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MammaPrint helps predict benefit of adjuvant chemotherapy in early-stage breast cancer
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NEW ORLEANS — A genomic test can help predict which patients with early-stage breast cancer will derive the most benefit from adjuvant chemotherapy, according to the initial results of the randomized phase 3 MINDACT trial presented at the American Association for Cancer Research Annual Meeting.
The findings could “de-escalate the use of adjuvant chemotherapy and spare many patients an aggressive treatment they will not benefit from,” said researcher Martine Piccart, MD, PhD, head of the medicine department at Jules Bordet Institute in Belgium and co-founder and chair of the Breast International Group.
Martine Piccart
Advanced breast cancer is largely an incurable disease. Consequently, oncologists prescribe adjuvant therapies to many women with early-stage disease in hopes of eradicating micrometastases.
However, adjuvant treatment particularly adjuvant chemotherapy is associated with long-term risks, so the potential survival benefit must be balanced with the potential for long-term risks such as secondary cancers, cardiac toxicity and reduced cognitive function, Piccart said.
The MINDACT trial the first prospective randomized controlled trial of a breast cancer recurrence genomic assay with level 1A clinical evidence compared the 70-gene signature MammaPrint (Agendia) with traditional clinical assessments to determine which patients with early-stage breast cancer could safely forego adjuvant chemotherapy.
The trial conducted at 111 centers in nine European countries included 6,693 women (median age, 55 years) who underwent surgery for early-stage breast cancer from 2007 to 2011. The majority had stage T1 (58%), node-negative (80%), hormone receptor-positive (88%), HER-2–negative (90%) disease.
Researchers evaluated study participants’ risk for tumor recurrence through MammaPrint analysis of tumor tissue, as well as through use of the Adjuvant! Online tool, which calculates recurrence risk based on common clinical and biological criteria.
The 2,745 study participants deemed at low risk for recurrence by both risk-assessment methods received no adjuvant chemotherapy.
The 1,806 participants categorized at high risk for recurrence by both methods received adjuvant chemotherapy.
The remaining 2,142 participants determined to have a high recurrence risk by one assessment method but at low recurrence risk by the other method were randomly assigned to adjuvant chemotherapy or no adjuvant chemotherapy.
Patients with hormone receptor-positive disease were eligible for adjuvant hormone therapy and could participate in a randomization that involved two endocrine therapy regimens.
Piccart and colleagues hypothesized that MammaPrint would outperform common clinical and biological criteria by reducing the prescription of adjuvant chemotherapy without compromising outcomes.
Researchers determined a 92% threshold for predicted 10-year OS without adjuvant chemotherapy using Adjuvant! Online criteria would be adequate.
After median follow-up of 5 years, 5.4% of women either died or experienced distant relapse.
Piccart and colleagues reported 5-year distant metastasis-free survival rates of 97.6% among women classified by both MammaPrint and Adjuvant! Online as having a low risk for recurrence, and 90.6% among those classified by both assessment methods as having a high risk for recurrence. Five-year distant metastasis-free survival among women for whom the two assessment methods yielded discordant recurrence risks had 5-year distant metastasis-free survival around 95%.
The primary statistical test in the analysis focused on women who were determined to be at low risk for recurrence by MammaPrint and high risk for recurrence by Adjuvant! Online who subsequently were randomly assigned to no adjuvant chemotherapy. This test was designed to establish trust in the MammaPrint genomic assay.
In this subgroup, researchers reported a 5-year distant metastasis-free survival rate of 94.7% (95% CI, 92.5-96.2).
The trial was not powered to answer the question of whether adjuvant chemotherapy benefits women with discordant risk assessments, Piccart said. However, an intent-to-treat analysis showed little separation in distant metastasis-free survival curves in these groups based on chemotherapy receipt.
“A statistician will tell you ... it is not totally impossible that there is a very small chemotherapy benefit,” Piccart said. “However, the relative reduction in risk ... would translate to a very small absolute benefit that would not justify the risks of chemotherapy.”
In the entire study population, use of the MammaPrint assay was associated with a 14% reduction in chemotherapy prescription vs. a clinical assessment.
Use of the assay was associated with a 46% reduction in chemotherapy prescriptions among patients determined to be at clinically high risk for breast cancer.
“This trial has played a major educational role ... and popularized the concept of biology-driven treatment,” Piccart said. “It demonstrated that genomics can provide important information in order to treat patients with early breast cancer in a more optimal way.” – by Mark Leiser
Reference:
Piccart M, et al. Abstract CT-039. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.
Di sclosure: Piccart reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Lajos Pusztai, MD, DPhil
MINDACT is an important study because it is the first randomized clinical trial that actually intended to prove the clinical value of using molecular profiling, a gene expression-based test, to select patients for adjuvant chemotherapy. The trial was designed to prospectively assess if a subset of patients can be identified by the test who have such good outcome without chemotherapy that this treatment can safely be avoided. A unique feature of MINDACT is that it also provided data on the outcome of patients for whom clinical and genomic risk assessment yielded discordant results.The study result is important in the sense that it confirms what the oncologist community has been practicing for several years, entirely based on retrospective data.
The trial accrued about 6,000 patients with early-stage breast cancer whose risk was assessed by both clinical variables and the genomic test. Those who had a discordant risk prediction based on clinical vs. genomic results were randomly assigned to receive chemotherapy or no chemotherapy and estrogen receptor-positive patients also received endocrine therapy. The results showed that low-risk individuals by the genomic test could safely forgo adjuvant chemotherapy. Their distant metastasis-free survival (DMFS) was particularly good, 97.6%, if both clinical and genomic assessment predicted good outcome.
Importantly, this is the first prospective trial that suggests patients who were predicted to be high risk clinically, but low risk by the MammaPrint test (n = 1,497) remain low enough risk (94.4% DMFS without chemotherapy) and do not seem to benefit in a clinically substantial way from adjuvant chemotherapy (95.9% DMFS with chemotherapy).
In all fairness, it also should be noted that when the discordance was observed in the opposite way (n = 657), or clinically low risk but high risk by MammaPrint, the results were similar.
Overall, DMFS was excellent without chemotherapy (95% DMFS) or with chemotherapy (95.8% DMFS). These data suggest genomically or clinically low-risk individuals with ER–positive cancer can avoid chemotherapy. But, use of the test decreases adjuvant chemotherapy use because a larger number of clinically high-risk individuals get reclassified as low risk by the test than the other way around. In these discordant cases, chemotherapy benefit seems to be very low.
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