1. Samson, Kurt

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Adding the oral fluoropyrimidine-based drug S-1 to endocrine therapy for women with HR-positive, HER2-negative (luminal) breast cancer appears to significantly reduce their risk of invasive recurrence for up to 5 years, according to the results of a large Japanese study presented at the 2019 San Antonio Breast Cancer Symposium (Abstract GS1-09).

Breast Cancer. Breas... - Click to enlarge in new windowBreast Cancer. Breast Cancer

Results of a phase III study showed the postoperative combination of S-1 and endocrine therapy increased disease-free survival and 5-year disease-free survival in a study group that included 1,932 women with stage I-III HR-positive, HER2-negative breast cancer with intermediate or higher risk of recurrence.


S-1 is an oral fluoropyrimidine derivative that is used for treating gastric, pancreatic, lung, head, neck, and breast carcinomas. It has been approved in Japan and in Europe, but not in the U.S. It is a combination drug composed of tegafur, a 5-fluorouracil prodrug that inhibits DNA synthesis and cell division, and gimeracil and oteracil, agents that promote tegafur activity and prevent gastrointestinal toxicity, respectively. Research has suggested that combining tegafur with endocrine therapy could improve a patient's ability to ward off subsequent invasive tumors.


"Although we have made remarkable progress with systemic therapy for breast cancer, many patients still experience disease recurrence," said Masakazu Toi, MD, PhD, Professor of Breast Surgery at Kyoto University Hospital, at a press conference.


HR-positive, HER2-negative breast cancer, also referred to as luminal breast cancer, is the most common breast cancer subtype, accounting for approximately 67 percent of cases, Toi noted.

Masakazu Toi, MD, Ph... - Click to enlarge in new windowMasakazu Toi, MD, PhD. Masakazu Toi, MD, PhD

Patients with this type of breast cancer are often treated with endocrine therapies and, in general, have a favorable 5-year relative survival rate; there is a risk of disease recurrence several years after treatment, he explained. "Because of the risk of recurrence, there is interest in identifying novel postoperative adjuvant therapies to be used in conjunction with endocrine therapy."


In the new phase III trial, Toi and his colleagues examined the efficacy of S-1 in combination with adjuvant endocrine therapy in 1,939 patients with stage I-III HR-positive, HER2-negative breast cancer and with intermediate or higher risk of recurrence. Patients from 139 cancer centers in Japan were randomized to receive either S-1 and endocrine therapy or endocrine therapy alone, with a median follow-up after treatment of 51.4 months.


Among 957 women in the S-1 treatment arm, there were 101 recurrences compared to 155 recurrences in 973 patients who only received endocrine therapy (10.6% vs. 15.9%). The estimated 5-year invasive disease-free survival (iDFS) for patients in the S-1 arm was 86.9 percent versus to 81.6 percent in untreated group of women.


"We found that the postoperative adjuvant usage of S-1, in combination with standard endocrine therapy, significantly reduced iDFS events and improved 5-year iDFS estimates," said Toi. Moreover, S-1 treatment proved to be well-tolerated and manageable, he continued. 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 postoperative adjuvant setting for patients with HR-positive, HER2-negative disease and an intermediate or higher risk of recurrence," Toi said. However, he noted that one 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.



The researchers previously investigated oral fluoropyrimidines like S-1 in postoperative adjuvant treatments for women with luminal primary breast cancer, but they wondered if administration to women with primary, luminal breast cancer, in combination with adjuvant endocrine therapy, might help reduce tumor recurrence.


The open-label, randomized, phase III clinical trial involved women with stage III ipsilateral, primary breast cancer, who were HR-positive and HER2-negative and who were determined to be at intermediate or high risk of recurrence. Recurrence risk was based on anatomical stage of a woman's cancer, pathological findings such as histologic grade, and centrally confirmed proliferative marker status.


For patients who underwent multidrug postoperative adjuvant or preoperative neoadjuvant chemotherapy, S-1 was administered following the multi-drug chemotherapy regimen. Women with no residual cancer in the breast and axillary node after the preoperative chemotherapy were excluded from the study.


S-1 was administered at a dosage of 80 mg/day, 100 mg/day, and 120 mg/day, depending on the body surface area of each patient, for 1 year using a 2-week-on/1-week-off schedule. The primary endpoint was invasive disease-free survival as defined as elapsed time from randomization to recurrence of invasive disease, occurrence of secondary invasive cancer, or death. Secondary endpoints included disease-free survival, distant disease-free survival, overall survival, and safety.


From February 2012 to February 2016, 1,959 patients were enrolled in the study and 1,932 were included in the analysis. The trial was terminated early after a predetermined primary endpoint mark was reached. The median follow-up was 51.4 months.


A total of 153 invasive disease deaths were reported in the control arm compared to 99 deaths in the S-1 arm, and the 5-year invasive disease-free survival rate was estimated to be 86.9 percent in the S-1 arm and 81.5 percent in women who only received endocrine therapy.


Kurt Samson is a contributing writer.