- Email: [email protected]
Future Perspectives in Cancer Screening and Early Detection
219
FUTURE PERSPECTIVES IN CANCER SCREENING AND EARLY DETECTION
A
s highlighted throughout this issue of Seminars in Oncology Nursing, cancer screening and the early detection of cancer is important to improve the survival from cancer and to decrease the morbidity associated with cancer treatment at later stages. Advances in genetic and genomic technologies have contributed to earlier detection of solid tumors in high-risk populations and holds promise for the future identification and monitoring of a variety of cancers using liquid biopsy techniques. Liquid biopsy enables detection of a variety of genetic/genomic/epigenetic molecules, such as microRNA, methylation of the DNA, and metabolic byproducts that are shed into the bloodstream by tumors. The use of these new technologies in cancer screening and early detection is under investigation and their role in this setting is still being defined. It is well known that cancer is a leading cause of death globally.1 Diagnosing and monitoring cancer is dependent on a number of diagnostic procedures. As a standard diagnostic procedure, solid tissue biopsies are invasive, potentially dangerous, and do not completely reflect the current tumor dynamics. In contrast, liquid tumor biopsy using blood is minimally invasive, safe, and amenable to serial biopsies, thereby providing the prospect of real-time cancer dynamic monitoring. Potential applications of ctDNA assays include early detection of metastatic disease, monitoring of minimal residual disease, patient selection for targeted therapies, and screening for mutations at the time of drug resistance. However, despite highly enthusiastic test-specific analytic and clinical validation metric reported in the literature, and in one case, a claim of being “. . .a new gold standard. . .”,2 disconcerting reports regarding ctDNA liquid biopsy assays are surfacing. A recent JAMA report revealed discordant results between two similar clinically available cancer genetic tests - assays that are performed on thousands of patients each year.3 One test, known as FoundationOne (Foundation Medicine Inc, Cambridge, MA), is a test based on tissue samples extracted from tumors (tDNA), the other, known as Guardant360 (Guardant Health, Redwood City, CA), is a test which gathers traces of tumor DNA from blood samples (ctDNA).4 The test results differed approximately 78% (n = 45) of the time.4 In addition, the accompanying pharmacogenomic results and recommendations differed 75% of the time.4 A recent study published in Oncotarget compared genomic alterations between tDNA and cell-free ctDNA. The results (n = 28) were shown to be discordant approximately 83% to 88% of the time, with a sensitivity of only 59.1% and a diagnostic accuracy in the range of 82% to 89%.5 Similarly, a recent study published in Clinical Cancer Research comparing 50 hotspot genes sequenced with ctDNA and tDNA reported a sensitivity of only 49.9%.6 Yet another recent study (n = 23) evaluated the concordance between a ctDNA and tDNA clinical test. Gene variants found in tumor samples were only present 25% of the time in blood test samples and the overall precision of the clinical ctDNA test was 40%.7 Consequently, it was concluded that many mutations would be missed if only cfDNA was used for analysis, and that liquid biopsies were not yet an adequate substitute for tissue biopsies.7
CHALLENGES AND LIMITATIONS First described in 1987, ctDNA is composed of small (approximately 166 bp) circulating DNA fragments that are shed into the bloodstream following apoptosis and/or necrosis of tumor cells, or via
220
FUTURE PERSPECTIVES IN CANCER SCREENING AND EARLY DETECTION
spontaneous release from cancer tissue and possibly circulating tumor cells.2,6 Stimulation of lymphocytes also results in the release of large amounts of cell-free DNA in the absence of cell death.1 The halflife of ctDNA is approximately 1.5 hours because of rapid hepatic and renal clearance.2 As highlighted by Chae et al,5 lack of concordance between ctDNA and tDNA tests may be a result of differences in assay platform, inter- and intra- tumor heterogeneity, interval treatment subclones, and potential germline DNA contamination. In addition, spatial and temporal factors can influence testing. Indeed, blood samples drawn at different times can produce different results because of differing cells populations in the blood at those times. Even the collection tube can have a notable effect on the results, especially given a small amount of starting DNA.2 Low-input DNA into a given assay can result in stochastic (irreproducible) data. The quantity of ctDNA can vary widely in cancer patients, from 0.01% to 90%.1,5 The total quantity of ctDNA can be a direct result of the type of cancer the patient has. For example, detectable ctDNA has been found to be low in patients with cancer of the brain, kidney, prostate, and thyroid.5 Tumor purity may be compromised because of the noncancerous cells in the tumor microenvironment that may also complicate the interpretation of ctDNA assays.5 Given a seemingly low specificity and a high sensitivity, variant detection of cell-free ctDNA may only be appropriate in certain situations and with certain patients. Chae et al5 suggested that ctDNA assays may be best suited to ”rule in” rather than ”rule out” certain genomic alterations. Similarly, Jovelet et al6 published a method to calculate a sensitivity prediction score for identification of patients in whom liquid biopsy would be a good surrogate biomarker when comparing tissue biopsy to ctDNA variant analysis. Larger prospective trials assessing concordance of ctDNA liquid biopsies are needed and are currently underway.5 Sun et al8 proposed the use of a technology that can identity the tissue of origin from genomic aberrations identified in plasma. One approach, known as methylation mapping, utilizes the phenomenon of tissue-specific methylation patterns.9 Consequently, genome-wide methylation (bisulfite) sequencing of plasma DNA should enable tissue-specific resolution of the cancer markers - something that would be independent of variant biomarkers.9 Using a process of deconvolution, the proportional contributions of the most important tissue types that are releasing ctDNA into the plasma could be inferred.9 Plasma DNA tissue mapping could also be inferred by copy-number variant detection. Copy number variants are genomic regions associated with significant deviation from the expected norm.10 In general, autosomal regions across the genome demonstrate a normalized status representing two copies, whereas sex chromosome-specific regions demonstrate one or two copies, as appropriate. Systematically comparing the tissue-related contribution of regions showing amplification and/or deletion in plasma for different tissue types could enable the identification of the likely source of such plasma DNA aberrations. In fact, Sun et al8 demonstrated this point as a pregnant woman undergoing noninvasive prenatal testing who exhibited plasma DNA copy-number aberrations in multiple chromosomes, which resulted in the unexpected detection of a B-cell lymphoma within the mother.
CONCLUSION While circulating tumor DNA genotyping has significant methodological and interpretive challenges and limitations that must be addressed before moving it from clinical trials, it is showing promise for use in the early detection and screening of solid tumors.11 One large validation study, the Multicenter Italian Lung Detection (MILD) trial, demonstrated that by using the combination of low-dose computed tomography and a plasma microRNA signature classifier false-positive rates of screening with low-dose computed tomography alone fell from 19.4% to 3.7%; a 5-fold reduction in the false-positive rate in patients at high risk of lung cancer.12 Though the study results hold promise, the clinical utility for this biomarker has not been proven; evidence of an impact on management of patients (ie, improved survival or decreased morbidity) will require a prospective study.13 The Early Detection Research Network14 provides information on the state of biomarker research for 10 solid tumors (head and neck, bladder, breast, prostate, ovarian, pancreas, colon, lung, esophagus, and liver). The interactive web site provides information on a variety of biomarkers from different types
FUTURE PERSPECTIVES IN CANCER SCREENING AND EARLY DETECTION
221
of cancer that are being investigated for use in early detection. These include genes (390), proteins (567), genetic (1), genomics (45), epigenetic (1), and proteomic (4) markers. For lung cancer, 174 biomarkers, primarily genetic, including miRNA, and proteins have been identified. Prostate cancer research has yielded the largest number of biomarkers to date, with a total of 387 potential biomarkers; 89% of which are genes. Ovarian cancer biomarkers are the second highest with 202 proteins and one gene. Breast cancer research has identified 189 proteins plus two genes and two genetic molecules.14 Overall, more proteins have been identified to have potential as biomarkers in early detection for five of the 10 cancers described; ovarian cancer, then breast, lung, and prostate, respectively. Genetic biomarkers have been primarily identified for prostate cancer, with a few described for lung, head and neck, breast, and ovarian malignancies. Other biomarkers of genomic, genetic, epigenetic (such as methylation) and proteomic changes have been identified, in that order.14 New technologies for early detection and screening of solid tumors are coming and already available through industry. Not all are currently approved by the US Food and Drug Administration for use in patient care (only research and clinical trials), but nurses, like other health care providers, should be aware of new products, their appropriate use, and the status of approval of their implementation. For example, 23andMe offers testing for BRCA1 and BRCA2 mutations, but only for the three variants (single sites) associated with Hereditary Breast and Ovarian Cancer Syndrome in women with an Ashkenazi Jewish heritage. Their web site now clarifies that it is not equivalent to clinical testing of these two genes and encourages individuals with a strong family history of breast and/or ovarian cancer to consult a physician or a genetics health care provider for guidance about genetic testing.15 Nurses knowledgeable in genetics/genomics and the evolving use in oncology clinical practice, like microRNA from circulating tumor cells, are poised to assist patients to comprehend the rationale of new approaches to screening and early detection of cancer. The hallmark of cancer early detection and screening is to shift the diagnosis of cancer to an earlier stage to improve survival and decrease the morbidity associated with cancer diagnosed at a later stage. There are many biomarkers in development with the potential to shift a cancer diagnosis to an earlier stage. Oncology nurses have an exciting opportunity to apply this new knowledge into their everyday practice of caring for patients who are at risk of developing cancer as the technologies mature and are ready for translation into clinical practice.
REFERENCES 1. Qin Z, Ljubimov VA, Zhou C, Tong Y, Liang J. Cell-free circulating tumor DNA in cancer. Chinese J Cancer. 2016;35:36. 2. Lanman RB, Mortimer SA, Zill OA, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS ONE. 2015;10:1-27. 3. Kuderer NM, Burton KA, Blau S, et al. Comparison of 2 commercially available next-generation sequencing platforms in oncology. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2016.4983. [Epub ahead of print]. 4. Harris R. When genetic tests disagree about best option for cancer treatment. National Public Radio. 2016. Available at: http://www.npr.org/sections/health-shots/2016/12/16/505864740/when-genetic-tests-disagree-about-best-option-for-cancer-treatment. Accessed 21 February 2017. 5. Chae YK, Davis AA, Carneiro BA, et al. Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA. Oncotarget. 2016;7:65364-65373. 6. Jovelet C, Ileana E, Le Deley M, et al. Circulating cell-free DNA tumor DNA analysis of 50 genes by next-generation sequencing in the prospective MOSCATO Trial. Clin Cancer Res. 2016;22:2960-2968. 7. Pishvaian MJ, Bender RJ, Matrisian LM, et al. A pilot study evaluating concordance between blood-based and patientmatched tumor molecular testing within pancreatic cancer patients participating in the Know Your Tumor (KYT) initiative. Oncotarget. 2016;November, 2016: 1-11;doi:10.18632/oncotarget.13225. 8. Sun K, Jiang P, Chan KC, et al. Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer and transplantation assessments. Proc Natl Acad Sci USA. 2015;112:E5503-E5512. 9. Lo YM. Noninvasive prenatal testing complicated by maternal malignancy: new tools for a complex problem. Npj Genomic Medicine. 2016;1:15002. 10. Bianchi DW, Chudova D, Sehnert AJ, et al. Noninvasive prenatal testing and incidental detection of occult maternal malignancies. Obstet Gynecol Survey. 2015;70:744-746. 11. Zhang S. One patient, two cancer DNA tests, two different results. 2016. The Atlantic. Available at: https://www.theatlantic.com/ health/archive/2016/12/cancer-biopsy-genetic-test/510656/. Accessed 21 February 2017. 12. Sozzi G, Boeri M, Rossi M, et al. Clinical utility of a plasma-based miRNA signature classifier within computed tomography lug cancer screening: a correlative MILD trial study. J Clin Oncol. 2014;32:768-773. 13. Massion P. Biomarkers to the rescue in a lung nodule epidemic. J Clin Oncol. 2014;32:725-726.
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FUTURE PERSPECTIVES IN CANCER SCREENING AND EARLY DETECTION
14. National Cancer Institute. Early Detection Research Network. 2017. Available at: https://edrn.nci.nih.gov/biomarkers#b_start=0&c0. Accessed 23 February 2017. 15. 23andMe. Available at: https://eu.customercare.23andme.com/hc/en-us/articles/204462364-Does-the-23andMe-serviceinclude-analysis-of-the-BRCA-gene- (accessed 23 February 2017).
Adam Coovadia, MS, MBA, MG(ASCP), CG(ASCP) Healthcare Genetics doctoral student, Clemson University, Clemson, SC Julia A. Eggert, PhD, AGN-BC, AOCN®, FAAN Professor, Coordinator Healthcare Genetics doctoral program, Clemson University, School of Nursing, Clemson, SC © 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.soncn.2017.02.010
FUTURE PERSPECTIVES IN CANCER SCREENING AND EARLY DETECTION
A
s highlighted throughout this issue of Seminars in Oncology Nursing, cancer screening and the early detection of cancer is important to improve the survival from cancer and to decrease the morbidity associated with cancer treatment at later stages. Advances in genetic and genomic technologies have contributed to earlier detection of solid tumors in high-risk populations and holds promise for the future identification and monitoring of a variety of cancers using liquid biopsy techniques. Liquid biopsy enables detection of a variety of genetic/genomic/epigenetic molecules, such as microRNA, methylation of the DNA, and metabolic byproducts that are shed into the bloodstream by tumors. The use of these new technologies in cancer screening and early detection is under investigation and their role in this setting is still being defined. It is well known that cancer is a leading cause of death globally.1 Diagnosing and monitoring cancer is dependent on a number of diagnostic procedures. As a standard diagnostic procedure, solid tissue biopsies are invasive, potentially dangerous, and do not completely reflect the current tumor dynamics. In contrast, liquid tumor biopsy using blood is minimally invasive, safe, and amenable to serial biopsies, thereby providing the prospect of real-time cancer dynamic monitoring. Potential applications of ctDNA assays include early detection of metastatic disease, monitoring of minimal residual disease, patient selection for targeted therapies, and screening for mutations at the time of drug resistance. However, despite highly enthusiastic test-specific analytic and clinical validation metric reported in the literature, and in one case, a claim of being “. . .a new gold standard. . .”,2 disconcerting reports regarding ctDNA liquid biopsy assays are surfacing. A recent JAMA report revealed discordant results between two similar clinically available cancer genetic tests - assays that are performed on thousands of patients each year.3 One test, known as FoundationOne (Foundation Medicine Inc, Cambridge, MA), is a test based on tissue samples extracted from tumors (tDNA), the other, known as Guardant360 (Guardant Health, Redwood City, CA), is a test which gathers traces of tumor DNA from blood samples (ctDNA).4 The test results differed approximately 78% (n = 45) of the time.4 In addition, the accompanying pharmacogenomic results and recommendations differed 75% of the time.4 A recent study published in Oncotarget compared genomic alterations between tDNA and cell-free ctDNA. The results (n = 28) were shown to be discordant approximately 83% to 88% of the time, with a sensitivity of only 59.1% and a diagnostic accuracy in the range of 82% to 89%.5 Similarly, a recent study published in Clinical Cancer Research comparing 50 hotspot genes sequenced with ctDNA and tDNA reported a sensitivity of only 49.9%.6 Yet another recent study (n = 23) evaluated the concordance between a ctDNA and tDNA clinical test. Gene variants found in tumor samples were only present 25% of the time in blood test samples and the overall precision of the clinical ctDNA test was 40%.7 Consequently, it was concluded that many mutations would be missed if only cfDNA was used for analysis, and that liquid biopsies were not yet an adequate substitute for tissue biopsies.7
CHALLENGES AND LIMITATIONS First described in 1987, ctDNA is composed of small (approximately 166 bp) circulating DNA fragments that are shed into the bloodstream following apoptosis and/or necrosis of tumor cells, or via
220
FUTURE PERSPECTIVES IN CANCER SCREENING AND EARLY DETECTION
spontaneous release from cancer tissue and possibly circulating tumor cells.2,6 Stimulation of lymphocytes also results in the release of large amounts of cell-free DNA in the absence of cell death.1 The halflife of ctDNA is approximately 1.5 hours because of rapid hepatic and renal clearance.2 As highlighted by Chae et al,5 lack of concordance between ctDNA and tDNA tests may be a result of differences in assay platform, inter- and intra- tumor heterogeneity, interval treatment subclones, and potential germline DNA contamination. In addition, spatial and temporal factors can influence testing. Indeed, blood samples drawn at different times can produce different results because of differing cells populations in the blood at those times. Even the collection tube can have a notable effect on the results, especially given a small amount of starting DNA.2 Low-input DNA into a given assay can result in stochastic (irreproducible) data. The quantity of ctDNA can vary widely in cancer patients, from 0.01% to 90%.1,5 The total quantity of ctDNA can be a direct result of the type of cancer the patient has. For example, detectable ctDNA has been found to be low in patients with cancer of the brain, kidney, prostate, and thyroid.5 Tumor purity may be compromised because of the noncancerous cells in the tumor microenvironment that may also complicate the interpretation of ctDNA assays.5 Given a seemingly low specificity and a high sensitivity, variant detection of cell-free ctDNA may only be appropriate in certain situations and with certain patients. Chae et al5 suggested that ctDNA assays may be best suited to ”rule in” rather than ”rule out” certain genomic alterations. Similarly, Jovelet et al6 published a method to calculate a sensitivity prediction score for identification of patients in whom liquid biopsy would be a good surrogate biomarker when comparing tissue biopsy to ctDNA variant analysis. Larger prospective trials assessing concordance of ctDNA liquid biopsies are needed and are currently underway.5 Sun et al8 proposed the use of a technology that can identity the tissue of origin from genomic aberrations identified in plasma. One approach, known as methylation mapping, utilizes the phenomenon of tissue-specific methylation patterns.9 Consequently, genome-wide methylation (bisulfite) sequencing of plasma DNA should enable tissue-specific resolution of the cancer markers - something that would be independent of variant biomarkers.9 Using a process of deconvolution, the proportional contributions of the most important tissue types that are releasing ctDNA into the plasma could be inferred.9 Plasma DNA tissue mapping could also be inferred by copy-number variant detection. Copy number variants are genomic regions associated with significant deviation from the expected norm.10 In general, autosomal regions across the genome demonstrate a normalized status representing two copies, whereas sex chromosome-specific regions demonstrate one or two copies, as appropriate. Systematically comparing the tissue-related contribution of regions showing amplification and/or deletion in plasma for different tissue types could enable the identification of the likely source of such plasma DNA aberrations. In fact, Sun et al8 demonstrated this point as a pregnant woman undergoing noninvasive prenatal testing who exhibited plasma DNA copy-number aberrations in multiple chromosomes, which resulted in the unexpected detection of a B-cell lymphoma within the mother.
CONCLUSION While circulating tumor DNA genotyping has significant methodological and interpretive challenges and limitations that must be addressed before moving it from clinical trials, it is showing promise for use in the early detection and screening of solid tumors.11 One large validation study, the Multicenter Italian Lung Detection (MILD) trial, demonstrated that by using the combination of low-dose computed tomography and a plasma microRNA signature classifier false-positive rates of screening with low-dose computed tomography alone fell from 19.4% to 3.7%; a 5-fold reduction in the false-positive rate in patients at high risk of lung cancer.12 Though the study results hold promise, the clinical utility for this biomarker has not been proven; evidence of an impact on management of patients (ie, improved survival or decreased morbidity) will require a prospective study.13 The Early Detection Research Network14 provides information on the state of biomarker research for 10 solid tumors (head and neck, bladder, breast, prostate, ovarian, pancreas, colon, lung, esophagus, and liver). The interactive web site provides information on a variety of biomarkers from different types
FUTURE PERSPECTIVES IN CANCER SCREENING AND EARLY DETECTION
221
of cancer that are being investigated for use in early detection. These include genes (390), proteins (567), genetic (1), genomics (45), epigenetic (1), and proteomic (4) markers. For lung cancer, 174 biomarkers, primarily genetic, including miRNA, and proteins have been identified. Prostate cancer research has yielded the largest number of biomarkers to date, with a total of 387 potential biomarkers; 89% of which are genes. Ovarian cancer biomarkers are the second highest with 202 proteins and one gene. Breast cancer research has identified 189 proteins plus two genes and two genetic molecules.14 Overall, more proteins have been identified to have potential as biomarkers in early detection for five of the 10 cancers described; ovarian cancer, then breast, lung, and prostate, respectively. Genetic biomarkers have been primarily identified for prostate cancer, with a few described for lung, head and neck, breast, and ovarian malignancies. Other biomarkers of genomic, genetic, epigenetic (such as methylation) and proteomic changes have been identified, in that order.14 New technologies for early detection and screening of solid tumors are coming and already available through industry. Not all are currently approved by the US Food and Drug Administration for use in patient care (only research and clinical trials), but nurses, like other health care providers, should be aware of new products, their appropriate use, and the status of approval of their implementation. For example, 23andMe offers testing for BRCA1 and BRCA2 mutations, but only for the three variants (single sites) associated with Hereditary Breast and Ovarian Cancer Syndrome in women with an Ashkenazi Jewish heritage. Their web site now clarifies that it is not equivalent to clinical testing of these two genes and encourages individuals with a strong family history of breast and/or ovarian cancer to consult a physician or a genetics health care provider for guidance about genetic testing.15 Nurses knowledgeable in genetics/genomics and the evolving use in oncology clinical practice, like microRNA from circulating tumor cells, are poised to assist patients to comprehend the rationale of new approaches to screening and early detection of cancer. The hallmark of cancer early detection and screening is to shift the diagnosis of cancer to an earlier stage to improve survival and decrease the morbidity associated with cancer diagnosed at a later stage. There are many biomarkers in development with the potential to shift a cancer diagnosis to an earlier stage. Oncology nurses have an exciting opportunity to apply this new knowledge into their everyday practice of caring for patients who are at risk of developing cancer as the technologies mature and are ready for translation into clinical practice.
REFERENCES 1. Qin Z, Ljubimov VA, Zhou C, Tong Y, Liang J. Cell-free circulating tumor DNA in cancer. Chinese J Cancer. 2016;35:36. 2. Lanman RB, Mortimer SA, Zill OA, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS ONE. 2015;10:1-27. 3. Kuderer NM, Burton KA, Blau S, et al. Comparison of 2 commercially available next-generation sequencing platforms in oncology. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2016.4983. [Epub ahead of print]. 4. Harris R. When genetic tests disagree about best option for cancer treatment. National Public Radio. 2016. Available at: http://www.npr.org/sections/health-shots/2016/12/16/505864740/when-genetic-tests-disagree-about-best-option-for-cancer-treatment. Accessed 21 February 2017. 5. Chae YK, Davis AA, Carneiro BA, et al. Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA. Oncotarget. 2016;7:65364-65373. 6. Jovelet C, Ileana E, Le Deley M, et al. Circulating cell-free DNA tumor DNA analysis of 50 genes by next-generation sequencing in the prospective MOSCATO Trial. Clin Cancer Res. 2016;22:2960-2968. 7. Pishvaian MJ, Bender RJ, Matrisian LM, et al. A pilot study evaluating concordance between blood-based and patientmatched tumor molecular testing within pancreatic cancer patients participating in the Know Your Tumor (KYT) initiative. Oncotarget. 2016;November, 2016: 1-11;doi:10.18632/oncotarget.13225. 8. Sun K, Jiang P, Chan KC, et al. Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer and transplantation assessments. Proc Natl Acad Sci USA. 2015;112:E5503-E5512. 9. Lo YM. Noninvasive prenatal testing complicated by maternal malignancy: new tools for a complex problem. Npj Genomic Medicine. 2016;1:15002. 10. Bianchi DW, Chudova D, Sehnert AJ, et al. Noninvasive prenatal testing and incidental detection of occult maternal malignancies. Obstet Gynecol Survey. 2015;70:744-746. 11. Zhang S. One patient, two cancer DNA tests, two different results. 2016. The Atlantic. Available at: https://www.theatlantic.com/ health/archive/2016/12/cancer-biopsy-genetic-test/510656/. Accessed 21 February 2017. 12. Sozzi G, Boeri M, Rossi M, et al. Clinical utility of a plasma-based miRNA signature classifier within computed tomography lug cancer screening: a correlative MILD trial study. J Clin Oncol. 2014;32:768-773. 13. Massion P. Biomarkers to the rescue in a lung nodule epidemic. J Clin Oncol. 2014;32:725-726.
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FUTURE PERSPECTIVES IN CANCER SCREENING AND EARLY DETECTION
14. National Cancer Institute. Early Detection Research Network. 2017. Available at: https://edrn.nci.nih.gov/biomarkers#b_start=0&c0. Accessed 23 February 2017. 15. 23andMe. Available at: https://eu.customercare.23andme.com/hc/en-us/articles/204462364-Does-the-23andMe-serviceinclude-analysis-of-the-BRCA-gene- (accessed 23 February 2017).
Adam Coovadia, MS, MBA, MG(ASCP), CG(ASCP) Healthcare Genetics doctoral student, Clemson University, Clemson, SC Julia A. Eggert, PhD, AGN-BC, AOCN®, FAAN Professor, Coordinator Healthcare Genetics doctoral program, Clemson University, School of Nursing, Clemson, SC © 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.soncn.2017.02.010