Adjuvant Chemo Shows Slight Benefit in Younger Women With Breast Cancer Who Have Mixed Clinical, Genomic Risk

Fatima Cardoso, MD

Patients with premenopausal breast cancer and discordant clinical and genomic risk had a small increase in distant metastasis if they did not receive adjuvant chemotherapy, according to a post hoc analysis of the MINDACT trial that were presented at the 2019 San Antonio Breast Cancer Symposium.¹

The difference was about 3% in absolute terms and was based on a data for patients who were younger than <50 years that were at high clinical risk of recurrence but low genomic risk by the 70-gene MammaPrint assay. In contrast, women >50 years had nearly identical 5-year distant metastasis-free survival (DMFS) rates with or without adjuvant chemotherapy.

The implications of the findings from the MINDACT trial² remain unclear, but are consistent with a trend seen in a subgroup analysis of the phase III TAILORx trial³ that also employed a genomic test to evaluate the need for adjuvant chemotherapy in patients with early breast cancer.

“This was an unplanned and underpowered subgroup analysis,” study investigator Fatima Cardoso, MD, of the Champalimaud Cancer Center in Lisbon, Portugal, said in a presentation during the meeting. “Cautious interpretation is needed because of the large confidence intervals associated with the hazard ratios. Nonetheless, the analysis suggests that in women younger than 50 years, who were in the clinical high risk/genomic low risk group (discordant), tamoxifen alone might not be the optimal treatment, although the difference seen between the chemotherapy and no-chemotherapy groups is small.”

“It is possible that this age-dependent effect is due to chemotherapy-induced ovarian function suppression,” Cardoso added. “Neither the MINDACT nor TAILORx trial is able to answer this question.”

MINDACT involved 6693 women with newly diagnosed, early breast cancer. Their risk of postoperative recurrence was evaluated by a clinical risk assessment tool and by the MammaPrint 70-gene assay. Patients at high risk by both assessments received adjuvant chemotherapy, while those with a low risk by both methods received no chemotherapy. Patients who had discordant clinical and genomic risk assessments were randomized to adjuvant chemotherapy or no chemotherapy. All patients with hormone receptor (HR)—positive disease received adjuvant endocrine therapy.

The primary endpoint was 5-year DMFS in patients with discordant findings randomized to no chemotherapy; the trial was statistically powered to demonstrate a significant outcome if DMFS exceeded 92%. Additionally, the primary test 5-year DMFS rate was significant if the 95% 2-sided confidence interval exceeded 92%. The results showed a 5-year DMFS of 94.7% and the 95% confidence intervals exceeded 92%.

The TAILORx trial involved more than 10,000 patients with HR-positive, HER2-negative early breast cancer. The primary results showed that adjuvant endocrine therapy was noninferior to chemotherapy plus endocrine therapy for patients with an intermediate risk of recurrence by the OncotypeDx genomic assay.

Subsequently, TAILORx investigators reported findings from a subgroup analysis, which suggested a differential benefit of chemotherapy for DMFS by age. Patients <50 years with an intermediate risk of recurrence had about a 3% higher risk of recurrence without chemotherapy versus less than 1% among older women.⁴

Within the range of values for intermediate risk, the analysis showed that younger women with a high clinical risk benefited substantially more from chemotherapy as compared with patients who had a low clinical risk. At the upper end of the range for intermediate-risk values, younger patients derived greater benefit from chemotherapy, irrespective of clinical risk.

Cardoso and colleagues sought to determine whether a similar age-related divergence in chemotherapy benefit might exist in the MINDACT population. The analysis included 1317 patients with clinical high risk/genomic low risk profile, 452 <50 and 865 ≥50.

The data showed that the younger patients had a 5-year DMFS of 93.1% without adjuvant chemotherapy, increasing to 96.1% if they were randomized to receive chemotherapy. The finding suggested that chemotherapy reduced relative risk of distant recurrence by 46% in younger women, albeit with overlapping confidence intervals (HR, 0.54; 95% CI, 0.24-1.22). In the >50 age group, 5-year DMFS was virtually identical with chemotherapy or without (95.4% vs 95.2%).

Calculated as distant metastasis-free interval (DMFI), the results were similar: a 2.5% absolute difference favoring chemotherapy in younger patients (96.1% vs 93.6%) and no difference in the older subgroup (96.3% vs 96.7%).

Cardoso said the small differences in the younger patients could reflect the use of endocrine therapy, primarily with tamoxifen, without ovarian function suppression. Only 8.3% of younger women with a clinical high risk/genomically low risk profile had ovarian function suppression.

References

1. Piccart MJ, Poncet C, Cardoso F, et al. Should age be integrated together with clinical and genomic risk for adjuvant chemotherapy in early luminal breast cancer? MINDACT results compared to those of TAILOR-X. Presented at: 2019 San Antonio Breast Cancer Symposium; San Antonio, TX. Abstract GS4-05.
2. Cardos F, van’t Veer LJ, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Eng J Med. 2016;375:717-729. doi: 10.1056/NEJMoa1602253.
3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Eng J Med. 2018.379:111-121. doi: 10.1056/NEJMoa1804710.
4. Sparano JA, Gray RJ, Makower DF, et al. Clinical outcomes in early breast cancer with a high 21-gene recurrence score of 26 to 100 assigned to adjuvant chemotherapy plus endocrine therapy a secondary analysis of the TAILORx randomized clinical trial [published online September 30, 2019]. JAMA Oncol. doi: doi:10.1001/jamaoncol.2019.4794.

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