjuvant setting and therefore we do not recommend or use these in the adjuvant setting. So what about stage two? A few more words about stage two. We know that there's a wide range of outcome within stage two. Metanalyses are conflicting in terms of benefit of adjuvant therapy. Most trials have very small percentages of stage two in there, and that's the complicating factor. One dedicated trial called the QUASAR trial or the Quick And Simple And Reliable trial, showed-- and about 92% of the patients were stage two-- that there was a small benefit adding 5-FU. Again, most patients are getting treated with no benefit, though. So what have we been done doing historically? We've been looking at the risk factors, either clinical or pathological features listed here, to suggest when a patient should be getting adjuvant therapy. And then came MSI, the more personalization with molecular biology. MSI, or microsatellite instability, occurs in about 50% of colorectal cancers. A very small subset, less than 2%, are inherited or Lynch syndrome patients. And you can see that they have an accelerated risk and high risk for colorectal cancer. So what does MSI mean? Well, we know from retrospective analyses on many of these trials that MSI is associated with lower stage, better prognosis, right-sided tumors, and lack of benefit of 5-FU. So it's a good prognostic factor and a negative predictive marker for chemotherapy benefit. So the pivotal metanalysis was done with a large sample set and confirmed these findings so that basically recommended now that MSI-high patients should not be getting therapy. So what do we know? Adjuvant stage three 5-FU to therapy for six months provides the majority of benefit. Very small benefits in stage two that are selected. Oxaliplatin can also improve survival and is recommended for all stage-three patients currently. Negative trials with all of our other tools, so they're not recommended. And the stage-two debate, when should we be giving adjuvant therapy? And we have some personalization factors by clinical and pathological features, as well as MSI-high patients should probably not get therapy. Just a slide about recurrence rates and time and follow up. The vast majority of patients are going to recur in the first three to five years, and therefore these are the NCCN guidelines for follow up after therapy that are listed here. Following for three to six months for the first two to three years with CEA levels and CT scan for three to five years yearly. Colonoscopy within a year after and then if normal every three to five years after. And then some other factors that have been associated with decreased recurrence. So what else do we know molecularly and biologically with this cancer? So we've talked about RAS, KRAS, and so-called extended RAS, which now amounts to about 55% of all colorectal cancer patients. We know that B-Raf mutation is relatively rare, but it has a worse prognosis. And we also know that as opposed to melanoma where a B-Raf inhibitor, specific inhibitors, have led to improved overall survival, when used in colorectal cancer that has not been the case. However, adding an anti-EGFR therapy, interestingly, with a B-Raf inhibitor, stops a negative feedback loop. It has showed some dramatic responses. So that will be a coming story in the next few years. And then there are other mutations that we are aware of. So this is the landscape going forward with clinical trial design in medical oncology, recognizing interpatient molecular hydrogenating with different mutations. Patients are being screened. This is an example of a trial coming out of Britain called FOCUS4 and I call it in a recent review on this topic an expansion platform design where patients get molecularly profiled and then placed into certain bins, asking a specific question of a chemotherapy specific for each of these molecular markers. However, as good and difficult as this is-- this could be considered a complex clinical trial design-- this is actually still oversimplifying the problem. This is just 70 patients coming through my particular clinic that we've done next-gen sequencing on with a 300-gene panel. And you can see here what's referred to as the high peak, long tail phenomenon, which means in red there are tumor suppressors. In blue there's oncogenes that there are few aberrations that are frequent like P53, APC, KRAS, et cetera. And then there are a number of other mutations, genomic events, that are impossible to predict beforehand unless you check each patient. And this is important in this era of molecularly targeted therapy, trying to target genomic driver events with a specific drug. So are we there yet in terms of personalizing our care with colon cancer? Well, if you look at it by stage, clearly we are and have been personalizing therapy in terms of what stage they have and what we can do in each of these different levels. We have oral 5-FU, we have IV 5-FU that we can use to personalize therapy, and we have all of the different tools in the stage-four setting that we can personalize to each patient also by clinical comorbidities and age. However, there's a lot of work to do when we talk about it from the molecular aspect, where currently all we do is RAS testing. That's the only standard. I talked about B-Raf and how it's on the way in terms of being a marker that will be useful. And then looking at newer clinical trial designs to try and tease this out a little bit better. And then finally one word is to be on the horizon is immunomodulation, where at ESMO this year that was really the topic of interest across all tumor types with checkpoint inhibitors, vaccines, et cetera, that I think will set different tones over the next 5 to 10 years in terms of survival outcomes in both the stage-four and perioperative setting. So I will stop there, and thanks for your attention. Published June 2, 2015 Created by
