MINDACT Trial: Why it Matters?

MINDACT:
- Was the first large prospective randomized trial to test whether the 70-gene signature (MammaPrint):
  - Could help spare adjuvant chemotherapy in patients with early breast cancer:
    - Especially when clinical risk and genomic risk disagreed
- Its key contribution was showing that some patients who appear high-risk by traditional clinicopathologic criteria:
  - Still have an excellent outcome without chemotherapy if they are genomically low-risk
Trial design:
- MINDACT enrolled 6,693 women with early-stage breast cancer
- Patients were assigned both a clinical risk estimate and a genomic risk estimate:
  - Clinical risk was based on:
    - A modified Adjuvant! Online tool
  - Genomic risk was based on:
    - The 70-gene signature
- Patients with concordant low risk generally avoided chemotherapy
- Those with concordant high risk received it
- Those with discordant risk:
  - Were randomized to treatment decisions based on either the clinical or genomic result:
    - The primary test population was the clinical high-risk / genomic low-risk group
Primary finding:
- In patients with high clinical risk but low genomic risk:
  - Who did not receive chemotherapy:
    - The 5-year distant metastasis-free survival (DMFS) was 94.7% (95% CI 92.5–96.2):
      - Which met the study’s predefined benchmark for safety
    - This was the practice-changing result:
      - It supported omission of chemotherapy in selected patients despite unfavorable conventional features
Longer-term follow-up:
- With longer follow-up, the benefit of chemotherapy in the clinical high-risk / genomic low-risk group remained small overall
- The 2021 update reported that the 8-year DMFS for this group was 92.0% with chemotherapy vs 89.4% without chemotherapy, an absolute difference of 2.6 percentage points
  - The authors concluded that the 70-gene signature continues to identify a group with excellent outcomes and only a limited average chemotherapy benefit
Age-related nuance:
- The most important nuance for multidisciplinary decision-making is age
- In the updated analysis, the apparent chemotherapy benefit was not seen in women older than 50 years, while a potentially clinically relevant benefit appeared in women 50 years or younger
  - This raises the same question seen in other adjuvant trials:
    - How much of the effect reflects true cytotoxic benefit versus ovarian suppression / menopausal effect in younger patients
      - For the surgeon, this means a low-genomic-risk result should still be interpreted in the context of menopausal status and age
Node-positive relevance:
- A major practical strength of MINDACT is that it included not only node-negative disease but also patients with 1 to 3 positive nodes:
  - Making it more broadly relevant than node-negative-only genomic trials
- For surgical oncologists, this is especially useful after lumpectomy or mastectomy when pathology shows limited nodal disease and the team is deciding whether anatomy alone should drive chemotherapy recommendations
Ultralow-risk subgroup:
- A later MINDACT analysis identified an ultralow-risk subgroup by the 70-gene assay
- These patients had exceptionally favorable outcomes:
  - Including an 8-year distant metastasis-free interval of 97.0% and 8-year breast cancer-specific survival above 99%
- This supports even more confidence in de-escalation discussions in carefully selected patients with highly favorable biology
What this means for the surgical oncologist:
- MINDACT matters because it reinforces that postoperative planning in early breast cancer is no longer based on tumor size, grade, and nodal status alone:
  - A patient with a large tumor or limited nodal involvement may still have a genomically low-risk cancer with only modest absolute chemotherapy benefit
- In practical terms:
  - A surgeon should think about which ER-positive / HER2-negative patients may benefit from genomic testing as part of adjuvant planning
  - A clinical high-risk / genomic low-risk result can support a discussion about omitting chemotherapy, particularly in older than 50 patients
  - In younger / premenopausal patients, especially with higher tumor burden or limited node-positive disease:
    - The discussion remains more nuanced and should be individualized
Bottom line:
- MINDACT showed that biology can meaningfully refine risk beyond standard pathology
- For the surgical oncologist, the main takeaway is that a patient who looks high-risk on anatomic grounds may still have a sufficiently favorable genomic profile to justify avoiding adjuvant chemotherapy:
  - Particularly if she is older than 50 years and has ER-positive / HER2-negative early breast cancer
Key references:
- 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. 2016;375:717-729.
- Piccart M, van’t Veer LJ, Poncet C, et al. 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. Lancet Oncol. 2021;22:476-488.
- Lopes Cardozo JMN, Drukker CA, Rutgers EJT, et al. Outcome of Patients With an Ultralow-Risk 70-Gene Signature in the MINDACT Trial. J Clin Oncol. 2022;40:1335-1345.