Long-term results of MINDACT confirm MammaPrint as a guidance for adjuvant chemotherapy in breast cancer patients

In 2016, the MINDACT trial demonstrated that the 70-gene MammaPrint signature was able to identify breast cancer patients for whom adjuvant chemotherapy (CT) could be safely omitted even in the presence of unfavorable standard clinical-pathological criteria. During ASCO 2020, long-term follow-up data of this trial were presented, with a median follow-up of 8.7 years. These updated results confirm MINDACT as a positive de-escalation trial. In fact, omitting chemotherapy in patients with a clinical high/genomic low risk continued to be safe with a gain in the distant-metastasis free survival (DMFS) of only 2.6% at 8 years for patients receiving adjuvant chemotherapy. Giving adjuvant chemotherapy in the subgroup of patients with a clinical high/genomic low risk profile only led to a 3.5% absolute increase in the disease-free survival rate at 8 years. The outcome of the study was somewhat less favorable in premenopausal women, where the absolute DMFS difference between patients who received adjuvant chemotherapy or not was more pronounced at 5%. According to the authors, however, this effect may be related to chemotherapy-induced ovarian suppression.

Introduction

The MINDACT trial investigated the clinical utility of MammaPrint, when compared to (or used along with) standard pathological criteria for the selection of patients unlikely to benefit from adjuvant chemotherapy. Patients characterized as low risk with both clinical and genomic assessments were spared chemotherapy, while patients characterized as high risk with both were advised to undergo chemotherapy. Those with discordant results were randomized to use either clinical or genomic (MammaPrint) risk evaluation to decide on chemotherapy treatment. Back in 2016, the MINDACT trial successfully met its primary endpoint by showing a 5-year DMFS rate of 94.7% for patients classified as clinically high/genomic low risk who received no chemotherapy. In this primary report, it was shown that the CT use among clinical high-risk patients could be reduced by 46% when the genomic risk strategy was used. The secondary endpoint of the study was to assess the value of chemotherapy in discordant risk groups in the intention to treat population, although it should be noted that the trial was not powered for this chemotherapy versus no chemotherapy comparison. For this secondary endpoint, an absolute difference of 1.5% in five-year DMFS was observed. Finally, compliance rates with assigned/randomised treatment was very high (80-99%). As a result, the use of MammaPrint has been endorsed by many guidelines. At ASCO 2020, Cardoso et al. presented the updated analysis of the MINDACT trial after a median follow-up of 8.7 years.

Results

The MINDACT trial enrolled 6,693 patients with early-stage breast cancer, all of which had their risk assessed by traditional clinical pathological factors using a modified version of ‘Adjuvant! Online’ as well as through the genomic signature, the 70-gene MammaPrint signature. Women with both low clinical and genomic risk did not receive chemotherapy whereas those patients with both a high clinical and genomic risk did receive such therapy. In patients with discordant risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy. Primary endpoint of the trial was the DMFS rate at 5 years in the primary test population of clinical-high/genomic-low risk (C-High/G-Low) patients who were randomised to receive no chemotherapy (N=644).

In the MINDACT trial, the group of C-High/G-Low patients included 1,551 patients, mostly postmenopausal (N=994) with a median age of 55 years old. The majority of patients (91%) was ER-positive, HER2-negative (ER+/HER2-) with a small percentage of HER2-positive patients. In the ER+/HER2- C-High/G-Low population, 48% of the patients was node positive and 29% had grade III disease. In the updated primary endpoint analysis, more than 90% of the patients has at least five years of follow-up. The DMFS at five years for the group of C-High/G-Low patients who were not treated with chemotherapy was reported at 95.1% (CI: 93.1-96.6%) confirming that MINDACT is a positive trial supported by sensitivity analysis. At a median follow-up of 8.7 years, the prognosis of all but one risk groups was excellent with low event rates (8-year DMFS rates above 90%). Only in patients with clinical high/genomic high-risk profile, the prognosis was worse with an 8-year DMFS rate of only 85.9%.

With respect to the secondary endpoint of DMFS in the group of patients with clinical high/genomic low chemotherapy versus no chemotherapy, it was shown that the difference in DMFS at five years is now 0.9% ± 1.1% (95.7% for patients treated with chemotherapy versus 94.8% for patients not treated with chemotherapy). At eight years, this difference mounts to 2.6% ± 1.6% (92.0% versus 89.4%, respectively). Of note, the majority of the observed events were distant recurrences (74.7%).

A final analysis looked into effect of chemotherapy according to age in the ER+/HER2- patients with high-risk clinical features who were classified as low-risk with the MammaPrint score. In this analysis, it is shown that the effect of giving chemotherapy in patients above the age of 50 in this risk group is very limited with an absolute DMFS difference at 8 years of only 0.2% (± 2.1%). However, this picture is slightly different in younger, mostly premenopausal patients (age ≤50 years). In this cohort of patients, the absolute difference in 8-year DMFS was reported at 5.0% (± 2.8%). Importantly, however, for 55% of younger (≤50 years) patients who did not receive chemotherapy, 5 years of tamoxifen was the only endocrine therapy that was used with only 16% of patients receiving ovarian function suppression. Based on this observation, the investigators concluded that the age-dependent effect of chemotherapy versus no chemotherapy could be the result of chemotherapy-induced ovarian function suppression instead of being a cytotoxic effect of the chemotherapy itself.

Conclusions

At a median follow-up of 8.7 years, the primary endpoint continues to be met in chemotherapy untreated C-High/G-Low risk women, confirming MINDACT as a positive de-escalation study. At eight years, the estimated DMFS gain for chemotherapy administration in C-High/G-Low is 2.6% and must be balanced with chemotherapy harmful side effects. Omitting chemotherapy in C-High/G-Low postmenopausal women continues to be safe and a fully preserved performance of MammaPrint to forego adjuvant CT is demonstrated. In premenopausal women, the difference seen with treatment with or without chemotherapy might be clinically relevant but it is important to note that this effect may possibly be related to chemotherapy-induced ovarian function suppression. Overall, in the C-Low/G-High risk patients, there is no advantage of guiding treatment based on the genomic risk.

Reference

Cardoso F, van ‘t Veer L, Poncet C, et al. MINDACT: Long-term results of the large prospective trial testing the 70-gene signature MammaPrint as guidance for adjuvant chemotherapy in breast cancer patients. Presented at ASCO 2020; Abstract 506.