Assessment of Residual Cancer Burden and Event-Free Survival in Neoadjuvant Treatment for High-risk Breast Cancer: An Analysis of Data From the I-SPY2 Randomized Clinical Trial.

IMPORTANCE: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. OBJECTIVE: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. DESIGN, SETTING, AND PARTICIPANTS: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. INTERVENTIONS: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. MAIN OUTCOMES AND MEASURES: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). RESULTS: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379.

Submission of the entire lymph node dissection for histologic examination in gynecologic-oncologic specimens. Clinical and pathologic relevance.

BACKGROUND AND AIMS: Lymph node (LN) status in gynecologic malignancies plays an important role in patient staging, management, and prognosis. Therefore, an adequacy of LN harvest is crucial. The aim of this study is to determine whether the submission of the entire LN dissection for histologic examination will affect patients' outcome or clinical stage. We also evaluated the time required and cost-effectiveness for the laboratory. MATERIALS AND METHODS: A prospective study of 134 surgical cases from various gynecologic malignancies was conducted. The LN dissection specimen was performed using a conventional manual node dissection method with all the remaining fat being submitted in additional cassettes. One pathologist evaluated (1) the number and status of palpable LNs identified by the conventional method as well as the number of tissue cassettes and (2) the number, size, and status of the non-palpable LNs as well as the number of tissue cassettes. RESULTS: The palpable LNs ranged from 0 to 36 with average 14.8 LNs per case (Poisson 95% CI: 14.1-15.4). The additional non-palpable LNs ranged from 0 to 16 with an average of 3.1 (Poisson 95% CI: 2.8-3.4). In only one case, a 3-mm non-palpable LN with metastasis was identified; however, it did not affect tumor staging or patient management. CONCLUSION: The impact on patient outcome is minimal and it does not prove to be cost and time effective when submitting the entire LN dissection specimen in gynecologic malignancies. However, this method could be justified in selective cases in which the manual node dissection does not reveal an adequate number of LNs.