Long-term analysis of the phase III MINDACT trial, with a median follow-up of 8.7 years, confirmed that the 70-gene signature MammaPrint assay can identify which patients with breast cancer can safely forgo adjuvant chemotherapy, reported Emiel Rutgers, MD, PhD, FRCS, a surgical oncologist at the Netherlands Cancer Institute, at the 12th European Breast Cancer Conference (EBCC 12), which was held virtually this year.1
“Clinically high-risk and genomically low-risk women with early breast cancer can safely omit chemotherapy.”— Emiel Rutgers, MD, PhD, FRCS
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“MINDACT is a de-escalation study. It asked whether patients who are at clinically high risk but genomically low risk can be spared adjuvant chemotherapy. The primary endpoint, distant metastasis–free survival at 5 years, is strongly confirmed by this 9-year follow-up,” stated Dr. Rutgers. “The conclusion continues to be that clinically high-risk and genomically low-risk women with early breast cancer can safely omit chemotherapy.”
MINDACT used a modified version of the Adjuvant! Online tool to determine clinical risk. Almost all tumors were the luminal subtype; about half the patients had node-positive disease; 58% had tumors larger than 2 cm; and 29% had grade 3 tumors.
With more than 90% maturity, the rate of distant metastasis–free survival for the clinically high-risk/genomically low-risk subset is now 95.1%, still above the predefined noninferiority boundary of 92%. Among MINDACT’s all four risk categories, distant metastasis–free survival rates were “excellent,” except for patients considered to be at high risk by both clinical and genomic criteria (despite treatment with chemotherapy), added Dr. Rutgers.
The updated analysis did reveal some differences according to age, he continued. “We demonstrated that a low genomic risk signature can guide the de-escalation of adjuvant chemotherapy in the presence of a high clinical risk in women aged 50 and older,” Dr. Rutgers said. For peri- and premenopausal women, however, the benefit of chemotherapy appears greater, warranting more discussions between patients and providers, he added.
MINDACT Details
The phase III MINDACT study enrolled 6,693 women with early-stage breast cancer; their genomic risk was determined using the 70-gene signature (MammaPrint) and their clinical risk, using a modified version of Adjuvant! Online.2 Women at low clinical and genomic risk did not receive chemotherapy, whereas those at high clinical and genomic risk did. In patients with discordant-risk results, either the genomic risk or the clinical risk was used to determine the use of chemotherapy.
The primary endpoint focused on patients with high-risk clinical features and a low-risk gene-expression profile. The study asked whether in the absence of chemotherapy, the lower boundary of the 95% confidence interval for 5-year survival without distant metastasis was 92% (ie, the noninferiority boundary) or higher.
A total of 1,550 patients (23.2%) were deemed to be at high clinical risk and low genomic risk. At 5 years, the rate of distant metastasis–free survival in this group was 94.7% without -chemotherapy.
Results at 8.7 Years
Across the entire MINDACT population of 6,693 patients, the updated analysis was based on 650 distant metastasis–free survival events, including distant relapses (68.8%) and deaths (31.2%); 1,166 disease-free survival events, including distant relapses (33.5%), locoregional relapses (15.5%), second primaries (44.4%), and deaths (6.5%); and 458 deaths.
“We saw an excellent prognosis and a low rate of events in all groups except the patients at clinically high risk/genomically high risk,” he said. “The low/low-risk group is doing very well. The two discordant-risk groups are completely comparable, and the high/high-risk group is doing somewhat worse.”
Comparing Subsets
After 8.7 years of follow-up, for the 749 women deemed at high clinical risk but low genomic risk, adjuvant chemotherapy provided only a small gain (2.6%) in distant metastasis–free survival compared with the 748 patients who did not receive chemotherapy (92.0% vs 89.4%).
Results for patients with node-negative and node-positive (one to three nodes) disease were similar. Outcomes were “excellent,” he reported, for patients with one to three positive nodes: 8-year distant metastasis–free survival was 91.2% with chemotherapy and 89.9% without chemotherapy, comparable to the rates in the node-negative subgroup.
Age Mattered
The distant metastasis–free survival rates at 8 years, however, varied according to age younger and older than 50, roughly dividing postmenopausal women from perimenopausal/premenopausal women. Although the absolute difference for chemotherapy vs no chemotherapy was 0.2% for older women (90.2% vs 90.0%), for the younger group, it was 5% (93.6% vs 88.6%) and possibly clinically relevant, noted Dr. Rutgers.
The benefit of chemotherapy emerged at year 4, after which the Kaplan-Meier curves started to separate. This suggests the effect may be one of ovarian suppression. “Both age groups have the same clinical characteristics and received similar chemotherapy regimens. The main difference is their menopausal status,” he pointed out.
KEY POINTS
- MINDACT’s long-term analysis based on 8.7 years of follow-up validated the primary analysis; it is safe for patients with early breast cancer to forgo adjuvant chemotherapy if they are deemed clinically at high risk but genomically at low risk.
- MINDACT used the 70-gene signature (MammaPrint) assay to assess genetic risk.
- The absolute benefit of chemotherapy was 2.6% for this patient subgroup at 8.7 years.
- Premenopausal women, however, had a 5% benefit, which may have been due to the effect of ovarian suppression causd by chemotherapy.
“The estimated small distant metastasis–free survival gain with chemotherapy in the clinically high-risk/genomically low-risk group must be balanced against harmful side effects. Omitting chemotherapy in clinically high-risk/genomically low-risk postmenopausal women continues to be safe,” Dr. Rutgers concluded.
“In younger women, the gain of 5% might be clinically relevant,” he said. “Of note, this effect may be related to chemotherapy-induced ovarian function suppression. The risk vs benefit of either treatment should be part of informed, shared decision-making for these women.”
Institutional Protocol
At the Netherlands Cancer Institute, the protocol for patients deemed to be at clinically high risk follows: All patients are further stratified as genomically high risk or low risk by -MammaPrint. In the postmenopausal group, the genomically low-risk patients do not receive chemotherapy, whereas the genomically high-risk patients do. In the premenopausal group, the genomically high-risk patients also receive chemotherapy, whereas the genomically low-risk patients discuss treatment options with their physicians: usually, either chemotherapy or ovarian function suppression, explained Dr. Rutgers.
DISCLOSURE: Dr. Rutgers reported no conflicts of interest.
REFERENCES
1. Rutgers E, 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. 12th European Breast Cancer Conference. Abstract 21. Presented October 3, 2020.
2. Cardoso F, van’t Veer LJ, Bogaerts J, et al: 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med 375:717-729, 2016.
