Genomic Chaos

Andrew Pecora, MD

Editor-in-Chief Chief Innovations Officer, Professor, and Vice President of Cancer Services John Theurer Cancer Center at Hackensack University Medical Center

George W. Sledge Jr, MD, the outgoing president of the American Society of Clinical Oncology (ASCO), gave a forward-looking talk during the recent annual ASCO meeting that he concluded by stating, “Oncologists need to prepare for a new era in which rapidly advancing genetic technology will change the way cancer is treated.” He added, “Physicians are entering an era of genomic chaos—a phrase that describes both the genetic madness that makes healthy cells turn into deadly cancers and the instability that incorporating rapidly advancing genetic technology into cancer care will bring.” Sledge acknowledged that the way clinical trials are run will need to change, and he encouraged physicians to face the onslaught of new technology head-on.

The elucidation of a specific BRAF gene mutational status (v600E), present in approximately half of patients with advanced life-threatening melanoma, is one example of the potential benefit of harnessing genomic chaos. B-Raf protein, a member of the Raf kinase family of serine/threonine-specific protein kinases, plays a central role in regulating the MAP kinase/ERK signaling pathways that affect cell growth and differentiation. B-Raf protein transcribed from mutated BRAF is capable of stimulation of downstream pathways, independent of upstream receptor signaling. As a result, several drugs have been developed that specifically target the mutation, shutting off mutated BRAF-driven pro-survival and growth. In one trial presented at ASCO (abstract LBA4; see page 17 in this issue), a BRAF inhibitor (vemurafenib) demonstrated unprecedented clinical outcomes, including a 63% reduction in the risk of dying at 6 months (84% alive) when compared with chemotherapy (ie, dacarbazine, 64% alive). Clinical responses usually are delayed, if observed at all, when treating advanced melanoma with chemotherapy. However, responses were observed within 2 to 3 days of starting vemurafenib.

Another “genomic” targeted therapy, crizotinib, has been in development for patients with anaplastic lymphoma kinase-positive (ALK ) advanced non— small cell lung cancer and is now showing promise. ALK, a member of the insulin receptor superfamily, is a membrane-associated tyrosine kinase receptor. A dependence receptor, ALK fuels the growth and survival of malignant cells and can be blocked by targeted agents such as crizotinib. In a trial presented at ASCO of 82 ALK patients treated with crizotinib (abstract 7507), 1- and 2-year overall survival (OS) was 77% and 64%, respectively, without yet reaching median overall survival. These data compared favorably with the 37 ALK control patients not treated with crizotinib (73% and 33%; median OS at 20 months) and 253 ALK-negative patients (49% and 33%; median OS at 11 months).

The pace of discovery is accelerating. Our healthcare delivery and payer systems need to remain flexible enough to accommodate rapid, significant changes in diagnostic and treatment paradigms as new genomic results mature into validated pathways to guide therapy development and choice. The so-called “black box” that hid the mechanisms of cancer from plain view is slowly but surely being dismantled through a genomic lens. Sledge’s call to arms is well-founded, and if heeded, we will be poised to turn genomic chaos into multiple genomic-guided treatment successes.