Clinical Data

Multi-gene panel testing provides additional information that may improve patient outcomes.

“We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. […] The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone.”

Howarth DR, et al. Initial results of multigene panel testing for hereditary breast and ovarian cancer and Lynch syndrome. Am Surg 2015 Oct; 81(10):941-4.

Patients with hereditary cancer syndromes are at high risk for a second primary cancer.

“Of patients with Hereditary Breast and Ovarian Cancer (HBOC) and Lynch syndrome (LS), 56 and 65.2%, respectively, met the National Comprehensive Cancer Network guidelines for hereditary cancer testing after their initial diagnosis based on their personal cancer history alone. A substantial number of women tested for LS or HBOC after being diagnosed with two successive primary cancers were diagnosed with a hereditary cancer syndrome. In many cases, the time interval between the diagnoses was long enough to allow for the implementation of surveillance and/or prophylactic measures.”

Saam J, et al. Hereditary cancer-associated mutations in women diagnosed with two primary cancers: an opportunity to identify hereditary cancer syndromes after the first cancer diagnosis. Oncology 2015; 88(4):226-33.

Multigene testing is likely to alter cancer risk assessment, clinical management, and familial testing recommendations.

“Multigene panel testing for patients with suspected HBOC risk identifies substantially more individuals with relevant cancer risk gene mutations than does BRCA1/2 testing alone. Identifying such mutations is likely to change management for the majority of these individuals and their families in the near term, and in the long term should lead to development of effective management guidelines and improved outcomes for at-risk individuals.”

Desmond A, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol 2015; 1(7):943-951.

Medical management changes occurred 77.8% of the time after a MyRisk positive result and 25.3% after a negative result.

“Integrating personal and family cancer history identified during the screening process with genetic test results can offer refined management recommendations. Over 74% of physicians used both the genetic test result and the personal and family cancer history from the MyRisk management tool (MMT) to make management decisions.”

Langer LR, et al. 25-Gene panel testing and integrated risk management tool impacts medical management in hereditary cancer syndrome evaluation. Scientific poster presented at the American Society for Clinical Oncology Annual Meeting in Chicago, IL, June 2014.

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Up to 50% of clinically significant findings missed by single-syndrome testing.

“Multi-gene hereditary cancer testing detected >1 pathogenic variants (PVs) in 6.7% of individuals. PVs were most common in BRCA1 and BRCA2 (42.2%) and 5 additional breast cancer-risk genes (32.9%). Up to 50% of all clinically significant findings would have been missed by single-syndrome testing.”

Rosenthal ET, et al. Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. Cancer Genetics 2017; 218-219:58-68.

Next generation sequencing (NGS) detects germline and somatic variants.

“Given the significant phenotypic overlap of many hereditary cancer syndromes, NGS panels enable the simultaneous analysis of multiple genes associated with increased cancer risks […]. This enables medical management decisions to be informed by gene-specific guidelines based on known risks associated with germline variants. However, the quantitative nature of NGS also enables the detection of somatic variants that may complicate genetic test interpretation.”

Coffee B, et al. Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel. Cancer Genetics 2017; 211:5-8.

Using a panel test could prevent inaccurate, or even limited, family histories from restricting testing options.

“Offering hereditary panel testing as a first and final, ‘single-tier’, option was explored. A ‘two-tiered’ approach, in which panel testing is offered reflexively following stricter criteria, was then applied to the same data. Within our cohort of 105 patients, the single-tier approach was associated with a higher mutation detection rate (6.7% vs 3.8%) and variant of uncertain significance (VUS) rate (0.94 vs 0.23 average per person) compared to a two-tiered approach.”

Yorczyk A, et al. Use of panel tests in place of single gene tests in the cancer genetics clinic. Clin Genet 2015 Sep; 88(3):278-82.

Many syndromes present with overlapping cancers – and have no distinct, recognizable phenotypes.

“Our data demonstrate a substantial phenotypic overlap among patients for multiple common inherited cancer syndromes, which likely complicates diagnosis and test selection. This supports the value of multigene panels to identify pathogenic mutations in the absence of a clinically specific phenotype.”

Saam J, et al. Patients tested at a laboratory for hereditary cancer syndromes show an overlap for multiple syndromes in their personal and familial cancer histories. Oncology 2015; 89(5):288-93.

NGS and Sanger sequencing were 100% concordant for the 3,923 collective variants across all genes.

“This study provides a thorough validation of the 25-gene NGS panel and indicates that this analysis tool can be used to collect clinically significant information related to risk of developing hereditary cancers.”

Judkins T, et al. Development and analytical validation of a 25-gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk. BMC Cancer 2015 Apr 2; 15:215.

Clinical Utility of Hereditary Cancer Panel Testing: Impact of PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D

“Testing for PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D changed management for those carrying PVs. Provider recommendations were aligned with guidelines, and patients adhered to recommendations, both of which are critical for reducing both long‐term cancer morbidity and mortality.”

Vysotskaia, et al. Clinical Utility of Hereditary Cancer Panel Testing: Impact of PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D Results on Patient Management and Adherence to Provider Recommendations. Cancer, 04 November 2019; https://doi.org/10.1002/cncr.32572.

Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk

“34% of the positive results were not included in the pre-test differential diagnoses generated by genetics experts, based on patient history.”

Idos, et al. Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk. JCO Precision Oncology, March 28, 2019; DOI: 10.1200/PO.18.00217.

Individuals with MSH6 and PMS2 mutations may present with HBOC phenotype.

“These results provide a new perspective on Lynch syndrome and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer (HBOC) phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with mismatch repair (MMR) mutations.”

Espenschied CR, et al. Multigene panel testing provides a new perspective on Lynch syndrome. J Clin Oncol 2017, 35.

Multigene panels should be used for the assessment of cancer risk beyond the classic predisposition syndromes.

“The use of multigene testing in the clinical setting will better define both the optimal care of patients with cancer (management of the primary cancer; definition of risk of second malignancies; and assignment of specific treatments like PARP inhibitors) and the management of unaffected individuals (earlier surveillance, chemoprevention and/or prophylactic surgery).”

Graffeo R, et al. Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care. Breast Cancer Res Treat 2016 Dec; 160(3):393-410. Epub 2016 Oct 12.

Clinical utility of panel testing in BRCA negative patients.

“This study demonstrates the clinical utility of multigene panels in a group of high risk individuals who previously tested negative for a BRCA1/2 mutation. This retesting approach revealed a pathogenic mutation in 11% of cases. Retesting led to significant change in clinical management in a majority of patients with actionable mutations (7 out of 11), as well as in those with mutations in genes which do not have specific management guidelines.”

Yadav S, et al. Outcomes of retesting BRCA negative patients using multigene panels. Fam Cancer 2016 Nov 22; 16(3): 319-28. doi:10.1007/s10689-016-9956-7.

Up to 79% of women from BRCA negative families desire multiplex genetic testing.

“Female first-degree relatives of breast cancer patients who tested negative for BRCA1/2 mutations (N = 149) completed a survey assessing multiplex genetic testing interest and risk communication preferences. Interest in testing was high (70%) and even higher if results could guide risk-reducing behavior changes such as taking medications (79%).”

Flores KG, et al. Factors associated with interest in gene-panel testing and risk communication preferences in women from BRCA1/2 negative families. J Genet Counsel 2016 Aug; 26(3): 480-90.doi:10.1007/s10897-016-0001-7.

70% of physicians changed management based on panel results.

“Multi-gene panel testing increases the yield of mutations detected and adds to the capability of providing individualized cancer risk assessment.”

Ricker C, et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Genetics 2016 April; 209(4):130-7.

Testing beyond a negative BRCA 1/2 result using multi-gene sequencing leads to greater detection of pathogenic mutations.

“Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp.”

Kurian AW, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014 Jul 1; 32(19):2001-9.

Greater sensitivity prevents more cancer, saving healthcare dollars.

“Compared with alternative tests, using BRACAnalysis® would save $624,000 and prevent 9 [breast cancer] and/or [ovarian cancer] cases per year for a 1-million member health system.”

Stenehjem D, et al. Economic analysis of alternative genetic tests for BRCA1 and BRCA2 mutations. Scientific poster presented at the 31st Annual Breast Cancer Conference in Miami, FL, March 2014.

Risk-reducing surgery improves mortality rates.

“Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.”

Domcheck S, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010; 304(9):967-75.

Department of Veterans Affairs (VA)-sponsored PRIME Care Trial demonstrates utility of GeneSight.

• When clinicians did NOT have access to GeneSight test results, their patients were approximately two times more likely to be prescribed medications with significant GDIs compared to when clinicians had access.
• When prescribing decisions could be informed by GeneSight, patients experienced a 28% greater likelihood of achieving depression remission over 24 weeks compared to TAU.

Oslin DW, et al. Effect of pharmacogenomic testing for drug-gene interactions on medication selection and remission of symptoms in major depressive disorder. The PRIME Care randomized clinical trial. JAMA. 2022;328(2):151-161.

Among older adults with depression, those in the GeneSight cohort had improved outcomes compared to TAU.

“[G]uided-care showed significantly improved response (Δ=13.6%, t=2.16, df=187; p=0.032) and remission (Δ=12.7%, t=2.49, df = 189; p=0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions […].”

Forester BP, et al. Combinatorial pharmacogenomic testing improves outcomes for older adults with depression. Am J Geriatr Psychiatry. 2020 Sep;28(9):933-945.

GeneSight cohort had better results in every category over the control group: symptom improvement, response, and remission.

“Although previous meta-analyses have demonstrated the utility of pharmacogenomic testing, the generalizability of those findings are limited by substantive differences in the individual pharmacogenomic tests. This meta-analysis of four studies reporting on the clinical utility of GeneSight Psychotropic testing demonstrates that utilization of this pharmacogenomic test to inform treatment decisions for patients with MDD with at least one prior medication failure is associated with improved patient outcomes compared with unguided care. This was true for all patient outcomes evaluated, including symptom improvement, response and remission.”

Brown LC, et al. Clinical utility of combinatorial pharmacogenetic testing for patients with depression: a meta-analysis. Pharmacogenomics. 2020 Jun;21(8):559-569.

HAM-D6 had improved outcomes when comparing two active MDD treatment arms, as within the GUIDED trial.

“The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms.”

Dunlop BW, et al. Comparing sensitivity to change using the 6-item versus the 17-item Hamilton Depression Rating Scale in the GUIDED randomized controlled trial. BMC Psychiatry 2019; 19:420.

Remission, response, and symptom improvement were statistically significant in the GeneSight-guided cohort when compared to the control group.

“By identifying and focusing on the patients with predicted gene-drug interactions, use of a combinatorial pharmacogenomic test significantly improved outcomes among patients with MDD who had at least 1 prior medication failure.”

Thase ME, et al. Impact of pharmacogenomics on clinical outcomes for patients taking medications with gene-drug interactions in a randomized, controlled trial. J Clin Psychiatry 2019;80(6).

50% improvement in remission with GeneSight-guided care.

“[T]his randomized controlled trial found that weighted and combined multi-gene pharmacogenomic testing significantly increased clinical response and remission rates for patients with Major Depressive Disorder in the guided-care arm versus Treatment As Usual. Pharmacogenomic testing predominantly helped those patients whose treatment resistance may have been related to genetically incongruent medications. Without testing, patients and clinicians are unaware of potential ongoing gene-drug interactions.”

Greden JF, et al. Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res 2019, 111:59-67.

Patients treated by primary care physicians improved more with GeneSight-guided care than those treated by psychiatrists.

“When outcomes were considered separately for patients < 65 and ≥ 65 years of age, all outcomes were significantly improved for patients treated by primary care providers compared to psychiatrists, regardless of age group.”

Tanner JA, et al. Combinatorial pharmacogenomics and improved patient outcomes in depression: Treatment by primary care physicians or psychiatrists. Journal of Psychiatric Research 2018; 104:157–62.

RCT showed 73% higher response rate in GeneSight-guided arm compared to unguided TAU arm.

“In the GeneSight arm, 36.0% of subjects were responders, which was defined as a 50% reduction in HAMD-17 at ten weeks, compared to 20.8% in the TAU [treatment as usual] arm (OR=2.14; 95% CI: 0.59-7.69). In the GeneSight arm, 20.0% achieved remission, defined as HAMD-17 less than or equal to 7, at ten weeks compared with the TAU arm at 8.3% (OR=2.75; 95% CI: 0.48-15.80).”

Winner JG, et al. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomic testing for major depressive disorder. Discov Med 2013 Nov; 16(89):219-27.

Faster reduction of symptoms observed in GeneSight-directed patients.

“The guided group experienced greater percent improvement in depression scores from baseline on all three depression instruments […] compared with the unguided group. Eight-week response rates were higher in the guided group than in the unguided group on all three measurements […]. Eight-week QIDS-C16 remission rates were higher in the guided group (P = 0.03). Participants in the unguided group who at baseline were prescribed a medication that was most discordant with their genotype experienced the least improvement compared with other unguided participants (HAMD-17, P = 0.007). Participants in the guided group and on a baseline medication most discordant with their genotype showed the greatest improvement compared with the unguided cohort participants (HAMD-17, P = 0.01).”

Hall-Flavin DK, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics 2013 Oct; 23(10):535-48.

GeneSight subjects achieved greater reduction in depression symptoms.

“The reduction in depressive symptoms achieved within the guided treatment group was greater than the reduction of depressive symptoms in the unguided treatment group using either the QIDS-C16 (P¼0.002) or HAM-D17 (P¼0.04).”

Hall-Flavin DK, et al. Using a pharmacogenomic algorithm to guide the treatment of depression. Transl Psychiatry 2012 Oct; 2(10): e172.

GeneSight improved antidepressant responders by 71%.

“Providing clinicians with the GeneSight interpretive report improved the proportion of antidepressant responders by 71% as compared with unguided patients. A 2.26-fold increase in the odds of clinical response was also found for the guided patients as compared with the unguided patients. These improvements paralleled changes in drug dosing or selection, in that a greater proportion of guided patients experienced medication changes. These changes resulted in 40% of the guided patients initially on red-category medications being shifted to yellow- or green-category medications, and 35% more patients prescribed green-category medications, by the study end.”

Altar CA, et al. Clinical utility of combinatorial pharmacogenomics-guided antidepressant therapy: evidence from three clinical studies. Mol Neuropsychiatry 2015; 1:125-55.

Only GeneSight predicted variation in outcomes for patients with depression.

“In summary, this evaluation of clinical validity shows that only the combinatorial pharmacogenomic test was significantly associated with improved patient outcomes. In addition, the combinatorial pharmacogenomic test was a superior predictor of medication blood levels across a larger group of medications relative to guidelines focused on only CYP2C19 and CYP2D6.”

Rothschild A, et al. Clinical validation of combinatorial pharmacogenomic testing and single-gene guidelines in predicting psychotropic medication blood levels and clinical outcomes in patients with depression. Psychiatry Res. 2021 Feb; 296:113649.

GeneSight predicts blood levels in patients with MDD better than historical single-gene analysis.

“With this combinatorial pharmacogenomic test, more patients were identified as appropriate candidates for clinically actionable dosing changes for citalopram and escitalopram from comprehensive and predictive information compared to single-gene testing and CPIC classifications.”

Shelton RC, et al. Combinatorial pharmacogenetic algorithm is predictive of citalopram and escitalopram metabolism in patients with MDD. Psychiatry Res. 2020 Aug;290:113017.

Combinatorial pharmacogenomic (CPGx™) GeneSight method predicts healthcare outcomes better than traditional, single-gene analysis.

“Multigenic combinatorial testing discriminates and predicts the poorer antidepressant outcomes and greater health-care utilizations by depressed subjects better than do phenotypes derived from single genes.”

Altar CA, et al. Clinical validity: combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes. Pharmacogenomics J 2015; 15:443-51.

Study validates analytical performance of combinatorial pharmacogenomics test.

“[C]ombinatorial pharmacogenomics test […] aid[s] in the appropriate medication selection for neuropsychiatric conditions. This study demonstrates that the combinatorial pharmacogenomics test is robust and reproducible, making it suitable for clinical use.”

Jablonski MR, et al. Analytical validation of a psychiatric pharmacogenomic test. Per Med 2018; 15(3): 189-97.

Pharmacogenetics improves the efficacy and/or safety of drug therapy for a subset of the total patient population.

“The benefit of pharmacogenetic-informed prescribing is not distributed uniformly across a cohort but is derived from a minority of patients.”

Suthers GK and Polasek TM. Letter to the editor: reply to Bousman et al. Pharmacogenomics 2019 Oct;20(15):1061-1062.

Most prescribing decisions were congruent with the test results.

“Between 10/6/2014 and 2/1/2018, 181 veterans underwent psychotropic PGx testing. The majority (68%) had a diagnosis of depression and 12% had a diagnosis of schizophrenia or bipolar disorder. Provider actions trended towards starting green bin medications and stopping red bin medications, although there were exceptions.”

Hull LE, et al. Early adoption of pharmacogenetic testing for veterans prescribed psychotropic medications. Pharmacogenomics 2019 Jul;20(11):781-9.

A ‘tipping point’ of evidence in support of pharmacogenetic-guided DSTs for antidepressant prescribing has been reached, particularly in the context of moderate to severe depression.

“Individuals receiving pharmacogenetic-guided DST therapy (n = 887) were 1.71 (95% CI: 1.17–2.48; p = 0.005) times more likely to achieve symptom remission relative to individuals who received treatment as usual (n = 850). Pharmacogenetic-guided DSTs might improve symptom remission among those with MDD.”

Bousman CA, et al. Pharmacogenetic tests and depressive symptom remission: a meta-analysis of randomized controlled trials. Pharmacogenomics 2019 Jan; 20(1):37-47.

While many tests can fall into the category of pharmacogenomic testing for mental health, they generate different results. These tests cannot be lumped together as a class and should be reviewed independently.

“The level of disagreement in medication recommendations across the pharmacogenetic decision support tools (DSTs) indicates that these tests cannot be assumed to be equivalent or interchangeable.”

Bousman CA and Dunlop BW. Genotype, phenotype, and medication recommendation agreement among commercial pharmacogenomic-based decision support tools. The Pharmacogenomics Journal 2018; 18:613–22.

Previous research suggests 6-item Hamilton Depression Rating Scale (HAM-D6) more sensitive than HAM-D17 at detecting differences between antidepressants and placebo.

“According to the published literature, HAM-D6 has proven to be superior to both HAM-D17 and MADRS in terms of scalability (each item contains unique information regarding syndrome severity), transferability (scalability is constant over time and irrespective of sex, age, and depressive subtypes), and responsiveness (sensitivity to change in severity during treatment).”

Timmerby N, et al. A systemic review of the clinimetric properties of the 6-item version of the Hamilton Depression Rating Scale (HAM-D6). Psychother Psychosom 2017;86:141–9.

Treatment-resistant depression (TRD) exacts substantial toll on quality of life and heavy price in treatment costs.

“Treatment-resistant depression exacts a heavy price in treatment costs and lost productivity, reaching into the tens of billions of dollars, but its effects on the lives of patients are just as devastating. In this literature review, the authors summarize 62 studies documenting the disease’s toll on quality of life, personal financial resources, and general health. The average patient in the included studies had experienced nearly four earlier episodes of depression, had not responded to 4.7 drug trials, and continued to meet or nearly meet criteria for severe depression.”

Mrazek DA, et al. A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv 2014 Aug 1; 65(8):977-87.

TRD associated with higher per-patient medical costs.

“The classification of TRD had a clinically meaningful and statistically significant association with increased medical expenditures. Holding all else equal, the classification of TRD was associated with a 29.3% higher costs (P < 0.001) in medical expenditures compared with patients not meeting the study definition of TRD.”

Olchanski N, et al. The economic burden of treatment-resistant depression. Clin Ther 2013; 35:512-22.

Using atypical antipsychotics may improve clinical response in MDD patients who are refractory to antidepressant therapy.

“With antidepressant therapy alone, the estimated clinical response rate at 6 weeks was 30%.”

Taneja C, et al. Cost-effectiveness of adjunctive therapy with atypical antipsychotics for acute treatment of major depressive disorder. Ann Pharmacother 2012; 46:642-49.

TRD imposes substantial cost on employers.

“Compared with major depressive disorder (MDD) controls, TRD-likely employees had significantly higher rates of mental-health disorders, chronic pain, fibromyalgia, and higher Charlson Comorbidity Index. Average direct 2-year costs were significantly higher for TRD-likely employees ($22,784) compared with MDD controls ($11,733), p < 0.0001. Average indirect costs were also higher among TRD-likely employees ($12,765) compared with MDD controls ($6885), p < 0.0001.”

Ivanova JI, et al. Direct and indirect costs of employees with treatment-resistant and non-treatment resistant major depressive disorder. Curr Med Res Opin 2010 Oct; 26(10):2475-84.

Individuals with TRD use more healthcare services.

“The average annual cost of employees considered TRD-likely was dollars US 14490 per employee, while the cost for depressed but TRD-unlikely employees was dollars US 6665 per employee, and dollars US 4043 for the employee from the random sample. TRD beneficiaries used more than twice as many medical services compared with TRD-unlikely patients, and incurred significantly greater work loss costs.”

Greenberg P, et al. Economic implications of treatment-resistant depression among employees. Pharmacoeconomics 2004; 22(6):363-73.

Fragile X syndrome carrier screening accompanied by genetic consultation has clinical utility in populations beyond those recommended by guidelines.

“Providers recommend, and patients request, ECS carrier screening outside of guidelines criteria, and patients take action to reduce the risk of an affected pregnancy regardless of whether they meet the criteria for screening.”

Johansen Taber K, Lim‐Harashima J, Naemi H, Goldberg J. Fragile X syndrome carrier screening accompanied by genetic consultation has clinical utility in populations beyond those recommended by guidelines. Mol Genet Genomic Med. 2019;7:e1024. https ://doi.org/10.1002/mgg3.1024

Clinical utility of expanded carrier screening: results-guided actionability and outcomes.

“ECS results impacted couples’ reproductive decision-making and led to alterned pregnancy management that effectively eliminates the risk of having affected offspring.”

Johansen Taber K, et al. Clinical utility of expanded carrier screening: results-guided actionability and outcomes. Genet Med. 2018 Oct 11; doi:10.1038/s41436-018-0321-0 [Epub ahead of print].

Inter-lab concordance of variant classifications establishes clinical validity of expanded carrier screening.

“We observe 99% concordance at the level of unique variants.”

Kaseniit KE, Collins E, Lo C, et al. Inter-lab concordance of variant classifications establishes clinical validity of expanded carrier screening. Clin Genet. 2019;96:236–245. https://doi.org/10.1111/cge.13582KASENIIT ET AL.245

A data-driven evaluation of the size and content of expanded carrier screening panels.

“ACOG’s 1-in-100 criterion limits at-risk couple detection and should be reconsidered.”

Ben-Shachar, R., Svenson, A., Goldberg, J.D. et al. A data-driven evaluation of the size and content of expanded carrier screening panels. Genet Med 21, 1931–1939 (2019). https://doi.org/10.1038/s41436-019-0466-5

Systematic design and comparison of expanded carrier screening panels.

“The described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.”

Beauchamp KA, et al. Systematic design and comparison of expanded carrier screening panels. Genet Med. 2018;20:55–63.

Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening.

“In a population of diverse races and ethnicities, expanded carrier screening may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies.”

Haque IS, et al. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316:734–742.

Systemic Classification of Disease Severity for Evaluation of Expanded Carrier Screenin Panels.

“Disease severity is a key criterion for carrier screening. Expanded carrier screening…requires an objective, systematic means of describing a given disease’s severity to build screening panels.”

Lazarin GA, Hawthorne F, Collins NS, Platt EA, Evans EA, Haque IS (2014) Systematic Classification of Disease Severity for Evaluation of Expanded Carrier Screening Panels. PLoS ONE 9(12): e114391. https://doi.org/10.1371/journal.pone.0114391

Sequencing as a first-line methodology for cystic fibrosis carrier screening.

“Modern NGS and variant interpretation enable accurate sequencing-based CF screening.”

Beauchamp, K.A., Johansen Taber, K.A., Grauman, P.V. et al. Sequencing as a first-line methodology for cystic fibrosis carrier screening. Genet Med 21, 2569–2576 (2019). https://doi.org/10.1038/s41436-019-0525-y

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification.

“Validated high-fidelity identification of different variant types—especially for diseases with complicated molecular genetics—maximizes at-risk couple detection.”

Hogan, G.J, et al. Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification. Clin. Chem. 2018;64:1063–1073. https://doi.org/10.1373/clinchem.2018.286823.

Noninvasive prenatal screening for patients with high body mass index: Evaluating the impact of a customized whole genome sequencing workflow on sensitiity and residual risk.

“Relative to traditional aneuploidy screening, a customized NIPS with high accuracy at low FF and a low test-failure rate is a superior screening option for women with high BMI.”

Muzzey D, Goldberg JD, Haverty C. Noninvasive prenatal screening for patients with high bodymass index: Evaluating the impact of a customized wholegenome sequencing workflow on sensitivity and residual risk. PrenatalDiagnosis. 2019;1–9.https://doi.org/10.1002/pd.5603MUZZEYET AL.9

Clinical experience across the fetal-fraction spectrum for a non-invasive prenatal screen with low-test failure rate.

“Our clinical experience spanning over 58,000 patients demonstrates that the customized WGS-based NIPS approach described in this study achieves high accuracy while also maintaining a low test-failure rate of 0.1%.”

Hancock S, Ben-Shachar R, Adusei C, Oyolu CB, Evans EA, Kang HP, Haverty C, Muzzey D. Clinical experience across the fetal-fraction spectrum for a non-invasive prenatal screen with low test-failure rate. Ultrasound Obstet Gynecol. 2019 Oct 31. doi: 10.1002/uog.21904.

Strategies to minimize false positives and interpret novel microdeletions based on maternal copy-number variants in 87,000 noninvasive prenatal screens.

“Our findings offer insight into the interpretation of NIPS results and inform the design of NIPS algorithms suitable for use in screening in the general obstetric population.”

Kaseniit, K.E., Hogan, G.J., D’Auria, K.M. et al. Strategies to minimize false positives and interpret novel microdeletions based on maternal copy-number variants in 87,000 noninvasive prenatal screens. BMC Med Genomics 11, 90 (2018). https://doi.org/10.1186/s12920-018-0410-6.

Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis.

“Screening by analysis of cfDNA in maternal blood in singleton pregnancies could detect > 99% of fetuses with trisomy 21, 98% of trisomy 18 and 99% of trisomy 13.”

Gil MM, Accurti V, Nicolaides KH, Plana MN, and Santacruz B. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017;50:302-14. PMID: 28397325.

The Clinical Utility of DNA-Based Screening for Fetal Aneuploidy by Primary Obstetrical Care Providers in the General Pregnancy Population.

“This first clinical utility study of cfDNA screening found higher uptake rates, patient understanding of basic concepts, and easy incorporation into routine obstetrical practices.”

Palomaki GE, Eklund EE, Kloza EM, Lambert-Messerlian GM, and O’Brien BM. The Clinical Utility of DNA-Based Screening for Fetal Aneuploidy by Primary Obstetrical Care Providers in the General Pregnancy Population. Genet Med. 2017;19:778-86. PMID: 28079901.

Noninvasive prenatal testing in the general obstetric population: Clinical performance and counseling considerations in over 85,000 cases.

“Analysis of over 85,000 samples submitted to the clinical laboratory suggests that whole genome sequencing-based NIPT continue to meet or exceed performance characteristics established by clinical valiidation studies for screening of fetal aneuploidy.”

Taneja PA, Bhatt S, Curnow KJ, de Feo E, Halks-Miller M, Kruglyak KM, et al. Noninvasive prenatal testing in the general obstetric population: clinical performance and counseling considerations in over 85 000 [sic] cases. Prenat Diagn. 2016;36(3):237-43. PMID: 26715197.

Prenatal screening for fetal aneuploidies with cell-free DNA in the general pregnancy population: a cost-effectiveness analysis.

“NIPT in the general pregnancy population leads to more prenatal identification of fetal trisomy cases as compared to FTS.”

Fairbrother G, Burigo J, Sharon T, and Song K. Prenatal screening for fetal aneuploidies with cell-free DNA in the general pregnancy population: a cost-effectiveness analysis. J Matern Fetal Neonatal Med. 2016;29:1160-4. PMID: 26000626.

An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population.

“Universal application of NIPT would increase fetal aneuploidy detection rates and can be economically justified.”

Benn P, Chapman S, Curnow KJ, Hornberger J, Michalopoulos SN, and Rabinowitz M. An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population. PloS One. 2015;10:e0132313. PMID: 26158465.

A Cost-Effectiveness Analysis of First Trimester Non-Invasive Prenatal Screening for Fetal Trisomies in the United States.

“From a societal perspective, universal NIPT is a cost-effective alternative to MSS and contingent NIPT.”

Walker BS, Ashwood ER, Grenache DG, Jackson BR, Nelson RE, and Schmidt RL. A Cost-Effectiveness Analysis of First Trimester Non-Invasive Prenatal Screening for Fetal Trisomies in the United States. PloS One. 2015;10:e0131402. PMID: 26133556.

Cell-free DNA Analysis for Noninvasive Examination of Trisomy.

“In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes.”

Norton ME, Brar H, Cuckle H, Hollemon D, Jacobsson B, Laurent LC, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372:1589-97. PMID: 25830321.

DNA Sequencing versus Standard Prenatal Aneuploidy Screening.

“In a general obstetrical population, prenatal testing with the use of cfDNA had significantly lower false positive rates and higher positive predictive values for detection of trisomies 21 and 18 than standard screening.”

Bianchi DW, CARE Study Group, Chudova DI, Craig JA, Das AF, Devers PL, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808. PMID: 24571752.

Change of therapy occurred in over 37% of patients, with the majority moving away from chemotherapy treatment.

“In over one third (37.7%) the results of the EndoPredict assay lead to a change of planned therapy. For a quarter of patients (25.4%) the originally planned chemotherapy could be omitted based on the result of the multi-gene assay.”

Müller BM, Keil E, Lehmann A, et al. The EndoPredict gene-expression assay in clinical practice – performance and impact on clinical decisions. PLoS One. 2013;8(6):e68252.

EndoPredict can identify patients who may safely forgo chemotherapy or extended endocrine therapy.

“…the data presented here demonstrate that the 12-gene assay identifies a population of women with node-positive disease who are at low enough risk for distant recurrence at the time of diagnosis that they may be adequately treated with only 5 years of adjuvant endocrine therapy.”

Filipits M, et al. Prediction of distant recurrence using Endopredict among women with ER+, HER2- node-positive and node-negative breast cancer treated with endocrine therapy only. Clin Cancer Res. 2019 May 7. [Epub ahead of print].

A high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease.

“Our results furthermore suggest that some women with a low EPclin score, but clinically high-risk tumours received unnecessary chemotherapy. In addition, women with high EPclin scores who only received endocrine therapy alone would have been good candidates for adjuvant chemotherapy.”

Sestak I, et al. Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus chemotherapy or endocrine therapy alone. Breast Cancer Res Treat. 2019 Apr 30. [Epub ahead of print].

Greater prognostic value compared to first generation tests.

• In all patients, EndoPredict was the best overall test in predicting distant recurrence (DR) in years 0-10 (C-index 0.753; LRx2=69.3)
• EndoPredict identified the largest group of low-risk patients with 10 years DR below 10 percent in both node-negative and node-positive disease
• EndoPredict was a better predictor for overall DR and for late-DR than Oncotype DX Recurrence Score

Sestak I, et al. Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer. JAMA Oncol. 2018 Apr; 4(4):545-553.

Provides classification more closely aligned with patient outcomes compared to Oncotype DX.^®

“EPclin provided more prognostic information than RS [Oncotype DX Recurrence Score] partly because of its integration with node and tumor size information but also because of a superior molecular component able to predict late events better than (RS).”

Buus R, Sestak I, Kronenwett R, et al. Comparison of EndoPredict and EPclin with Oncotype DX recurrence score for prediction of risk of distant recurrence after endocrine therapy. J Natl Cancer Inst. 2016 Jul 10;108(11). pii: djw149. doi:10.1093/jnci/djw149. Print 2016 Nov.

More women classified as low risk.

“The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.”

Dubsky P, Filipits M, Jakesz R, et al. on behalf of Austrian Breast and Colorectal Cancer Study Group (ABCSG). EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer. Ann Oncol. 2013 Mar; 24(3):640-7.

EndoPredict demonstrates strong stratification of patients into one of two risk categories.

“The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy.”

Dubsky P, Brase JC, Jakesz R, et al. The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients. Br J Cancer 2013; 109(12):2959–64.

Stronger prognostic power than conventional risk factors.

“The multigene EndoPredict (EP) risk score provided additional prognostic information to the risk of distant recurrence of breast cancer patients, independent from clinicopathologic parameters. The EP score outperformed all conventional clinicopathologic risk factors.”

Filipits M, Rudas M, Jakesz R, et al. A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res 2011; 17(18):6012–20.

12-gene molecular assay is reproducible and robust.

“Combined with the previous clinical validation studies, this analytical validation demonstrates that the LDT version of the 12-gene molecular assay can be utilized for evaluating risk of distant recurrence in ER+/HER2- invasive breast cancer.”

Warf MB, et al. Analytical validation of a 12-gene molecular test for the prediction of distant recurrence in breast cancer. Future Sci 2017 June [Epub ahead of print]. doi:10.4155/fsoa-2017-0051.

Reproducible performance characteristics with good precision.

“The EndoPredict (EPclin) test showed reproducible performance characteristics with good precision and negligible laboratory-to-laboratory variation.”

Kronenwett R, Bohmann K, Prinzler J, et al. Decentral gene expression analysis: analytical validation of the Endopredict genomic multianalyte breast cancer prognosis test. BMC Cancer 2012 Oct 5; 12:456.

EndoPredict’s impact in a cohort of young women with breast cancer.

“The EndoPredict test successfully assisted the clinical decision-making process in premenopausal patients, with a clinically significant change in overall decision-making, with the greatest impact seen in chemotherapy reduction, and a high rate of therapeutic adherence.”

Villarreal-Garza C, et al. Change in therapeutic management after the EndoPredict assay in a prospective decision impact study of Mexican premenopausal breast cancer patients. PLoS One. 2020 Mar 11; 15(3):e0228884.

EndoPredict satisfies 1B evidence according to prognostic biomarkers assessment proposed by Simon, et al.

Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 2009; 101:1446–52.

Fragile X syndrome carrier screening accompanied by genetic consultation has clinical utility in populations beyond those recommended by guidelines.

“Providers recommend, and patients request, ECS carrier screening outside of guidelines criteria, and patients take action to reduce the risk of an affected pregnancy regardless of whether they meet the criteria for screening.”

Johansen Taber K, Lim‐Harashima J, Naemi H, Goldberg J. Fragile X syndrome carrier screening accompanied by genetic consultation has clinical utility in populations beyond those recommended by guidelines. Mol Genet Genomic Med. 2019;7:e1024. https ://doi.org/10.1002/mgg3.1024

Clinical utility of expanded carrier screening: results-guided actionability and outcomes.

“ECS results impacted couples’ reproductive decision-making and led to alterned pregnancy management that effectively eliminates the risk of having affected offspring.”

Johansen Taber K, et al. Clinical utility of expanded carrier screening: results-guided actionability and outcomes. Genet Med. 2018 Oct 11; doi:10.1038/s41436-018-0321-0 [Epub ahead of print].

Inter-lab concordance of variant classifications establishes clinical validity of expanded carrier screening.

“We observe 99% concordance at the level of unique variants.”

Kaseniit KE, Collins E, Lo C, et al. Inter-lab concordance of variant classifications establishes clinical validity of expanded carrier screening. Clin Genet. 2019;96:236–245. https://doi.org/10.1111/cge.13582KASENIIT ET AL.245

A data-driven evaluation of the size and content of expanded carrier screening panels.

“ACOG’s 1-in-100 criterion limits at-risk couple detection and should be reconsidered.”

Ben-Shachar, R., Svenson, A., Goldberg, J.D. et al. A data-driven evaluation of the size and content of expanded carrier screening panels. Genet Med 21, 1931–1939 (2019). https://doi.org/10.1038/s41436-019-0466-5

Systematic design and comparison of expanded carrier screening panels.

“The described approaches enable principled, quantitative evaluation of which diseases and methodologies are appropriate for pan-ethnic expanded carrier screening.”

Beauchamp KA, et al. Systematic design and comparison of expanded carrier screening panels. Genet Med. 2018;20:55–63.

Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening.

“In a population of diverse races and ethnicities, expanded carrier screening may increase the detection of carrier status for a variety of potentially serious genetic conditions compared with current recommendations from professional societies.”

Haque IS, et al. Modeled fetal risk of genetic diseases identified by expanded carrier screening. JAMA. 2016;316:734–742.

Systemic Classification of Disease Severity for Evaluation of Expanded Carrier Screenin Panels.

“Disease severity is a key criterion for carrier screening. Expanded carrier screening…requires an objective, systematic means of describing a given disease’s severity to build screening panels.”

Lazarin GA, Hawthorne F, Collins NS, Platt EA, Evans EA, Haque IS (2014) Systematic Classification of Disease Severity for Evaluation of Expanded Carrier Screening Panels. PLoS ONE 9(12): e114391. https://doi.org/10.1371/journal.pone.0114391

Sequencing as a first-line methodology for cystic fibrosis carrier screening.

“Modern NGS and variant interpretation enable accurate sequencing-based CF screening.”

Beauchamp, K.A., Johansen Taber, K.A., Grauman, P.V. et al. Sequencing as a first-line methodology for cystic fibrosis carrier screening. Genet Med 21, 2569–2576 (2019). https://doi.org/10.1038/s41436-019-0525-y

Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification.

“Validated high-fidelity identification of different variant types—especially for diseases with complicated molecular genetics—maximizes at-risk couple detection.”

Hogan, G.J, et al. Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification. Clin. Chem. 2018;64:1063–1073. https://doi.org/10.1373/clinchem.2018.286823.

Test results are used as an aid in identifying patients who are or may become eligible for treatment with the targeted therapies. Please review the PMA Intended Use Statement for myChoice CDx for more information.

Panel testing increases number of women identified as carrying PV compared with BRCA testing alone.

“[…] panel testing increased the number of women identified as carrying a PV [pathogenic variant] in this cohort compared with BRCA testing alone. Furthermore, the proportion of women identified who carried a PV in this cohort did not decrease between ages 40 and 59 years.”

Buys SS, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 2017. 123(10): 1721-30. doi:10.1002/cncr.30498.

Pathogenic variants in BRCA1 and BRCA2 confer 3.8- to 8.4-fold increased risk for prostate cancer.

“Genetic test results are uncovering additional cancer risks for men and their families. Risks for colon cancer, pancreatic cancer, melanoma, and male breast cancer in men with or at risk for [prostate cancer] have been identified, which necessitates guidelines-based screening/management or referral for discussion of screening options. Furthermore, male and female blood relatives […] now have insight into which specific mutations may predispose to cancer risk in their family and can pursue site-specific mutation testing through guidelines-based cancer screening approaches.”

Giri VN, Obeid E, Gross L, et al. Inherited mutations in men undergoing multigene panel testing for prostate cancer: emerging implications for personalized prostate cancer genetic evaluation [published online May 4, 2017]. JCO Prec Oncol. doi: 10.1200/PO.16.00039.

38.8% of pathogenic variants are identified in ATM, CHEK2 or PALB2, increasing the number of women who are potential candidates for breast MRI or other risk reduction measures.

“Expanding genetic testing beyond BRCA1/2 significantly increases the number of women who are candidates for breast MRI and other risk reduction measures, most of whom would not have been identified through family history assessment.”

Rosenthal ET, et al. Increased identification of candidates for high-risk breast cancer screening through expanded genetic testing. J Am Coll Radiol 2017; 14:561-8. doi:10.1016/j.jacr.2016.10.003.

Multi-gene panel testing provides additional information that may improve patient outcomes.

“We performed a retrospective review of consecutive patients undergoing genetic testing after initiating use of multigene panel testing at Loma Linda University Medical Center. From February 13 to August 25, 2014, 92 patients were referred for genetic testing based on National Comprehensive Cancer Network guidelines. Testing was completed in 90 patients. Overall, nine (10%) pathogenic mutations were identified: five BRCA1/2, and four in non-BRCA loci. Single-site testing identified one BRCA1 and one BRCA2 mutation. The remaining mutations were identified by use of panel testing for hereditary breast and ovarian cancer. […] The use of panel testing more than doubled the identification rate of clinically significant pathogenic mutations that would have been missed with BRCA testing alone.”

Howarth DR, et al. Initial results of multigene panel testing for hereditary breast and ovarian cancer and Lynch syndrome. Am Surg 2015 Oct; 81(10):941-4.

Patients with hereditary cancer syndromes are at high risk for a second primary cancer.

“Of patients with Hereditary Breast and Ovarian Cancer (HBOC) and Lynch syndrome (LS), 56 and 65.2%, respectively, met the National Comprehensive Cancer Network guidelines for hereditary cancer testing after their initial diagnosis based on their personal cancer history alone. A substantial number of women tested for LS or HBOC after being diagnosed with two successive primary cancers were diagnosed with a hereditary cancer syndrome. In many cases, the time interval between the diagnoses was long enough to allow for the implementation of surveillance and/or prophylactic measures.”

Saam J, et al. Hereditary cancer-associated mutations in women diagnosed with two primary cancers: an opportunity to identify hereditary cancer syndromes after the first cancer diagnosis. Oncology 2015; 88(4):226-33.

Multigene testing is likely to alter cancer risk assessment, clinical management, and familial testing recommendations.

“Multigene panel testing for patients with suspected HBOC risk identifies substantially more individuals with relevant cancer risk gene mutations than does BRCA1/2 testing alone. Identifying such mutations is likely to change management for the majority of these individuals and their families in the near term, and in the long term should lead to development of effective management guidelines and improved outcomes for at-risk individuals.”

Desmond A, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol 2015; 1(7):943-951.

Medical management changes occurred 77.8% of the time after a MyRisk positive result and 25.3% after a negative result.

“Integrating personal and family cancer history identified during the screening process with genetic test results can offer refined management recommendations. Over 74% of physicians used both the genetic test result and the personal and family cancer history from the MyRisk management tool (MMT) to make management decisions.”

Langer LR, et al. 25-Gene panel testing and integrated risk management tool impacts medical management in hereditary cancer syndrome evaluation. Scientific poster presented at the American Society for Clinical Oncology Annual Meeting in Chicago, IL, June 2014.

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More than 12 percent of men with prostate cancer carry an inherited genetic mutation.

“Of the 1162 men in the study, 64 percent had a history of prostate cancer, while 36 percent had a history of prostate cancer and at least one additional cancer. The results showed that 12.1 percent of men with prostate cancer were positive for one or more hereditary cancer mutations in the genes tested. Additionally, the positive rate was significantly higher among men with prostate cancer plus one other cancer (14.7 percent). The inherited mutations were found in genes with a well-known prostate cancer risk (i.e., BRCA2) as well as genes historically associated with other cancer types including breast and colon. These findings suggest that hereditary cancer testing in men with prostate cancer may aid in medical management decision making to reduce overall cancer risk.”

Reid R, et al. Inherited germline mutations in men with prostate cancer. Presented at 2018 Genitourinary Cancer Symposium. J Clin Oncol 2018; 36 (suppl 6S; abstr 357).

Up to 50% of clinically significant findings missed by single-syndrome testing.

“Multi-gene hereditary cancer testing detected >1 pathogenic variants (PVs) in 6.7% of individuals. PVs were most common in BRCA1 and BRCA2 (42.2%) and 5 additional breast cancer-risk genes (32.9%). Up to 50% of all clinically significant findings would have been missed by single-syndrome testing.”

Rosenthal ET, et al. Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. Cancer Genetics 2017; 218-219:58-68.

Germline cancer susceptibility gene mutations found in ~10% of CRC patients.

“Germline cancer susceptibility gene mutations are carried by 9.9% of patients with CRC [colorectal cancer]. MSI/MMR [microsatellite instability/mismatch repair deficiency] testing reliably identifies LS [Lynch syndrome] probands, although 7.0% of patients with CRC carry non-LS mutations, including 1.0% with BRCA1/2 mutations.”

Yurgelun MB, et al. Cancer susceptibility gene mutations in individuals with colorectal cancer. J of Clin Onc 2017. J of Clin Onc 2017; 35(10): 1086-95.

Next generation sequencing (NGS) detects germline and somatic variants.

“Given the significant phenotypic overlap of many hereditary cancer syndromes, NGS panels enable the simultaneous analysis of multiple genes associated with increased cancer risks […]. This enables medical management decisions to be informed by gene-specific guidelines based on known risks associated with germline variants. However, the quantitative nature of NGS also enables the detection of somatic variants that may complicate genetic test interpretation.”

Coffee B, et al. Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel. Cancer Genetics 2017; 211:5-8.

Prostate cancer is an indication for BRCA and Lynch syndrome testing.

“There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome.”

Giri VN, et al. Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. JCO 2017.

Combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients than localized PCa patients.

“…our study provides additional evidence that the mutation status of ATM and BRCA1/2 distinguishes the risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time.”

Na R, et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur Urol. 2017 May;71(5):740-747. doi: 10.1016/j.eururo.2016.11.033. Epub 2016 Dec 15. PubMed PMID: 27989354; PMCID: PMC5535082.

33.3% of mutation positive patients did not meet testing criteria for gene in which they carried a mutation.

“Multigene panel testing should be considered for all patients with early-onset colorectal cancer.”

Pearlman R, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol 2017; 3(4):464-71.

Frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of men with localized prostate cancer.

“…the identification of a germline mutation in a DNA-repair gene provides information that is key to relatives, both male and female, and that can prompt “cascade” counseling to identify cancer predisposition and deploy risk-reduction strategies. Prospective studies assessing the prognostic and predictive significance of mutations in DNA-repair genes with regard to clinical outcomes are now needed to inform personalized care.”

Pritchard CC, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. NEJM 2016 Aug 4;375(5):443-53. doi: 10.1056/NEJMoa1603144. Epub 2016 Jul 6. PubMed PMID: 27433846; PubMed Central PMCID: PMC4986616.

Testing with a gene panel increased the number of positive test results in ovarian cancer patients by 53.8% over BRCA1/2 testing alone.

“Our results demonstrate the benefits of multigene panels for patients with personal history of ovarian cancer, particularly for the identification of moderate-penetrance mutations that would not otherwise be identified by single-syndrome testing.”

Langer LR, et al. Hereditary cancer testing in patients with ovarian cancer using a 25-gene panel. JCSO 2016 July; 14:314-19.

Myriad MyRisk identified 70% more deleterious mutations than BRCA testing alone, with 42% of these in women over age 45.

“Among sequential patients with breast cancer, 10.7% were found to have a germline mutation in a gene that predisposes women to breast or ovarian cancer, using a panel of 25 predisposition genes. Factors that predict for BRCA1/2 mutations do not predict for mutations in other breast/ovarian cancer susceptibility genes when these genes are analyzed as a single group.”

Tung N, et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 2016 May 1; 34(13):1460-8.

Platinum compounds have moderate anti-tumour activity in molecularly unselected patients with advanced prostate cancer.

“…the identification of predictive biomarkers and the clinical evaluation of platinum compounds in molecularly selected patients with advanced prostate cancer is thus important and should be supported to improve the prognosis of these patients.”

Hager S, et al. Anti-tumour activity of platinum compounds in advanced prostate cancer-a systematic literature review. Ann Oncol. 2016 Jun;27(6):975-84. doi: 10.1093/annonc/mdw156. Epub 2016 Apr 6. Review. PubMed PMID: 27052650.

Panel testing may replace targeted genetic testing.

“Because clinical criteria for Lynch syndrome (LS) analysis appear to identify a substantial number of probands with unexpected actionable mutations in high-penetrance non-LS cancer susceptibility genes, panel testing ultimately may replace targeted genetic testing in patients with suspected LS, except when tumor testing suggests a specific underlying mismatch repair (MMR) mutation.”

Yurgelun MB, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology 2015 Sep; 149(3):604-13.

Using a panel test could prevent inaccurate, or even limited, family histories from restricting testing options.

“Offering hereditary panel testing as a first and final, ‘single-tier’, option was explored. A ‘two-tiered’ approach, in which panel testing is offered reflexively following stricter criteria, was then applied to the same data. Within our cohort of 105 patients, the single-tier approach was associated with a higher mutation detection rate (6.7% vs 3.8%) and variant of uncertain significance (VUS) rate (0.94 vs 0.23 average per person) compared to a two-tiered approach.”

Yorczyk A, et al. Use of panel tests in place of single gene tests in the cancer genetics clinic. Clin Genet 2015 Sep; 88(3):278-82.

Clinical implications of the results of multiple studies on gBRCAm in men with and without PCa.

“…men with a suspected or confirmed germline BRCA mutation are a small but clinically important patient group. It is important that we identify the potential BRCA mutation carriers among the great numbers of men with PCa or increased PSA levels in our daily clinical practice, and that we manage them and their families adequately.”

Bratt O, et al. Clinical Management of Prostate Cancer in Men with BRCA Mutations. Eur Urol. 2015 Aug;68(2):194-5. doi: 10.1016/j.eururo.2014.11.005. Epub 2014 Nov 15. PubMed PMID: 25465969.

Many syndromes present with overlapping cancers – and have no distinct, recognizable phenotypes.

“Our data demonstrate a substantial phenotypic overlap among patients for multiple common inherited cancer syndromes, which likely complicates diagnosis and test selection. This supports the value of multigene panels to identify pathogenic mutations in the absence of a clinically specific phenotype.”

Saam J, et al. Patients tested at a laboratory for hereditary cancer syndromes show an overlap for multiple syndromes in their personal and familial cancer histories. Oncology 2015; 89(5):288-93.

Panel testing benefits appropriately selected patients.

“The frequency of mutations in genes other than BRCA1/2 was 4.3% in the NGS 25-gene panel, and most mutations (3.9%) were in genes associated with breast/ovarian cancer. Multiple-gene sequencing may benefit appropriately selected patients, especially those with a personal or family history of more than 1 possible genetic syndrome.”

Tung N, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2015 Jan 1; 121(1):25-33.

gBRCAm are associated with worse prostate cancer outcomes.

“Our study demonstrates that BRCA carriers treated for localized PCa have worse outcomes than noncarriers because they relapse and progress earlier to lethal metastatic disease.”

Castro E, et al. Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer. Eur Urol. 2015 Aug;68(2):186-93. doi: 10.1016/j.eururo.2014.10.022. Epub 2014 Nov 6. PubMed PMID: 25454609.

BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis.

“…our results show that a wide spectrum of pathogenic mutations in the BRCA1 and BRCA2 genes confers a more aggressive PCa phenotype with a higher probability of locally advanced and metastatic disease and that the presence of a germline BRCA2 mutation is a prognostic marker associated with poorer survival.”

Castro E, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May 10;31(14):1748-57. doi: 10.1200/JCO.2012.43.1882. Epub 2013 Apr 8. PubMed PMID: 23569316; PubMed Central PMCID: PMC3641696.

NGS and Sanger sequencing were 100% concordant for the 3,923 collective variants across all genes.

“This study provides a thorough validation of the 25-gene NGS panel and indicates that this analysis tool can be used to collect clinically significant information related to risk of developing hereditary cancers.”

Judkins T, et al. Development and analytical validation of a 25-gene next generation sequencing panel that includes the BRCA1 and BRCA2 genes to assess hereditary cancer risk. BMC Cancer 2015 Apr 2; 15:215.

Germline Testing in Pancreatic Ductal Adenocarcinoma and Immediate Implications for Clinical Practice.

“Germline mutations have been identified in key genes with an aggregate frequency of 3.8% to 9.7%, several of which are therapeutically actionable with platinum, PARPi, and checkpoint inhibitor therapy. Potential therapeutic targets need to be actively sought and identified.”

Rainone, et al. An Emerging Paradigm for Germline Testing in Pancreatic Ductal Adenocarcinoma and Immediate Implications for Clinical Practice: A Review. JAMA Oncol 2020 Feb 13; doi: 10.1001/jamaoncol.2019.5963.

Clinical Utility of Hereditary Cancer Panel Testing: Impact of PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D

“Testing for PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D changed management for those carrying PVs. Provider recommendations were aligned with guidelines, and patients adhered to recommendations, both of which are critical for reducing both long‐term cancer morbidity and mortality.”

Vysotskaia, et al. Clinical Utility of Hereditary Cancer Panel Testing: Impact of PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D Results on Patient Management and Adherence to Provider Recommendations. Cancer, 04 November 2019; https://doi.org/10.1002/cncr.32572.

Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk

“34% of the positive results were not included in the pre-test differential diagnoses generated by genetics experts, based on patient history.”

Idos, et al. Multicenter Prospective Cohort Study of the Diagnostic Yield and Patient Experience of Multiplex Gene Panel Testing For Hereditary Cancer Risk. JCO Precision Oncology, March 28, 2019; DOI: 10.1200/PO.18.00217.

A broad overview of outcomes and data relevant to evaluating the utility of a pan-cancer strategy for clinical testing.

“Half the [Pathogenic Variants] identified among individuals who met only HBOC testing criteria were in genes other than BRCA1/2… These findings suggest that genetic testing with a pan-cancer panel in this cohort provides improved clinical utility over traditional single-gene or single-syndrome testing.”

Rosenthal, et al. Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. Cancer Genetics 2017 December; https://doi.org/10.1016/j.cancergen.2017.09.003.

Individuals with MSH6 and PMS2 mutations may present with HBOC phenotype.

“These results provide a new perspective on Lynch syndrome and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer (HBOC) phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with mismatch repair (MMR) mutations.”

Espenschied CR, et al. Multigene panel testing provides a new perspective on Lynch syndrome. J Clin Oncol 2017, 35.

Aggressive prostate cancer at early age associated with BRCA1, BRCA2 and ATM.

“Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.”

Na R, et al. Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death. European Urology 2017 May; 71(5): 740-7. doi: 10.1016/j.eururo.2016.11.033.

Multigene panels should be used for the assessment of cancer risk beyond the classic predisposition syndromes.

“The use of multigene testing in the clinical setting will better define both the optimal care of patients with cancer (management of the primary cancer; definition of risk of second malignancies; and assignment of specific treatments like PARP inhibitors) and the management of unaffected individuals (earlier surveillance, chemoprevention and/or prophylactic surgery).”

Graffeo R, et al. Time to incorporate germline multigene panel testing into breast and ovarian cancer patient care. Breast Cancer Res Treat 2016 Dec; 160(3):393-410. Epub 2016 Oct 12.

“Canonical” genetic workup fails to detect patients with other mutations.

“The findings of this large population-based study [Pearlman R, et al.] demonstrate that the incorporation of multigene panel genetic testing in the evaluation of patients with CRC [colorectal cancer] will increase the diagnosis of individuals with genetic predisposition to cancer and will expand current knowledge regarding the associated phenotypes, further supporting the cost-effectiveness of testing that can guide management for patients with cancer and their at-risk relatives.”

Vilar E and Stoffel EM, et al. Universal genetic testing for younger patients with colorectal cancer. JAMA Oncol 2016 Dec 15. doi:10.1001/jamaoncol.2016.5193.

Clinical utility of panel testing in BRCA negative patients.

“This study demonstrates the clinical utility of multigene panels in a group of high risk individuals who previously tested negative for a BRCA1/2 mutation. This retesting approach revealed a pathogenic mutation in 11% of cases. Retesting led to significant change in clinical management in a majority of patients with actionable mutations (7 out of 11), as well as in those with mutations in genes which do not have specific management guidelines.”

Yadav S, et al. Outcomes of retesting BRCA negative patients using multigene panels. Fam Cancer 2016 Nov 22; 16(3): 319-28. doi:10.1007/s10689-016-9956-7.

Up to 79% of women from BRCA negative families desire multiplex genetic testing.

“Female first-degree relatives of breast cancer patients who tested negative for BRCA1/2 mutations (N = 149) completed a survey assessing multiplex genetic testing interest and risk communication preferences. Interest in testing was high (70%) and even higher if results could guide risk-reducing behavior changes such as taking medications (79%).”

Flores KG, et al. Factors associated with interest in gene-panel testing and risk communication preferences in women from BRCA1/2 negative families. J Genet Counsel 2016 Aug; 26(3): 480-90.doi:10.1007/s10897-016-0001-7.

70% of physicians changed management based on panel results.

“Multi-gene panel testing increases the yield of mutations detected and adds to the capability of providing individualized cancer risk assessment.”

Ricker C, et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Genetics 2016 April; 209(4):130-7.

RAD51C and RAD51D genes play a role in invasive EOC.

“[…] results confirm that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes and suggest that they confer levels of risk of epithelial ovarian cancer (EOC) that may warrant their use alongside BRCA1 and BRCA2 in routine clinical genetic testing.”

Song H, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol 2015 Sept; 33(26):2901-14.

Several genes beyond BRCA1 and 2 have robust evidence associating them with breast cancer risk.

“We have […] reviewed the genes for which the evidence of association with breast cancer is sufficiently robust to be incorporated into personalized risk prediction.”

Easton DF, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015 Jun; 372:2243-225.

Appropriate surgical intervention improves overall survival.

“We conclude that contralateral risk-reducing mastectomy is associated with improved overall survival in BRCA1/2 mutation carriers with a history of primary breast cancer.”

Heemskerk-Gerritsen, et al. Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis. Int J Cancer 2015 Feb; 136(3):668-77.

PALB2 mutation carriers have a significant increased risk of breast cancer.

“Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers.”

Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014 Oct; 371(6):497-506.

Testing beyond a negative BRCA 1/2 result using multi-gene sequencing leads to greater detection of pathogenic mutations.

“Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp.”

Kurian AW, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 2014 Jul 1; 32(19):2001-9.

Greater sensitivity prevents more cancer, saving healthcare dollars.

“Compared with alternative tests, using BRACAnalysis® would save $624,000 and prevent 9 [breast cancer] and/or [ovarian cancer] cases per year for a 1-million member health system.”

Stenehjem D, et al. Economic analysis of alternative genetic tests for BRCA1 and BRCA2 mutations. Scientific poster presented at the 31st Annual Breast Cancer Conference in Miami, FL, March 2014.

Appropriate prophylactic surgery improves survival rates.

“This study suggests that women who are positive for BRCA mutations and who are treated for stage I or II breast cancer with bilateral mastectomy are less likely to die from breast cancer than women who are treated with unilateral mastectomy.”

Metcalfe K, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. BMJ 2014 Feb; 348:g226.

Oophorectomy reduces risk of ovarian, fallopian tube, or peritoneal cancer in women with a BRCA1 or BRCA2 mutation.

“Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube, or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.”

Finch APM, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014 May; 32(15): 1547-53.

Panel testing for multiple genes saves thousands of healthcare dollars – and identifies more genes contributing to ovarian cancers.

“More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.”

Walsh T, et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 2011 Nov 1; 108(44):18032-7.

Risk-reducing surgery improves mortality rates.

“Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.”

Domcheck S, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010; 304(9):967-75.

Noninvasive prenatal screening for patients with high body mass index: Evaluating the impact of a customized whole genome sequencing workflow on sensitiity and residual risk.

“Relative to traditional aneuploidy screening, a customized NIPS with high accuracy at low FF and a low test-failure rate is a superior screening option for women with high BMI.”

Muzzey D, Goldberg JD, Haverty C. Noninvasive prenatal screening for patients with high bodymass index: Evaluating the impact of a customized wholegenome sequencing workflow on sensitivity and residual risk. PrenatalDiagnosis. 2019;1–9.https://doi.org/10.1002/pd.5603MUZZEYET AL.9

Clinical experience across the fetal-fraction spectrum for a non-invasive prenatal screen with low-test failure rate.

“Our clinical experience spanning over 58,000 patients demonstrates that the customized WGS-based NIPS approach described in this study achieves high accuracy while also maintaining a low test-failure rate of 0.1%.”

Hancock S, Ben-Shachar R, Adusei C, Oyolu CB, Evans EA, Kang HP, Haverty C, Muzzey D. Clinical experience across the fetal-fraction spectrum for a non-invasive prenatal screen with low test-failure rate. Ultrasound Obstet Gynecol. 2019 Oct 31. doi: 10.1002/uog.21904.

Strategies to minimize false positives and interpret novel microdeletions based on maternal copy-number variants in 87,000 noninvasive prenatal screens.

“Our findings offer insight into the interpretation of NIPS results and inform the design of NIPS algorithms suitable for use in screening in the general obstetric population.”

Kaseniit, K.E., Hogan, G.J., D’Auria, K.M. et al. Strategies to minimize false positives and interpret novel microdeletions based on maternal copy-number variants in 87,000 noninvasive prenatal screens. BMC Med Genomics 11, 90 (2018). https://doi.org/10.1186/s12920-018-0410-6.

Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis.

“Screening by analysis of cfDNA in maternal blood in singleton pregnancies could detect > 99% of fetuses with trisomy 21, 98% of trisomy 18 and 99% of trisomy 13.”

Gil MM, Accurti V, Nicolaides KH, Plana MN, and Santacruz B. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. 2017;50:302-14. PMID: 28397325.

The Clinical Utility of DNA-Based Screening for Fetal Aneuploidy by Primary Obstetrical Care Providers in the General Pregnancy Population.

“This first clinical utility study of cfDNA screening found higher uptake rates, patient understanding of basic concepts, and easy incorporation into routine obstetrical practices.”

Palomaki GE, Eklund EE, Kloza EM, Lambert-Messerlian GM, and O’Brien BM. The Clinical Utility of DNA-Based Screening for Fetal Aneuploidy by Primary Obstetrical Care Providers in the General Pregnancy Population. Genet Med. 2017;19:778-86. PMID: 28079901.

Noninvasive prenatal testing in the general obstetric population: Clinical performance and counseling considerations in over 85,000 cases.

“Analysis of over 85,000 samples submitted to the clinical laboratory suggests that whole genome sequencing-based NIPT continue to meet or exceed performance characteristics established by clinical valiidation studies for screening of fetal aneuploidy.”

Taneja PA, Bhatt S, Curnow KJ, de Feo E, Halks-Miller M, Kruglyak KM, et al. Noninvasive prenatal testing in the general obstetric population: clinical performance and counseling considerations in over 85 000 [sic] cases. Prenat Diagn. 2016;36(3):237-43. PMID: 26715197.

Prenatal screening for fetal aneuploidies with cell-free DNA in the general pregnancy population: a cost-effectiveness analysis.

“NIPT in the general pregnancy population leads to more prenatal identification of fetal trisomy cases as compared to FTS.”

Fairbrother G, Burigo J, Sharon T, and Song K. Prenatal screening for fetal aneuploidies with cell-free DNA in the general pregnancy population: a cost-effectiveness analysis. J Matern Fetal Neonatal Med. 2016;29:1160-4. PMID: 26000626.

An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population.

“Universal application of NIPT would increase fetal aneuploidy detection rates and can be economically justified.”

Benn P, Chapman S, Curnow KJ, Hornberger J, Michalopoulos SN, and Rabinowitz M. An Economic Analysis of Cell-Free DNA Non-Invasive Prenatal Testing in the US General Pregnancy Population. PloS One. 2015;10:e0132313. PMID: 26158465.

A Cost-Effectiveness Analysis of First Trimester Non-Invasive Prenatal Screening for Fetal Trisomies in the United States.

“From a societal perspective, universal NIPT is a cost-effective alternative to MSS and contingent NIPT.”

Walker BS, Ashwood ER, Grenache DG, Jackson BR, Nelson RE, and Schmidt RL. A Cost-Effectiveness Analysis of First Trimester Non-Invasive Prenatal Screening for Fetal Trisomies in the United States. PloS One. 2015;10:e0131402. PMID: 26133556.

Cell-free DNA Analysis for Noninvasive Examination of Trisomy.

“In this large, routine prenatal-screening population, cfDNA testing for trisomy 21 had higher sensitivity, a lower false positive rate, and higher positive predictive value than did standard screening with the measurement of nuchal translucency and biochemical analytes.”

Norton ME, Brar H, Cuckle H, Hollemon D, Jacobsson B, Laurent LC, et al. Cell-free DNA analysis for noninvasive examination of trisomy. N Engl J Med. 2015;372:1589-97. PMID: 25830321.

DNA Sequencing versus Standard Prenatal Aneuploidy Screening.

“In a general obstetrical population, prenatal testing with the use of cfDNA had significantly lower false positive rates and higher positive predictive values for detection of trisomies 21 and 18 than standard screening.”

Bianchi DW, CARE Study Group, Chudova DI, Craig JA, Das AF, Devers PL, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med. 2014;370:799-808. PMID: 24571752.

University of Leeds Collaborates on Prolaris Clinical Utility Study

Long-term study demonstrates improved clinical outcomes for patients.

“The use of a combined clinical and molecular score (CCR) has been shown to provide significantly improved prognostic information over clinicopathologic factors alone. […] The durability of AS was similar to previously published rates, with approximately two-thirds of patients remaining on active surveillance (AS) after 4 years; however, the increased AS selection rate at the time of diagnosis reported here increased the overall number of men who remained on AS.”

Kaul S, et al. Clinical outcomes in men with prostate cancer who selected active surveillance using a clinical cell-cycle risk score. Per Med. 2019 Sep 4. [ePub ahead of print.]

Significant impact on personalized treatment decisions.

“The cell cycle progression test has a significant impact in assisting physicians and patients reach personalized treatment decisions.”

Shore N, Kella N, Moran B, et al. Impact of the cell cycle progression test on physician and patient treatment selection for localized prostate cancer. J Urol 2016 March; 195:612-18.

Physicians ordering Prolaris modified treatment decisions.

“Test results led to changes in treatment with reductions and increases in interventional treatment that were directionally aligned with prostate cancer risk specified by the test.”

Crawford ED, Scholz MC, Kar AJ, et al. Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry. Curr Med Res Opin 2014 Jun; 30(6):1025-31.

Prolaris predicts progression to metastatic disease after both surgery and radiation.

“Both CCP and CCR scores provided independent prognostic information for predicting progression to metastatic disease after both surgery and radiation. These results further demonstrate their potential use as a risk stratification tool in patients with newly-diagnosed prostate cancer.”

Canter DJ, et al. Analysis of the prognostic utility of the cell cycle progression (CCP) score generated from needle biopsy in men treated with definitive therapy. Prostate Cancer and Prostatic Diseases 2019.

Prolaris predictor of metastatic disease, with no difference in predictive performance between races or treatment groups.

“Contrary to expectation, this study provides no evidence that African American men have more aggressive disease than non-African American men after accounting for all available molecular and clinicopatholgic prognostic information.”

Canter DJ, et al. Comparison of the prognostic utility of the cell cycle progression score for predicting clinical outcomes in African American and Non-African American men with localized prostate cancer. Eur Urol 2019 March; 75(3):515-22.

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Prolaris superior to PTEN and Ki-67 for predicting outcome in prostate cancer after RP.

“Of the three biomarkers, only the CCP score remained significantly associated in a multivariable Cox model (p = 0.026). The best model incorporated CAPRA-S and CCP scores as predictors, with HRs of 1.32 and 1.24, respectively.”

Léon P, et al. Comparison of cell cycle progression score with two immunohistochemical markers (PTEN and Ki-67) for predicting outcome in prostate cancer after radical prostatectomy. World J Urol 2018 Sep; 36(9):1495-1500.

Patient’s 10-year prostate cancer-specific mortality shown graphically, compared to a cut-point used to guide patient selection for active surveillance.

“The cell-cycle risk score threshold appropriately dichotomized patients into low- and high-risk groups for 10-year prostate-cancer mortality, and may enable more appropriate selection of patients for active surveillance.”

Lin DW, et al. Identification of men with low-risk biopsy-confirmed prostate cancer as candidates for active surveillance. Urologic Oncology 2018; 36(6): 310.e7-310.e13.

Prolaris added significantly to prediction of BCR in multivariate analysis, both in overall cohort and subset of men meeting NCCN low risk criteria.

“In a cohort of NCCN low-risk patients, the CCP score improved clinical risk stratification of patients at increased risk of BCR [biochemical recurrence], which suggests the CCP score could improve the assessment of candidacy for active surveillance and guide optimal treatment selection in these patients with otherwise similar clinical parameters.”

Tosoian JJ, Chappidi MR, Bishoff JT, et al. Prognostic utility of biopsy-derived cell cycle progression score in patients with National Comprehensive Cancer Network low-risk prostate cancer undergoing radical prostatectomy: implications for treatment guidance. BJU Int 2017; 120:808-14.

Identify men likely to benefit from radiation after BCR.

“Among patients treated by radical prostatectomy who develop [biochemical recurrence], [cell cycle progression] score may predict systemic disease and could be used to help guide subsequent therapeutic interventions.”

Koch MO, Cho JS, Kaimakliotis HZ, et al. Use of the cell cycle progression (CCP) score for predicting systemic disease and response to radiation of biochemical recurrence. Cancer Biomarkers 2016 Jun; 17:83–8.

Safely manage patients conservatively.

“The [cell cycle progression] score provides significant pretreatment prognostic information that cannot be provided by clinical variables and is useful for determining which patients can be safely managed conservatively, avoiding radical treatment.”

Cuzick J, Stone S, Fisher G, et al. Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer. 2015; 113:382–9.

Guiding appropriate clinical care.

“[…] the [cell cycle progression] score can be used at disease diagnosis to better define patient prognosis and enable more appropriate clinical care.”

Bishoff JT, Freedland SJ, Gerber L, et al. Prognostic utility of the CCP score generated from biopsy in men treated with prostatectomy. J Urol 2014 Aug; 192(2):409–14.

Predicting biochemical recurrence in men with prostate cancer.

“[…] the [cell-cycle progression] score significantly predicted outcome and provided greater prognostic information than was available with clinical parameters.”

Freedland SJ, Gerber L, Reid J, et al. Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation therapy. Int J Radiat Oncol Biol Phys 2013 Aug; 86(5):848-53.

More accurate risk stratification.

“The cell-cycle progression (CCP) score may improve accuracy of risk stratification for men with clinically localized prostate cancer, including those with low-risk disease.”

Cooperberg MR, Simko JP, Cowan JE, et al. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol 2013 Apr 10; 31(11):1428-34.

Strongest independent predictor of cancer death outcome.

“For conservatively managed patients, the [cell-cycle progression] score is the strongest independent predictor of cancer death outcome yet described and may prove valuable in managing clinically localised prostate cancer.”

Cuzick J, Berney DM, Fisher G, et al. Transatlantic Prostate Group. Prognostic value of a cell cycle progression signature for prostate cancer death in conservatively managed needle biopsy cohort. Br J Cancer 2012 Mar 13; 106(6):1095-9.

Prognostic value demonstrated in two cohorts with prostate cancer.

“The results of this study provide strong evidence that the cell cycle progression (CCP) score is a robust prognostic marker, which […] could have an essential role in determining the appropriate treatment for patients with prostate cancer.”

Cuzick J, Swanson GP, Fisher G, et al. Transatlantic Prostate Group. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol 2011 Mar; 12(3):245-55.

Validated in prostate biopsy and radical prostatectomy samples.

“Study indicates that this prognostic gene signature is robust and reproducible, and is analytically validated for use on [formalin-fixed, paraffin-embedded] prostate biopsy and radical prostatectomy samples.”

Warf MB, Reid JE, Brown KL, et al. Analytical validation of a cell cycle progression signature used as a prognostic marker in prostate cancer. J Mol Biomark Diagn 2015 Sep; 9(9):901-10.

In patients with clinical favorable risk of cancer, GEC testing significantly increased the use of AS.

“[T]he rate of active surveillance (AS) was 57.9% among those without the gene expression classifier (GEC – Decipher Prostate Biopsy, Oncotype DX Prostate, and Prolaris) test compared with 75.9% among those with a GEC result below the threshold and 46.2% among those with a test result above the threshold. […] On multivariable analysis, patients with favorable-risk prostate cancer who were classified as GEC low risk were more likely to be managed on AS than those without testing (odds ratio, 1.84; P=.006).”

Hu J, et al. Clinical utility of gene expression classifiers in men with newly diagnosed prostate cancer. JCO Precis Oncol 2018. https://doi.org/10.1200/PO.18.00163.

Radical prostatectomy does not significantly reduce mortality.

“After nearly 20 years of follow-up among men with localized prostate cancer, surgery was not associated with significantly lower all-cause or prostate-cancer mortality than observation. Surgery was associated with a higher frequency of adverse events than observation but a lower frequency of treatment for disease progression, mostly for asymptomatic, local, or biochemical progression.”

Wilt TJ, Jones KM, Barry MJ, et al. Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med 2017; 377:132-42.

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RP associated with decreased sexual and urinary function.

“In this cohort of men with localized prostate cancer, radical prostatectomy (RP) was associated with a greater decrease in sexual function and urinary incontinence than either external beam radiation therapy (EBRT) or active surveillance after 3 years and was associated with fewer urinary irritative symptoms than active surveillance; however, no meaningful differences existed in either bowel or hormonal function beyond 12 months or in other domains of health-related quality-of-life measures.”

Barocas DA, Alvarez J, Resnick MJ, et al. Association between radiation therapy, surgery, or observation for localized prostate cancer and patient-reported outcomes after 3 years. JAMA 2017; 317(11): 1126-40.

Patients on AS experience fewer disruptive side effects.

“Of 1141 enrolled men, 314 pursued active surveillance (AS) (27.5%), 469 radical prostatectomy (41.1%), 249 external beam radiotherapy (21.8%), and 109 brachytherapy (9.6%). […] Compared with active surveillance, mean sexual dysfunction scores worsened by 3 months for patients who received radical prostatectomy, external beam radiotherapy, and brachytherapy. Compared with active surveillance at 3 months, worsened urinary incontinence was associated with radical prostatectomy; acute worsening of urinary obstruction and irritation with external beam radiotherapy and brachytherapy; and worsened bowel symptoms with external beam radiotherapy.”

Chen RC, Basak R, Meyer AM, et al. Association between choice of radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance and patient-reported quality of life among men with localized prostate cancer. JAMA 2017; 317(11): 1141-50.

Urinary, sexual, and bowel function and quality of life better on AS.

“The findings of the ProtecT trial have clarified the distinct effects of prostate-cancer treatments on urinary, sexual, and bowel function and condition-specific quality of life. The negative effect of prostatectomy on urinary continence and sexual function, particularly erectile function, was greatest at 6 months, and although there was some recovery, the effect was worse than in the other treatment groups over 6 years; however, prostatectomy was associated with no change in bowel function. At 6 months, the negative effect of radiotherapy with neoadjuvant androgen deprivation therapy on sexual function, particularly erectile function, was only a little less than that of prostatectomy, and bowel function, urinary voiding, and nocturia were worse in the radiotherapy group than in the other groups. However, there was then considerable recovery in the radiotherapy group for these measures, apart from more frequent bloody stools. In the active-monitoring group, sexual (including erectile) function and urinary continence and function were affected much less than in the radical-treatment groups initially but worsened gradually over time, as increasing numbers of men received radical treatments and age-related changes occurred; bowel function was unchanged.”

Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med 2016 Oct 13; 375(15):1425-37.

Active surveillance of prostate cancer does not increase death rate.

“At a median of 10 years, prostate-cancer–specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments.”

Hamdy FC, Donovan JL, Lane A, et al. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 2016; 375:1415-24.

Active surveillance an option for low-risk men.

“Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention.”

Tosoian JJ, Mamawala M, Epstein JI, et al. 1Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. J Clin Oncol 2015; 33:3379-85.

Better sexual and urinary health for those in AS.

“In this study, no differences in mental health outcomes were observed, but urinary and sexual health-related quality-of-life (HRQoL) were worse for patients who underwent radical prostatectomy (RP) compared with those who underwent active surveillance (AS) for up to 3 years. These data offer support for the management of low-risk PCa with AS as a means for postponing the morbidity associated with RP without concomitant declines in mental health.”

Jeldres C, Cullen J, Hurwitz LM, et al. Prospective quality-of-life outcomes for low-risk prostate cancer: Active surveillance versus radical prostatectomy. Cancer 2015; 121:2465-73.

Treatment outcomes affect long-term urinary, bowel & sexual function.

“[…] men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up.”

Resnick MJ, Koyama T, Fan KH, et al. Long-term functional outcomes after treatment for localized prostate cancer. N Engl J Med 2013; 368:436-45.

Avoiding unnecessary treatments reduces associated side effects.

“Men with localized [prostate cancer] on [active surveillance] were more often sexually active than similar men who received radical therapy, especially [radical prostatectomy].”

Van den Bergh RCN, Korfage IJ, Roobol MJ, et al. Sexual function with localized prostate cancer: active surveillance vs radical therapy. BJU Int 2012; 110:1032-39.

Data may be interpreted or applied differently resulting in discordant results.

“Although all testing laboratories use guidelines from the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) as the foundation for variant classification, there are still differences in how laboratories interpret and ultimately classify some variants.”

Mundt E, et al. Complexities of variant classification in clinical hereditary cancer genetic testing. JCO 2017; 35:3796-99.

In silico algorithms do not provide reliable evidence regarding the clinical significance of missense variants in genes associated with hereditary cancer.

“In a clinical laboratory, samples are tested due to clinical suspicion of hereditary cancer risk. Accurate variant classification using multiple lines of evidence is vital for appropriate clinical management based on NCCN guidelines. In this setting, incorrect variant classification based on in silico tools comes with more immediate consequences to the patient.”

Kerr ID, et al. Assessment of in silico protein sequence analysis in the clinical classification of variants in cancer risk genes. J Community Genet 2017. doi:10.1007/s12687-016-0289-x.

Clinical History Weighting Algorithm aids in the reclassification of variants.

“The need for improved variant classification tools has become more urgent as hereditary cancer genetic testing is increasingly performed with large panels of genes, or even entire exomes, rather than smaller subsets of genes associated with individual conditions like Lynch syndrome (LS). The use of panels including genes for multiple hereditary cancer syndromes has already demonstrated that pathogenic mutations in LS-associated genes are frequently identified in individuals who might not have been ascertained for LS testing based on their personal and family histories of colorectal cancer and endometrial cancer. While this validates the benefits of a broader pan-cancer panel approach to testing, it is inevitable that analysis of more genes leads to the identification of more VUSs [variants of uncertain significance].”

Morris B, et al. Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm. BMC Genetics (2016) 17:99.

Myriad identifies approximately 75 new variants every day, including 5-10 new BRCA1 and BRCA2 variants.

“Although the VUS rate for Myriad’s MyRisk^® panel was 41.7% in 2014, Myriad’s experience and investment in variant classification allowed for the development and improvement of multiple classification tools, leading to a substantial reduction in the VUS rate by 2016. The VUS rate is currently 28.6%. Although new variants are seen daily in genes on the MyRisk^® panel, it is expected that the VUS rate will continue to decrease with the current tools now utilized for variant classification at Myriad.”

Mundt E and Chen D. Lowering the rate of variants of uncertain significance on Myriad’s MyRisk^® hereditary cancer panel. White paper June 2016

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Clinical data for many variants contradicts expected pathogenic classification.

“[O]ur laboratory has identified a subset of such variants in hereditary cancer genes for which compelling contradictory evidence emerged after the initial evaluation following the first observation of the variant. Three representative examples of variants in BRCA1, BRCA2 and MSH2 that are predicted to disrupt splicing, prematurely truncate the protein, or remove the start codon were evaluated for pathogenicity by analyzing clinical data with multiple classification algorithms. Available clinical data for all three variants contradicts the expected pathogenic classification. These variants illustrate potential pitfalls associated with standard approaches to variant classification as well as the challenges associated with monitoring data, updating classifications, and reporting potentially contradictory interpretations to the clinicians responsible for translating test outcomes to appropriate clinical action.”

Rosenthal ET, et al. Exceptions to the rule: Case studies in the prediction of pathogenicity for genetic variants in hereditary cancer genes. Clinical Genetics 2015; 88(6): 533-41.

Interpretation of genetic data is challenging.

“Because the primary aim of clinical testing is to provide results to inform medical management, a variant classification program that offers timely, accurate, confident and cost-effective interpretation of variants should be an integral component of the laboratory process. Here we describe the components of our laboratory’s current variant classification program (VCP), based on 20 years of experience and over one million samples tested, using the BRCA1/2 genes as a model. Our VCP has lowered the percentage of tests in which one or more BRCA1/2 variants of uncertain significance (VUSs) are detected to 2.1% in the absence of a pathogenic mutation, demonstrating how the coordinated application of resources toward classification and reclassification significantly impacts the clinical utility of testing.”

Eggington JM, et al. A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clinical Genetics 2014; 86(3):229-37.

Accurately classifying variants as pathogenic or benign is critical for improved patient management.

“The history weighting algorithm [at Myriad] is a powerful tool that accurately assigns actionable clinical classifications to variants of uncertain clinical significance. While being developed for reclassification of BRCA1 and BRCA2 variants, the history weighting algorithm is expected to be applicable to other cancer- and non-cancer-related genes.”

Pruss D, et al. Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 2014; 147:119–32.

Functionality of curated missense mutations in tumor suppressor genes dependent upon user knowledge and process when using existing algorithms SIFT, Align-GVGD, PolyPhen-2 and Xvar.

“Accurately predicting the impact of missense mutations on protein function depends on the algorithm used, the type of sequence alignment provided, and on the number of sequences in the alignment. In addition to problems of interpretation there are technical difficulties as well. In our experience, when simply submitting a list of missense mutations to an algorithm the user must be able to: (1) manipulate the input format specified by each algorithm, (2) build an optimal protein sequence alignment, if required, (3) be knowledgeable of Unix system commands, (4) interpret server error messages, and (5) transform the output to a working format for further studies.”

Hicks S, et al. Prediction of missense mutation functionality depends on both the algorithm and sequence alignment employed. Human Mutation 2011, 32(6): 661–8.

Accurate variant classification is vital to ensuring appropriate medical management.

“There is a growing move to consult public databases following receipt of a genetic test result from a clinical laboratory; however, we show that up to 26.7% of variants in BRCA1 and BRCA2 have discordant classifications between ClinVar and a reference laboratory. The findings presented in this paper serve as a note of caution regarding the utility of database consultation.”

Gradishar W, et al. Clinical variant classification: A comparison of public databases and a commercial testing laboratory. Published ahead of print on April 13, 2017 as 10.1634/theoncologist.2016-0431.

Conflicting variant interpretations between commercial labs reported to PROMPT.

“We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments–approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. […] Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions.”

Balmaña J, et al. Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. J Clin Oncol 2016, 34: 4071-8. doi: 10.1200/JCO.2016.68.4316.

29% rate of discordance observed in variant interpretation.

“Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider.”

Amendola LM, et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet 2016; 98(6):1067-76.

Substantial disparity of variant classifications among databases.

“Our results show substantial disparity of variant classifications among and within publicly accessible variant databases. Although locus-specific variant databases (LSDBs) have been well established for research applications, our results suggest that several challenges inhibit their wider use in clinical practice. Healthcare providers should exercise caution when using these research tools for clinical purposes.”

Vail PJ, et al. Comparison of locus-specific databases for BRCA1 and BRCA2 variants reveals disparity in variant classification within and among databases. J Community Genet 2015 Oct; 6(4):351-9.

Clinical classification of hereditary sequence variants in disease-related genes directly affects clinical management of patients and their relatives.

“Carriers of mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 causing Lynch syndrome have a substantially increased risk of colorectal and endometrial cancers, along with increased risk of ovarian, gastric, small bowel, urothelial, brain, hepatobiliary, pancreatic, bladder, kidney, prostate and breast cancers. However, intensive management reduces mortality. […] InSiGHT has merged multiple gene mutation and variant repositories to create the InSiGHT Colon Cancer Gene Variant Database for MMR and other colon cancer susceptibility genes, hosted by the Leiden Open Variation Database (LOVD).”

Thompson BA, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature Genetics 2014; 46:107–115.

Data shows detection of RE insertions is an important component of hereditary cancer genetic testing.

“Our comprehensive testing strategy resulted in a substantial increase in the number of reported oncogenic RE insertions, several of which may have possible found effects.”

Qian Y, et al. Identification of pathogenic retrotransposon insertions in cancer predisposition genes. Cancer Genetics 2017; 216-217:159-169.

Optimizing the delivery of health services.

“Overuse and underuse are symptoms of a health-care system that does not reflect the ethics of medicine. They undermine the capacity of countries to achieve sustainable universal health coverage and to ensure that health care is a human right. Action is possible and necessary.”

Saini V, et al. Addressing overuse and underuse around the world. The Lancet, published online January 8, 2017.