MINDACT Points To Possible Undertreatment Of Younger Women With Luminal Breast Cancer

By Will Pass

Adjuvant endocrine therapy alone may be insufficient for some younger women with luminal breast cancer, based to an unplanned analysis of the phase 3 MINDACT trial.

In this age group, among women classified as high clinical risk and low genomic risk, adding chemotherapy was linked with a 3.6% increase in 5-year distant metastasis-free survival (DMFS), reported coauthor Fatima Cardoso, MD, during a presentation at the San Antonio Breast Cancer Symposium.

According to Dr. Cardoso, these findings build upon similar, recent results from the phase 3 TAILORx trial, which found that certain women in the 40- to 50-year age group, depending on risk factors, derived clinically meaningful benefit from the addition of chemotherapy to endocrine therapy.


Dr. Fatima Cardoso
In the MINDACT trial, patients who were classified as high-risk, both on a genomic and clinical basis, were given chemotherapy, while patients classified as low-risk by both parameters were not given chemotherapy. Patients with a discordant risk profile (i.e. low genomic risk and high clinical risk or high genomic risk and low clinical risk) were randomized so that treatment was guided by either genomic risk or clinical risk. The investigators used MammaPrint, a 70-gene assay, to determine genomic risk level.

Among the 6,693 patients enrolled in the MINDACT trial, 5,402 had luminal breast cancers. Of these, 1,358 were randomized to receive chemotherapy or not. Only two DMFS events occurred within the subgroup of patients younger than 40 years, so this age group was excluded from the analysis because of a lack of data, leaving 399 patients aged 40-50 years and 894 patients older than 50 in the present dataset.

Disease features were comparable between these two subgroups; for both, median tumor size was 2.2 cm, approximately half of the patients had negative nodal status, two-thirds had grade 2 tumors, one-fourth had grade 3 tumors, and tumor sizes were similar between groups. Dr. Cardoso noted that only 7.0% of patients in the younger subgroup received a luteinizing hormone-releasing hormone (LHRH analog).
According to Dr. Cardoso, these findings build upon similar, recent results from the phase 3 TAILORx trial, which found that certain women in the 40- to 50-year age group, depending on risk factors, derived clinically meaningful benefit from the addition of chemotherapy to endocrine therapy.
Presenting findings, Dr. Cardoso focused on patients with high clinical risk and low genomic risk; those between 40 and 50 years who were treated with chemotherapy had a 5-year DMFS estimate of 96.2%, compared with 92.6% for patients who did not receive chemotherapy. In contrast, 5-year DMFS estimates were similar for patients older than 50 regardless of whether they received chemotherapy (95.2%) or not (95.4%).

Dr. Cardoso cautioned that the above survival disparity concerning women 40-50 years cannot be called “statistically significant” because of the descriptive nature of the statistics; however, she went on to emphasize that the finding raises questions worthy of consideration and further investigation.

“It seems to suggest that in women younger than 50 classified as high clinical risk and low genomic risk by MammaPrint, tamoxifen alone might not be the optimal treatment,” said Dr. Cardoso of Champalimaud Cancer Center in 
Lisbon, Portugal. “We see a smaller difference than what was seen in TAILORx, and it is very possible that this age dependent effect is due to chemotherapy-induced ovarian function suppression and not to the direct cytotoxic effect of chemotherapy; however, neither MINDACT nor TAILORx are able to answer … these questions [with certainty].”

During the discussion that followed Dr. Cardoso’s presentation, lead author of the TAILORx trial, Joseph A. Sparano, MD, of Albert Einstein College of Medicine, noted that after accounting for timepoint differences, the findings from MINDACT and TAILORx are highly similar.


Dr. Joseph A. Sparano
“I just want to point out that your results may not be all that different [from TAILORx],” Dr. Sparano said. “I believe you quoted distant recurrence rates at 5 years. The numbers that we reported for TAILORx were at 9 and 5 years, and about half of the recurrences occurred by year 5, so I think that if you aligned [the data] at the timepoints, you’re findings are exactly concordant with those observed in TAILORx.”

“You’re right,” Dr. Cardoso said. “And also it will be very interesting to see with longer follow-up, which we will have for MINDACT next year, so we will repeat the analysis with the same follow-up as TAILORx.”

One audience member asked Dr. Cardoso about potential clinical implications of the MINDACT findings.

“I think we need to look to previous trials, for example, [the ESO-ESMO 4th international consensus guidelines for advanced breast cancer (ABC 4)] compare [cyclophosphamide, methotrexate, and fluorouracil (CMF)] with endocrine therapy and ovarian suppression, showing it is as good or maybe better [than chemotherapy]. … Maybe instead of giving chemotherapy, you can give a less toxic way of inducing ovarian suppression.”

Another conference attendee, referring to the different genomic panels used in TAILORx (a 21-gene assay) and MINDACT (a 70-gene assay), asked if some patients should be tested with both panels.

Dr. Cardoso said no, clinicians should stick to just one genomic panel, as the use of two tests can lead to discordant results, which are “particularly bothersome and complex for the patient.” Furthermore, she reminded clinicians to continue using clinical and pathologic risk factors, which remain independently prognostic, even as genomic tools become more advanced.

Dr. Cardoso went on to describe a larger problem in genomic research surrounding patient age groups.

“When we [designed] MINDACT, there was very, very little data [concerning] genomic tests for younger women,” she said. “Still today we have [much less] data on genomic tests for younger women as we have for postmenopausal women. All the genomic signatures were developed in postmenopausal sets. So what we need to do is probably run a trial specifically for premenopausal women. However, I don’t know where we’re going to get the money, but if you have the money, I’ll run the trial.”

MINDACT was funded by the European Commission Sixth Framework Program, Novartis, Sanofi-Aventis, Eli Lilly, and others. The investigators reported additional relationships with Roche, Astra Zeneca, Genomic Health, and others.