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Precision medicine: The genomic signature ‘is the diagnosis’
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As a physician/medical oncologist with extensive experience in clinical trials, patient care and genomics, I would maintain that all patients with cancer should have genomic sequencing.
However, at this time, this does not need to entail full genomic sequencing.
There is a growing consensus that certain patients with cancer should have genomic sequencing, such as those who have exhausted conventional treatments; individuals with rare tumors for which the diagnosis is uncertain or there is no treatment; and patients with cancers of unknown primary. It is time to expand the availability of this technology to all patients with a malignancy.
Razelle Kurzrock
Earlier this year, President Obama announced a major initiative in precision medicine, also referred to as “personalized medicine.”
Both designations embody the concept of a revolutionary new way of treating patients with cancer. Precision medicine is a fitting term because the therapies are designed to be “precise” and impact the specific defects that fuel the tumor while sparing normal tissue. Personalized medicine also is an apt term because the precise anomalies that drive cancers differ from patient to patient; therefore, a “personalized” approach is needed.
The two major new pillars of precision/personalized cancer medicine are genomically driven targeted therapy and immunotherapy. When used correctly, these treatments are “precise” and “personalized.” Fortunately, novel agents that are genomically targeted or that arm the immune system are becoming rapidly available in the clinic.
Although most cancers have traditional treatments with proven efficacy, we should recognize that — for many patients — standard therapies have life-altering, debilitating effects. Many patients fear our therapies nearly as much as the cancer itself. Further, canonical treatments — especially for those suffering from metastatic disease — often increase survival by only a few weeks or months. For some unresectable tumors, more than 50% of patients are dead at 2 years, and for malignancies such as pancreatic cancer, more than 90% of patients will die by 24 months. The fact that some treatments statistically increase survival should not deter us from the effort to improve standard therapies. We must not rest on our laurels.
One of the important reasons for the small (even if statistically significant) improvement in survival with some traditional treatments is because a minor subset of patients benefit from the therapy. The majority derive no salutary effects, and some may be harmed. With the use of organ-based histologic diagnosis, we have been unable to select the potential responders. With genomic sequencing — as well as the emergence of transcriptomic and proteomic biomarkers — the equation changes, as matching patients with cognate targeted and immune therapies becomes feasible.
The startling pace of discoveries in the field also is relevant. Full genomic sequencing can be performed for less than $5,000. Clinical-grade sequencing with panels of several hundred cancer-related genes can be obtained in the latter price range. Our understanding of pathways has grown quickly, as has the number of targeted and immunotherapeutic drugs. It is widely believed that only a minority of patients have actionable aberrations. However, with the advent of more comprehensive sequencing panels and the rapid entry of new drugs into the clinic, our recent survey of more than 400 patients with diverse cancers discerned actionable aberrations in 90% of them. In 70% of patients, there was an aberration actionable by an FDA-approved drug, but the drug was on label in only 20% of cases. The reason that patients cannot be matched to agents often is because the medication cannot be made available to them, not because of the lack of an agent.
In addition to potential actionability, it is becoming increasingly clear that molecular aberrations can also predict prognosis. As an example, patients with colorectal cancer and BRAF mutations often do poorly. Knowing prognosis is crucial to a patient’s ability to make decisions about their care.
The most important argument for performing genomics routinely, however, is that the genomic signature “is” the diagnosis. For decades, we peered at the surface of cells under a light microscope to diagnose patients. It is a fundamental principle of oncology — and all of medicine — that all illnesses warrant a diagnosis, and that principle applies regardless of whether the diagnosis is “actionable.” Even if we suspect a disease that has no treatment, we must first diagnose the patient.
We no longer need to be limited to the light microscope. We have a powerful tool — the “molecular microscope” — that allows us to look deep into the cell and identify the precise defects that define a patient’s tumor. Genomics is the diagnosis, and every patient deserves a diagnosis.
Reference:
Schwaederle M, et al. Mol Cancer Therapeutics. 2015;Published online ahead of print April 7.
For more information:
Razelle Kurzrock, MD, is chief of the division of hematology and oncology, senior deputy director of clinical science, and director of the Center for Personalized Cancer Therapy and Clinical Trials Office at UC San Diego Moores Cancer Center. She can be reached at rkurzrock@ucsd.edu.
Disclosure: Kurzrock reports consultant roles with Sequenom, ownership interest in RScueRx, and research protocols and funding from Foundation Medicine and Merck Serono.