For mesothelioma or any other cancer, targeted single-agent chemo always ends in drug resistanceIn oncology news that comes not as a setback so much as a confirmation of what scientists suspected, a study in the journal Nature has confirmed that any targeted single-agent chemotherapy regimen, no matter how effective, will ultimately fail.
Researchers from two institutions - the Johns Hopkins Kimmel Cancer Center and Italy's Institute for Cancer Research and Treatment - used statistical modeling and DNA testing to prove that all malignancies, including mesothelioma, will eventually become resistant to a single line of chemo.
Fortunately, combination chemo regimens are de rigueur for treating mesothelioma, as is multi-modal therapy.
Evolution at its purest
In their investigation, the two teams examined how often a particular set of genetic mutations - called KRAS variations - arise when patients receive EGFR inhibitors, or drugs that block the epidermal growth factor receptor, which is commonly involved in malignant growth.
Statistical modeling predicted that, in cases of any specific cancer (the team chose colon cancer), resistant cells are likely to already exist in a tumor. When a targeted single agent blasts away the vast majority of malignant cells, what remains, in theory, are the very few cells whose mutations predispose them to resistance to the drug used.
These cells would then quickly repopulate tissue with new, more resistant tumors. In an ironic twist, such a cycle is a perfect example of the evolutionary principle of survival of the fittest - in this case, the fittest cells are those with EGFR inhibitor-resistant mutations.
But theory is one thing, and praxis quite another. Does this effect actually occur in real cancer?
Researchers monitored the health of 28 colon cancer patients, all of whom were given EGFR inhibitors. Regardless of whether a patient had detectable KRAS mutations or not, all eventually developed resistant to the targeted single agent. The results indicated that even when KRAS mutations are not detected, they almost certainly exist in a few tumor cells.
Fortunately, this was expected
The teams made very clear that these findings were neither devastating nor unexpected. Scientists have long understood that the most effective way to achieve progression-free survival is to use multi-drug chemo cocktails, plus other modalities. Hence, mesothelioma patients almost always receive two- or three-drug chemo, as well as surgery and radiation.
The findings may also help researchers determine the utility of certain targeted drugs, depending on the illness treated.
For example, numerous studies have shown that mesothelioma tumors may develop KRAS mutations, invalidating the use of EGFR inhibitors. Further negating their use, a new paper in the journal Oncology Reports found that many mesothelioma tumors lack any EGFR receptors at all.
Scientists try to predict survival after surgery for advanced mesothelioma, http://ejcts.oxfordjournals.org/content/early/2012/12/12/ejcts.ezs648.abstract, 12/21/12
Study reviews two chemotherapy regimens for operable mesothelioma, http://ar.iiarjournals.org/content/32/12/5393.full.pdf+html, 12/11/12
Study: Multimodal therapy for mesothelioma should be tailored to each patient, http://icvts.oxfordjournals.org/content/early/2012/11/21/icvts.ivs465.full, 11/30/12
Response to chemotherapy may identify candidates for mesothelioma surgery, http://annonc.oxfordjournals.org/content/early/2012/11/06/annonc.mds537.short, 11/29/12
Tomotherapy may be safe for mesothelioma patients after surgery, http://journals.lww.com/jto/Abstract/2012/12000/Tomotherapy_after_Pleurectomy_Decortication_or.18.aspx, 11/29/12
Chemotherapy delivery through thigh may help mesothelioma patients, http://radiology.rsna.org/content/early/2012/11/09/radiol.12111858.abstract, 11/21/12
Researchers compare outcomes of mesothelioma surgeries, http://art.torvergata.it/handle/2108/72282, 11/20/12
Mesothelioma treatment receives orphan drug designation, http://www.morphotek.com/news-events/News-Archive/2012-News/FDA-Grants-Orphan-Drug-Status-to-Morphotek-s-Amatu.aspx, 11/14/12