SABCS 2021

The complementary phase III SOFT, TEXT and PERCHE trials were launched in 2003 to answer three questions in the adjuvant treatment setting for HR+ early breast cancer in premenopausal women:¹

• SOFT: is there a benefit to adding OFS to tamoxifen, particularly in patients who remain premenopausal after chemotherapy?
• TEXT and SOFT: when OFS is given, do patients benefit from receiving exemestane versus tamoxifen?
• PERCHE (closed early): when the benefit from chemotherapy is uncertain and if maximal endocrine therapy consisting of OFS and oral endocrine therapy is planned, is there a benefit to patients receiving adjuvant therapy as well?

Dr Meredith Regan from the Dana-Farber Cancer Institute, Harvard Cancer Center, Boston, MA, US, joined SABCS 2021 on 8 December to give an update on the ~12.5-year follow-up results from the TEXT and SOFT trials.

The TEXT trial included 2,672 patients who were randomised 1:1 to receive exemestane + OFS (E+OFS) or tamoxifen + OFS (T+OFS) for 5 years. In the SOFT trial, 3,066 patients were randomised 1:1:1 to receive E+OFS, T+OFS or tamoxifen alone for 5 years. In TEXT and SOFT, the numbers of patients who had received prior chemotherapy were 1,607 and 1,628 respectively.

Results from TEXT and SOFT after 5 and 8 years of median follow-up had previously shown that addition of OFS to tamoxifen reduced disease recurrence and death. There was a further reduction in distant recurrence but not in death with E+OFS versus T+OFS. The absolute benefit of OFS varied depending on underlying risk of recurrence and patients with lower-risk clinical-pathological features fared well with tamoxifen alone.^1-4

The analysis presented by Dr Regan was preplanned and focused on distant recurrence, overall survival and later treatment benefits. At the median follow-up of 12 years for SOFT and 13 years for TEXT, 76% of the initial study population was alive. The average age of study participants was 43 years at the time of enrolment.

Dr Regan reported the 12-year follow-up results from SOFT:

• Proportion of patients who were distant recurrence-free:
  • 84.8% in the tamoxifen arm
  • 87.8% in the E+OFS arm (absolute risk reduction (ARR) vs tamoxifen: 3.0%; HR: 0.74, 95% CI: 0.50-1.12)
  • 86.2% in the T+OFS arm (ARR vs tamoxifen: 1.4%; HR: 0.85, 95% CI: 0.58-1.26)

• Proportion of patients who were alive:
  • 86.8% in the tamoxifen arm
  • 89.4% in the E+OFS arm (ARR: 2.6% vs T+OFS; HR: 0.70, 95% CI: 0.50-0.98)
  • 89.0% in the T+OFS arm (ARR vs tamoxifen: 2.3%; HR: 0.86, 95% CI: 0.63-1.18)

When results from the two trials were examined together, it was found that ARR in distant recurrence was 1.8% with E+OFS versus T+OFS (HR: 0.90, 95% CI: 0.70-1.17) at 13-year median follow-up. ARR in overall survival was 1.0% with E+OFS versus T+OFS (HR: 0.77, 95% CI: 0.62-0.97).

Dr Regan then shifted the focus of her talk to the analyses of the cohorts that had and had not received prior chemotherapy. In the SOFT trial, percentages of patients in the no chemotherapy cohort who were distant recurrence-free at 12 years were 97.7% in the E+OFS arm, 95.9% in the T+OFS arm and 95.8% in the tamoxifen arm. Overall survival rates were 97.1%, 95.2% and 95.8% in the E+OFS, T+OFS and tamoxifen arms of this cohort, respectively.

In the cohort that had received prior chemotherapy at 12-year median follow-up:

• Proportion of patients who were distant recurrence-free:
  • 75.1% in the tamoxifen arm
  • 79.6% in the E+OFS arm (ARR vs tamoxifen: 4.5%; HR: 0.81, 95% CI: 0.51-1.29)
  • 77.7% in the T+OFS arm (ARR vs tamoxifen: 2.6%; HR: 0.92, 95% CI: 0.59-1.44)

• Proportion of patients who were alive:
  • 78.9% in the tamoxifen arm
  • 82.9% in the E+OFS arm (ARR vs tamoxifen: 4.0%; HR: 0.72, 95% CI: 0.50-1.05)
  • 83.6% in the T+OFS arm (ARR vs tamoxifen: 4.7%; HR: 0.86, 95% CI: 0.60-1.22)

Dr Regan stated "in looking together at both SOFT and TEXT chemotherapy cohorts […] there remained overall modest, moderate, relative reductions in distant recurrence with exemestane ovarian suppression compared with tamoxifen ovarian suppression, which resulted in absolute reductions in distant recurrence at 12 years of 1.9% in SOFT and 2.4% in TEXT [(HR: 0.88; 95% CI: 0.56-1.41 for SOFT, HR: 1.1, 95% CI: 0.75-1.61 for TEXT)]." ARR in overall survival rates with E+OFS versus T+OFS were -0.7% in SOFT (HR: 0.84, 95% CI: 0.57-1.22) and 2.6% in TEXT (HR: 0.74, 95% CI: 0.53-1.03).

In the SOFT and TEXT trials, 88% of the overall study population was HER2-negative. In this cohort, the 12-year ARR in overall survival with E+OFS versus T+OFS was 3.3% in both trials (HR: 0.85, 95% CI: 0.61-1.20 in SOFT, HR: 0.81, 95% CI: 0.61-1.08 in TEXT). As for the rest of the study population, "tamoxifen ovarian suppression seems to be preferred for those with HER2-positive disease" remarked Dr Regan.

When the results were analysed by risk factors it was found that absolute reductions in the study outcomes were clinically more substantial (~10%) for patients at higher clinical risk. Of the patients with low clinical risk, >95% were alive at 12 years in all three treatment arms.

In summary, the 12- and 13-year median follow-up results from SOFT and TEXT showed that distant recurrences and deaths continued in the study population. Persistent meaningful relative reductions in distant recurrence and deaths with OFS occurred with appropriate selection of patients that received OFS. And finally, reduction in distant recurrence with E+OFS versus T+OFS was consistent with postmenopausal women.

CI: confidence interval; HR: hazard ratio; SOFT: Suppression of Ovarian Function Trial; TEXT: Tamoxifen and EXemestane Trial