Update of evidence regarding prognostic genomic tests in early breast cancer in Spain

The prognostic genomic tests in breast cancer are being incorporated progressively in the health system and apparently and their use has an impact on the therapeutic decision.

This report tries to answer the following questions:

1. Does the genetic testing of a prognostic-predictive nature (MammaPrint®, Oncotype DX ™, EndoPredict® or Prosigna ™), in patients with breast cancer ER+/HER2- in the early stages, identify those patients with the highest risk of recurrence and candidates for personalized adjuvant therapies, thereby reducing mortality and/or recurrence of disease by assigning the most appropriate treatment?
2. Does the genetic testing of a prognostic-predictive nature (MammaPrint®, Oncotype DX ™, EndoPredict® or Prosigna ™), in patients with breast cancer ER+/HER2- in the early stages, help to decide on the most appropriate adjuvant therapy, avoiding its administration to patients who would not benefit?

AETSA has performed a systematic review of the literature and developed this report, which contains updated evidence on the validity and clinical utility of the genetic tests (Prosigna ™, Oncotype DX ™, EndoPredict® and MammaPrint®). Scientific evidence published between 2013 and 2017 was taken into account. Furthermore, the major national and international agencies and units of Health Technology Assessment were consulted.

Eventually, one reference on EndoPredict®, three on Prosigna ™, six on MammaPrint® and 16 on Oncotype DX ™ were considered for this update of evidence.

Results

EndoPredict®: in postmenopausal patients with ER+, HER2 - the EP index looks like an independent prognostic factor for local recurrence at ten years; high-risk patients had a higher local recurrence than low-risk group (p=0,005). Adjuvant RT reduced local recurrence rate in both high and low-risk patients.

There were none Prosigna™ clinical utility studies found. The focus of one of the Prosigna™ studies was on its clinical validity, and it analyzed the prognostic value for the distant recurrence risk in patients with positive nodes. The other two reports evaluated the impact on the therapeutic decision, observing that the result did modify the therapeutic decision, in favour of hormonal therapy in low-risk patients and in favour of chemotherapy in high-risk patients.

The evidence on the clinical utility of Mammaprint has been limited to one randomized control trial (MINDACT; n=6693) in which the intention-to-treat analysis of the groups with disagreement between clinical and genomic risk found no statistically significant differences in disease-free survival, metastasis-free survival and overall survival at 5 years among patients with or without chemotherapy. Also, the Mammaprint test has demonstrated to have an impact on the therapeutic decision, mostly in those cases where there was disagreement with the clinical risk. The impact on the recommendation of chemotherapy varied in the different studies, not being precise the net reduction of chemotherapy.

Regarding Oncotype, the outcomes of the TAYLORx study (n>1600) corresponding to intermediate-risk patients randomized to QT or non-QT are not yet available. The results of clinical validity collected in this update come from the cohorts of patients with low risk (SR ≤ 11) without chemotherapy. These patients have shown a disease-free survival of 93.8 % at five years and 98.4 % at three years. The studies on the impact of Oncotype DX on the therapeutic decision have permitted the realization of a quantitative analysis of its results (meta-analysis) to obtain global estimators. The test involved a change in the therapeutic choice in 31 % of the cases; the change in patients with positive lymph nodes was 41 %; in patients without lymph node involvement was 28%. According to Oncotype DX, the change in the therapeutic decision by risk group was more significant in the groups of low-risk (34 %) and intermediate-risk (31 %) than in the high-risk group (19 %). Also, the test involved a 15 % diminution in the treatment with chemotherapy. This diminution was expressed more in patients with positive lymph nodes (36 %) than in patients without lymph node involvement (11 %). By risk group, the test involved a 35 % and 11 % reduction in chemotherapy in the low and intermediate risk groups, respectively; and entailed a 20 % increase in chemotherapy for the high-risk group.

Conclusions

As for clinical validity:

• EndoPredict® seems to be an independent prognostic factor for 10-year local recurrence in postmenopausal patients with early breast cancer ER+, HER2-, although it may be not suitable for customizing local therapy;
• ROR index (Prosigna ™) seems to be an independent prognostic factor for 10-year distant recurrence in postmenopausal HR+ patients early breast cancer with 1-3 positive nodes, although it provided less prognostic information in this subgroup than in node-negative patients.

As for clinical utility:

• A 5-year follow-up MammaPrint identifies those patients with breast cancer in early stages with and without lymph node involvement who demonstrate a low risk of recurrence and who could, perhaps, avoid chemotherapy. These results give us hope, but a longer follow-up time is necessary for confirmation; the plausible long-term chemotherapy benefit in these patients is unknown;
• Oncotype seems to identify early breast cancer patients ER+, HER2- and negative-nodes with low risk that could avoid chemotherapy, despite the fact that the definitive results of the clinical trial on its usefulness are not yet available;
• Gene expression tests impact on decision making by modifying the therapeutic recommendation and generally reducing the adjuvant chemotherapy.

See the full report in Spanish (with summary in English) here.

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