Recently by Scott Kopetz, M.D.

Kopetz_Head.jpgFor metastatic colorectal cancer, there has been increasing recognition that certain molecular changes in the genes of the tumor (often called biomarkers) can help predict the benefit from certain chemotherapies like cetuximab

One of the most frequently used biomarkers is the KRAS mutation, which predicts lack of efficacy to cetuximab and panitumumab. This has been replicated in at least a dozen large randomized studies. Several recent developments have added complexities to what had appeared to be a clear biomarker and a consistent treatment algorithm. 

Recently, investigators from Europe reported that this relationship may not be straightforward for one of the more common mutations in KRAS (Tejpar, Bardelli et al., JAMA '10). Related work has identified other less common, mutations in additional regions of the KRAS gene, but the clinical implications of this are also not clear for these mutations. Adding to this complexity is the recognition that additional genes, including BRAF and NRAS, may also modulate this sensitivity. 

Recently BRAF was included in the treatment recommendations from the National Comprehensive Cancer Network (NCCN) which are commonly used as a guideline for best practices in the community.   However, as additional data was acquired, this relationship became less clear and there are calls for this to be removed from the guidelines until further clarity is provided. 

These findings collectively reiterate several broad themes in clinical oncology: 

  1. Biomarkers are a constantly evolving field for colorectal cancer and many other tumor types.
  2. Dissemination of the best practice patterns for biomarkers will require a new model of physician education. 

An effort to include broader interpretation of biomarkers in test results to physicians is one necessary step to improve care. As the biomarker field continues to add complexity to clinical care, it provides opportunities for integration of electronic decision models into patient care.  Ultimately, this added complexity will improve the outcomes of patients, and should be embraced and included with recognition of the evolution of this field. 

For biomarkers, nothing is constant but change.

Recent cancer research has led to an increased understanding that there are gene changes in cancers that could be the key to effectively killing the tumor.

Such strategies have provided significant gains in several tumor types, as exemplified by chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST). In these tumors, the gene mutations are present in almost all of the patients' tumors and use of targeted chemotherapy treatments have provided meaningful benefits. 


Kopetz2.jpg In contrast to these "rare disease, common mutation" examples, results presented at this year's ASCO meeting addressed the similar problem in more common tumor types such as breast, lung and colon cancers.

In lung cancer, treatment with a new drug was very successful in the small percent of patients with a particular genetic change in their tumor (awkwardly denoted the "ELM4-ALK trans-location"). In contrast to the uniform genetic change seen in almost all CML patients, this ELM4-ALK trans-location is only present in less than 5% of lung cancer patients. Similarly, mutations in the BRAF gene in colon cancer (in 5% of tumors) is associated with some sensitivity to a novel BRAF inhibitor, according to the research I presented at the meeting. 

Also at ASCO, MD Anderson investigators reported on mutations in a gene called PIK3CA (present in 2% to 20% of patients), which appears to identify patients sensitive to experimental inhibitors of this pathway. 


While the treatment results in these patients are impressive, the requirement to screen 20 patients to identify one patient who may benefit is a significant logistical challenge. Such efforts require the development of new tests and validation steps to make sure that these molecular changes are accurately identified in patients' tumors. In addition, there are unique problems that arise in this "common disease, rare mutation" scenario. 

Patients are commonly choosing between immediate treatment with standard chemotherapy or waiting several weeks without therapy to see if their tumor is one of the rare ones that may benefit from these novel therapies. At other times, there may not be a sufficient amount of tumor available for testing, requiring patients to undergo additional biopsies to obtain enough material for these increasingly important tests.

In addition, the state of oncology commonly changes faster than insurance companies can keep up. As these molecular tests become part of routine cancer care, reimbursement problems can occur. Even small, preliminary clinical trials require coordination between multiple institutions to successfully identify enough patients. 

At MD Anderson, these challenges are being met through a new Institute of Personalized Medicine, which is developing these new tools necessary for the "common disease, rare mutation" research, and working to minimize these roadblocks to implementation. The goal of such Herculean efforts is to have patients' tumors undergoing screening for many of these genetic changes prior to determining therapies. It is hoped that as such testing becomes commonplace for clinical care, many of these barriers will be reduced.

Ultimately, we believe that surmounting the "common tumor, rare mutation" problems will be the best path forward for improving the collective outcomes of cancer patients.

Assistant Professor, Department of Gastrointestinal Medical Oncology

Kopetz2.jpgThis past weekend, experts in gastrointestinal malignancies gathered to review interval advances in the field at the ASCO Gastrointestinal Cancer Symposium. Of the studies presented, three are worth noting that are likely to change the standard therapies or provide exciting research opportunities.

Neuroendocrine Tumors

Treatment for neuroendocrine tumors has made recent advances, exemplified by a study reported at the meeting for the oral tyrosine kinase inhibitor sunitinibPancreatic neuroendocrine tumor (PNET) is one of the most common subtypes of an uncommon tumor. PNETs traditionally have been treated variably with somatostatin analogs, interferon or cytotoxic chemotherapy, although several recent studies have demonstrated promising molecularly targeted treatment approaches.

Laboratory studies have suggested that treatment with agents that inhibit blood vessel formation may provide benefit. Sunitinib is an inhibitor of vascular endothelial growth factor signaling, one of the main drivers of new blood vessel growth.

In an international randomized Phase III study, 340 patients with advanced PNET were planned to be enrolled in a study comparing observation alone to a daily oral dose of sunitinib. After only 171 were enrolled, the study was stopped as it was already evident that patients treated with sunitinib had improvements in their cancer and were living longer.

On average, patients had their disease controlled for 11.4 months with sunitinib treatment, compared to an average time to tumor growth of 5.5 months with no therapy. Similarly, sunitinib-treated patients lived twice as long. Side effects from the treatment were modest, and included development of high blood pressure and irritation/redness of the palms and soles. If validated, these results will open a new treatment option for patients with advanced pancreatic neuroendocrine tumors.

Pancreatic Cancer

Traditional pancreatic cancers have been difficult to treat and very few advances have been made in the field over the past few years. Recent data has suggested that the insulin-like growth factor receptor (IGFR) pathway may be a promising candidate for treatment of many cancers, including pancreatic cancer based on limited laboratory studies.

One of the first and largest studies to evaluate an inhibitor of IGFR in combination with chemotherapy was recently completed at M. D. Anderson and reported by Milind Javle, M.D., in an oral session. In this study, patients were treated with a monoclonal antibody to IGFR in combination with chemotherapy. The study demonstrated that the combination was safe, with some patients having prolonged disease control. A Phase II portion of the study is ongoing using a novel adaptive study design, which allocates more patients to the treatment arm that appears to be performing the best.

Importantly, Dr. Javle and his colleagues are concurrently collecting important information to understand how the tumor is responding on a molecular level to the novel therapies. This combination of concurrent molecular studies and novel study design was praised by the expert discussant at the meeting as an optimal model for future studies in pancreatic cancer.

Colon Cancer

Significant effort has been focused on new techniques to detect and prevent colon cancer. One recent advance was presented by K.P. Raj, M.D., on the role of polyamines in colon cancer development.

Previously animal studies suggest that very high levels of diet intake of polyamines can increase colon cancer, while decreasing polyamines can reduce colon cancer development. Polyamines come from two sources: they are synthesized in the body as well as ingested in the normal diet, with highest levels in orange juice, red meat, peas, corn and nuts, among others.

A large chemoprevention study of DFMO and sulindac had previously shown a 70% reduction in new precancerous lesions. In this study, 375 patients with prior precancerous lesions were randomized to DFMO/sulindac or placebo, with all patients obtaining normal screening colonoscopies. DFMO and sulindac inhibit new synthesis of polyamines in the body, among other potential mechanisms of actions. Dr. Raj analyzed the dietary intake of polyamines in patients on this study to determine the role for the dietary forms of polyamine in cancer formation.

These results demonstrated that patients who reported high dietary intake of polyamines had larger and more advanced colon polyps prior to starting the study. For patients with lower reported dietary intake of polyamine, treatment with DFMO and sulindac resulted in a 94% reduction in advanced cancers. In contrast, in patients with high dietary intake of polyamines, there was no benefit seen with the chemoprevention. Further studies are needed to understand this finding, but it suggests that in high-risk patients, chemoprevention may only be beneficial with appropriate dietary modifications. 

Collectively, these findings reiterate the active ongoing research in gastrointestinal malignancies, while highlighting areas where significant improvements are needed in our ability to detect, diagnosis and treat gastrointestinal cancers.

We often hear about progress in common tumors such as breast and colon cancer, but are making slower progress in many rare malignancies. There are many reasons for this discrepancy, including lower levels of research funding, less public awareness and, importantly, difficulties in finding enough patients with a given rare tumor to perform rigorous scientific studies.  

Adenocarcinomas of the small bowel are an excellent example of this, as there are only an estimated 2,000 cases a year compared to the 150,000 cases of colon cancer diagnosed per year. However, concerted efforts by Dr. Michael Overman in the Department of Gastrointestinal Medical Oncology and Dr. George Chang in the Department of Surgical Oncology at M. D. Anderson have resulted in a better understanding of the disease.

They reported (#4596) a better method to judge the risk of recurrence for patients who have their small bowel cancer resected. By analyzing outcomes of 1,991 patients with adenocarcinoma of the small bowel from a national database, they were able to distinguish patients at moderate risk (42%) and high risk (63%) of the cancer returning in five years. Similarly, if enough lymph nodes were taken at the time of surgery and analyzed, those patients with no cancer in the lymph nodes had excellent outcomes (only a 12% chance of recurrence). These results will be very informative in discussing the role of chemotherapy after surgical resection of localized small bowel adenocarcinoma.

Dr. Overman and colleagues recently reported one of the only modern trials of small bowel adenocarcinoma in the Journal of Clinical Oncology (J Clin Oncol. 2009 Jun 1;27(16):2598-603). Compared to older chemotherapies, this regimen resulted in the best reported outcome to date by using a combination of capecitabine, oxaliplatin and the anti-angiogenic agent bevacizumab. Future studies in this disease plan to evaluate antibodies to the epidermal growth factor receptor.  

An article written by Amy Marcus, a Pulitzer Prize winning reporter at The Wall Street Journal, which accompanies Dr. Overman's study gives one perspective on how to move forward (Journal of Clinical Oncology, Vol 27, No 16 (June 1), 2009: pp. 2575-2577). She suggests that the key component to moving research forward in rare malignancies is the existence of active patient advocacy for the disease. Indeed, she offers examples of how individual patients advocated for (and participated in) research of their rare tumors and the progress they are able to make.   

How, then, can we make progress in these rare diseases? To paraphrase Margaret Mead: Never doubt that a small group of patients, scientists and advocates can change the world of rare malignancies. Indeed, that is the only thing that ever has.

Scott Kopetz, M.D., Assistant Professor, Department of Gastrointestinal Medical Oncology, from ASCO 2009

ASCO 2009

There are a few properties that distinguish cancer cells from normal cells, and these differences are critical to understanding how to target cancer cells while sparing normal tissue and minimizing toxicity.  One of these differences in a cancer cell is the loss of the machinery to repair DNA.  Traditional chemotherapies commonly attempt to kill cancer cells by inducing DNA damage, with the expectation that normal cells have multiple DNA repair enzymes that can repair such damage, while cancer cells are unable to adequately repair this damage.  In the event that DNA damage cannot be repaired, cells undergo cell death.  

Research being presented during this meeting suggests a promising new approach to exploit these critical differences between cancer and normal cells.  One of these DNA repair enzymes, PARP, appears to play a critical role in DNA repair in tumor cells.  In normal cells, there are many repair enzymes with overlapping function, so that the loss of one does not cause significant difficulty in DNA repair.  In cancer cells, however, there is already a loss of several of the DNA repair enzymes, implying that further inhibition of the remaining enzymes will result in impaired ability to repair DNA damage.  As described by Dr. Litton in her blog, breast cancer researchers have recently reported that the combination of DNA injuring chemotherapy and an inhibitor of the DNA repair enzyme PARP, BSI-201, showed remarkable activity in a phase II study.  It appears that by preventing the cancer cell from repairing the damage to this chemotherapy, the cancer cell developed such high levels of DNA damage that cell death was inevitable.  As a result of these results and earlier basic science research, further research is being pursued to combine DNA damaging chemotherapy with PARP inhibitors in other tumor types. One such study, being conducted by Dr. Stacey Moulder at M. D. Anderson combines irinotecan with BSI-201.

However, additional research suggests that PARP inhibitors may be particularly beneficial in patients who inherit a defect in one of the other DNA repair enzymes.  This defect, called BRCA mutations, results in a family predisposition to certain cancers.  When given alone in patients without this mutation, there was no evidence of clinical benefit for this PARP inhibitor, as I presented at last year's ASCO.  However, in patients whose tumor contains this mutation, there is evidence of activity in breast and ovarian cancer, as presented again this year at ASCO.  There is a subset of pancreatic cancer patients who have mutation in BRCA, and an ongoing trial at MDACC, lead by Dr. David Fogelman, is exploring the combination of BSI-201 and gemcitabine in this patient group.  We are excited by this trial as it combines a DNA damaging chemotherapy with the PARP inhibitor in patients predicted to be most sensitive to this approach.

Whether by combination with DNA damaging chemotherapy, or when given to a uniquely susceptible subgroup of patients, this research strategy is certainly raising our hopes for adding another targeted treatment to our armamentarium in the clinic.

ASCO 2009

kopetz1.jpgResearch presented at ASCO this year improves our understanding of how cancer cells make use of factors that regulate normal cell growth.  Our normal cells grow, divide, and use energy in the form of glucose under very tight control.  The result is a coordinated system of cells that only multiply when the conditions are right in the body, meaning that we have enough energy to support the increased numbers of cells.  This system normally regulates our body size and circulating energy levels, and is related to obesity and diabetes.

We increasingly understand how one part of this system (called the insulin-like growth factor receptor or IGFR) is co-opted by cancer cells in order to maintain their growth.  Work presented this morning by Dr. Shroff, a medical oncology fellow working with Dr. Dongyu Li in the Department of Gastrointestinal Medical Oncology, demonstrated that variations in the IGFR gene resulted in differences in outcomes for patients with advanced pancreas cancer.  This effect was fairly strong, as survival time was twice as long in patients with the "good" gene variation.  In the discussion that followed the presentation, it was noted that this IGFR system may play a significant role in the growth and spread of pancreas cancer.

The next goal is to take advantage of this finding to improve outcomes for cancer patients.  Fortunately, there are a number of chemotherapies in development that may block the IGFR system.   One such agent in development in lung cancer, as reported by Dr. Daniel Karp in the Department of Thoracic/Head and Neck Medical Oncology, is showing an impressive benefit in patients with a certain type of non-small cell lung cancer.  In updated results he presented at ASCO (#8072), he reported a response rate of above 60% in patients treated with an IGFR inhibitor plus chemotherapy, with several patients with dramatic responses.  We hope these are only the first of several good reports for agents targeting IGFR, as this approach has the potential to benefit not just patients with pancreas and lung cancer, but a host of broader tumor types.


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