Precision Cancer Medicine: New Era for Translating Lab Research Is Emerging

OncologyLive, September 2013, Volume 14, Issue 9

It is well recognized that advances in cancer management have most often resulted from a close collaboration between clinical and laboratory investigative efforts.

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

It is well recognized that advances in cancer management have most often resulted from a close collaboration between clinical and laboratory investigative efforts. Fundamental biological concepts developed and refined in the nonclinical setting have led to the exploration of novel antineoplastic approaches, resulted in the development of effective new anticancer agents, and permitted serious treatment-related adverse events to be avoided or mitigated. Examples of this long-standing relationship include preclinical studies of cytotoxic anticancer agents prior to their entry into clinical trials and the establishment of fundamental principles of radiobiology that have led to numerous advances in the field of radiation oncology.

Now, there is a potentially unique role for this important link between the laboratory and clinic in the rapidly evolving arena of precision cancer medicine.

Consider, for example, the observation that the presence of HER2 overexpression in a breast cancer characterizes tumors in a population of patients with this malignancy who have a statistically defined poor prognosis, but where treatment of that specific subgroup with an antineoplastic agent that targets this abnormality can substantially improve outcome.1 That finding was made more than a decade ago, part of a body of research that has helped define optimal uses for trastuzumab.

Since that era, the speed at which such laboratory-based observations in precision medicine can be translated into clinical benefit has accelerated rather substantially. A wonderful example of this phenomenon is the relatively rapid development of a clinical therapeutic concept that resulted from the translational laboratory observation that the presence of specific activating mutations in the epidermal growth factor receptor in non-small cell lung cancer (NSCLC) defines the patient population who are most likely to achieve clinical benefit from the administration of small-molecule tyrosine kinase inhibitors directed at this receptor.2 Following confirmation of these observations, clinical trials were conducted that resulted in a fundamental change in the management paradigm for patients with NSCLC whose tumors express this molecular abnormality.3

More recently, a focused research effort described in another landmark publication found that NSCLC tumors that possess a mutation in ROS1 are sensitive to the inhibitory effects of an FDA-approved antineoplastic agent, crizotinib, directed at a quite different molecular abnormality (ALK rearrangement).33

The potential clinical relevance of the rapid impact of such discoveries in the laboratory related to novel molecular abnormalities is moving to clinical settings where effective antineoplastic therapies are critically needed.

For example, a recent report described the provocative relationship between the expression of an oncofetal gene, SALL4, and the presence of a particularly aggressive form of primary hepatocellular cancer.4 Although SALL4 is expressed in the human fetal liver, it is not observed in the normal adult liver. However, its reemergence in liver cancer predicts for a particularly poor clinical course (hazard ratio 2.87 for overall survival in a multivariate analysis for the presence vs absence of SALL4 expression).

Perhaps of greatest interest, in vivo experiments conducted in a xenograft model revealed that blocking the interactions of SALL4 resulted in inhibition of tumor formation. Further, the absence of SALL4 expression in the normal adult liver provides a strong rationale for specifically targeting this gene and its protein product as a rational investigative strategy for the management of hepatocellular carcinoma.

Of course, until an antineoplastic agent is developed and subsequently tested for clinical efficacy, it remains unknown whether or not it is a valid therapeutic concept. However, truly elegant basic and translational laboratory research combined with the efforts of clinical investigators involved in the realm of molecular/genomic medicine have rather dramatically transformed cancer management to benefit patients. And it is virtually certain the pace of such impressive efforts will increase in the future.

Maurie Markman, MD, editor-in-chief, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America.


  1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792.
  2. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small cell lung cancer (EURTAC): a multicentre, open-label, randomized phase 3 trial [published online ahead of print January 26, 2012]. Lancet Oncol. 2012;13(3):239-246.
  3. Bergethon K, Shaw AT, Ou S-H I, et al. ROS1 rearrangements define a unique molecular class of lung cancers [published online ahead of print January 3, 2012]. J Clin Oncol. 2012; 30(10):863-870.
  4. Yong KJ, Gao C, Lim JSJ, et al. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N Engl J Med. 2013; 368:2266-2276.