Laura van ’t Veer, Ph.D., Co-Leader, Breast Oncology Program and Director, Applied Genomics at UCSF Helen Diller Family Comprehensive Cancer Center and Co-founder and Chief Research Officer at Agendia speaks about 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age.
Link to Article:
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(21)00007-3/fulltext
Details
Abstract
The MINDACT trial found that patients with high clinical and low genomic risk breast cancer who did not undergo chemotherapy had a 5-year remote metastasis-free survival rate of 947 percent (95 percent CI 9255–962). We present long-term follow-up findings as well as an age-based exploratory study.
Methodologies
MINDACT was a phase 3 multicenter, randomized study that took place in 112 clinical and community hospitals across nine European countries. Patients aged 18–70 years old with histologically documented primary invasive breast cancer (stage T1, T2, or operable T3), up to three positive lymph nodes, no remote metastases, and a WHO performance status of 0–1 were enrolled, and their genomic risk (as calculated by the MammaPrint 70-gene signature) and clinical risk (as determined by an updated version of Adjuvant! Online) were established. Chemotherapy was not given to patients with low clinical and genomic risk, but it was given to patients with moderate clinical and genomic risk (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk outcomes (those with a high clinical risk but a moderate genomic risk, and those with a low clinical risk but a high genomic risk) were randomly allocated (1:1) to undergo chemotherapy or not, depending on either the clinical or genomic risk. The randomization was performed centrally and was stratified by organization, risk category, and clinical–pathological features using a minimisation methodology. There was no concealment of treatment distribution. The primary goal was to see whether the 5-year distant metastasis-free survival rate of patients with high clinical risk and low genomic risk who did not receive chemotherapy had a lower 95 percent confidence interval than the predefined non-inferiority boundary of 92 percent. Patients of high clinical risk and low genomic risk who adhered to the drug allocation with no chemotherapy and saw no improvement in risk post-enrolment made up the primary research group. For patients with hormone receptor-positive and HER2-negative disorder, we present revised follow-up, as well as an exploratory study of a possible age impact (50 years vs >50 years) and an analysis by nodal status. Intention-to-treat analysis was used for these studies. ClinicalTrials.gov (NCT00433589) and the European Clinical Trials website (EudraCT2005–002625–31) have also reported this report. The recruitment process is now complete, and long-term follow-up is underway.
Conclusions
A total of 6693 patients were registered between February 8, 2007 and July 11, 2011. On February 26, 2020, the median follow-up was 87% (IQR 78%–97%). The 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk who did not receive chemotherapy (primary research group, n=644) was 951% (95 percent CI 931%–966), which is higher than the predefined non-inferiority boundary of 92 percent, confirming the previous study and proving MINDACT as a promising de-escalation experiment. In the intention-to-treat population, patients with high clinical risk but low genomic risk were randomly allocated to undergo chemotherapy (n=749) or not (n=748). In the intention-to-treat population, the 8-year figures for distant metastasis-free survival were 920 percent (95 percent CI 896–938) for chemotherapy versus 894% (868%–915) for no chemotherapy (hazard ratio 066; 95 percent CI 048–092). An exploratory analysis confined to patients with hormone receptor-positive, HER2-negative disease (1358 [90.7 percent] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) reveals different effects of chemotherapy administration on 8-year distant metastasis-free survival depending on age: 936% (95 percent CI 893%–963) with chemotherapy ver. In the exploratory analysis by nodal status in these patients, 8-year distant metastasis-free survival was 917% (95 percent CI 881–943) with chemotherapy and 892% (852–922) without chemotherapy in 699 node-negative patients (absolute difference 25% percentage points [SE 23, 95 percent CI 213 to 72]) and 912% (872–940) versus 899% (858–928) for 65 patients.
Representation
With a longer follow-up approaching nine years, the 70-gene signature continues to demonstrate the potential to classify a subgroup of women with elevated clinical risk, including patients with low genomic risk, who have excellent distant metastasis-free survival when treated with endocrine therapy alone. The extent of the gain from combining chemotherapy and endocrine therapy for these women remains limited (26%), and nodal positivity has little impact. However, this advantage tends to be age-dependent in an underpowered exploratory study, since it is only observed in women less than 50 years old, where it crosses a clinically significant threshold of 5 percentage points. Despite the fact that it could be attributable to chemotherapy-induced ovarian function repression, it should be seen as part of an educated, joint decision. More research is required in younger women who could need enhanced endocrine therapy in order to avoid chemotherapy.Details
Abstract
The MINDACT trial found that patients with high clinical and low genomic risk breast cancer who did not undergo chemotherapy had a 5-year remote metastasis-free survival rate of 947 percent (95 percent CI 9255–962). We present long-term follow-up findings as well as an age-based exploratory study.
Methodologies
MINDACT was a phase 3 multicenter, randomized study that took place in 112 clinical and community hospitals across nine European countries. Patients aged 18–70 years old with histologically documented primary invasive breast cancer (stage T1, T2, or operable T3), up to three positive lymph nodes, no remote metastases, and a WHO performance status of 0–1 were enrolled, and their genomic risk (as calculated by the MammaPrint 70-gene signature) and clinical risk (as determined by an updated version of Adjuvant! Online) were established. Chemotherapy was not given to patients with low clinical and genomic risk, but it was given to patients with moderate clinical and genomic risk (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk outcomes (those with a high clinical risk but a moderate genomic risk, and those with a low clinical risk but a high genomic risk) were randomly allocated (1:1) to undergo chemotherapy or not, depending on either the clinical or genomic risk. The randomization was performed centrally and was stratified by organization, risk category, and clinical–pathological features using a minimisation methodology. There was no concealment of treatment distribution. The primary goal was to see whether the 5-year distant metastasis-free survival rate of patients with high clinical risk and low genomic risk who did not receive chemotherapy had a lower 95 percent confidence interval than the predefined non-inferiority boundary of 92 percent. Patients of high clinical risk and low genomic risk who adhered to the drug allocation with no chemotherapy and saw no improvement in risk post-enrolment made up the primary research group. For patients with hormone receptor-positive and HER2-negative disorder, we present revised follow-up, as well as an exploratory study of a possible age impact (50 years vs >50 years) and an analysis by nodal status. Intention-to-treat analysis was used for these studies. ClinicalTrials.gov (NCT00433589) and the European Clinical Trials website (EudraCT2005–002625–31) have also reported this report. The recruitment process is now complete, and long-term follow-up is underway.
Conclusions
A total of 6693 patients were registered between February 8, 2007 and July 11, 2011. On February 26, 2020, the median follow-up was 87% (IQR 78%–97%). The 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk who did not receive chemotherapy (primary research group, n=644) was 951% (95 percent CI 931%–966), which is higher than the predefined non-inferiority boundary of 92 percent, confirming the previous study and proving MINDACT as a promising de-escalation experiment. In the intention-to-treat population, patients with high clinical risk but low genomic risk were randomly allocated to undergo chemotherapy (n=749) or not (n=748). In the intention-to-treat population, the 8-year figures for distant metastasis-free survival were 920 percent (95 percent CI 896–938) for chemotherapy versus 894% (868%–915) for no chemotherapy (hazard ratio 066; 95 percent CI 048–092). An exploratory analysis confined to patients with hormone receptor-positive, HER2-negative disease (1358 [90.7 percent] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) reveals different effects of chemotherapy administration on 8-year distant metastasis-free survival depending on age: 936% (95 percent CI 893%–963) with chemotherapy ver. In the exploratory analysis by nodal status in these patients, 8-year distant metastasis-free survival was 917% (95 percent CI 881–943) with chemotherapy and 892% (852–922) without chemotherapy in 699 node-negative patients (absolute difference 25% percentage points [SE 23, 95 percent CI 213 to 72]) and 912% (872–940) versus 899% (858–928) for 65 patients.
Representation
With a longer follow-up approaching nine years, the 70-gene signature continues to demonstrate the potential to classify a subgroup of women with elevated clinical risk, including patients with low genomic risk, who have excellent distant metastasis-free survival when treated with endocrine therapy alone. The extent of the gain from combining chemotherapy and endocrine therapy for these women remains limited (26%), and nodal positivity has little impact. However, this advantage tends to be age-dependent in an underpowered exploratory study, since it is only observed in women less than 50 years old, where it crosses a clinically significant threshold of 5 percentage points. Despite the fact that it could be attributable to chemotherapy-induced ovarian function repression, it should be seen as part of an educated, joint decision. More research is required in younger women who could need enhanced endocrine therapy in order to avoid chemotherapy.