A phase III study sponsored by the Comprehensive Support Project of the Public Health Research Foundation and Taiho Pharmaceuticals, a subsidiary of Otsuka Holdings, shows that the addition of S-1 (Teysuno®, TS-1)*, an oral fluoropyrimidine-based drug, to adjuvant (post-operative) endocrine therapy improves outcomes for patients with hormone receptor-positive, HER2-negative breast cancer.
This is the conclusion of research presented during the 2019 San Antonio Breast Cancer Symposium (SABCS) held December 10 – 14, 2019 in San Antonio, Texas.
The post-operative combination significantly increased invasive disease-free survival (iDFS) and improved five-year iDFS estimates in patients with hormone receptor (HR)-positive, HER2-negative breast cancer.
“Although we have made remarkable progress with systemic therapy for (primary) breast cancer, many patients still experience disease recurrence,” said Masakazu Toi, MD, Ph.D, professor of breast surgery at Kyoto University Hospital.
The researchers previously investigated a role for oral fluoropyrimidines in postoperative adjuvant treatments. In the study presented during the SABCS, the investigators aimed to verify the usefulness of S-1 in combination with adjuvant endocrine therapy for (primary) breast cancer with luminal disease.
Luminal Breast cancer
HR-positive, HER2-negative breast cancer, also referred to as luminal breast cancer, is the most common breast cancer subtype, accounting for approximately 67% of cases.
Patients with this subtype of breast cancer are often treated with endocrine therapies, which work in various ways to prevent hormones from activating cancer growth. Although this subtype is associated with a favorable five-year relative survival rate, there is a risk of disease recurrence several years after treatment, Toi noted.
“Because of the risk of recurrence, there is interest in identifying novel post-operative adjuvant therapies to be used in conjunction with endocrine therapy,” he added.
S-1 is a combination drug composed of tegafur, an antimetabolite which is a 5-fluorouracil (5FU) prodrug that inhibits DNA synthesis and cell division, and gimeracil (5-chloro-2,4-dihydroxypyridine), a dihydropyrimidine dehydrogenase inhibitor which, as an adjunct, which increases the concentration and effect of tegafur in normal tissue, and oteracil, an orotate phosphoribosyltransferase inhibitor which minimizes the toxicity of 5FU in the gut.
Earlier prospective studies with S-1 conducted in China in patients with metastatic breast cancer, who had previously relapsed from one chemotherapy regimen, demonstrated encouraging efficacy and safety of the agent in a as second-line treatment.
Other studies suggested that combining tegafur with endocrine therapy could improve anti-tumor efficacy.
In this study, Toi and colleagues examined the efficacy of S-1 in combination with adjuvant endocrine therapy in patients.
As part of an open-label, phase III trial, the investigators enrolled 1,939 patients with stage I-III HR-positive, HER2-negative breast cancer with intermediate or higher risk of recurrence in the full analysis set. The study included patients from 139 centers in Japan. The participating patients had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative status and intermediate or higher risk of recurrence and were randomized (1:1) to receive either S-1 and endocrine therapy or standard endocrine therapy alone as adjuvant treatment.
Based on the body surface area of each patient, the administered dose of S-1 was either 80 mg/day, 100 mg/day, or 120 mg/day. The drug was administered for one year with a 2 weeks on/1 week off administration schedule.
The primary endpoint was invasive disease-free survival (iDFS), defined as time from randomization to invasive disease recurrence, occurrence of second invasive cancer event, or death, and was analyzed on an intent-to-treat basis. Secondary endpoints included disease-free survival (DFS), and distant disease-free survival, overall survival (OS), and safety profile.
The median follow-up after treatment was 51.4 months. Among the 957 patients in the S-1 arm, 101 experienced disease recurrence, compared to 155 of the 973 patients in the control arm (10.6% versus 15.9%), translating to 153 iDFS events in the control arm and 99 events in the S-1 arm [hazard ratio, 0.63 (95%CI, 0.49-0.81); p-value, 0.0003].
The estimated five-year iDFS was 86.9% for patients in the S-1 arm compared to 81.6% in the control arm. The investigators observed distant recurrence as the first disease event was in 6.8% of patients in the S-1 arm and in 9.5% of patient in the control arm.
“We found that the postoperative adjuvant use of S-1 in combination with standard endocrine therapy significantly reduced iDFS events and improved five-year iDFS estimates in patients with HR-positive and HER2-negative breast cancer,” Toi observed.
Furthermore, Toi said that the the treatment with S-1 was well tolerated and manageable. Major toxicities associated with S-1 treatment included signs of bone marrow suppression, such as decreased neutrophil counts; gastrointestinal toxicities, such as nausea and diarrhea; hyperpigmentation; and fatigue.
“Our findings support the addition of S-1 to standard endocrine therapy in the post-operative adjuvant setting for patients with HR-positive, HER2-negative disease and an intermediate or higher risk of recurrence,” said Toi.
“A limitation of the study is that it only included patients from Japan, and the toxicity profile may be slightly different between Asian and non-Asian patients,” Toi concluded.
* S-1, also known as Teysuno® or TS-1, is, in combination with cisplatin, approved in Europe, for the treatment of head and neck cancer, colorectal cancer, non–small-cell lung, breast, pancreatic, and biliary tract cancers in several countries in Asia. The drug has not beem approved by the U.S. Food and Drug Administration (FDA).
Post Operative Therapy with Endocrine and TS-1 (POTENT) trial.
 Toi M, Imoto S, Ishida T, Ito Y, Iwata H, Masuda N, Mukai H, et al. Addition of S-1 to endocrine therapy in the post-operative adjuvant treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative primary breast cancer: A multicenter, open-label, phase 3 randomized trial (POTENT trial). Presented during during the 2019 San Antonio Breast cancer Symposium (GS1-09) [Abstract]
 Yuan P, Di LJ, Liu W, et al. Phase II multi-center clinical study on using S-1 to treat advanced breast cancer after resistance to anthracycline and taxane drugs in Chinese patients. Int J Clin Exp Med. 2015;8(2):3072–3079. Published 2015 Feb 15.[Article]
 Liu TW, Chen LT. S-1 with leucovorin for gastric cancer: how far can it go?. Lancet Oncol. 2016;17(1):12–14. doi:10.1016/S1470-2045(15)00478-7.