Determining the Tumor Type Is the First Step in Precision Medicine

Advances in genomics and knowledge of tumor biology have uncovered different types of genetic alterations that can predict response to specific molecularly targeted anticancer drugs. These predictive biomarkers may be mutations in individual genes (eg, BRAF V600E), structural rearrangements (eg, EML4-ALK), or copy number variation (eg, HER2 gene amplification). Although these specific genetic alterations are often found in different tumor types, published evidence indicates that biomarker status alone—without tumor type context—does not always predict the efficacy of targeted agents. For example, whereas vemurafenib treatment led to a significant benefit in melanoma patients with a BRAF V600E mutation, this drug did not have a significant benefit in patients with colorectal cancer with the same mutation.1,2 Likewise, breast and gastric cancer patients whose tumors show amplification of HER2 may benefit from trastuzumab, while lung cancer patients with the same amplification have not shown benefit in response to anti-HER2 targeted therapy.3

Tumor Type Plus Biomarkers Allow for Optimal Therapy Selection

Gene expression assays and next generation sequencing in metastatic cancer

There is sometimes confusion concerning the application of gene expression–based molecular classification assays and next-generation sequencing (NGS) assays.

Gene expression–based molecular classification assays, such as CancerTYPE ID®, measure the relative expression of panels of messenger RNA (mRNA) to provide a diagnostic classification of tumor type and subtype. CancerTYPE ID (a 92-gene assay) is used to investigate carcinomas of unknown primary (CUP) or challenging differential diagnoses. Since this assay employs quantitative reverse transcription polymerase chain reaction (RT-PCR) methodology, it is particularly suited to cases where limited tumor tissue is available (as little as 300 non-necrotic cells).

In contrast to the molecular diagnosis of tumor type provided by the CancerTYPE ID gene expression–based assay, NGS technology provides insight into a tumor’s genetic alterations (mutations, structural rearrangements, and gene amplifications/deletions). However, NGS does not provide a diagnostic classification of tumor type or subtype. Many different tumor types can harbor the same genetic alterations; however, response to a particular molecularly targeted therapy in one tumor type does not indicate the likelihood of a therapeutic response in a different tumor type.

Clinical application of tumor type plus biomarker assay results

The importance of tumor type and biomarker status on clinical decision making is highlighted by the BRAF V600E/K mutation in melanoma that predicts response to the oral kinase inhibitors vemurafenib and dabrafenib. While a wide range of malignancies, such as colorectal, lung, pancreaticobiliary, and other nonmelanoma solid tumors, are known to harbor BRAF V600E/K mutations, the clinical response of these tumors to BRAF inhibitors is markedly lower than response with melanoma, which is reported to be more than 80% in BRAF V600E/K-positive melanoma tumors.13 In a phase 2 “basket” trial of nonmelanoma solid tumors carrying the BRAF V600E/K mutation, vemurafenib showed limited antitumor activity in gliomas, head and neck cancer, pancreatic cancer, esophageal and gastric cancers, sarcoma, and CUP. A partial response to vemurafenib was observed in non–small-cell lung cancer (NSCLC) with the BRAF V600E/K mutation.14 Dr Jose Baselga, the study’s principal investigator and corresponding author, was quoted as saying, “What we’ve learned is that the driver mutation matters, but the tissue of origin is also important.”15

Different Tumor Types Positive for the BRAF V600E/K Mutation Respond Differently to Treatment

Identifying the correct tumor type when a differential diagnosis exists is critical for optimal treatment selection. For example, consider a female patient presenting with lung nodules that were identified on imaging and whose results from biopsy are negative for estrogen receptor (ER), progesterone receptor (PR), HER2, and thyroid transcription factor-1 (TTF-1). These clinicopathologic results can lead to a differential diagnosis of the lung nodules deriving from metastatic breast cancer or from a lung primary tumor. CancerTYPE ID would be useful in this scenario to provide a molecular diagnosis of tumor type that is not dependent on the loss of protein marker expression that confounds the immunohistochemistry (IHC) characterization. A molecular diagnosis of lung adenocarcinoma or lung squamous cell carcinoma, both of which are histological types of NSCLC, may allow the patient to be eligible for an approved immunotherapy.

The emerging role of next-generation sequencing in metastatic cancer

NGS has allowed for the rapid identification of genetic drivers of cancer, which has led to new drug discoveries. For tumor samples, NGS can sequence hundreds of genes simultaneously to identify the small number of specific, clinically relevant biomarkers for cancer types such as colon, NSCLC, and breast. The additional information may be helpful to patients with a definitive tumor type diagnosis to become eligible for clinical trials involving molecularly targeted agents. NGS, however, does not provide a molecular diagnosis of tumor type and subtype to distinguish between tumor types within a differential diagnosis.

Several tumor-type agnostic clinical trials, also known as basket studies, are underway that aim to explore the clinical utility of using molecular biomarker status to select treatment. Results from the randomized, phase 2 SHIVA trial indicate that the use of molecularly targeted agents in other tumor types outside of their indication does not improve survival, although statistically significant results are difficult to conclude based on the small number of patients.18 The standard remains identification of the tumor type, when possible, followed by specific biomarkers with proven predictability in the tumor type identified. CancerTYPE ID is an adjunctive assay that provides the clinical context of tumor type preceding NGS.

In summary, CancerTYPE ID provides valuable information on tumor type that allows the clinician to integrate potential predictive biomarkers within the context of an established tumor type. An accurate diagnosis of tumor type followed by predictive biomarkers can help physicians make the best treatment decisions.

References

  1. Chapman PB, Hauschild A, Robert C, et al. N Engl J Med. 2011;364(26):2507-2516.
  2. Kopetz S, Desai J, Chan E, et al. J Clin Oncol. 2010;28(15s suppl):Abstract 3534.
  3. Krug LM, Miller VA, Patel J, et al. 2005;104(10):2149-2155.
  4. Di Fiore F, Blanchard F, Charbonnier F, et al. Br J Cancer. 2007;96(8):1166-1169.
  5. Lièvre A, Bachet JB, Le Corre D, et al. Cancer Res. 2006;66(8):3992-3995.
  6. Amado RG, Wolf M, Peeters M, et al. J Clin Oncol. 2008;26(10):1626-1634.
  7. Malka D, Cervera P, Foulon S, et al. Lancet Oncol. 2014;15(8):819-828.
  8. Slamon DJ, Godolphin W, Jones LA, et al. 1989;244(4905):707-712.
  9. Bang YJ, Van Cutsem E, Feyereislova A, et al. 2010;376(9742):687-697.
  10. Fisher B, Costantino J, Redmond C, et al. N Engl J Med. 1989;320(8):479-484.
  11. Falkson CI, Ibrahim J, Kirkwood JM, et al. J Clin Oncol. 1998;16(5):1743-1751.
  12. Rusthoven JJ, Quirt IC, Iscoe NA, et al. J Clin Oncol. 1996;14(7):2083-2090.
  13. Flaherty KT, Puzanov I, Kim KB, et al. N Engl J Med. 2010;363(9):809-819.
  14. Hyman DM, Puzanov I, Subbiah V, et al. N Engl J Med. 2015;373(8):726-736.
  15. Lewis R. Lancet Oncol. 2015;16(13):e482.
  16. Falchook GS, Millward M, Hong D, et al. Thyroid. 2015;25(1):71-77.
  17. Planchard D, Kim TM, Mazières J, et al. Ann Oncol. 2014;25(5):1-41.
  18. Le Tourneau C, Delord JP, Gonçalves A, et al. Lancet Oncol. 2015;16(13):1324-1334.

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CancerTYPE ID Intended Use and Limitations
CancerTYPE ID is indicated for use in tumor specimens from patients diagnosed with malignant disease and is intended to aid in the classification of the tissue of origin and tumor subtype in conjunction with standard clinical and pathological assessment by a qualified physician. CancerTYPE ID is not intended to predict patient survival benefit, treatment efficacy or to distinguish between benign versus malignant lesions. Tumor types not included in the CancerTYPE ID reference database may exhibit RNA expression patterns that are similar to RNA expression patterns within the reference database. This test was developed and performance characteristics have been determined by Biotheranostics, Inc. It has not been cleared or approved by the U.S. Food and Drug Administration. This test is used for clinical purposes. It should not be regarded as investigational or for research. How this information is used to guide patient care is the responsibility of the physician. Biotheranostics is certified under the Clinical Laboratory Improvement Amendments of 1988 as qualified to perform high-complexity clinical laboratory testing.