Personalized Cancer Medicine: Individual Patient Therapy through Next-Gen Sequencing

On Dancey et al., 2012 in Cell and 
On Roychowdhury et al.,2011 in Sci Transl Med

Human Cancer is a complex, multi-factorial and heterogeneous disease. Among others these features make it challenging to manage and treat. However, in its most simplified form cancer is a disease of acquired or inherited mutations.

There can be hundreds of thousands of mutations in a given cancer. Most of these are "passenger" mutations which are gained along the progression of the cancer and have no functional effect. The "driver" mutations on the other hand are important for the progression of cancer and are causally responsible for disturbing the normal balance of the cell and leading to the tumor formation. The driver mutations are also important for diagnostic and prognostic purposes and even for therapeutic targeting. There are a couple of thousands of recurrent mutations reported in human cancer (International Cancer Genome Consortium (ICGC) database).

However, although not the norm, as few as 4 or 5 driver mutations can be enough to carry a given cancer. Therefore, it makes sense that perturbing the pathways of these few mutations that the cancer depends on can have a big therapeutic effect. However, since the disease is very heterogeneous, these few driver mutations are different for every patient. With the sanger sequencing it is impossible to detect the mutated genes out of the 3 billion bases that make up the genome. High throughput next generation sequencing technology (NGS) is a game changer in this sense. With NGS, it is now possible to know the bulk sequence of a given human genome in a couple of weeks.

The current standard chemotherapy for cancer involves harsh treatment that targets all the dividing cells of the body. This one-size-fits-all therapy does not take into account that every cancer is different aside from the histopathology and the clinical history of the patients.

Personalized Medicine (PM) is a term that gained a different meaning with the advent of the Next Generation Sequencing technologies (NGS). It depends on the ability to sequence all or almost all of the mutational repertoire of a given patient and make an informed treatment choice based on this knowledge (which is different for each patient).

However, determining the mutation landscape of a cancer is far from being enough. Among the thousands of driver mutations identified in human cancer, only a small subset is researched enough to have any diagnostic prognostic and therapeutic implications. Therefore, substantial clinical and basic research is needed to increase effectiveness of PM and improve cancer patient care.

Although the cost of the high throughput sequencing associated with PM has been a major concern,  there are now several competing companies and technologies which let the cost dropping every day. In a pilot study published recently by Roychowdhury et al., a package including (i) shallow genome sequencing of the tumor, (ii) exome sequencing of the tumor and the matched normal tissue, (iii) paired-end transcriptome sequencing of the tumor cost $5400 and decreased to $3600 in the 6 months during the course of the study (the study was published in November 2011).


The closest alternative to the NGS, the Sanger sequencing of a single gene or small gene panel, has some value if the tumor has the mutation, but this approach gives no additional information. Even if the tumor is positive for the mutation, there might be other mutations complicating the treatment associated with the mutation. For example, for colorectal cancer patients the EGFR antibodies are ineffective in the background of  KRAS mutations and RTK activation makes some cancer cells resistant to the inhibitors of mutated BRAF.


One additional novelty came coincidentally with the PM is the xenograft tumor models. A piece of the patients tumor is grafted to a test animal to create a personalized model of one patient's cancer.  This will enable trial and error to find best treatment before testing on the patient. In addition when combined with NGS it will enable researching on the individual patient's disease even after the treatment is over and to find the best treatment in  cases with similar genomic profile.

The hope is that with the cancer genome sequencing is getting cheaper and more prevalent in basic and clinical research, the repertoire of recurrent and actionable mutations will continue to increase and the personalized medicine will be more effective in treating this deadly disease.


Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study
Sameek Roychowdhury, Matthew K. Iyer, Dan R. Robinson, Robert J. Lonigro, Yi-Mi Wu, Xuhong Cao, Shanker Kalyana-Sundaram, Lee Sam, O. Alejandro Balbin, Michael J. Quist, Terrence Barrette, Jessica Everett, Javed Siddiqui, Lakshmi P. Kunju, Nora Navone, John C. Araujo, Patricia Troncoso, Christopher J. Logothetis, Jeffrey W. Innis, David C. Smith, Christopher D. Lao, Scott Y. Kim, J. Scott Roberts, Stephen B. Gruber, Kenneth J. Pienta, Moshe Talpaz, and Arul M. Chinnaiyan 

Sci Transl Med 30 November 2011


The Genetic Basis for Cancer Treatment Decisions
Janet E. Dancey, Philippe L. Bedard, Nicole Onetto, Thomas J. Hudson,
Cell, Volume 148, Issue 3, 3 February 2012,