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Practicing personalized medicine, or predictive medicine is no more a dream. It is real and it is performed at the genetic level. The breakthrough capability is made possible through the effective use of next-generation sequencing technologies provided by genomic firms that have constantly upgraded their gene analysis techniques and programs. Currently, millions of DNA sequences can be read simultaneously in a single experiment. What we are witnessing here is a quantum leap beyond the methods used since the sequencing of the first human genomes, i.e., twenty years ago.
The next-generation sequencing
technologies enable the differential diagnosis of the same disease, for
example colorectal cancer, based on the cancers’ genetic expressions,
rather than on their morphologies. This capability enables the selection
of effective treatments based on biomarkers analysis. The revolutionary
practices will save patients from torture with ineffective drugs on a
case by case basis, hence, save millions of dollars in unnecessary
spending on experimentation with investigational and marketed drugs on
thousands of patients.
In the news, Amgen (AMGN) was the first to use the new technologies on colorectal cancer to enable using its drug Vectibix (panitumumab) only on colorectal cancers expected to respond to it. A new biomarker analysis of the pivotal Phase 3 "408" trial of Vectibix® plus best supportive care (BSC) compared to BSC alone used massively parallel, next-generation sequencing technology to investigate whether mutations in nine genes in colorectal cancer are predictive of response to Vectibix in metastatic colorectal cancer (mCRC). Highlighted results were presented at the opening press conference at the American Association for Cancer Research (AACR) 101st Annual Meeting 2010 in Washington, D.C.
Tumor samples from 288 patients,
which had previously been analyzed for KRAS exon 2 mutations, were
analyzed in this study for mutations in nine genes: KRAS (exon 3), NRAS,
BRAF, PIK3CA, PTEN, AKT1, EGFR, beta-catenin (CINN1B) and TP53. All
nine genes are either direct or indirect components of the EGFR
signaling pathway. The study enabled scientists to learn that Vectibix
improves progressive-free survival in patients with KRAS wild-type (WT)
tumors and had no effect in patients with KRAS mutant tumors. Mutations
in NRAS, another member of the RAS gene family, were associated with
lack of response to Vectibix. Patients with both KRAS WT and NRAS WT
tumors had improved progressive-free survival receiving Vectibix,
compared with those receiving BSC. Further investigation in larger
studies is required to determine the predictive value of BRAF mutations.
Commenting on the study, Marc Peeters, M.D., Ph.D., Department of Oncology, Antwerp University Hospital and the study's principal investigator said, "To our knowledge, this is the first time next-generation sequencing has been used to analyze tumor samples from a Phase 3 clinical trial and demonstrate how advancing technologies can be quickly applied to ongoing clinical research. The KRAS gene mutation is a well-established biomarker for a lack of response to anti-EGFR treatment and has played a pivotal role in the advancement of personalized medicine. We are excited to be taking another step forward in the advancement of additional biomarkers with the study results presented today. In addition to the excitement of this being among the first times this technology has been used in Phase 3 research, the superior sensitivity of next-generation sequencing revealed unexpected genotypic complexity in many patient tumors,”
It is known now that one hundred nine tumors have more than one mutant gene, and 20 had more than one mutation in a single gene.
Results from studies performed over the last twenty-five years indicate that KRAS plays an important role in cell growth regulation. In mCRC, EGFR transmits signals through a set of intracellular proteins. Upon reaching the nucleus, these signals instruct the cancer cell to reproduce and metastasize, leading to cancer progression. Anti-EGFR antibody therapies work by blocking the activation of EGFR, thereby inhibiting downstream events that lead to malignant signaling. However, it is hypothesized that in patients whose tumors harbor a mutated KRAS gene, the KRAS protein is always turned "on," regardless of whether the EGFR has been activated or therapeutically inhibited. KRAS mutations occur in approximately 40 – 50 percent of mCRC patients.
You know what this means? It means that we are giving treatments that inactivate EGFR to patients who do not benefit from them. These patients amount to half of the cancer inflicted patients. Avoiding this practice promises less pain and torture for those patients and less money spent on futile treatments. In addition, other effective treatments could be pinpointed for those patients.
Again, we remind, the heroes’
behind this huge advancement in addition to Amgen, are the genomic
firms. These firms are the backbone of the biotechnology and drug
industries. Without them, no revolution in medical sciences can take
place. Most of the genomic firms are scientifically sound and are
evolving their technologies and kits and moving from research purposes
to revolutionizing the medical practices from the diagnosis of diseases,
to differential diagnosis of different types of the same diseases.
Their sequencing and analysis capabilities are making possible
pinpointing effective therapeutics for each subtype of diseases.
We are no more knocking at the door. Trust us, we are already in.