Matthew J. Ellis, MB, PhD
Matthew J. Ellis, MB, PhD, Director of the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston, commented on the POETIC trial for The ASCO Post.
“This is a wonderful study that validates a point that our research team has also made over the years—that Ki67 is much more prognostic when assessed on tissue that has been treated with endocrine therapy, as opposed to a measurement taken at baseline,” he said.
Dr. Ellis was referring to ACOSOG Z1031, which assessed Ki67 in patients with breast cancer 1 month after starting neoadjuvant endocrine therapy and used the same cutpoints as the POETIC trial.1 A fall in Ki67 level was predictive of favorable tumor response and an improved prognosis; these patients were continued on endocrine therapy. Patients with high on-treatment Ki67 (> 10%) at 1 month were deemed endocrine-resistant and switched to neoadjuvant chemotherapy or immediate surgery.
“Our work together with the POETIC team firmly supports the conclusion that the on-treatment Ki67 assay is a low-cost, simple approach to determining prognosis,” he said.
Elaborating on the value of this association, Dr. Ellis pointed out that in POETIC, patients with Ki67 levels ≥ 10% had an event rate of about 4% per year, “which is very high, as most patients had small breast cancers.” In the setting of locally advanced disease in Z1031, where tumors are larger, the event rate rose to 7% per year. “This is approximately equivalent to an Oncotype DX recurrence score of over 26 or a Prosigna ROR score of over 60 in node-positive patients,” he noted.
Treatment Resistance
The study also speaks to the problem of intrinsic endocrine therapy resistance, he continued. “The POETIC trial is a great data set for dissecting the molecular mechanisms of intrinsic resistance where the tumors are ‘broken’ with respect to the -connection between estrogen receptor and the cell cycle at the moment of diagnosis,” he said. “As we discussed in our recent paper in Cancer Discovery on the mechanisms of intrinsic resistance,2 we think this biology, in part, can be explained by defects in DNA repair that sever the link between the estrogen receptor and cyclin-dependent kinase (CDK)4/6–dependent cell-cycle regulation, thus producing cell proliferation that is not suppressible by inhibition of the estrogen receptor funtion. Tumors that have ‘nonsuppressible proliferation’ obviously need another form of treatment. Our research suggests CDK4/6 inhibitors may be part of the answer. Thus, we are beginning to tie this all together, with an increased focus on more effective interventions for patients with endocrine-resistant tumors.”
The ongoing phase III ALTERNATE trial, he said, is comparing fulvestrant (Faslodex), to anastrozole (and the combination). The question being asked is whether more effective neoadjuvant endocrine therapy with fulvestrant can reduce the need for adjuvant chemotherapy treatment by pushing more tumors into an adequate endocrine response. Tumors are biopsied 4 weeks after patients start endocrine therapy. If the Ki67 level is < 10%, the tumor’s proliferation is considered “favorable,” and the patient remains on endocrine therapy for a total of 6 months before surgery. If the level is higher, patients are transitioned to chemotherapy or sent directly to surgery. For the patients continuing on neoadjuvant endocrine therapy to surgery, those with pathologic stage I or IIA disease and a surgical specimen Ki67 value of < 2.7% are managed with adjuvant endocrine therapy alone. More than 1,000 patients have been accrued, and the trial is projected to be completed early in 2019.
These neoadjuvant endocrine therapy studies are “ushering in a new era of thinking that has been evolving for some time.” Instead of immediate surgery for estrogen receptor–positive, HER2-negative disease, a period of preoperative endocrine therapy can very effectively identify patients with resistant tumors who need additional systemic therapy vs those in whom endocrine monotherapy is adequately effective, Dr. Ellis said. ■
DISCLOSURE: Dr. Ellis has provided ad hoc consulting for AstraZeneca, Pfizer, Novartis, and Lilly and he receives royalty payments from Nanostring on an issued patent for the Prosigna breast cancer prognostic test.
REFERENCES
1. Ellis MJ, Suman VJ, Hoog J, et al: Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: Clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype—ACOSOG Z1031. J Clin Oncol 29:2342-2349, 2011.
2. Haricharan S, Punturi N, Singh P, et al: Loss of MutL disrupts CHK2-dependent cell-cycle control through CDK4/6 to promote intrinsic endocrine therapy resistance in primary breast cancer. Cancer Discov 7:1168-1183, 2017.
