Non-inferior survival outcomes in high clinical/low genomic risk breast cancer patients who forego chemotherapy

April 2021 Cancer trials Tobias Rawson

The phase III MINDACT trial has previously reported that breast cancer patients with a high clinical risk, but low genomic risk, may forego adjuvant chemotherapy. In an updated analysis with a median follow-up of 8.7 years, this conclusion is reinforced. Furthermore, nodal disease does not appear to influence clinical outcome in these patients. In younger patients, the clinical benefit of adding chemotherapy to endocrine therapy was more pronounced, although this observation may be the result of chemotherapy-induced ovarian function suppression (OFS).

Expert opinion

The MINDACT trial shows excellent survival for women with high clinical risk and low genomic risk treated without chemotherapy at 5 years. Similar to what was reported in TAILORx, the updated results of MINDACT indicate that relying on the genomic signature to forego adjuvant chemotherapy is safer in older women with a high clinical risk than in younger women. The potential benefit of chemotherapy, given in addition to endocrine therapy, to younger women might be linked to chemotherapy-induced ovarian function suppression, although further research is needed before this can be confirmed. Dr. Lybaert agrees: “Both Mammaprint and Oncotype Dx are tools that can help us during breast cancer multidisciplinary oncology consultations to decide whether or not chemotherapy can be withheld in a large proportion of women with early-stage breast cancer. However, caution is needed in younger, pre-menopausal patients, in whom MINDACT, TAILORx en RxPONDER all suggest a more pronounced benefit of adjuvant chemotherapy. This observation is strikingly similar in the three studies and warrants further investigations.

Introduction

Effective cytotoxic and targeted agents have improved clinical outcomes for breast cancer (BC) patients globally. However, over-treatment is a potential reality for some patients, resulting in otherwise unnecessary toxicities. For some BC patients, de-escalation may be an appropriate management strategy. The phase III MINDACT trial has previously concluded that BC patients with high clinical risk and low genomic risk may be able to omit chemotherapy, reporting a 5-year distant metastasis-free survival of 94.7%. Now, long-term outcomes are reported in an updated analysis with a median follow-up of 8.7 years. The multicentre MINDACT trial enrolled 6,693 BC patients with non-metastatic, invasive disease (T1, T2 or operable T3) with up to 3 positive auxiliary lymph nodes, who were also chemo-, endo- and radiotherapy naïve in both the adjuvant and neoadjuvant settings. The genomic and clinical risk of these patients was evaluated and patients with discordant results (low/high genomic and high/low clinical risk) were randomised 1:1 to receive adjuvant chemotherapy or not. Patients with both low clinical and genomic risk did not receive adjuvant chemotherapy, whilst patients with both high clinical and genomic risk did. An additional analysis also investigated the benefit of adjuvant chemotherapy in these patients in relation to age (≤50 vs. >50 years) and nodal status.

Comparable overall survival rates in high clinical/low genomic risk patients regardless of chemotherapy use

At a median follow-up of 8.7 years, the updated 5-year distant metastasis free survival (DMFS) rate for patients with high clinical and low genomic risk, who did not receive chemotherapy (N= 644) was reported at 95.1%. Among patients with a  discordant risk score, the 8-year DMFS rate reported at 92.0% for patients who received chemotherapy vs. 89.4% for patients who did not (HR[95%CI]: 0.66[0.48-0.92]). The overall survival (OS) between these two subsets of patients was also comparable, at 95.7% and 94.3%, respectively (HR[95%CI]: 0.69[0.45-1.05]). Also, patients with a low clinical but high genomic risk had comparable 8-year DMFS and OS rates. In this cohort patients who did not receive chemotherapy had an 8-year DMFS of 90.8%, vs. 92.3% in those who did receive chemotherapy (HR[95%CI]: 0.85[0.53-1.37]). Similarly, the OS in these patients were 93.0% vs. 93.8%, respectively (HR[95%CI]: 0.94[0.54-1.67]). Stratified by nodal status, long term outcomes were similar for high clinical/low genomic risk patients with HER2-negative (HER2-) disease. At 8 years, the DMFS for node-negative patients who received chemotherapy (N= 349) was 91.7%, compared to 89.2% for those who did not receive chemotherapy (N=350) (HR[95%CI]: 0.60[0.38-0.96]). In patients with 1 to 3 positive nodes, the DMFS at 8 years was 91.2% with chemotherapy (N= 326) vs. 89.9% without (N= 332) (HR[95%CI]: 0.84[0.51-1.37]).

In contrast, age did prove to have an influence on clinical outcome in hormone receptor-positive, HER2- patients with high clinical/low genomic risk. However, this effect may be the result of OFS following the use of chemotherapy in premenopausal women. Women over 50 did not gain a benefit from chemotherapy, with 8-year DMFS rates of 90.2% with (N= 441) and 90.0% without chemotherapy (N= 453) (HR[95%CI]: 0.82[0.55-1.24]). Conversely, a benefit was seen with chemotherapy in women ≤50, with DMFS rates of 93.6% (N= 235) and 88.6% (N= 229), respectively (HR[95%CI]: 0.54[0.30-0.98]).

Reference

Piccart M 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. S1470-2045(21): 00007-3. [epub].

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