NEW YORK (GenomeWeb) – A new report filed with German healthcare regulators currently sees no benefit from gene expression-based breast cancer tests used in breast cancer treatment decisions.
Submitted on Oct. 31, 2016 by the Institute for Quality and Efficiency in Healthcare (IQWiG) — a contractor for the German government that evaluates new medical interventions — the report became publicly available last month.
In an English-language summary provided by IQWiG, the authors of the report stated: "There is currently no hint of a benefit or harm of a biomarker-based strategy to support the decision for or against adjuvant chemotherapy in primary breast cancer." The report added that most of the data from eight studies on the topic were unusable in its analysis, "due to the high proportion of patients not considered in the analyses."
"It's disappointing," Agendia Chief Clinical and Business Development Officer Bastiaan van der Baan told GenomeWeb. The firm's MammaPrint test is one of several gene expression-based assays that would stand to benefit from broader reimbursement in Germany and Agendia issued a statement responding to the release. "It's an important report but the decision [for reimbursement] might be made [based] on more than just this report. We can safely reduce the amount of chemo given, that's a clear health benefit with level 1-A evidence. The test should be available for patients in Germany," he said.
The report concludes a two-year project commissioned by the German Federal Joint Committee (G-BA) to evaluate whether biomarker-based tests can improve patient care by advising against a chemotherapy regimen in certain breast cancer cases. IQWiG presented a preliminary report in November 2015, but held out for several key studies due out the following year, including the MINDACT study, which collected data from the MammaPrint test.
Led by dozens of researchers from across Europe, the MINDACT study published results last August in the New England Journal of Medicine, suggesting that almost 95 percent of women with a high-risk score from a standard recurrence test but a low-risk score from a genomic classifier survived for five years with no recurrence.
More than 2,000 patients had discordant results between standard and genomic risk assessments, with 1,550 at low risk according to MammaPrint and high risk according to Adjuvant! Online, an online tool that estimates risk and benefit of additional chemotherapy based oninformation like patient age and tumor size. As part of the trial, these patients were randomly assigned to receive adjuvant chemo or not.
The results provide level 1A clinical evidence, but have started to draw criticism. In December, for example, NEJM published two letters critical of the study design and interpretation.
MINDACT was not the only clinical study IQWiG considered for the report. It found eight relevant trials, but said that six were grossly incomplete, due to missing patients or lack of consent for the sample to be used in new studies.
"If the evidence base is so incomplete, in particular for the important long-term analyses, then this can lead to biased conclusions. The results of these studies could therefore not be used for the benefit assessment," IQWiG said in a statement.
While the report recognized the MINDACT results, "one cannot speak of a clear benefit of the test investigated in the MINDACT study. This is because, on the one hand, the follow-up period of five years is too short; many cases of distant metastasis, that is, metastasis not in the vicinity of the affected breast, occur only after several years," IQWiG said.
Van der Baan disputed this conclusion. "The trial is mature," he said, noting it was specifically designed with a five-year endpoint by leading oncologists. "Meta analysis of the benefits of chemo show that most, if not all, chemo benefit is in the first five years."
Moreover, IQWiG questioned the tradeoff between chemotherapy-related harm and the possibility of later metastasis.
"Unfortunately, most statements on the disadvantages of chemotherapy are rather vague," Daniel Fleer, IQWiG project manager for non-drug interventions, said in a statement. "It is repeatedly stated that an estimated 2 to 3 percent of patients undergoing chemotherapy suffer serious harm, for instance, permanent damage to internal organs such as the heart or kidney, or even die. However, these are only very rough estimates that are simply cited, often without any supporting evidence." He said the MINDACT study provides data on the risk of omitting chemotherapy, but not on the side effects that are important for decision making. "For the time being, one of the two components required to make an informed decision thus remains unclear," he said. "At the moment, one cannot in good faith advise a woman with a high clinical risk and low genomic risk to omit chemotherapy. The actual 'added value' of the biomarker test for women affected can only be judged when further results of ongoing studies become available."
IQWiG also included data from a 2014 study investigating whether Myriad's EndoPredict test could help determine the type of chemotherapy given to a patient, but said in the report extract that it "did not show a benefit."
The report lands as Agendia is touting the results of the PRIMe study, short for Prospective study to measure the Impact of MammaPrint on adjuvant treatment in hormone receptor-positive HER2-negative breast cancer patients, which was conducted in Germany and recently reported at the San Antonio Breast Cancer Conference. These results suggest that MammaPrint has a significant effect on treatment decisions. "In almost a third of the cases, the treatment decision changed if you added MammaPrint to the total package [of information]," van der Baan said. "There's high adherence to MammaPrint results. Clinicians are ready to act upon this kind of info when provided." He noted that the data were collected before the MINDACT results were published.
There's no guarantee that the G-BA will be as unimpressed with the study data as IQWiG was. Agendia plans to make its case directly to the reimbursement committee, van der Baan said.
Elsewhere, reimbursement regulators seem willing to consider the new evidence in studies like MINDACT. Last May, for example, Medicare contractor Noridian quickly retired a draft local coverage determination proposing to limit coverage for using such tests to guide decisions about chemo for breast cancer.