The Future of Precision Medicine in Oncology

Key points

Need for precision medicine in oncology

Precision medicine in oncology is focused on identifying which therapies will be most effective for each patient based on genetic characterization of their cancer. Traditional chemotherapy is cytotoxic and destroys all cells that are rapidly dividing. The foundation of precision medicine is targeted therapies, first developed in the late 1990s. Targeted therapies inhibit specific molecules involved in tumor growth and dissemination of cancer cells. Studies have also been performed to discover

Types of biomarkers: diagnostic, predictive, prognostic, and pharmacodynamic

“A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathologic processes, or biological responses to a therapeutic intervention is the definition given by the Biomarkers Working Group.”⁴ This biomarker should serve as a sign of a normal or abnormal process or of a condition or disease.⁵ The Food and Drug Administration (FDA) defines biomarkers into 4 general categories, mainly related to uses in therapy development. Several

Food and Drug Administration–cleared tests versus laboratory developed tests

In this discussion, tests that have been cleared by the FDA (FDA) and laboratory developed tests (LDTs) are included; however, there are distinctions between them. An LDT is a type of in vitro diagnostic test that is designed, manufactured, and used within a single laboratory. LDTs currently are not required to go through premarket review and other stringent requirements of FDA-cleared tests because they were considered simple tests.⁶ Due to an increase of LDT use and complexity, on September

Precision medicine in breast cancer

Breast cancer (BCa) is the most commonly diagnosed cancer for women both in the United States and globally. BCa is the second ranking cancer responsible for female mortality in the United States, causing an estimated 40,730 deaths in 2015.7, 8 The major types of targeted therapy in BCa include endocrine therapy, anti-HER2 therapy, PI3K, BRCA1/2, and CK4/6 inhibitors (Table 1). Some of the first targeted agents in oncology were developed against hormone receptor (estrogen receptor and

Diagnostic, prognostic, or predictive tests

There are several prognostic and predictive assays using breast tumor tissue. Some of the most well-known predictive assays are Oncotype DX (Genomic Health, Redwood City, CA), MammaPrint (Agendia, Uíge, Angola), and Prosigna PAM50 (NanoString Technologies, Seattle, WA) and have been recently reviewed.¹² Likely the most well-known prognostic assay is the Oncotype DX, which uses reverse transcriptase (RT)–polymerase chain reaction (RT-PCR) to analyze expression of 16 cancer-related genes and 5

Precision medicine in non–small cell lung cancer

Lung cancer is the leading cause of cancer mortality. Lung cancer can be divided into small cell lung cancer (10%–15%) and non–small cell lung cancer (NSCLC) (85%).⁸ The main NSCLC predictive biomarkers found in NSCLC include ALK fusion oncogene (anaplastic lymphoma kinase) and sensitizing epidermal growth factor receptor (EGFR) mutation. Currently, there are 3 FDA-cleared companion biomarker assays used to detect these biomarkers that are associated with different targeted therapies (Table 2).

Diagnostic, prognostic, or predictive tests

Other emerging biomarkers in NSCLC as listed in the 2016 NCCN guidelines include KRAS, HER2, and BRAF V600E mutations; ROS1 and RET gene arrangements; MET amplification; and MET exon skipping mutation. For example, KRAS mutations can serve as a prognostic biomarker indicative of patient survival independent of treatment received¹⁸ and as a predictive biomarker showing lack of therapeutic efficacy to EGFR targeted therapies.¹⁹ Although FDA-cleared KRAS mutational detection assays have been

Precision medicine in prostate cancer

Prostate cancer (PCa) is the most common solid tumor in men in the United States, ranking 5th in mortality and more than 230,00 cases diagnosed each year.²⁰ The main historical PCa biomarker is prostate-specific antigen (PSA). PSA screening has, however, garnered criticism over the years due to the possibility of over-detection, which has led to efforts to find other improved biomarkers.7, 12, 21 The majority of effort in PCa biomarker development is to distinguish PCa from benign prostatic

Diagnostic, prognostic, or predictive tests

FDA-cleared tests

1. 1.

   Prostate Health Index (Beckman Coulter, Brea, CA; in partnership with the National Cancer Institute Early Detection Research Network): measures 3 forms of PSA to better distinguish PCa from benign prostatic conditions

2. 2.

   Prosensa (Gen-Probe, San Diego, CA): nucleic acid amplification test measuring PCa antigen 3 expression in urine to better distinguish PCa from benign prostatic conditions

3. 3.

   CELLSEARCH Circulating Tumor Cell Kit (Janssen Diagnostics)

Precision medicine in melanoma

Rates of melanoma have risen faster than any other cancer over the past 2 decades with 75,000 new cases diagnosed each year.²³ These figures are thought to be underestimated, because many superficial and in situ melanomas treated in outpatient setting are not reported.²⁴

Unlike other cancers, melanoma does not respond to chemotherapy or radiation, which has led to the development of immune and targeted therapies (Table 4). Approximately 50% to 60% of patients with metastatic melanoma have an

Diagnostic, prognostic, or predictive tests

Other kinase inhibitors are also being developed against additional mutations found in Melanoma as listed in the 2016 NCCN guidelines, including BRAF, NRAS, c-kit, GNA11 and GNAQ. KIT is the most notable example because there is already an FDA-cleared tyrosine kinase inhibitor used against Bcr-Abl in chronic myelogenous leukemia and gastrointestinal stromal tumors harboring a KIT mutation. A phase II study of 43 patients with KIT-mutated metastatic melanomas demonstrated a 23% overall response

Precision medicine in colorectal cancers

Colorectal cancer is the third most common cancer in both men and women, with an estimated 49,190 expected US deaths in 2016.²⁹ Much effort has been put into targeted therapies and diagnostic tests for this disease. Three main classes of targeted therapies have been approved to treat metastatic colorectal cancer, including multikinase inhibitors, angiogenic inhibitors, and anti-EGFR antibodies. These therapies are summarized in Table 5. Multikinase inhibitors include regorafenib, dabrafenib,

Diagnostic, prognostic, or predictive tests

In April of 2015, the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society for Clinical Oncology released a new set of recommendations and consensus opinions in anticipation of new guidelines for the Evaluation of Molecular Markers for Colorectal Cancer. The consensus guidelines strongly recommend RAS mutational testing for patients who are being considered for anti-EGFR therapy, KRAS, and NRAS (codons 12, 13 of

Introduction to liquid biopsies

A new precision medicine strategy in the field of oncology is the liquid biopsy. The use of liquid biopsies allows physicians increased longitudinal access to genetic material, providing greater opportunity for biomarker detection. Traditionally, tissue from a tumor is evaluated for malignancy using dyes, microscopes, and highly trained pathologists. Some tissue micrographs yield equivocal results due to poor staining or poor sample selection. In most cases, surgeons have only a single

Circulating tumor cells

CTCs are cells that have been shed from a tumor and may be capable of forming metastases. Metastasis is the most dangerous and deadly facet of cancer and is responsible for 90% of cancer related deaths.³³ The metastatic process is accomplished by a CTC successfully carrying out a series of processes. First, the CTC must detach from the primary tumor and intravasate into the blood stream (see Fig. 2). Once in circulation, the CTC must survive a journey in the blood stream and extravasate into

Cell-free nucleic acids

cfNAs circulating in blood were first described by Mandel and Metais in 1948³⁸; however, it was not until 1994 when NRAS gene fragments were detected in cancer patients’ blood, that the scientific community recognized cfNA’s potential importance.39, 40 Since then, cfNA has become an essential tool in the liquid biopsy arsenal, gaining popularity over CTCs because cfNA isolation is deemed easier to obtain. cfNA is hypothesized to be released passively during apoptotic or necrotic events, with

Extracellular vesicles

EVs are the newest and least developed of liquid biopsy sources. EVs are membranous structures released by cells to the external environment. Their main function is intercellular communication, serving as vehicles to transfer cell of origin specific proteins, lipids, and nucleic acids between cells.⁴⁵ EVs can be distinguished into 4 categories mainly based on their size, cell origin, and secretion mechanisms. This nomenclature is still hotly debated (see Strotman LN, Linder M: Extracellular

Future of precision medicine in oncology

The idea of using liquid biopsies is appealing due to several limitations of tissue biopsies:

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  Biopsies are invasive and not practical for monitoring progression and recurrence overtime.

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  Tumor sample size can be limited due to its size and location, limiting the molecular testing that can be done.

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  Cancer is a heterogeneous disease with molecular signatures that differ spatially and evolve over time as the disease progresses or due to therapy selective pressures.

These limitations drive the