Neoadjuvant Trials in ER+ Breast Cancer: A Tool for Acceleration of Drug Development and Discovery

Abstract

Neoadjuvant therapy trials offer an excellent strategy for drug development and discovery in breast cancer, particularly in triple negative and HER2-overexpressing subtypes, where pathologic complete response is a good surrogate of long term patient benefit. For estrogen receptor (ER)-positive breast cancers, however, use of this strategy has been challenging because of the lack of validated surrogates of long term efficacy and the overall good prognosis of the majority of patients with this cancer subtype. We review below the clinical benefits of neodjuvant endocrine therapy for ER+/HER2-negative breast cancer, its use and limitations for drug development, prioritization of adjuvant and metastatic trials, and biomarker discovery.

Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 12 weeks' exemestane exposure in patients with estrogen receptor‐positive breast cancer: A multicenter, open‐label, phase II study

“…Ki67 labeling index, determined by immunohistochemical assessment of surgical pathology specimens, could be the most useful and practical laboratory parameter in the clinical management of breast cancer patients. Its clinical validity is reasonably well established . It has been shown to differentiate groups of patients according to outcome.…”

“…These include problems establishing its analytical validity, such the lack of standardization of immunohistochemical assessment of Ki67 labeling index and the difficulty in assigning cutpoints for high versus low Ki67 labeling index . Despite these caveats, the use of Ki67 labeling index values after an initial period of neoadjuvant treatment with an aromatase inhibitor to triage postmenopausal patients with ER‐positive breast cancer to continued endocrine therapy, chemotherapy, or immediate surgery has been useful approach in clinical settings, and some authors consider a degree of variability in Ki67 labeling to be acceptable …”

“…Its clinical validity is reasonably well established. 6 It has been shown to differentiate groups of patients according to outcome.…”

“…Neoadjuvant therapy provides clinicians with the opportunity to assess tumor responsiveness to treatment. Research efforts have been focused on establishing an index for predicting benefit from and evaluating the effectiveness of neoadjuvant endocrine therapy in patients with ER‐positive breast cancer . Such an index could be used to identify patients most likely to benefit from neoadjuvant endocrine therapy and guide subsequent clinical decision making, for example by enabling physicians to tailor neoadjuvant therapy to maximize its effectiveness in individual patients.…”

“…Research efforts have been focused on establishing an index for predicting benefit from and evaluating the effectiveness of neoadjuvant endocrine therapy in patients with ER-positive breast cancer. 6 Such an index could be used to identify patients most likely to benefit from neoadjuvant endocrine therapy and guide subsequent clinical decision making, for example by enabling physicians to tailor neoadjuvant therapy to maximize its effectiveness in individual patients. Thus, patients with an inadequate response to neoadjuvant endocrine monotherapy could be switched to another treatment, for example a combination of endocrine therapy and chemotherapy, or immediate surgery.…”