Tumor Genetic Screening Programs: A Call to Action

open access

...... Perhaps the most important question raised by the study by Meric-Bernstam et al³ is whether enrollment onto a genotype-matched protocol is really the metric by which these important profiling efforts should be judged. We would instead argue that the standard should be whether these programs identify sufficient patients with specific alterations to allow researchers to design and conduct previously impractical, but potentially transformative, precision medicine studies. Meric-Bernstam et al found that mutations in only three actionable genes (PIK3CA, KRAS, and BRAF) were present in > 5% of the patients tested. Moreover, far lower rates of actionable alterations in many other genes, including AKT, EGFR, and ERBB2, were observed across a wide variety of tumor types. These findings clearly demonstrate the necessity of uncoupling highly multiplexed next-generation genomic screening from the therapeutic studies that seek to enroll these rare genetic subpopulations. To be certain, this type of outcome is much more difficult to measure but ultimately far more clinically meaningful. In sum, despite the challenges highlighted, we feel that the type of genomic screening initiative undertaken by Meric-Bernstam et al will be an increasingly critical part of a robust clinical trials program, and the authors should be applauded for their efforts.

REFERENCES

1. 1.↵
   1. MacConaill LE,
   2. Garcia E,
   3. Shivdasani P,
   4. et al.

   (2014) Prospective enterprise-level molecular genotyping of a cohort of cancer patients. J Mol Diagn 16:660–672.

   CrossRefMedlineGoogle Scholar
2. 2.↵
   1. Kris MG,
   2. Johnson BE,
   3. Berry LD,
   4. et al.

   (2014) Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA 311:1998–2006.

   CrossRefMedlineGoogle Scholar
3. 3.↵
   1. Meric-Bernstam F,
   2. Brusco L,
   3. Shaw K,
   4. et al.

   Feasibility of large-scale genomic testing to facilitate enrollment onto genomically-matched clinical trials. J Clin Oncol, doi: 10.1200/JCO.2014.60.4165.
4. 4.↵
   1. Frampton GM,
   2. Fichtenholtz A,
   3. Otto GA,
   4. et al.

   (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31:1023–1031.

   CrossRefMedlineGoogle Scholar
5. 5.↵
   1. Drilon A,
   2. Wang L,
   3. Arcila ME,
   4. et al.

   Broad, Hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res, [epub ahead of print on January 7, 2015].

   Google Scholar
6. 6.↵
   1. Jänne PA,
   2. Shaw AT,
   3. Pereira JR,
   4. et al.

   (2013) Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: A randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14:38–47.

   CrossRefMedlineGoogle Scholar
7. 7.↵
   1. Falchook GS,
   2. Lewis KD,
   3. Infante JR,
   4. et al.

   (2012) Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: A phase 1 dose-escalation trial. Lancet Oncol 13:782–789.

   CrossRefMedlineGoogle Scholar
8. 8.↵
   1. Kopetz S,
   2. Desai J,
   3. Chan E,
   4. et al.

   (2010) PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol 28(suppl):269s, abstr 3534.

   Google Scholar
9. 9.↵
   1. Yaeger R,
   2. Cercek A,
   3. O'Reilly EM,
   4. et al.

   (2015) Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients. Clin Cancer Res 21:1313–1320.

   Abstract/FREE Full Text
10. 10.↵
    1. Yasuda H,
    2. Park E,
    3. Yun CH,
    4. et al.

    (2013) Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 5:216ra177.

    Abstract/FREE Full Text