The Standardized Definitions for Efficacy End Points (STEEP) criteria were developed in 2007 by experts from the National Cancer Institute and the National Clinical Trials Network to provide consistent, standardized definitions of end points in adjuvant BC trials. These were subsequently updated in 2021 (STEEP 2.0). However, there have been a lack of similar standardized criteria for neoadjuvant therapy in BC. Neoadjuvant therapy is used in locally advanced disease to improve operability, to downstage operable tumors to permit breast conservation, and is the standard of care in triple-negative BC and in human epidermal growth factor receptor 2–positive (HER2+) BC.

The NeoSTEEP group was charged with developing neoadjuvant systemic therapy end points in early BC clinical trials with efficacy outcomes, which include both pathologic and time-to-event survival end points. The group was also tasked with outlining trial design considerations affecting end point assessment. This nomenclature is especially important in the drug approval process and when clinicians are evaluating clinical trial data literature. The lack of standardization for definitions of both pathologic response and long-term efficacy end points makes cross-trial comparisons difficult at best.

Definitions of outcomes in clinical trials involving neoadjuvant therapies for BC have varied depending on the study. The NeoSTEEP group defined pathologic complete response (pCR), which is associated with long-term survival outcomes, as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes. Additional designations include pCR-no DCIS (ductal carcinoma in situ) and residual cancer burden (RCB), which is associated with long-term survival outcomes in patients receiving neoadjuvant chemotherapy. RCB-0 is the same as pCR, whereas RCB-I indicates minimal residual disease, RCB-II refers to moderate residual disease, and RCB-III applies to extensive residual disease or progression on neoadjuvant therapy.

Neoadjuvant trials also need to assess time-to event survival end points such as event-free survival (EFS) and overall survival (OS). These end points include both progression and deaths due to toxicity before surgery as events. Other end points defined in NeoSTEEP include BC-EFS, DP/DRFS (distant progression and recurrence-free survival), IDFS (invasive disease-free survival), IBCFS (invasive breast cancer-free survival), and DRFS (distant recurrence-free survival). All of these end points can be assessed when death occurs, either from BC, a non-BC cause, or from an unknown cause. Depending on the end point, they can also be assessed for local-regional progression before surgery, for distant progression before surgery, for invasive ipsilateral breast tumor recurrence, for local regional invasive recurrence, for distant recurrence, for invasive contralateral BC, for ipsilateral or contralateral DCIS, and for a second primary non-BC invasive cancer. Some of these end points correlate with those in STEEP 2.0, which standardized terminology for adjuvant BC therapy.

NeoSTEEP stresses that baseline clinical and imaging evaluation of the breast and regional nodes is standard for neoadjuvant trials. Various modalities are available to determine the patient’s baseline clinical stage. Imaging is also useful during neoadjuvant therapy to assess treatment response, to determine if disease progression has occurred, and to assist in surgical treatment planning. A response is considered “non-pCR” if the disease progresses while on neoadjuvant therapy, resulting in discontinuation of treatment. In trials with a large number of patients with locally advanced BC, breast conservation eligibility rates pre-and postneoadjuvant therapy could serve as a secondary end point.

The article also describes nodal staging considerations at the time of surgery.

In unselected hormone-receptor-positive (HR+) BC, reported pCR rates range from 7% to 11% in chemotherapy studies and 2% to 6% with endocrine monotherapy or endocrine therapy combined with targeted therapy. The NeoSTEEP group does not recommend a specific end point for neoadjuvant endocrine therapy. In patients in immunotherapy trials who do not achieve pCR, RCB may predict survival benefit. There is limited information on the efficacy of new treatment regimens in patients with inflammatory BC.

Approximately 1.5% to 3% of newly diagnosed BC patients present with synchronous bilateral BC. Of these, there is discordance in estrogen or HER2 receptor status in 10% to 20% of cases. Each cancer needs to be evaluated separately for pathologic response and should be treated as two discreet primary lesions.

The article stresses the importance of assessing quality of life and patient-reported outcomes (PROs), as these may differ between patients undergoing adjuvant versus neoadjuvant treatment. The BREAST-Q is a validated multidomain tool to examine the impact of different local therapeutic strategies and the effect of axillary treatment on PROs.

From a regulatory standpoint, the FDA encourages the use of pCR as the main pathologic end point in preoperative studies; however, the association between pCR and long-term outcome may vary depending on the BC subtype. pCR should be assessed in conjunction with measures of safety and efficacy including time-to-event end points such as EFS, IDFS, and OS.

This article offers valuable insight for pharmacists whether they are actively conducting neoadjuvant BC clinical trials or interpreting the medical literature.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.