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Masonic Cancer Clinic
Clinics and Surgery Center
909 Fulton St., SE, Suite 202
Minneapolis, MN 55455

For all cancer care locations, visit mhealth.org/cancer

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Precision Medicine and the Next Generation of Targeted Cancer Therapies

The Cancer and Cardiovascular Research Building 
Cancer represents the second leading cause of death in the United States.1 Epidemiologists estimate that 1,735,350 new cancer cases and 609,640 deaths will occur in 2018. Prostate, lung, and colorectal cancers make up 42% of the expected cancers in men, while in women, breast, lung, and colorectal cancers constitute 50% of the disease.1  About a quarter of deaths arise from lung cancer.

From 2005 to 2014, however, cancer incidence has declined about 2% annually in men and remained stable in women. Several factors have contributed to this trend, and increased screening, improvements in diagnostic technology, and targeted therapies have improved patient survival for several cancers.1 

Precision medicine—characterizing molecular abnormalities in tumors—has become important for identifying targetable genes and determining optimal therapy.2,3 Subsets of lung cancer, for example, can now be defined by specific mutations,4  a significant development given that most primary lung cancers are detected when advanced and unresectable, limiting therapeutic options for patients. These gene mutations can activate oncogenes, such as EGFR, KRAS, NRAS, BRAF, or ERBB2, and chromosomal rearrangements involving tyrosine kinase receptor genes ALK, ROS1, RET, and NTRK1 can produce oncogenic fusion proteins (e.g., EML4-ALK).2,3,4 Tyrosine kinase driver mutations are believed present in about 60% of lung adenocarcinomas and can be selectively targeted.5,6 About 20% of U.S. lung cancer patients have an EGFR mutation, and approved therapies for lung adenocarcinoma manifesting such mutations are erlotinib, afatinib, and gefitinib, and osimertinib.4,6 

(Osimertinib has recently been approved for all EGFRmutation cancers.)

Reflex biomarker testing with next generation sequencing can expedite successful therapy by identifying an increasing number of targetable mutations.5,6 Molecular profiling can also reveal mutations that arise during the course of treatment when cancers develop resistance, allowing physicians to change therapy as needed.7 In addition to generating lung cancer therapies, the identification of molecular abnormalities has led to targeted therapies for other cancers: imatinib for Philadelphia chromosome-positive leukemia, vemurafenib for malignant melanoma, and immune checkpoint inhibitors for tumors possessing mutation repair deficiencies.

Assessing gene biomarkers at diagnosis speeds disease identification and allows physicians to bypass additional testing and delays in initiating therapy. Reflex testing can also bring enhanced precision to diagnosis and help avoid the implementation of suboptimal therapy.6  Reflex testing at diagnosis is the standard of care for University of Minnesota Health Cancer Care patients, and when used for thoracic cancer patients, it reduced the average time to initiation of biomarker-guided therapy from 38 days to 16 days (unpublished data). (See Case Study for further discussion.)

By examining actionable mutations within the tumor, the first approach to precision medicine has already yielded improved therapeutic strategies. As the field advances, next generation sequencing can identify broad, comprehensive genomic profiles, which can define specific cancer subtypes with different therapeutic susceptibilities. This clinical precision medicine platform can be applied to many cancers and disease processes, and its “bedside-to-bench” approach can guide future clinical and basic research questions. The technology allows fast determination of genetic profiles and helps differentiate clinically relevant mutations from coincidental changes. Information generated is expected to enhance elucidation of cancer mechanisms, improve gene panels for testing, and aid development of new therapies for different cancers.4,8

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30. doi: 10.3322/caac.21442
  2. Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018;6:75. doi:10.1186/s40425-018-382-2 
  3. Lindeman NI, Cagle PT, Aisner DL, et al. Updated Molecular Testing Guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018 142(3):321-346. doi: 10.5858/arpa.2017-0388-CP 
  4. Hensing T, Chawla A, Batra R, Salgia R. A personalized treatment for lung cancer: molecular pathways, targeted therapies, and genomic characterization. Adv Exp Med Biol. 2014;799:85-117. doi: 10.1007/978-1-4614-8778-4_5
  5. Yamamoto G, Kikuchi M, Kobayashi S, et al. Routine genetic testing of lung cancer specimens derived from surgery, bronchoscopy and fluid aspiration by next generation sequencing. Int J Oncol. 2017 50(5):1579-1589. doi:10.3892/ijo.2017.3935
  6. Cheema PK, Menjak IB, Winterton-Perks Z, et al. Impact of reflex EGFR/ALK testing on time to treatment of patients with advanced nonsquamous non-small-cell lung cancer. J Pract Oncol. 2017 13(2):e130-e138. doi: 10.1200/JOP.2016.014019
  7. Liu Y, Li Y, Ou Q, et al. Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib. Lung Cancer. 2018 118:1-5. doi:10.1016/j.lungcan.2018.01.015 
  8. Henzler C, Schomaker M, Yang R, et al. Optimization of a microfluidics-based next generation sequencing assay for clinical oncology diagnostics. Ann Transl Med. 2018;6(9):162. dx.doi.org/10.21037/atm.2018.05.07

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