Gene expression test

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The gene expression test is a commercially available method for gene expression analysis , especially when selecting an individually optimized breast cancer therapy . This test can be performed as a service by a suitable laboratory or offered in the form of configured reagents. These optimized reagents also allow less specialized laboratories to carry out the analysis. Gene expression tests are part of what is known as “stratified” or personalized medicine , in which genomic features (prognostic biomarkers ) are used to optimize the treatment of diseases individually.

properties

Gene expression tests for gene expression analysis are usually either in the form of microarrays for genome-wide available or analysis in the form of a DNA sequencing in high-throughput after RNA purification , and after reverse transcription . Low-density arrays ( Low Density Arrays ) with low cover are increasingly less common for research purposes. In contrast to tests for research purposes, the gene expression tests for clinical applications are mostly limited to the analysis of a few genes. At present, gene expression tests are primarily used in clinics when selecting an individually optimized therapy for breast cancer.

First generation gene expression tests only analyze the mRNA expression of a tumor. Newer gene expression tests also include information from other sources.

Gene expression tests for breast cancer therapy selection

Expression tests currently offered for the selection of therapies for breast cancer are z. B. MammaTyper, MammaPrint, Oncotype DX, PAM50 ROR, genomic grade index (GGI), EndoPredict, BCI and Curebest 95GC. All gene expression tests have in common that they are intended to identify a subgroup of breast cancer patients who can be optimally treated without chemotherapy . A change in the choice of therapy through gene expression tests does not necessarily result in a change in the survival rate of the patient, which is why gene expression tests for changing the choice of therapy should be assessed with caution.

EndoPredict

EndoPredict is a second generation gene expression test that links the mRNA expression of 11 genes to the size of the tumor and the number of axillary lymph nodes affected by tumor cells . As a result, it indicates the probability with which a patient without chemotherapy will get cancer again within ten years after the operation. Endopredict does not recommend the effectiveness of adjuvant chemotherapy.

EndoPredict has been clinically and analytically validated as a CE-marked diagnostic test. It can be performed with RNA from formalin-fixed and paraffin-embedded tissue from the surgical specimen or from a diagnostic punch biopsy. Based on the published data, the Working Group for Gynecological Oncology (AGO) has certified the EndoPredict as evidence level 1 in its guidelines since 2013.

A patient with a low tumor risk according to EndoPredict has a 96% certainty of remaining tumor-free for at least ten years even without the use of chemotherapy . About 65% of all patients with estrogen receptor- positive, HER2-negative primary breast cancer have a low tumor risk according to the EndoPredict result. EndoPredict is significant in predicting early and late metastases and thus allows a statement to be made about the expected long-term course of the disease and a correspondingly adapted individualized therapy.

Mammaprint

Mammaprint examines the gene expression of 71 genes. Mammaprint gives both a statement about the prognosis and a recommendation on the effectiveness of adjuvant chemotherapy.

Mammatyper

MammaTyper is a gene expression test that enables quantitative detection of the mRNA expression status of the four biomarker genes ERBB2 ( HER2 ), ESR1 (ER), PGR (PR) and MKI67 (proliferation marker Ki-67 ) in human breast cancer tissue. The combination of the results for the four markers allows a molecular subtyping of tumor tissue according to the St. Gallen classification into the five subtypes Luminal A-like, Luminal B-like (HER2 positive), Luminal B-like (HER2 negative), HER2 positive (non-luminal) and triple negative (ductal). MammaTyper uses total RNA extracted from formalin-fixed and paraffin-embedded ( FFPE ) tumor tissue. The gene expression is analyzed using qRT-PCR .

Oncotype DX

The Oncotype DX Breast Recurrence Score® Test is a gene expression test for patients with a hormone receptor positive / HER2neu negative breast cancer. It is the only breast cancer test with which a predictive statement (precise prediction of the chemotherapy benefit) can be made beyond the sole risk of relapse or recurrence. He examines the activity of a total of 21 genes to determine the potential benefit of adjuvant chemotherapy and the likelihood of recurrence . The Oncotype DX test is performed on a biopsy specimen or on a piece of tumor tissue removed during surgery to remove the tumor. The activity of the tumor's genes is checked. The result of the analysis is communicated to the patient in the form of their Recurrence Score® value. This value is between 0 and 100. The result enables a precisely personalized assessment of the patient's situation.

A Recurrence Score result between 0 and 25 means that treatment with anti-hormone therapy alone is sufficient. Patients with this low Recurrence Score value do not require chemotherapy. The often serious short- and long-term side effects can be spared them.

A Recurrence Score result between 26 and 100 means a higher risk of relapse. Treatment with combined chemotherapy and anti-hormone therapy is very likely to make an important contribution to reducing the likelihood of distant relapses in these cases.

Study situation

Data from prospective clinical studies and outcome data from more than 96,000 patients are only available for the Oncotype DX breast cancer test. The test thus has the highest possible level of evidence, which clearly confirms its usefulness in clinical practice. Since its launch in 2004, the Oncotype DX breast cancer test has been used in over a million patients worldwide. The results of the largest study to date on the adjuvant treatment of breast cancer - TAILORx - are particularly significant. . In 10,273 patients included, the study impressively showed the limitations of the classic pathological factors commonly used so far, as well as the gain in important information through the Recurrence Score value, which is provided by the Oncotype DX breast cancer test. This led to a globally recognized adaptation of the treatment guidelines

The TAILORx study showed that a decision based solely on classical pathology would have led to a misjudgment for the majority of patients. For 73% of all patients for whom a decision in favor of chemotherapy would have been made on the basis of classical pathology, the Oncotype DX breast cancer test was able to prove that additional chemotherapy is not beneficial. Much more serious, it could also be shown that in the group of patients who have the greatest benefit from chemotherapy (Recurrence Score result> = 26), 43% of the patients have a “low risk” assessment based on the classic Pathology and would have been significantly under-treated. This could have had very serious consequences for these patients. According to the evaluation of the study data, anti-hormone therapy alone could have led to a significantly faster occurrence of a relapse or, in extreme cases, to the occurrence of metastasis with fatal consequences for the patient.

Prosigna

Prosigna is a gene expression test for breast cancer which is based on the PAM-50 gene signature (group of 50 genes) and is FDA- approved and CE-certified in Europe . This test can not only estimate the risk of relapse (ROR) of the individual patient, it also provides information about the biological subtype of the tumor.

The Prosigna test was examined in several cohorts of prospective randomized studies with consistent results (MA 5, MA-12, TransATAC, ABCSG-8, GEICAM 9906). The meta-analysis of the TransATAC and ABCSG-8 studies (including Gnant et al., ASCO 2013, main lecture) showed that the test provides additional prognostic information to the classic prognostic factors. A group of patients (also in the node-positive situation) could be identified (40–50%) who had an excellent prognosis even without chemotherapy.

Application in Germany

Biomarker-based tests in the treatment of early breast cancer have been recognized as standard benefits by statutory health insurances in Germany since January 2020 . In the plenary session on June 20, 2019, the Federal Joint Committee (G-BA) included the Oncotype DX test as the first and currently only multi-gene test for breast cancer in standard care. The test has been part of the standardized assessment standard of the statutory health insurance (EBM) since January 1, 2020. Statutory health insurance patients with node-negative early breast cancer and their attending physicians now have comprehensive access to the Oncotype DX® breast cancer test. The decision of the G-BA follows the addendum of the final report of the German Institute for Quality and Efficiency in Health Care (IQWiG) published in September 2018.

At a workshop on “Methodological issues in stratified medicine” in 2013, a national panel of experts advised against assuming the costs. The reason given was doubts about the evidence of the underlying test designs, so-called prospective-retrospective studies, which currently do not make an evidence classification possible. In 2014, the Mamma Organ Commission of the Gynecological Oncology Working Group recommended its use in patients only if all other criteria do not allow a therapeutic decision. Overall, she is of the opinion that the routine use of gene expression tests cannot yet be generally recommended.

In 2016, the Institute for Quality and Efficiency in Health Care rated the benefits of Mammaprint as "unclear"; for the other products there were no suitable studies available.

In its meeting on May 18, 2017, the Federal Joint Committee decided to commission the Institute for Quality and Efficiency in Health Care (IQWiG) with the creation of a decision-making aid for patients on biomarker tests in breast cancer.

Individual evidence

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