At the time the TAILORx trial was initiated and the 21-gene recurrence score assay became available for clinical use, there was comfort and there was a high enough level of evidence to suggest that women with a very low recurrent score could be spared chemotherapy, and that there was a subset of women who had very high recurrent scores that benefited from chemotherapy. But there was equipoise or uncertainty about the benefit of chemotherapy in the vast majority of patients who had a mid-range recurrent score. The TAILORx trial was designed to address that uncertainty or that area of equipoise, and it definitively addressed it. It demonstrated that endocrine therapy was not inferior to chemoendocrine therapy in women who had an Oncotype DX recurrent score of 11 to 25. That has now made its way into clinical practice. It's now been incorporated into all of the standard practice guidelines, so it's had a great influence and impact on clinical practice.
The Oncotype has been integrated into standard practice not only in patients with negative axillary lymph nodes, but also in patients with one to three positive nodes. There does remain some uncertainty about the clinical utility of the test in women 50 or under or premenopausal, including women who are node negative and have a recurrent score of 21 to 25 or 16 to 25 and have high clinical risk features because in those patients there did seem to be some benefit from chemotherapy. A similar phenomenon was also seen in the RxPONDER trial in patients with one to three positive nodes randomized to chemotherapy or not, who had a recurrent score of zero to 25. There, there seemed to be some chemotherapy benefit even in patients who had a lower recurrent score.
What remains uncertain is what's driving that chemotherapy benefit. One hypothesis is that it may be the chemotherapy-induced menopause may be driving that benefit because it's mainly women who are between the ages of 45 and 50, or in other words, women who are closest to having a natural menopause and are most likely to have a chemotherapy-induced menopause that are deriving or that are experiencing that benefit. So that does remain an unanswered question.
The results of the TAILORx trial and RxPONDER now have greatly reduced the need for adjuvant chemotherapy in women with up to three positive axillary nodes who have estrogen-receptor positive, HER2 negative breast cancer. With longer follow-up, we are finding that women continue to be at risk for recurrence beyond five years. That rate is about one-half percent per year, and it's similar in years one through five compared with years six through 12. It's actually quite consistent. With longer follow-up, we're seeing higher rates, though, of invasive disease-free survival events, which include second primary breast cancers and second primary other cancers.
We're also seeing local regional recurrences, so we continue to see events beyond five years, and the annual event rate of these other events is in the range of about 1% per year. The long-term follow-up indicating that we are continuing to see relapses beyond five years is consistent with the results of many other trials and meta-analyses of these trials showing that there continues to be this persistent risk of relapse many years after a breast cancer diagnosis with this specific type of breast cancer, estrogen-receptor positive, HER2 negative breast cancer.
