Wednesday, January 18, 2017

TAGESSPIEGEL on IQWIG Breast Cancer


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12/2016: German Newspaper TAGESSPEIGEL

Debate over Gentest in breast cancer continues

Chemo yes or no? This decision to make due to a gene expression test is too uncertain for breast cancer patients, writes the IQWiG - and thus fires again the dispute. 




BY ADELHEID MÜLLER-LISSNER

Difficult Decision. It is not always clear which breast cancer patient really needs chemotherapy. Gene expression tests should help
 .  

"Overall, the IQWiG concludes that there is currently no evidence for a benefit or harm to a biomarker-based strategy to decide whether or not to undergo adjuvant chemotherapy for primary breast cancer."

MORE AFTER BREAK




For outsiders, this rate may sound specialist-chinese. The analysis published today by the Institute for Quality and Efficiency in Health Care (IQWiG), commissioned by the Federal Joint Committee (G-BA), is likely to be affected by affected women.

With the tests, whose usefulness is questioned here, they ultimately combine the hope of saving themselves with a lengthy, strenuous and possibly purchased with life-long health problems.

"To withhold a test from a woman, despite all the recommendations from the scientific side and the big breast cancer congresses in the USA and here in Germany, is similar in my eyes to a personal injury," says one of the emotional (open) letters of affected women In 2013 with the then Federal Minister of Health Daniel Bahr.

Who needs a chemo? Whom does she do more than she does?

Why is? Around 70,000 women are diagnosed with breast cancer every year in Germany. The question of whether further treatment is necessary in addition to an operation is then quickly in the room. With the greatest anxiety, the women usually wait for a supportive chemotherapy. It is intended to prevent the cancer from returning and spreading elsewhere in the body. Women who have only a minimal risk of such a relapse would be unnecessarily burdened with the toxic treatment for cells. Others are very likely to save their lives. But who belongs to which group?

"The chemotherapy has improved the cure rate in breast cancer - but it has been chemotherapy too much," says gynecologist Isabell Witzel, head of the breast center at the University Hospital in Hamburg (UKE). The guidelines list criteria for the physicians to address and discuss them in their tumor conferences. This includes questions such as: How big is the tumor? Are lymph nodes infected? How fast do cancer cells grow? What is the proportion of cells that multiply? Last but not least: Do receptors for female sex hormones, which influence the growth, and large amounts of the growth factor HER2 in the cancer tissue are found? Usually, the answers are a clear decision.

The tests determine which genes are active in the tumor

But there are controversial borderline cases - especially when the tumor has receptors for estrogen and progesterone when it is HER2-negative and no or at most three lymph nodes are infected. "The patient's individual risk must be discussed here," says Michael Untch, chief physician of the women's clinic and head of the Interdisciplinary Breast Center at the Helios Clinic in Berlin-Buch. Tests that help in the decision are basically welcome.

In the meantime, pathologists are investigating the two proteins uPA and PAI 1 more frequently during the surgical operation, in order to estimate the prognosis of breast cancer patients without involvement of the lymph nodes.

And there have been several tests on the market, with which one can find out how strong up to 70 different genes in the tumor are active. Partially, one can use paraffin-preserved tissue for this purpose. Oncotype DX, EndoPredict, PAM 50 and MammaPrint - these are currently the best known names.

According to IQWiG, such tests are questionable [?under consideration] for about 20,000 women every year.

The experts of the IQWiG were waiting for a large study

They should be used "only in selected patients, if all other criteria do not permit a therapy decision," according to a current opinion of the Arbeitsgemeinschaft Gynäkologische Onkologie.

The 2012 breast cancer guideline, which is currently being revised, states: "The use of analyzes for gene expression to assess prognosis or therapy responses is not sufficiently validated and therefore can not be recommended."

The IQWiG had retained its final assessment in order to await the results of the so-called Mindact study on the MammaPrint test from the Dutch company Agendia. Six other studies had previously excluded the investigators from the analysis because of missing data or not quite appropriate questions. The PlanB study of the West German study group (WSG) on the Oncotype DX test produced encouraging results, but can only date with an observation period of three years.


"You can not advise against conscience chemotherapy"

For the Mindact study, which focuses on IQWiG, 6696 women were diagnosed with the risk that the cancer could report again after the first treatment, according to the conventional criteria and the gene expression test MammaPrint. If clinical and genetic assessments were consistent with the risk, a clear decision for or against chemotherapy could be made. If they diverged from one another, this important point was randomly placed with the consent of the participants. In August, the first results of the investigation were published in the "New England Journal of Medicine".

It was important for the assessment of the IQWiG as to how those 46 per cent of the women after five years had, which had a favorable result in the biomarker test, but high clinically recognizable risks. 94.4 percent of the women in this group who had not received chemotherapy had not received any long-distance resettlement of the tumor, 95.9 percent of women with chemotherapy had spared this fate, a statistically insignificant difference of 1.5 percent . Due to various uncertainties, however, he could also be up to four percent, according to the IQWiG. "At the present time, a woman with a clinically high and genetically low risk can not advise against a good chemotherapy chemotherapy", says the press release.

"A Conclusion beyond the clinical routine" [Outside of today's clinical practice]

In the other scale, however, the hardships and also the possible late effects of chemotherapy occur. The side effects at the heart can be seen years later. "The calculation of the IQWiG has been set up outside the clinical routine and would hardly be reproduced by a patient who is undergoing six-month chemotherapy," says Oleg Gluz, Oberarzt at the Brustzentrum Niederrhein in Mönchengladbach and Scientific Coordinator of the WSG.

The situation was exacerbated by the fact that the patients were generally older than those included in studies during the care day. Up to now there have been only vague statements on the side effects, says Daniel Fleer from the IQWiG Department of Non-Medication, who supervised the report. The authors of the Mindact study, gathering information about this, missed the opportunity to make public their findings on the undesirable effects [harms] of chemotherapy.

That the tests could spare some women a too far-reaching therapy is, however, only one side of the coin. If a test with a low clinical risk poses a high risk in the gene signature, it can look exactly the opposite. However, Untch criticizes the fact that chemotherapy is of use in these cases, but it has not yet been proved, even if the advertising brochures of some manufacturers are different. It would be very difficult to decide if a woman with an average risk of chemotherapy should be advised. "Again, the data is unclear," he says.

"The evaluation puts us back in the 1980s"

The IQWiG calls for long-term results. "Five years of follow-up are much too short," says Brecht-cancer expert Untch. Especially in patients who have breast cancer antennas for female sex hormones and is Her2 negative, metastases often occur much later - "up to 25 years after the diagnosis". On this point the IQWiG's perspective is understandable, says Stefan Wiemann, head of the Molecular Genome Analysis department at the German Cancer Research Center in Heidelberg. "The five-year period of the Mindact study is, in fact, inadequate to make a final assessment of the predictive power of this test."

Should use of the test be delayed under these circumstances? This is a difficult question, especially for doctors who have to make therapy decisions daily with their patients. According to Untch, the tests were on the market precisely because the so-called group had so much uncertainty as to whether they still needed chemotherapy in addition to antihormonal treatment. There is something more secure now, says his colleague Isabell Witzel. "The Mindact study confirms that in low-risk women, according to genetic testing but high clinical risk, chemotherapy can be dispensed with." Oleg Gluz demands that at least the well-tested tests are paid by the health insurance companies in these patients. "Unfortunately, the IQWiG assessment in Germany is returning to the 1980s, 1990s, when the knowledge of tumorbiology was still insufficient."


Politics on the back of the patients

The scenario is tricky. This is partly due to the fact that diagnostic tests are different from those for medicinal products. The breast cancer expert Rolf Kreienberg, president of the Arbeitsgemeinschaft der Wissenschaftliche Medizinische Fachgesellschaften and external expert for the IQWiG investigation, calls for such tests to clarify the evidence before the market launch by studies "so that a clear starting position exists and not with the Patients or their back policy. "

In this case it is too late. Patients can only hope that in five years more clarity will prevail.

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