The primary analysis of the MINDACT trial confirms the value of genomic profiling for patients with early breast cancer with zero to three positive lymph nodes, according to MINDACT investigators and breast cancer specialists who heard the results at the 2016 American Association of Cancer Research Annual Meeting.
In MINDACT, investigators compared the ability of the 70-gene signature (ie, MammaPrint) vs traditional clinical and pathologic criteria to identify patients with early-stage breast cancer who might safely forgo chemotherapy without compromising outcome.1 The test identified a group of patients with equally good outcomes, whether they received adjuvant chemotherapy or not. The 5-year distant metastasis-free survival was almost 95% for patients deemed at high risk clinically but at low risk by MammaPrint who did not receive chemotherapy.
“MINDACT is the only trial that pits tumor biology against tumor anatomy with a few biologic features added. It confirmed that the genomic strategy leads to a reduction in chemotherapy prescriptions,” said Martine Piccart, MD, PhD, Head of the Medicine Department at the Jules Bordet Institute in Brussels, Belgium, and co-founder and Chair of the Breast International Group.
The researchers determined that chemotherapy would be warranted in 50% of patients by clinical assessment, dropping to 36% by genomic assessment. In patients deemed to be at high risk by clinical assessment, the use of MammaPrint was associated “with almost a halving” in the use of chemotherapy, reported Dr. Piccart. The findings give good reason for clinicians “to trust” genomic assessment, she noted, adding that the findings provide level 1a evidence.
Overtreatment of early breast cancer is a concern. For good-prognosis patients, adjuvant chemotherapy offers only a 2% to 3% absolute gain in survival, which is counterbalanced by long-term side effects and a considerable socioeconomic burden, Dr. Piccart emphasized. MINDACT aimed to identify a subset of patients with good outcomes regardless of chemotherapy.
MINDACT Population
From 2007 to 2011, Dr. Piccart and colleagues screened 11,288 patients with early-stage breast cancer from 9 countries, ultimately enrolling 6,693 women who underwent surgery. Patients were largely node-negative (80%) and hormone receptor–positive (88%), but the population also included patients with one to three positive nodes (20%) as well as some HER2-positive patients (10%).
MammaPrint (70-Gene Profile)
- MINDACT enrolled almost 7,000 patients (mostly with hormone receptor–positive, HER2-negative disease).
- It compared the 70-gene signature with clinical risk calculation from Adjuvant! Online in identifying early-stage estrogen receptor–positive patients with up to three positive nodes unlikely to benefit from adjuvant chemotherapy.
- The primary statistical test was conducted on patients deemed clinically high risk but genomically low risk who were randomized not to receive chemotherapy.
- The 5-year distant metastasis–free survival for this group was 94.7%.
- MINDACT was underpowered to determine whether chemotherapy is beneficial in patients who had discordant test results.
The women were then divided into groups based on concordance or discordance between the test results. Thus, 2,745 patients were classified as low risk by both risk assessments (g-Low/c-Low), and 1,806 were considered at high risk by both (g-High/c-High). In the discordant group, 592 were categorized as high risk by MammaPrint and low risk clinically (g-High/c-Low), and 1,550 were categorized as low risk by MammaPrint and high risk clinically (g-Low/c-High).Participants were categorized as being at low or high risk for recurrence by two different methods: genomically, using MammaPrint, and clinically, using Adjuvant! Online.
Adjuvant chemotherapy was prescribed to patients who were at high risk by both tests and was withheld for those considered at low risk by both assessments. Discordant patients were randomly assigned to receive adjuvant chemotherapy or no chemotherapy. All estrogen receptor–positive patients could receive endocrine therapy.
The primary statistical test was distant metastasis–free survival at 5 years in the c-High/g-Low group that did not receive adjuvant chemotherapy. The null hypothesis was set at 92%, ie, for a successful result, the 95% confidence interval (CI) could not exceed 92%.
Results by Risk Group
“Patients who were low risk by both assessments did extremely well,” Dr. Piccart reported. “Their 5-year distant metastasis–free survival was close to 98% without chemotherapy. Patients who were high risk by both, and received chemotherapy, did somewhat worse, 90.6%. The discordant groups had outcomes between these two discordant groups (Table 1).”
For the primary statistical test, determined for the c-High/g-Low group that did not receive adjuvant chemotherapy, the 5-year distant metastasis–free survival was 94.7% (95% CI = 92.5%–96.2%), with a 95% CI that excludes 92%, “which was the definition of a successful trial,” she said.
Impact of Chemotherapy Not So Clear
MINDACT was not powered to answer whether chemotherapy benefited the patients in the discordant groups. In the intent-to-treat analysis, for the c-High/g-Low group, distant metastasis–free survival was 95.9% with chemotherapy and 94.4% without (hazard ratio [HR] = 0.78, P = .267). For the c-Low/g-High patients, distant metastasis–free survival rates were 95.8% and 95.0%, respectively (HR = 1.17, P = .657).
“The curves are almost superimposable,” Dr. Piccart observed, “but a statistician would tell you that, looking at the hazard ratio (0.78), it’s not totally impossible that there is a very small chemotherapy benefit. This would be a very small absolute benefit that would not justify the risks of chemotherapy.”
Impact in Europe
Dr. Piccart added that in Europe, MINDACT has “popularized the concept of biologically driven treatment” and has shown that “genomics can provide important information to help treat early breast cancer patients more optimally.”
In a press briefing, she indicated that no genomic test is currently reimbursable in most European countries, and she hopes these findings will change that. She also indicated that MammaPrint no longer requires fresh frozen tissue samples but can be processed with fresh tissue, making it easier for clinicians to use.
“In Europe, MammaPrint should gain in popularity,” she predicted, “but for the United States, it’s a question mark, because Oncotype DX is very well established there.” ■
Disclosure: Dr. Piccart reported no potential conflicts of interest.
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