Addition of S-1 to adjuvant endocrine therapy increases invasive DFS in breast cancer subset
SAN ANTONIO — The addition of the oral fluoropyrimidine S-1 to adjuvant endocrine therapy significantly extended invasive disease-free survival among certain women with hormone receptor-positive, HER2-negative breast cancer, according to results of the randomized phase 3 POTENT trial presented at San Antonio Breast Cancer Symposium.
The study — conducted in Japan — also showed the regimen exhibited a manageable safety profile.
“Our findings support the addition of S-1 to standard endocrine therapy in the postoperative
adjuvant setting for patients with hormone receptor-positive, HER2-negative disease and an intermediate or higher risk of recurrence,” researcher Masakazu Toi, MD, PhD, professor of breast surgery at Kyoto University Hospital in Japan, said during a press conference.
Hormone receptor-positive, HER2-negative breast cancer — also called luminal breast cancer — is the most common breast cancer subtype, according for about two-thirds of cases. Standard adjuvant therapy includes an anthracycline and/or taxane.
Five-year relative survival for this subtype is high, but a risk for recurrence remains several years after treatment.
“Because of the risk of recurrence, there is interest in identifying novel postoperative adjuvant therapies to be used in conjunction with endocrine therapy,” Toi said.
Chemotherapy with oral FU is active in metastatic disease, and several adjuvant trials with oral FU have shown positive signals, according to study background.
Toi and colleagues hypothesized that the addition of S-1 (Taiho Pharmaceutical) to standard endocrine therapy could improve survival outcomes.
S-1 is a combination drug based on a biochemical modification of fluorouracil. It contains tegafur — a 5-FU prodrug that inhibits DNA synthesis and cell division — as well as gimeracil, which promotes tegafur activity, and oteracil, which prevents gastrointestinal toxicity.
The agent is approved in Europe and Asia for use in combination with cisplatin for gastric cancer. it also is approved in Asia for treatment of head and neck cancer, colorectal cancer, non-small cell lung cancer, metastatic breast cancer, pancreatic cancer and biliary tract cancers.
The POTENT trial included 1,939 women (age range, 20 to 75 years) from 139 centers in Japan. All patients had stage I to stage III hormone receptor-positive, HER2-negative breast cancer with intermediate or high risk for recurrence. Investigators assessed recurrence risk based on anatomical stage, pathological findings — including histologic grade — and centrally confirmed proliferative marker status.
They all had performance status of 0 or 1, as well as sufficient organ function.
Investigators enrolled all patients within 1 year of surgery and within 6 months after starting adjuvant endocrine therapy.
Researchers randomly assigned women to receive adjuvant endocrine therapy with or without S-1. The drug was administered orally twice daily on a 14-days-on, 7-days off schedule for 1 year. The dose was based on body surface area and creatinine clearance (range, 80 mg/day to 120 mg/day).
Treatment groups were well balanced with regard to age (51 years for endocrine therapy alone vs. 52 years for S-1), body weight (median, 55.4 kg vs. 55.1 kg), histologic grade, node-negative status (36.7% vs. 36.1%) and invasive diameter.
Invasive DFS served as the primary endpoint. Secondary endpoints included OS, distant DFS, DFS, safety and predictive value of biomarkers.
Median follow-up was 51 months, and the trial was terminated early because the primary endpoint was met.
Results showed a statistically significant improvement in invasive DFS with the addition of S-1 to endocrine therapy (HR = 0.63; 95% CI, 0.49-0.81).
Five-year estimates of invasive DFS were 86.9% with S-1 plus endocrine therapy and 81.6% with endocrine therapy alone. Researchers reported 101 events in the S-1 group and 155 events in the endocrine therapy alone group.
The S-1 regimen appeared well-tolerated, Toi said.
Patients who received the combination experienced higher rates of decreased neutrophils (all grade, 42% vs. 12.1%; grade 3 or higher, 7.5% vs. 0.7%), decreased platelets (all grade, 32.2% vs. 8.6%; grade 3 or higher, 0.5% vs. 0.4%), increased alanine aminotransferase (all grade, 42.9% vs. 20.3%), increased aspartate aminotransferase (all grade, 38.6% vs. 13.8%), nausea (all grade, 34.5% vs. 3.6%), diarrhea (32.3% vs. 2.5%), fatigue (all grade, 39.1% vs. 9.1%) and hyperpigmentation (all grade, 50.3% vs. 3.4%).
Toi and colleagues acknowledged their enrollment of women only from Japan was a limitation of the study, given that the toxicity profile of S-1 plus endocrine therapy could be different between Asian and non-Asian patients.
In clinical trials, lower doses of S-1 have been used for white patients compared with Asian patients due to known pharmacogenetic differences that affect metabolism of oral fluoropyrimidines. – by Mark Leiser
Reference: Toi M, et al. Abstract GS1-09. Presented at: San Antonio Breast Cancer Symposium; Dec. 10-14, 2019; San Antonio.
Disclosures: Taiho Pharmaceutical and Comprehensive Support Project of the Public Health Research Foundation supported this study. Toi reports research grants or honoraria from, advisory roles with, or additional funds from AFI Technology, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Eisai, Genomic Health, JBCRG Association, Konica Minolta, Kyoto Breast Cancer Research Network, Kyowa Kirin, Nippon Kayaku, Novartis, Pfizer, Shimadzu, Taiho, Takeda and Terumo. Please see the abstract for all other authors’ relevant financial disclosures.