Increasing Access to Targeted Therapies via Liquid Biopsy
Biocept’s Target Selector™ platform features a range of liquid biopsy tests to assess NCCN guideline-driven-clinically actionable cancer biomarkers from a patient’s blood sample.
|Test||Technology||Result Interpretation||CPT Codes||Method||Targeted Therapies|
|ALK||FISH||Translocation||88377||CTC||Xalkori®, Zykadia®, Alecensa®, Alunbrig®|
|AR||Expression||Expression||88346 or 88350||CTC||Zytiga®, Xtandi®|
|BRAF||Sequencing||Mutation||81210||ctDNA||Zelboraf®, Tafinlar®, Mekinist®|
|Enumeration||86152/86153 88346x1, 88350x2||CTC|
|Sequencing||Mutation||81235||ctDNA||Tarceva®, Gilotrif®, Iressa®, Tagrisso®|
|ER||Expression||Expression||88346 or 88350||CTC||Nolvadex®, Aromatase Inhibitors|
|FGFR1||FISH||Amplification||88377||CTC||Nolvadex®, Faslodex®, Femara®, Arimidex®, Aromasin®|
|HER2||FISH||Amplification||88377||CTC||Herceptin®, Perjeta®, Tykerb®, Kadcyla®|
|MET||FISH||Amplification||88377||CTC||Xalkori®, Cabometyx®, Exelixi®, Tivantinib®|
|PD-L1||Expression||Expression||88346 or 88350||CTC||Keytruda®, Opdivo®|
|PR||Expression||Expression||88346 or 88350||CTC||Nolvadex®, Aromatase Inhibitors|
|ROS1||FISH||Translocation||88377||CTC||Xalkori®, Zykadia®, Alecensa®|
ALK gene rearrangements are found in 2-7% of non-small cell lung cancer (NSCLC) cases, and detection is used to qualify patients for possible therapeutic intervention. In these rearrangements, the anaplastic lymphoma kinase (ALK) gene is fused to the echinoderm microtubule-associated protein-like 4 (EML4) gene. Multiple variants of this oncogenic EML4-ALK fusion have been reported; all involve the same cytoplasmic portion of the ALK protein, but with different truncations of EML4. Importantly, ALK rearrangements most commonly occur in the absence of EGFR or KRAS mutations.1
ALK gene rearrangements, or the resulting fusion proteins, may be detected in tumor specimens using fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), or reverse transcription polymerase chain reaction (RT-PCR).2 Biocept’s Target Selector™ liquid biopsy platform has the ability to identify ALK gene translocations in patients using a simple blood sample.
Detection of an ALK fusion is used to determine the likelihood of response to crizotinib (Xalkori®) or ceritinib (Zykadia®), two commercially available tyrosine kinase inhibitors.3 Additionally, alectinib (Alecensa®) and brigatinib (Alunbrig®) are approved for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.
Targeted Therapies: Crizotinib (Xalkori®), ceritinib (Zykadia®), alectinib (Alecensa®), and brigatinib (Alunbrig®).
Methodology: Biocept’s ALK liquid biopsy test is performed on circulating tumor cells (CTCs), using FISH analysis to identify ALK gene rearrangements.
The androgen receptor (AR) regulates the growth of prostate epithelial cells. For patients with metastatic prostate cancer or castration-resistant prostate cancer (CRPC), the detection of AR expression can guide the selection of a personalized treatment strategy. For untreated prostate cancer, AR-positive tumors are more likely to respond to hormonal therapy (i.e., androgen suppression therapy). Drug treatments that target AR to treat prostate cancer include abiraterone (Zytiga®) and enzalutamide (Xtandi®), which improve survival in patients with CRPC.4,5
AR expression is also associated with other cancers, such as salivary duct carcinoma and triple negative breast cancer (TNBC). Patients with TNBC test negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounting for 10–20% of all breast cancer patients. The expression of AR in TNBC may have prognostic and predictive value.6
Targeted Therapies: Abiraterone (Zytiga®) and enzalutamide (Xtandi®).
Methodology: Biocept’s AR liquid biopsy test is performed on circulating tumor cells (CTCs), using fluorescently labeled antibodies to detect AR protein.
The BRAF serine/threonine kinase helps to relay intracellular signals that stimulate cell growth. In 2002, it was shown that the BRAF gene is mutated in a range of human cancers.7 These cancers now include malignant melanoma, colorectal, thyroid, lung, and ovarian cancers, with the highest frequency in malignant melanoma. Detection of BRAF V600 mutations can predict response to anti-EGFR therapy in colon cancer,8determine prognosis in thyroid and colon cancers,9 and inform the selection of targeted drug therapies (e.g., BRAF inhibitors).
Targeted drug therapies designed to treat cancers driven by BRAF mutations have demonstrated improvements in patient survival.10 Four of these drugs, vemurafenib (Zelboraf®),11 dabrafenib (Tafinlar®), trametinib (Mekinist®), and cobinetinib (Cotellic®) are approved by the FDA for the treatment of late-stage melanoma. In June 2017, the FDA approved dabrafenib (Tafinlar®) in combination with trametinib (Mekinist®) to treat patients with metastatic non-small cell lung cancer whose tumors harbor the BRAF V600E mutation.
Targeted Therapies: Vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), trametinib (Mekinist®), and cobinetinib (Cotellic®).
Methodology: Biocept’s BRAF liquid biopsy test is performed on circulating tumor DNA (ctDNA) and identifies all mutations in the targeted genomic region.
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase, and mutations in the EGFR gene are associated with a number of cancers, including colorectal, anal, head and neck, breast, ovarian, brain, prostate, and lung. These EGFR mutations typically affect the kinase domain, leading to its constitutive activation and uncontrolled cell division.12
Somatic EGFR mutations are present in a subset of lung adenocarcinomas (~10%), with two mutations accounting for ~90% of these cases: 1) a point mutation within exon 21 (L858R), and 2) a short in-frame deletions within exon 19.13 When one of these mutations is identified in a patient with NSCLC, EGFR 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 6–12 months, resistance to these targeted therapies inevitably emerges. Research into resistance mechanisms has identified a secondary EGFR mutation, T790M, which drives resistance in ~60% of patients with acquired EGFR-TKI resistance.14
In November 2015, osimertinib (Tagrisso®) was approved for the treatment of patients with metastatic NSCLC who have progressed on or after EGFR-TKI therapy, and whose tumors harbor the EGFR T790M mutation. Several more EGFR T790M inhibitors (called third-generation EGFR-TKIs) are in late-stage clinical development. These include olmutinib and PF-06747775, from Boehringer Ingelheim and Pfizer, respectively.
Targeted Therapies: Afatinib (Gilotrif®), gefitinib (Iressa®), erlotinib (Tarceva®), and osimertinib (Tagrisso®).
Methodology: Biocept’s EGFR liquid biopsy test is performed on circulating tumor DNA (ctDNA) and identifies all mutations in the targeted genomic region.
Estrogen receptors (ERs) are a group of receptors that bind to and are activated by the hormone estrogen 17β-estradiol.15 Binding of estrogen to its receptor promotes cell growth, and ER is commonly expressed in both primary and metastatic breast cancers. In fact, ~75% of invasive breast cancers express ER. Thus, for patients with newly diagnosed or recurring metastatic breast cancer, the assessment of ER expression levels is standard of care, and accurate assessment can play a major role in treatment outcomes. This is because ER expression is a strong predictive factor for response to hormone therapies.16
Several drugs have been developed that inhibit ERs in different ways. Drugs that block estrogen from binding ER include tamoxifen (Nolvadex®) and fulvestrant (Faslodex®). Selective estrogen receptor modulators (SERMs) reduce estrogen levels, and include letrozole (Femara®), anastrozole (Arimidex®), and exemestane (Aromasin®). Importantly, these hormone therapies are recommended for women with ER-positive breast cancers, but they do not help women whose tumors lack ERs.
Targeted Therapies: Tamoxifen (Nolvadex®), fulvestrant (Faslodex®), letrozole (Femara®), anastrozole (Arimidex®), and exemestane (Aromasin®).
Methodology: Biocept’s ER liquid biopsy test is performed on circulating tumor cells (CTCs), using fluorescently labeled antibodies to detect ER protein.
Fibroblast growth factor receptor 1 (FGFR1) is one of four fibroblast growth factor receptors, which are involved in diverse cellular processes, such as cell division, cell growth and maturation, the formation of blood vessels, and wound healing. Up to 10% of breast cancer patients have tumors that overexpress FGFR117, and the FGFR1 gene is amplified in ~20% of patients diagnosed with squamous cell lung cancer (predominantly former/current smokers). In different types of lung cancer, such as adenocarcinoma, FGFR1 amplification is quite rare.18
Recent studies suggest that the FGFR pathway can be targeted by FGFR inhibitors, thus assessing the FGFR1 status of a tumor can help select the most beneficial pharmacologic intervention.19 There are several pharmacologic agents that have been, or are being developed to inhibit FGFR signaling. These include highly selective FGFR1 inhibitors, and multi-kinase inhibitors. Only four agents have been approved by the FDA 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®).
Targeted Therapies: Ponatinib (Iclusig®), pazopanib (Votrient®), regorafenib (Stivarga®), and lenvatinib (Lenvima®).
Methodology: Biocept’s FGFR1 liquid biopsy test is performed on circulating tumor cells (CTCs), using FISH analysis to identify FGFR1 gene rearrangements.
The human epidermal growth factor receptor 2 (HER2, also called ERBB2 or NEU) is associated with several forms of cancer. Approximately 15–30% of breast cancer patients have tumors that overexpress HER2, and 7–34% of gastric cancers are HER2 positive.20, 21 HER2 overexpression is also associated with salivary duct carcinomas.
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: 1) small molecule tyrosine kinase inhibitors, such as lapatinib (Tykerb®), 2) new HER2/HER3 antibodies, such as pertuzumab (Perjeta®), and 3) 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. Because of these efforts, HER2-positive breast cancer is no longer associated with poor prognosis if HER2-targeted therapies are administered.22 Recent guidance by the US FDA suggests that pathologic response to HER2-targeted therapy given preoperatively may allow for an earlier assessment of clinical benefit in the adjuvant setting.
Targeted Therapies: Trastuzumab (Herceptin®), pertuzumab (Perjeta®), emtansine (Kadcyla®), and lapatinib (Tykerb®).
Methodology: Biocept’s HER2 liquid biopsy test is performed on circulating tumor cells (CTCs), using FISH analysis to identify changes in HER2gene copy number.
KRAS is a member of the Ras family of small GTPases, primarily regulating cell division by helping relay signals from the cell membrane to the nucleus. Wildtype KRAS is a tumor suppressor that is frequently mutated during tumor progression.23 Once the KRAS gene mutates, it acquires oncogenic properties and seems to be causally involved in the development of various human cancers.24,25 KRAS mutations are found in ~90% of pancreatic cancers, 30–50% of colon cancers, and ~25% of lung cancers.
Activating mutations in the KRAS gene impair the ability of the KRAS protein to switch from the active to the inactive state, leading to constitutive activation, cell transformation, and increased resistance to cancer therapies (namely, chemotherapy and therapies that target EGFR). In patients with advanced colorectal cancer or NSCLC, KRAS mutations are associated with resistance to EGFR-TKIs and poor survival. In contrast, the absence of a KRAS mutation predicts a greater likelihood of response to EGFR-targeted therapies (e.g., cetuximab and panitumumab) and improved survival.26 As a result, it is important to test for mutations in the KRAS gene to determine eligibility for EGFR-targeting therapies.
A number of drug classes have been developed that target clinically actionable proteins 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 KRAS inhibitors.
Targeted Therapies: Cetuximab (Erbitux®) and panitumumab (Vectibix®)
Methodology: Biocept’s KRAS liquid biopsy test is performed on circulating tumor DNA (ctDNA) and identifies all mutations in the targeted genomic region.
MET (or c-MET) was first discovered as an oncogene that encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). MET can be mutated or overexpressed in a number of human epithelial cancers, including lung (3%), colon (5%), kidney (5%), and upper digestive system (10%). Activating the MET receptor in malignant cells activates a number of signaling transduction pathways, altering a number of biological process and driving metastasis.27, 28, 29
MET deregulation in lung cancer is associated with poor outcomes and resistance to anti-EGFR therapies.30 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 MET. These agents are dual- or multi-TKIs, blocking MET together 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). Determining which patient harbor MET mutations, and are therefore more likely to respond to MET kinase inhibitors, could contribute to better clinical outcomes.
Targeted Therapies: Crizotinib (Xalkori®), cabozantinib (Cabometyx®), cabozantinib (Exelixis®) and (Tivantinib®)
Methodology: Biocept’s MET liquid biopsy test is performed on circulating tumor cells (CTCs), using FISH analysis to identify MET gene rearrangements.
Programmed death-1 (PD-1) is an immune checkpoint receptor expressed by T cells. Expression of PD-L1 has been described for many tumor types, including melanoma, both squamous and non-squamous NSCLC, breast, ovarian, pancreatic, esophageal, kidney, bladder, and hematopoietic malignancies.35,36,37,38,39,40 Upregulation of PD-1 plays a key role in T-cell exhaustion, which hampers the ability of the immune system to destroy cancer cells. When PD-1 binds its ligand PD-L1 (programmed death ligand-1), a signal is transduced, telling the T-cell to leave other cells alone. This checkpoint is in place to protect normal cells from immune attack, but some cancer cells co-opted this system, expressing high levels of PD-L1 to evade the immune system. Detecting PD-L1 in tumor cells identifies cancer patients that may benefit from treatment with immunotherapy agents. These agents, called PD-1 or PD-L1 inhibitors (or checkpoint inhibitors) have been shown to increase immune responses to cancers and improve patient survival.41
In 2014, the FDA granted accelerated approval for pembrolizumab (Keytruda®) to treat advanced or unresectable melanoma, making it the first PD-1 inhibitor cleared in the US. Later the same year, the FDA approved nivolumab (Opdivo®) for melanoma. In 2015, nivolumab became the first immunotherapy agent approved for the treatment of lung cancer. Finally, in 2016 the FDA granted accelerated approval for the PD-L1 inhibitor, atezolizumab (Tecentriq®), to treat bladder cancer; this drug was subsequently approved for lung cancer. Other PD-1/PD-L1 targeted treatments are in clinical development, either alone or in combination with other agents, and in various types of cancer.
Targeted Therapies: Pembrolizumab (Keytruda®), nivolumab (Opdivo®), and atezolizumab (Tecentriq®)
Methodology: Biocept’s PD-L1 liquid biopsy test is performed on circulating tumor cells (CTCs), using fluorescently labeled antibodies to detect PD-L1 protein.
The progesterone receptor (PR), much like the estrogen receptor, is a nuclear receptor that is frequently expressed in breast cancer cells. Cancer cells that express PR depend on progesterone to grow, and are therefore susceptible to hormone therapy. Determining the hormone receptor status of a breast tumor is therefore an important step toward determining whether the patient is likely to respond to a targeted therapy.42Common therapies for PR-positive breast tumors either lower estrogen/progesterone levels (e.g., aromatase inhibitors) or prevent estrogen/progesterone from binding their receptors (e.g.,Tamoxifen).
Targeted Therapies: Tamoxifen (Nolvadex®) and Aromatase Inhibitors
Methodology: Biocept’s PR liquid biopsy test is performed on circulating tumor cells (CTCs), using fluorescently labeled antibodies to detect PR protein.
The RET proto-oncogene encodes a receptor tyrosine kinase whose ligand is glial cell line-derived neurotrophic factor (GDNF), as well as two other proteins highly related to GDNF. The RET gene is susceptible to rearrangements, resulting in growth-promoting chimeric or fusion proteins that are found in 10–20% of sporadic papillary thyroid carcinomas (PTCs),43 and 1–2% of NSCLCs. In NSCLC, RET rearrangements most commonly occur in the absence of mutations in EGFR, KRAS, ALK, or ROS1, and tend to affect young never-smokers. Sporadic PTC is the most common type of thyroid cancer, representing 75–80% of all thyroid cancer cases. The close association between RET rearrangements and PTC strongly suggests that they play a causative role in tumor development.
The FDA has approved multi-kinase inhibitors that exhibit activity in cancers harboring RET alterations, including cabozantinib (Cabometyx®) and vandetanib (Caprelsa®). Searches are ongoing for additional compounds that can effectively counteract RET gene rearrangements or fusions.
Targeted Therapies: Cabozantinib (Cabometyx®) and vandetanib (Caprelsa®)
Methodology: Biocept’s RET liquid biopsy is performed on circulating tumor cells, using FISH analysis to identify RET gene rearrangements.
The proto-oncogene ROS1 encodes a protein tyrosine kinase. The ROS1 gene is structurally similar to ALK, and ROS1 gene rearrangements are found in 1–2% of NSCLC cases. While the precise role played by ROS1 during normal development has not been identified, tumors harboring ROS1 fusions are remarkably responsive to TKIs.44 As a result, there is great interest in identifying ROS1 rearrangements in patients to determine which should receive TKI-based therapies. Pre-clinical and early clinical evidence suggest that tumors associated with a ROS1 rearrangement 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.
Targeted Therapies: Crizotinib (Xalkori®), ceritinib (Zykadia®), and alectinib (Alecensa®)
Methodology: Biocept’s ROS1 liquid biopsy test is performed on circulating tumor cells (CTCs), using FISH analysis to identify ROS1 gene rearrangements.
- Inamura K, Takeuchi K, Togashi Y, et al. (2009). “EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset.” Mod Pathol. 22(4):508–515.
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- Bono JS, Logothetis CJ, Molina A, et al. (2011). “Abiraterone and increased survival in metastatic prostate cancer”. N Engl J Med. 364:1995–2005.
- Sher H, Fizazi K, Saad F, et al. (2012). “Increased survival with enzalutamide in prostate cancer after chemotherapy”. N Engl J Med. 367:1187–1197.
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- Mao C, Liao RY, Qiu LX, et al. (2011). “BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis”. Mol Biol Rep. 38(4):2219–2223.
- Roth AD, Tejpar S, Delorenzi M, et al. (2010). “Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial”. J Clin Oncol. 28(3):466–474.
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