One of the basic tenets of targeted therapy in cancer treatment is that drugs are developed to target a particular abnormality or aberration that occurs due to the cancer. For example, the breast cancer drug Herceptin targets the HER-2 gene, which occurs in 25-30% of all women with breast cancer. It therefore makes sense to appropriately screen patients prior to treatment to determine which women are most likely to benefit from the therapy.
Similarly, patients with a suspected sarcoma or gastro-intestinal tumour can be tested to see if they are KIT positive, meaning they most likely have a rare form of the disease known as gastro-intestinal stromal tumour or GIST for short. These patients can be selected to receive Gleevec as initial therapy and Sutent should they later become resistant to the treatment. Both drugs target the KIT mutation and have been shown to be effective in inhibiting is activity, which drives the tumour growth.
Gleevec made a major impact on CML by inhibiting BCR-ABL function in Philadelphia positive patients and there are now several other tyrosine kinase inhibitors on the market, namely Sprycel and Tasigna, both of which are able to target some mutations that Gleevec is ineffective against. These additional mutations are not common, but once they develop they can induce resistance to treatment. It would therefore make sense to use these therapies once the mutations develop and allow patients to continue responding to targeted therapies in a very cost effective way. Other agents are also in development for additional mutations that develop, including T315l, which none of the current drugs inhibit. Testing and monitoring CML patients regualrly will allow oncologists to essentially personalise therapy for each patient as necessary.
More recently, therapies have been approved that target the Epithelial Growth Factor Receptor (EGFR) in lung and colorectal cancer. However, in this case, both tumours over express EGFR by some 80-90%, but not all patients respond to targeted treatments. Doctors were baffled to try and determine which patients would most likely benefit since other factors were clearly at play. Eventually, meta analyses confirmed that Tarceva, works very well in female, non-smoking Asians with adenocarcinomas of the lung, for example. Other patients may benefit, but those patients did particularly well with that drug.
In lung cancer, Avastin has been shown to effectively inhibit angiogenesis via the vascular endothelial growth factor receptor. Data emerged that it was not suitable for squamous patients after doctors reported adverse events such as hypertension and bleeding, which is related to the leakage in the tumour vasculature. The drug is therefore approved for use in patients with non-squamous lung histology.
Clearly, histology is becoming important in lung cancer because Alimta, an anti-folate therapy from Lilly has also shown better responses in non-squamous and adenocarcinoma patients compared to squamous ones. The Ciuleanu study reported at ASCO last year compared Alimta as maintenance therapy to best supportive care after induction chemotherapy. The difference may seem small - 4.5 and 4.7 months for non-squamous and adenocarcinoma patients, compared to 2.8 months for squamous cell and 2.6 for best supportive care, but it is a step in the right direction.
The other interesting fact that emerged in lung cancer is that not only is histology important, but also the type of EGFR mutation may predict response to Erbitux and Vectibix, two EGFR inhibitors that have been approved. Previously, it was unclear why some patients responded and others did not; the response rate is in the order of 10-20%. The picture became a little clearer when it was realised in 2005 that another mutation, KRAS, was an important driver of tumour activity, not EGFR, essentially causing resistance to develop:
William Pao
At ASCO last year, another piece of the jigsaw puzzle fell into place. Several groups reported that the type of mutation was important, ie whether it was mutated or wild type KRAS. It seemed that the KRAS mutation explained nearly 40% of the non-responders, so those patients who had mutated KRAS were unlikely to respond to Erbitux or Vectibix therapy. It therefore makes sense to test for KRAS upfront to determine eligibility for treatment. This means that the patient will also be spared from taking a drug that is ineffective; false hope does no one any favours nor does wasting money on expensive treatments. A far better use of resources would be to target the drug where it is most likely to work. Researchers are now busy trying to work out what other factors affect efficacy to EGFR inhibitors other than the KRAS mutation status.
{Update} ASCO have just announced that they have released a provisional clinical opinion (PCO) recommending routine KRAS gene testing to guide treatment for metastatic colorectal cancer. You can download the PCO here.
Interestingly, the wild type and mutated type mutations have been seen before - in KIT positive GISTs, where the type of mutation is increasingly dictating whether patients get Gleevec or Sutent as initial therapy, therefore increasing the chances of a positive response and tailoring treatment to the patients most likely to respond. This is much more cost effective than the traditional method of one drug followed by the other drug, when matching the drug to the mutation means that the patients will have a better chance of responding early and for longer.
In breast cancer, gene profiling has been down extensively for some years although the HER-2 mutation has been the only significant way of separating patients so far. It is hoped in the near future that new trials and tests will determine which patients are more likely to respond to different drug regimens, based on the underlying genetic profiling.
All in all, we can clearly see that cancers are increasing being segmented into different subsets based on either the underlying histology or mutational status. These subsets can then be treated as different disease types and therapy tailored according to those drugs most likely to induce the best response at the most efficient cost. In the old world, all patients got chemotherapy regardless and not only does that come with side effects as well as targeting normal cells and cancer cells, but it's also very inefficient.
As we learn more about the science and biology of each tumour type, personalized medicine allows us to reduce side effects by using more targeted drugs with the goal of stopping the particular aberration in the cancer cells as well as increasing the chances of a good response. Things can only get better and that's very good news indeed for cancer patients.
Sources:
William Pao, Theresa Y. Wang, Gregory J. Riely, Vincent A. Miller, Qiulu Pan, Marc Ladanyi, Maureen F. Zakowski, Robert T. Heelan, Mark G. Kris, Harold E. Varmus (2005). KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib PLoS Medicine, 2 (1) DOI: 10.1371/journal.pmed.0020017
D. A. Eberhard (2005). Mutations in the Epidermal Growth Factor Receptor and in KRAS Are Predictive and Prognostic Indicators in Patients With Non-Small-Cell Lung Cancer Treated With Chemotherapy Alone and in Combination With Erlotinib Journal of Clinical Oncology, 23 (25), 5900-5909 DOI: 10.1200/JCO.2005.02.857
E. Van Cutsem, I. Lang, G. D'haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P. Rougier (2008). KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Journal of Clinical Oncology, 26 (25): Abstr.(2)
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Tejpar, M. Peeters, Y. Humblet, J. B. Vermorken, G. De Hertogh, W. De
Roock, J. Nippgen, A. von Heydebreck, C. Stroh, E. Van Cutsem (2008).
Relationship of efficacy with KRAS status (wild type versus mutant) in
patients with irinotecan-refractory metastatic colorectal cancer
(mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab
(q1w): The EVEREST experience (preliminary data Journal of Clinical Oncology, 26(25): Abstr. (4001)
Michael C Heinrich, Christopher L Corless, Charles Blanke, George D Demetri, Heikki Joensuu, Meg von Mehren, Laura S McGreevey, Cecily L Wait, Diana Griffith, C-J Chen, Andrea Haley, Beate Kiese, Brian Druker, Peter Roberts, Burt Eisenberg,, Sam Singer, Sandra Silberman, Sasa Dimitrijevic, Christopher D Fletcher, Jonathan A Fletcher (2002). KIT mutational status predicts clinical response to STI571 in patients with metastatic gastrointestinal stromal tumors (GISTs) Journal of Clinical Oncology
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B. Liegl, J. A. Fletcher, C. L. Corless, C. D. Fletcher, C. P. Raut, R. Donsky, M. M. Bertagnolli, C. Le, G. D. Demetri, M. C. Heinrich (2008). Correlation between KIT mutations and sunitinib (SU) resistance in GIST Journal of Clinical Oncology, 26 (abstr. 92)
T. E. Ciuleanu, T. Brodowicz, C. P. Belani, J. Kim, M. Krzakowski, E. Laack, Y. Wu, P. Peterson, S. Adachi, C. C. Zielinski (2008). Maintenance Pemetrexed Improves Progression-free Survival for NSCLC Journal of Clinical Oncology, 26 (Abstr. 8011)
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Personalized Cancer Medicine Is Here, Now
As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate treatments for cancer patients. More emphasis is needed matching treatment to the patient. Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival.
Findings presented at the Annual Meeting of the European Society for Clinical Investigation in Uppsala, Sweden and the Annual Meeting of the American Assoication for Cancer Research (AACR) in San Diego, CA concluded that "functional profiling" with cell-based assays is relevant for the study of both "conventional" and "targeted" anti-neoplastic drug agents (anti-tumor and anti-angiogenic activity) in primary cultures of "fresh" human tumors.
Cell-based Assays with "cell-death" endpoints can show disease-specific drug activity, are useful clinical and research tools for "conventional" and "targeted" drugs, and provide unique information complementary to that provided by "molecular" tests. There have been more than 25 peer-reviewed publications showing significant correlations between cell-death assay results and patient response and survival.
Many patients are treated not only with a "targeted" therapy drug like Tarceva, Avastin, or Iressa, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual proteins often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.
There is a tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of live "fresh" tumor tissue, applying different chemotherapy treatments to it, and examining the results to see which drug or combination of drugs does the best job killing the tumor cells. A cell-based assay test with "functional profiling," using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive).
Funtional profiling measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected, functional profiling is measuring them through the surrogate of measuring if the cell is alive or dead.
For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR-inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.
As an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer.
The funtional profiling technique makes the statistically significant association between prospectively reported test results and patient survival. It can correlate test results that are obtained in the lab and reported to physicians prior to patient treatment, with significantly longer or shorter overall patient survival depending upon whether the drug was found to be effective or ineffective at killing the patient's tumor cells in the laboratory.
This could help solve the problem of knowing which patients can tolerate costly new treatments and their harmful side effects. These "smart" drugs are a really exciting element of cancer medicine, but do not work for everyone, and a pre-test to determine the efficacy of these drugs in a patient could be the first crucial step in personalizing treatment to the individual.
Literature Citation:
Weisenthal, L.M. Functional profiling with cell culture-based assays for kinase and anti-angiogenic agents Eur J Clin Invest 37 (suppl. 1):60, 2007
Nagourney, R.A. Functional Profiling of Human Tumors in Primary Culture: A Platform for Drug Discovery and Therapy Selection (AACR: Apr 2008-AB-1546)
Posted by: gpawelski | June 07, 2009 at 11:15 AM
The study shows that molecular profiling of patients can identify specific treatments for individuals, helping keep their cancer in check for significantly longer periods, and in some cases even shrinking tumors
Posted by: Pharmacy | January 15, 2010 at 02:44 AM