Breast Cancer. End of era for BRCA1 / 2 and NGS panels?
BREAST CANCER - GENETIC TESTS (UPDATE)
ONLY 5 out of 100 (5%) women with a history of breast cancer who will undergo a BRCA1 / 2 genetic test, will get a result with a clearly pathogenic mutation. Also, 13 out of the 100 (13%) women who will undergo molecular testing with multiple genes NGS panels, for breast cancer, will get a result with a clearly pathogenic mutation.
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Women who undergo conventional genetic testing using gene panels on the NGS platform will receive, for the most part (> 87%), a report without clinical significance. (Data from a study by the Mayo Clinic and Ambry Genetics, in approximately 150,000 molecular tests.
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The gap left by this high percentage (> 87%) of UNCLEAR genetic results (which means prolonged anxiety and worry of women in control), comes to fill the Polygenic Risk Score (PRS). A combination of many mutations of different genes, which individually have no clear clinical significance. On the contrary, from the combination of these mutations / polymorphisms, with the use of specific mathematical models but also with the addition of a detailed medical and family history, a Score (PRS) emerges, which classifies the examined as High or Low risk.
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PRS is clinically useful in breast cancer, as shown by important studies, such as the one posted by ACMG (see PUBLICATION), but also many works in reputable journals, such as the joint work of oncology centers,
Dana-Farber Cancer Institute, Boston, MA,, Memorial Sloan Kettering Cancer Center and Stanford University School of Medicine, Stanford, CA, June 2020, from which the following conclusions can be drawn:
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"Women with a family history of breast cancer are frequently referred for hereditary cancer genetic testing, yet <10% are found to have pathogenic variants in known breast cancer susceptibility genes."
"The validation and implementation of a PRS for women without pathogenic variants in known breast cancer susceptibility genes offers potential for risk stratification to guide surveillance recommendations."
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The use of PRS in breast cancer has already entered clinical practice, placing women at high or low risk. Two of America's largest private genetic testing centers (Myriad Genetics and Ambry Genetics) have added to their portfolio the use of PRS for breast cancer.
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HOW can a PRS check be done, WHERE can it be done and HOW MUCH does it cost?
Illumina (the leading genetic analysis equipment company, diagnostic kit, etc.) recently upgraded its "legendary" Trusight Cancer panel of 94 genes for predisposition to cancer (not just breast cancer) to the Hereditary Cancer panel. increasing the genes from 94 to 113, while also adding 77 SNPs for Polygenic Risk Score.
I make Copy and Paste From the Illumina site "TruSight Hereditary Cancer Panel targets 113 genes related to cancer predisposition. Also includes 125 SNPs. Of these, 77 are used for polygenic risk scoring (PRS)."
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Research around PRS (not only for breast cancer, but also for heart disease, Alzheimer's, Diabetes, etc.) has spread rapidly in recent years, resulting in new studies being upgraded with new predictive models that quickly went from 77 SNPs at 85 then at 210 and reaching today the model of 313 SNPs. The best prediction at the moment is in the 313 SNPs model, in combination with other risk factors (eg age, alcohol use, mammography data, etc.) and the use of risk models such as BOADICEA and Tyrer-Cuzick breast cancer risk models.
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It seems, according to the latest published research, that the new Illumina panel with 77 SNPs is inferior to the update 313 PRS model. Another improved molecular analysis procedure should be sought.
The appropriate genetic test that can extract (detect) the 313 SNPs and consequently the PRS (and at the same time can be used for any future model of more or different SNPs, at no extra cost) is the complete sequencing of the human genome , Whole Genome Sequencing (WGS). ATTENTION not Whole Exome Sequencing, but WGS, as many of the PRS mutations are located in intron regions.
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The obvious question: Where is the audit done and what is the cost?
The cost of WGS is decreasing exponentially, and today it is well below € 1000 while the price drop continues and tends to approach € 100.
According to current data, the cost of WGS + PRS is about € 100 more expensive than an "obsolete" panel of 36 genes.
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Conclusion: For a lady who will be offered a genetic test for breast cancer, there are the following 3 options:
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A) BRCA1 / 2: It is not proposed as an option unless the extra cost of a larger panel is prohibitive for the examinee.
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B) NGS panel of small number of genes, WITHOUT PRS. According to the data presented above, from important studies / publications, a percentage of> 90% of women who will be tested with a corresponding panel (30-40 genes), will get a vague report. Cost about 700 €. Not recommended.
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C) WGS + PRS. Clearly, the most complete choice allows the assessment of risk, high or low, in the event that no clearly pathogenic mutations are found in the genes under study. WGS + PRS also adapts to any future changes to control different genetic targets. Cost about 800 €.
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UPDATE1: Last minute information. EOPYY covers 85% of the cost of a genetic test for breast cancer, providing a handwritten prescription from the treating physician. With these data the WGS + PRS control can reach the levels of 120 €.
(Obviously there are conditions for the approval of compensation by EOPYY).
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UPDATE2: WGS + PRS provides risk assessment not only for Breast Cancer but also for Ovarian Cancer.