biocept faq

Biomarker Test Index

ALK

ALK gene rearrangements are found in 2-7% of non-small cell lung carcinoma (NSCLC) cases, and detection is used to qualify patients for possible therapeutic intervention. This aberration most commonly occurs independently of EGFR and KRAS gene mutations. Since the discovery of the echinoderm microtubule-associated protein-like 4 (EML4) gene fused to the anaplastic lymphoma kinase (ALK) gene in 2007, multiple variants of the oncogenic EML4-ALK fusion have been reported. All encode for the same cytoplasmic portion of the ALK protein, but with different truncations of EML4.

ALK gene rearrangements, or the resulting fusion proteins, may be detected in tumor specimens using fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and reverse transcription polymerase chain reaction of cDNA (RT-PCR).1 Biocept’s Target Selector™ liquid biopsy platform has demonstrated the ability to identify ALK gene translocations in patients using a simple blood sample.

Detection of an ALK fusion is used determine the likelihood of response to crizotinib (Xalkori®), a commercially available tyrosine kinase inhibitor. Additionally, ceritinib (Zykadia®) and alectinib (Alecensa®) are approved for patients with ALK-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib.

Biocept’s ALK liquid biopsy test utilizes FISH analysis of circulating tumor cells to identify ALK gene rearrangements.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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AR

The androgen receptor (AR) is responsible for regulating the growth of prostate epithelial cells. Detection of AR expression can play a role in personalized medicine for patients with metastatic prostate cancer or castration-resistant prostate cancer (CRPC). In untreated prostate cancer, AR positive cells are more likely to be responsive to hormonal therapy. Drug treatments for prostate cancer that target AR include abiraterone (Zytiga®) and enzalutamide (Xtandi®), which have been shown to improve survival in patients with CRPC (de Bono et al, 2011; Scher et al, 2012).

AR expression is also associated with other cancers such as salivary duct carcinoma and triple negative breast cancer (TNBC) where patients test negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC accounts for 10-20% of breast cancer patients, and AR expression may have prognostic and predictive value in patients with TNBC.

Biocept’s AR expression liquid biopsy test is performed on circulating tumor cells (CTCs) using utilizing fluorescently labeled antibodies.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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BRAF

BRAF is a human gene that encodes a protein called B-Raf, which sends intracellular signals involved in cell growth. In 2002, it was shown that the BRAF oncogene was mutated in some human cancers.2 A wide range of cancers have been shown to harbor BRAF mutations including malignant melanoma, colorectal, thyroid, lung, and ovarian cancers. The highest frequency is found in malignant melanoma. At the genetic level, 40% of melanomas that lack a BRAF mutation harbor a NRAS mutation which appears to similarly activate the same cell signaling pathway in which B-Raf resides, the so-called mitogen-activated kinase-like protein kinase (MAPK) pathway.3  This pathway is involved in a variety of fundamental cellular processes such as proliferation, differentiation, motility, stress response, apoptosis, and survival. Abnormalities in MAPK signaling play a critical role in the development and progression of cancer.

Detection of BRAF V600 mutations E, K, D, and others can be useful to select melanoma patients for targeted drug therapy, determine prognosis in thyroid and colon cancers, and predict response to anti-EGFR therapy in colon cancer.

Targeted drug therapies designed to treat cancers driven by BRAF mutations have demonstrated improvements in patient survival.4  Two of these drugs, vemurafenib (Zelboraf®) and dabrafenib (Tafinlar®) are approved by the FDA for the treatment of late-stage melanoma.

Biocept’s BRAF liquid biopsy test is performed on ctDNA and identifies all mutations in the targeted region.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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EGFR

Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor tyrosine kinase that belongs to the HER/ErbB protein family. Mutations that lead to EGFR overexpression have been associated with a number of cancers, including colon, anal, head and neck, breast, ovarian, brain, prostate, and squamous-cell carcinoma of the lung (80% of cases). Somatic mutations involving EGFR lead to its constant activation, which produces uncontrolled cell division.5

Somatic mutations in the tyrosine kinase domain of EGFR are present in a subset of lung adenocarcinomas. Two types of mutations account for approximately 90% of mutated cases: a specific point mutation (L858R) which occurs in exon 21, and short in-frame deletions which occur in exon 19. When these mutations are identified in non-small cell lung cancer (NSCLC) patients, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as afatinib (Gilotrif®), gefitinib (Iressa®) and erlotinib (Tarceva®), have demonstrated clinical response rates as high as 80%. However, after about 6 to 12 months, NSCLC tumors develop acquired resistance to these targeted therapies. Research into such resistance has identified the secondary EGFR T790M mutation, which occurs in approximately 60% of patients with acquired resistance to EGFR-TKIs.

In November 2015, osimertinib (Tagrisso®) was approved for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, who have progressed on or after EGFR-TKI therapy. Several additional EGFR T790M-inhibitors (also called 3rd-generation EGFR-TKIs) are in late-stage clinical development, such as olmutinib and PF-06747775, from Boehringer Ingelheim and Pfizer, respectively.

Biocept’s EGFR liquid biopsy test is performed on ctDNA and identifies all mutations in the targeted region.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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ER

Estrogen receptors (ERs) are a group of proteins found inside and on cells. They are receptors activated by the hormone, estrogen 17β-estradiol.6 There are two known ER isoforms, ERα and ERβ, which are members of the nuclear receptor family of intracellular receptors. ER is a weak prognostic factor, but a strong predictive factor for response to endocrine therapies, both in adjuvant and metastatic settings. Assessment of ER in breast cancer is primarily used to predict response to hormonal therapies such as tamoxifen, other selective estrogen receptor modulators (SERMs), and aromatase inhibitors.

For patients with recurring or newly diagnosed metastatic breast cancer, the identification of hormonal (ER) and HER2 receptors is standard of care, and accurate assessment can play a major role in treatment outcomes. Biocept offers both ER and HER2 testing in a liquid biopsy to assess these biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

ER-positive and progesterone receptor (PR)-positive breast cancer cells have receptors that attach to their respective hormones. As a result, cell growth is promoted. There are several drugs that use different approaches to block hormones from binding to these receptors. Hormone therapy is recommended for women with hormone receptor-positive (ER-positive and/or PR-positive) breast cancers, but it does not help women whose tumors are hormone receptor-negative (both ER- and PR-negative). Drugs used to block estrogen include tamoxifen (Nolvadex®) and fulvestrant (Faslodex®). Additionally, selective estrogen receptor modulators (SERMs) are used to reduce estrogen levels and include letrozole (Femara®), anastrozole (Arimidex®), and exemestane (Aromasin®).

Biocept’s ER expression liquid biopsy test is performed on circulating tumor cells (CTCs) using utilizing fluorescently labeled antibodies.

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FGFR1

Fibroblast growth factor receptor 1 (FGFR1) is one of four fibroblast growth factor receptors involved in processes such as cell division, regulation of cell growth and maturation, formation of blood vessels, wound healing, and embryonic development. The FGFR1 gene encodes for this protein, which spans the cell membrane, with one end of the protein inside the cell and the other end projecting from the outer surface of the cell. This positioning allows the FGFR1 protein to interact with other proteins called fibroblast growth factors (FGFs) outside the cell and to receive signals that help the cell respond to its environment.

Up to 10% of breast cancer patients have FGFR1 overexpression (Hynes and Dey 2010, and Turner et al. (2010) noted that this protein has been associated with ER-positive status and luminal B–type breast cancer. In lung cancer, amplifications of FGFR1 are predominantly found in former/current smokers diagnosed with squamous cell lung cancer, with up to 20% of this population having FGFR1 overexpression. In lung cancer patients with other histologies such as adenocarcinoma, FGFR1 amplification is a rare event (less than 2%; Dutt et al. 2011; Turner and Seckl 2010; Weiss et al. 2010).

Recent studies suggest that the FGFR pathway may be susceptible to FGFR inhibitors, thus determining protein overexpression has potential for pharmacologic intervention (Liang et al. 2012). There are several pharmacologic agents that have been, or are being developed for inhibition of FGFR/FGF signaling. These include both highly selective inhibitors and multi-kinase inhibitors. Only four agents are FDA-approved for use in cancer, although their approvals were not based on their activity against FGFR. These multi-kinase inhibitors are: ponatinib (Iclusig®), pazopanib (Votrient®), regorafenib (Stivarga®), and lenvatinib (Lenvima®).

Biocept’s FGFR1 liquid biopsy test utilizes FISH analysis of circulating tumor cells to identify FGFR1 gene rearrangements.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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HER2

The ERBB2 gene encodes for the protein receptor, human epidermal growth factor receptor 2 (HER2 or HER2/neu), which is associated with several forms of carcinoma. Approximately 15-30% of breast cancer patients have over expression of HER2, and 7-34% of patients with gastric cancer are HER2 positive.7 8 HER2 overexpression is also associated with salivary duct carcinomas.

A tumor may be HER2-positive if the diagnostic test shows a higher than normal number of HER2 genes in cells, or receptors on cell surfaces. There are distinct differences between breast and gastric cancers from a diagnostic scoring standpoint, although similar testing methods are used. Proper testing procedures must also be followed for the diagnosis of patients with either breast carcinoma or gastric carcinoma to ensure accurate determination of HER2 status and treatment recommendations for the specific cancer.

By 1998, antibody therapy targeting the HER2 pathway was shown to significantly improve progression-free and overall survival in metastatic disease. In 2005, evidence of improvement in disease-free and overall survival from trastuzumab (Herceptin®) adjuvant trials, or administration after surgery, became available. However, not all patients with HER2 overexpression benefit from this widely used agent. Second-generation studies in metastatic disease led to the approval of several new HER2-targeted therapies using small molecule tyrosine kinase inhibitors such as lapatinib (Tykerb®), new HER2/HER3 antibodies such as pertuzumab (Perjeta®), and the antibody chemotherapy conjugate ado-trastuzumab emtansine (Kadcyla®). These successes supported the launch of second-generation adjuvant trials testing single and dual HER2-targeted agents, administered concomitantly or sequentially with chemotherapy. HER2-positive breast cancer in the setting of HER2-targeted therapy is no longer associated with poor prognosis, and recent guidance by the US Food and Drug Administration suggests that pathologic response to HER2-targeted therapy given preoperatively may allow for an earlier assessment of clinical benefit in the adjuvant setting.

Biocept’s HER2 liquid biopsy test utilizes FISH analysis of circulating tumor cells to identify HER2 gene copy changes.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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KRAS

The KRAS gene (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) encodes a small GTPase transductor protein called KRAS. KRAS is involved in the regulation of cell division as a result of its ability to relay external signals to the cell nucleus. It has been demonstrated that the wild-type KRAS gene is a tumor suppressor that is frequently lost during tumor progression in many types of cancer.9 Once the KRAS gene mutates, it acquires oncogenic properties and seems to be causally involved in the development of various human cancers.10 11 KRAS mutations are found in approximately 90% of pancreatic cancers, 30-50% of colon cancers, and approximately 25% of lung cancers. Ovarian cancer can also harbor KRAS oncogene mutations.

Activating mutations in the KRAS gene impair the ability of the KRAS protein to switch between active and inactive states, leading to cell transformation and increased resistance to chemotherapy and biological therapies targeting epidermal growth factor receptors (EGFR).

In patients with advanced colorectal cancer (CRC) or non-small cell lung cancer (NSCLC), absence of a KRAS mutation predicts a greater likelihood of response to EGFR-targeted therapies (e.g., cetuximab and panitumumab) and improved survival with such treatment. The presence of a KRAS mutation in codon 12 or 13 is associated with a high likelihood of resistance to therapies targeting EGFR (≥93%). As a result, there is a need to test for mutations in the KRAS gene and to determine the eligibility for therapies targeting EGFR.

A number of drug classes have been developed that target clinically actionable biomarkers downstream of KRAS, but no currently available drug inhibits KRAS directly. MEK inhibitors, such as selumetinib (AstraZeneca) have shown pre-clinical and clinical evidence of activity in KRAS mutant cancers, and work is being done to discover and develop direct-acting KRAS inhibitors.

Biocept’s KRAS liquid biopsy test is performed on ctDNA and identifies all mutations in the targeted region.
Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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MET

MET (or c-MET) was first discovered as an oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). MET receptor tyrosine kinase can be mutated or overexpressed in a number of epithelial human cancers, including 3% of lung, 5% of colon, 5% of kidney, and 10% of upper digestive system cancers. The MET pathway is also associated with mesothelioma. The MET receptor is activated by its ligand HGF, and in malignant cells triggers a number of intracellular signaling transduction pathways resulting in alteration of biological functions including metastasis.12 13 14

MET deregulation in lung cancer is associated with poor outcome and resistance to anti-EGFR therapy. It is anticipated that targeted therapy against MET and its pathway will lead to significant inhibition of cancer growth and metastasis. Multiple antibodies against MET and small molecule MET-inhibitors are currently in clinical trials for the treatment of various cancer types.

Currently, crizotinib (Xalkori®) and cabozantinib (Cabometyx®) are the only FDA-approved therapies that target c-MET (HGF receptor). These agents are dual- or multi-tyrosine kinase inhibitors, blocking MET jointly with other cancer-related pathways. Several compounds targeting the MET pathway are under investigation in clinical trials. These include foretinib (Exelixis), capmatinib (Novartis), tivantinib (ArQule Inc.), and glesatinib (Mirati Therapeutics). In the future, differentiation of MET inhibitors into specific kinase targets will need to be made. Determining specific patient subsets based on genetic profiles that are more likely to respond to MET kinase inhibitors could contribute to better clinical outcomes.

Biocept’s MET liquid biopsy test utilizes FISH analysis of circulating tumor cells to identify MET gene rearrangements.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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PD-L1

Programmed death-1 (PD-1) is an immune checkpoint receptor on T cells in the immune system. Expression of PD-L1 has been described in many tumor types such as melanoma, lung cancers (both squamous and non-squamous non-small cell lung cancer), breast and ovarian, pancreatic and esophagus adenocarcinoma, kidney tumors and bladder cancers, as well as in hematopoietic malignancies.15 16 17 18 19 20 Upregulation of the PD-1 receptor plays a key role in the debilitating process of T-cell exhaustion, which hampers the ability of the immune system to destroy cancerous cells. The PD-1 receptor has two ligands, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2). When the PD-1 receptor binds to PD-L1, it signals cytotoxic T-cells to leave other cells alone. This checkpoint mechanism of the immune system is in place to protect normal cells, but some cancer cells have large amounts of PD-L1, which helps them evade immune attack. Detection of PD-L1 is indicated as an aid in identifying cancer patients for treatment with immunotherapy agents. These agents, called PD-1 or PD-L1 inhibitors (AKA “checkpoint inhibitors”) have demonstrated the ability to increase the immune response in many cancer types, and improve patient survival.

In 2014, the Food and Drug Administration granted accelerated approval for pembrolizumab (Keytruda®) to treat advanced or unresectable melanoma, making it the first PD-1 inhibitor cleared in the US. Later in 2014, the FDA approved nivolumab (Opdivo®) for melanoma patients. In 2015, nivolumab became the first immunotherapy agent approved for the treatment of lung cancer. In addition to the many approved indications for pembrolizumab and nivolumab, there are many ongoing studies testing these drugs in combination with other agents and in various cancer types including head and neck, and brain cancers. In 2016, the FDA granted accelerated approval for atezolizumab (Tecentriq®), a PD-L1 inhibitor, for the treatment of bladder cancer. This drug was subsequently approved for lung cancer. Other PD-1/PD-L1 targeted treatments are in clinical development.

Biocept’s PD-L1 expression liquid biopsy test is performed on circulating tumor cells (CTCs) using fluorescently labeled antibodies.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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PR

The progesterone receptor (PR) is a protein found inside cells. Upon binding of the steroid hormone progesterone to PR, PR enters the nucleus and binds to DNA, leading to the production of specific proteins. The main physiological functions of PR include mammary gland and to a lesser degree mammary ductal development (Hilton HN, 2015; Aupperlee MD, 2013).

Clinically, breast cancer cells can be tested for hormone sensitivity, also referred as hormone receptor status, where tumor cells positive (by antibody stain) for estrogen receptor (ER) and/or PR, suggest that the patient may respond to a targeted therapy. About 80% of breast cancers are hormone receptor positive.

Progesterone and estrogen fuel cells, including breast tumor cells, to grow by binding to their hormone receptors, ER and PR. Common therapies, as a result of an ER and/or PR positive test, either lower estrogen levels (aromatase inhibitors) or stop estrogen from acting on breast cancer cells (ex. Tamoxifen (Nolvadex®)).

Biocept’s PR expression liquid biopsy test is performed on circulating tumor cells (CTCs) utilizing fluorescently labeled antibodies.

Biocept’s Target SelectorTM platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

Our previous publication “Correlation of hormone receptor status between circulating tumor cells, primary tumor, and metastasis in breast cancer patients” (Kalinsky K et al, 2015), demonstrated concordance between tumor biopsies and CTCs, testing for ER and PR, using Biocept’s CTC platform.

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RET

The RET proto-oncogene encodes a cell membrane tyrosine kinase receptor protein whose ligands belong to the family of extracellular glial cell line-derived neurotrophic factor (GDNF) signaling molecules. RET gene rearrangements that result in growth-promoting chimeric or fusion proteins are found in 1-2% of adenocarcinoma-containing non-small cell lung cancer (NSCLC) and 20-40% of sporadic papillary thyroid carcinoma (PTC). RET rearrangements in NSCLC are generally mutually exclusive of mutations in EGFR, KRAS, ALK, and ROS1. Lung cancer patients with this alteration tend to be younger and lack smoking history. Sporadic PTC is the most common type of thyroid cancer representing 75-80% of all thyroid cancer cases.21 The cause of RET gene rearrangements in sporadic PTC is not known, but the close association between their presence and the PTC phenotype indicates that they play a causative role in tumor development.

FDA-approved multi-kinase inhibitors with activity in cancers harboring RET alterations include cabozantinib (Cabometyx®) and vandetanib (Caprelsa®). Research is ongoing for additional compounds with activity in diseases associated with RET gene rearrangements or fusions.

Biocept’s RET assay utilizes FISH analysis of circulating tumor cells to identify RET gene rearrangements.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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ROS1

The proto-oncogene tyrosine-protein kinase ROS1 is an enzyme that in humans is encoded by the ROS1 oncogene. ROS1 has structural similarity to the anaplastic lymphoma kinase (ALK) protein, and ROS1 gene rearrangements are found in 1-2% of non-small cell lung carcinoma (NSCLC) cases. While the exact role of the ROS1 protein has not been identified in normal development, ROS1-positive tumors associated with lung and other cancers have been found to be remarkably responsive to small molecule tyrosine kinase inhibitors. As a result, interest in identifying ROS1 rearrangements as a therapeutic target in cancer has increased.

Pre-clinical and early clinical evidence suggests ROS1-rearranged tumors may be sensitive to dual ALK/MET inhibitors. Recently, the small molecule tyrosine kinase inhibitor, crizotinib (Xalkori®), was approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1-positive.
Biocept’s ROS1 assay utilizes FISH analysis of circulating tumor cells to identify ROS1 gene rearrangements.

Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess clinically actionable cancer biomarkers from a patient’s blood sample. Liquid biopsy is non-invasive, and can be a useful testing option in conjunction with tissue biopsy or when tissue biopsy is insufficient or unavailable. The company’s tests are performed in its CLIA-certified, CAP-accredited laboratory located in San Diego, CA.

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