Axel Grothey, MD


June 17, 2011

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Hello. I'm Axel Grothey, Professor of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota. Welcome to this edition of Medscape Oncology Insights on gastrointestinal (GI) cancer. Today I want to talk about the use of biomarkers with treatment selection in GI malignancies, integrating some of the presentations from ASCO® 2011 here in Chicago, on what to measure and when.

Biomarkers in Stage II Colon Cancer

Let's talk about adjuvant colon cancers to start with, particularly in stage II colon cancer, where treatment decisions are difficult for physicians and for patients. Stage II patients might or might not benefit from adjuvant therapy with fluoropyrimidine and oxaliplatin, which is standard of care in stage III disease. So what are the guidelines? What are the markers that can help us in making treatment decisions? In my clinical practice, I have a very pragmatic approach to stage II colon cancer. I try to identify patients at high risk for recurrence and patients at low risk who do not need systemic adjuvant chemotherapy. There is a group in between, the intermediate-risk group, which might require further insights into biomarkers and perhaps a marker signature.

Patients at High Risk for Recurrence. Let's break down my treatment algorithms. The first is a stage II colon cancer patient who is considered a candidate for chemotherapy. If I see a patient who has T4 disease (in particular T4-B disease), I know that these patients have outcomes similar to stage III patients. I normally treat those patients as I would treat a stage III patient, meaning that I mainly use a FOLFOX [folinic acid, fluorouracil (5-FU), oxaliplatin], FLOX (bolus weekly 5-FU and oxaliplatin), capecitabine, oxaliplatin-based regimen, which is a more aggressive therapy for an aggressive cancer.

The second group of patients who are at high risk for recurrence are patients with clearly fewer than 12 lymph nodes identified in the specimen. Fewer than 12 might be a little bit arbitrary, so if it's 11, do you really give adjunct chemotherapy with oxaliplatin or not? But the number of lymph nodes really does matter. It also shows you how thorough the pathology and the surgical evaluations were. These are the high-risk tumors. What about low-risk tumors?

Patients at Low Risk for Recurrence. A group of patients with low-risk tumors can be identified by using immunohistochemistry alone, testing for the expression levels of mismatch repair enzymes. Mismatch repair enzyme deficiency is, as we commonly know, associated with genetic abnormalities like Lynch syndrome (hereditary nonpolyposis colorectal cancer). These are few patients, younger patients with a genetic predisposition. Another way to lose mismatch repair enzymes is by methylation of a DNA promoter region. It sounds complicated, but it in fact leads to the lack of expression of these mismatch repair enzymes, which can be stained by immunohistochemistry. This mismatch repair-deficient phenotype can be tested by using immunohistochemistry on stage II tumors in our patients because patients with mismatch repair-deficient tumors have an excellent prognosis. More than 95% of these patients have 3-year disease-free survival, they do not need further chemotherapy, their prognosis is already excellent. There is some discussion and some evidence that patients with mismatch repair-deficient phenotype (we can also call them microsatellite instability [MSI]-high because they have MSI) might be resistant to 5-FU. There is really no need to subject these patients to fluoropyrimidine, capecitabine, or 5-FU. Now these are patients with an excellent prognosis.

Patients With Poor Prognosis. What about the 70% of patients with poor prognosis? Do we have any biomarkers that can help us make treatment decisions for these patients? Now we are talking about marker signatures. One kind of the most commonly cited marker signatures that is actually being marketed in the United States is a test called Oncotype DX® (Genomic Health, Inc., Redwood City, CA), which is a marker panel that gives some prognostic information about this intermediate group of patients -- the average T3, N0, nonmismatch repair-deficient tumor. This test is available right now and can separate patients out a little bit further in terms of their prognostic outcome. Unfortunately, this test is not predictive, meaning we cannot identify which patient population will actually benefit from fluoropyrimidine and perhaps even from oxaliplatin-based therapy. Oncotype DX® is not the only player in town in terms of marker signature. Other assays are more familiar in Europe, some using fresh frozen tissue to look at the marker signature and give prognostic information.

Another marker is the GCC [guanylyl cyclase], which is quite interesting, because GCC is a protein that is normally only expressed in intestinal cells. So if you look for traces of this protein using molecular technology like quantitative PCR [polymerase chain reaction] in lymph nodes. When you detect traces of this protein in lymph nodes, it means that some intestinal cells have made their way through these lymph nodes or got stuck there, or have transitioned on. There is some evidence that the detection of GCC in lymph nodes in stage II patients, even if they clinically have no lymph node metastasis, that this actually indicates a poor prognosis and a high risk for metastasis. There is a lot going on in adjuvant therapy for colon cancer mainly focusing on stage II disease.

KRAS in Palliative Colorectal Cancer

Let's move to palliative colorectal cancer. I do believe that the KRAS story -- the detection and the realization that only wild-type KRAS tumors can or should be treated with EGF [epidermal growth factor] receptor antibodies -- is actually the greatest advance we have seen since bevacizumab and cetuximab were approved as component palliative therapy in colorectal cancer in early 2004. For the last 7 years we have not seen a new drug in colorectal cancer, but we have seen refinements in terms of biomarker-driven treatment decisions. The bottom line is, when I see a patient with metastatic colorectal cancer, I test for KRAS right up front because I would like to know what kind of trumps I have in my hand in the course of a patient's disease, even if I do not use EGF-receptor antibodies right up front for most of my patients.

The KRAS story (KRAS wild-type, KRAS mutant tumors) is very well described -- we don't need to waste a lot of time talking about this -- but there is a little twist that actually came out at ASCO® this year. In recent publications focusing on "are all KRAS mutations created equal?" KRAS is coded by a long gene that has hot spots for mutation codon 12, 13, and 61. So far, when you describe a patient who has wild-type KRAS, or KRAS mutation, we don't really spend a lot of time describing the actual mutation or the molecular alteration that happened. There is a subset of patients with so-called "KRAS G13-D" mutations that actually might still respond to EGF-receptor therapy. It's not easy to tease that out because it's not a large percentage of patients, perhaps 15%-18% of patients with KRAS mutations, but if those patients could benefit from EGF-receptor therapy, they should be allowed to receive these drugs.

In a retrospective analysis published in the Journal of American Medical Association[1] last year, there was a suggestion that a patient with KRAS G13-D mutations still had some benefit from cetuximab-based therapy. It was a pooled analysis of patients from clinical trials and outside of clinical trials. At this year's ASCO®, there was a presentation[2] about a more prospective evaluation of the OPUS [Oxaliplatin and Cetuximab in First-line Treatment of Metastatic Colorectal Cancer] and the CRYSTAL [Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer] trials, 2 large trials that looked at cetuximab in first-line therapy in colorectal cancer. Interestingly, these patients with KRAS G13-D mutations seemed to have some benefit from the use of cetuximab added to chemotherapy FOLFIRI [folinic acid, 5-FU, and irinotecan] and FOLFOX. The data are not perfectly solid yet because of a small sample size, and some of the interactions are not statistically significant, but I think it highlights where we are going in oncology and in GI cancer and colorectal cancer specifically, that not all mutations are created equal. We might have to look more into what kind of mutations can be found in tumors. Mutations can be related to different phenotypes.

BRAF and Other Players in CRC

Beyond KRAS, the other factors that are associated with so-called resistance to EGF-receptor therapy or potential resistance to EGF-receptor therapy, one of the candidates was BRAF mutations. There was a lot of interest in BRAF mutations in recent years. BRAF is just a step down from KRAS, and when we design our bubble diagrams on PowerPoint slides, we think we understand molecular biology. If KRAS mutations are negative predictors for cetuximab and panitumumab, BRAF mutations should be, too, but the story is not that easy. A BRAF-mutated tumor is a very different animal from a KRAS-mutated tumor because BRAF mutations are associated with very poor outcome for patients. These patients who make up about 7% or perhaps 10% of patients in colorectal cancer have a very poor prognosis. They live only about 12 months in spite of all our efforts with conventional systemic chemotherapy, with or without antibodies. These patients have a very distinct gene expression pattern that is still very different from the KRAS mutant tumors. BRAF was initially considered a negative predictive marker for cetuximab and panitumumab, but again in some more detailed analysis from randomized trials it now appears that patients might have some benefit from cetuximab, and potentially panitumumab when they receive these agents in conjunction with chemotherapy in BRAF-mutated tumors. The story is not clear yet, but what is clear is that BRAF mutation identifies a very distinct group of patients with colorectal cancer who require better therapy. We need to do better in these patients, and there is a lot of effort right now to identify molecular-targeted agents, and combinations of agents for these BRAF- mutated tumors, which will hopefully improve outcomes for these patients.

The other players to which I alluded, the PF3 kinase mutations on one of the pathways downstream of EGF-receptor P10, which is a tumor suppressor product that needs high expression levels for the treatment to work. The idea is that the higher the EGF-receptor ligand expression, the better an anti-EGF receptor therapy can actually work. A lot of factors can play a role, and if we combine all these factors and find, for example, a patient who is quadruple negative, no mutations at all, with retained expression of P10, this might be the patient who has a high chance of benefit from EGF-receptor-targeted therapy right up front or in the course of the treatment.

One of the things that came out at ASCO® is that there may be more differences between, for example, the primary tumor gene expression levels and mutations compared with metastasis, so there is some heterogeneity that we have to account for. To date, we probably haven't done as much as we should. To get the gist of it we might have to really resort to biopsies of metastasis or perhaps growing metastasis on therapy to see what is happening down the line and then adjust our therapy once we have all these new molecular-targeted agents at hand that we have been talking about for quite some time.

Biomarkers in Gastric Cancer

Let's move away from colorectal cancer and go to gastric cancer. One of the highlights in recent years was the discovery that trastuzumab, an anti-HER2 agent that has activity in gastric cancer in combination with chemotherapy. In my clinical practice, I test all patients with gastric and gastroesophageal junction adenocarcinomas for HER2 expression, and the patients who benefit most are patients with either IHC [immunohistochemistry] 3+ (meaning high protein expression) or 2+ in FISH [fluorescence in situ hybridization] positivity, so very similar to the refinement that we initially used in breast cancer. High protein expression and high expression levels of HER2 predict for the activity of trastuzumab added to chemotherapy.

There is a lot going on in biomarker research in GI malignancies, also way beyond the tumors we just touched upon. Hopefully, we'll see more practical implementation of these biomarkers with improvements for outcomes for our patients in future ASCO®. Thanks for joining me. This is Axel Grothey for Medscape Oncology Insights at ASCO® 2011.


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