Wednesday, January 18, 2017

German Tech Assessment of Breast Cancer Molecular Prognostics

Direct Google Translation

Cited in my January 2017 blog:

[This study focuses on MINDACT because a prior broader review of the field was negative.  The question was whether MINDACT would significantly update the 2015 review.]

See responses in German press at:

Biomarker tests in breast cancer: decision about chemotherapy remains difficult

Preliminary MINDACT results make it possible to estimate the disadvantages of a therapy disability / scarcely practical advantage

The Institute for Quality and Efficiency in Health Care (IQWiG) has examined the utility that certain breast cancer patients have in biomarker tests to decide for or against adjuvant systemic chemotherapy. These are women with primary hormone receptor-positive, HER2 /neu-negative breast cancer and up to three infected lymph nodes.

When the Institute presented its preliminary report in November 2015 [one year ago], the data was not sufficient to prove the benefit or damage of such tests.

However, results of further relevant studies were announced for early 2016. At the request of the Joint Federal Committee (G-BA), the IQWiG therefore waited after the scientific discussion on the preliminary report.


In the summer of 2016, the first results of one of these studies, MINDACT, were published, which could be included in the final report and are now the focus of the debate. The new study data provide valuable information on the possible consequences of a chemotherapy waiver due to a biomarker test result.

However, a clear benefit of the test under MINDACT can not be said.

On the one hand, the observation period of five years is too short: many long-distance metastases - ie, metastases away from the affected breast - occur only in the following years.

On the other hand, it is questionable whether one to two per cent more deaths are really insignificant due to a recurrence and spread of cancer because of a decision to avoid chemotherapy.

Biomarkers should show who benefits from chemotherapy

The IQWiG should investigate the benefits of using biomarkers for the therapy decision of women, who are unclear as to whether they would ever experience a recurrence of the disease (a recurrence) or whether their cancer would respond to chemotherapy. If [they will not recur], chemotherapy is an unnecessary burden. This is open in patients with primary hormone receptor-positive, HER2 /neu-negative breast carcinoma, with a maximum of three lymph nodes infected.

With chemotherapy after a successful tumor surgery one wants to switch off possible micrometastases and thus prevent a recurrence. However, most patients do not suffer from a recurrence without such chemotherapy. Based on established factors such as age, lymph node status and grading, the group of patients who really benefit from chemotherapy can not be determined reliably. From so-called biomarkers, it is hoped that the use of such additional therapy will be safe.

Many study results could not be considered
In the evaluation of the literature, eight studies proved to be relevant to the question.

In six of these studies, the data of many patients are missing, for example because samples were already consumed for other analyzes or were not suitable for the test, or because no consent was given to the reuse of the samples.

If the data base is so incomplete, especially for the important long-term evaluations, this can lead to misrepresentations. The results of these studies could not therefore be used for the benefit assessment.

In another study, the decision was examined between two chemotherapies, but not a possible renunciation of chemotherapy. Therefore, the following [review] is exclusively the eighth study, MINDACT.

Almost every second with a high clinical risk score has a favorable test result

In this randomized controlled study, the tumor tissue of nearly 7,000 women with breast carcinoma in the early stage after tumor surgery was also tested with a biomarker, namely MammaPrint, in addition to clinical risk assessment. In this test the reading of 70 genes is determined. On the basis of this so-called gene expression profile, the risk that the cancer is producing remote metastases is either classified as low or high.

Most of the study participants met the inclusion criteria for the present assessment. In half of the women, the conventional clinical risk classification was low. In the other half, the clinical classification posed a high risk that distant metastases would develop later - possibly after many years. Once these have occurred, two out of three affected women die from cancer within ten years.

The additional biomarker test revealed a low genetic risk score for 46 percent of women with high clinical risk. In order to determine whether women with such a contradictory risk assessment benefit from chemotherapy,

Five-year results only allow cautious assessment

In the opinion of the IQWiG, the experts agreed on the following: Distant metastases and other consequences of breast cancer can still occur many years later, so that the situation must be kept in view for at least ten years. However, MINDACT's first results were published after five years. Therefore, no reliable assessments of the advantages and disadvantages of a chemotherapy renunciation due to low biomarker risk indicators are possible. The IQWiG could only make a rough estimate of the results to be expected after ten years.

"No one knows exactly whether the differences between the groups with and without chemotherapy will grow or shrink in the next few years, or there will be the same number of additional metastases in both groups," says Stefan Lange, deputy head of IQWiG.

"But the results now available are the best we can work with at the moment. It is good that this great and carefully planned study was carried out. Among the more than 70,000 women who receive a breast cancer diagnosis in Germany in one year, roughly 20,000 are unaware of whether they benefit from chemotherapy. These women and their doctors provide MINDACT with important data to discuss the pros and cons of chemotherapy and the limited power of biomarker tests.

Hurdle skipped barely - or ripped down?

The study authors primarily wanted to check whether a decision on the biomarker results in a decision based on the clinical risk factor. To this end, they determined in advance that, after five years - statistically confirmed - at least 92 percent of women with a clinically high and genetically low risk level who did not receive chemotherapy still had to live and be free from metastases. In fact, this was 94.7 percent, with the 95 percent confidence interval ranging from 92.5 percent to 96.2 percent. The crucial lower limit of this interval is haarscharf over the hurdle of 92 per cent, whereby according to the authors the non-defeat is proven.

This is, however, an unorthodox understanding of non-subordination: instead of looking at only one study arm, one would have had to compare the distance of metastasis with women with and without chemotherapy. Also, the hurdle of 92 percent after five years is not derived - in contrast to the limit value set by the IQWiG, namely, 95 percent relapse-free survival after ten years. This limit is already below today. Other specialists are more liberal than the IQWiG and demand that after ten years at least 90 percent of the participants have to be free of metastases. This criterion is also not expected to be met: as experts say that many recurrences occur late, the confidence interval should fall below 90% in the next five years.

One and a half percent difference - or even four?

For the order given by the G-BA to the IQWiG, other results of this study are more important anyway: if women with high clinical and low genetic risk factors receive chemotherapy or do without them, the figures differ after five years Of women with local recurrences or distant metastases and, in particular, deaths? The study authors have determined that 95.9 percent of women were free of metastases after five years without chemotherapy and 94.4 percent without chemotherapy: a statistically not significant difference of about one and a half percent, which, however, due to the uncertainty due to the restricted number of participants also up to scarce Four percent.

For the affected women, however, the survival of the disease and the so-called overall survival are at least as relevant as the survival of the survivor of metastases. In the study, all three endpoints were in the same direction. Therefore, if 1000 women fail to undergo chemotherapy due to a low biomarker tester result, there are about 32 additional relapses (including deaths) and 11 additional deaths. Because of the uncertainty, however, there could also be 61 additional recurrences of all kinds and 26 additional deaths.

How many deaths from therapy are insignificant?
"According to the authors, the differences are so small that they can spare chemotherapy for women," says Stefan Lange. "I would like to discuss this more closely with the affected women and experts. In the debates, for example, the introduction of colorectal cancer or prostate cancer screening, presumed increases in survival rates by a fraction of a percentage point than absolutely necessary targets are put into the field. And here it should be insignificant, if up to 260 more dying of the approximately 10,000 women per year, who according to the manufacturers could give up the chemotherapy by the new tests, die up to 260 more? "

How is chemotherapy harmed against cancer?
This would be understandable if there were very clear advantages to the higher risk. A woman whose tumor has a high clinical criterion and a low risk of distant metastases according to genetic criteria must balance the potential side effects and sequelae of chemotherapy on the one hand and a higher risk of developing distant metastases as well as dying of cancer.

Unfortunately, most statements on the disadvantages of chemotherapies are quite vague, "explains Daniel Fleer from the Department of Non-Mediated Procedures, who supervised the biomarker report at IQWiG. "It is often said that two or three percent of the chemotherapies are estimated to cause serious damage, such as permanent damage to internal organs such as the heart or kidney, and even death. These are, however, only 'house numbers', which are often placed in the room without documents. Thanks to MINDACT, the affected women now know much better than before what the risks of a renunciation of chemotherapy are. However, no information is given to the decisive side effects. So what lies in the other scale is unclear. "

Overall, the IQWiG concludes that for any of the currently available biomarkers, there is evidence of a benefit or damage to a biomarker-based strategy for the decision to or against adjuvant chemotherapy in the primary breast carcinoma. At present, a woman with a clinically high and genetically low risk can not advise against chemotherapy. The actual 'added value' of the biomarker tests for those affected can only be assessed if further results of the ongoing studies are available.

The expiration of the report creation

The preliminary results, the so-called preliminary report, had been published by IQWiG in November 2015 and submitted for discussion. After the end of the opinion procedure, the preliminary report was revised and sent to the client as a final report in October 2016. The written submissions will be published in a separate document in parallel with the final report. The report was prepared jointly with external experts.

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