Prediction of node-negative breast cancer outcome by histologic grading and S-phase analysis by flow cytometry - An Eastern Cooperative Oncology Group study (2192)

Histologic evaluation and reporting of invasive breast cancer has effective ly used Nottingham combined histologic grade (NCHG). This approach to predi ct outcome in invasive breast cancer has not been tested in multicenter coo perative trials. Histologic slides from selected breast cancer cases entere d on node-negative Eastern Cooperative Oncology Group trials were assigned grades. Two pathologists evaluated cases for NCHG defined from differentiat ion. mitotic index, and nuclear grade. The study population consisted of se parate samples from low- and high-risk strata, where low risk was estrogen receptor positive with a tumor size of less than 3 cm and high risk was est rogen receptor negative or tumor size greater than or equal to 3 cm. The ra te of agreement was generally good, with 80% of cases classified the same f or mitotic count and 76% of the cases classified the same for combined grad e. There were no cases disagreeing from the lowest to the highest of the th ree categories. The median follow-up is 11.6 years, but for analysis of sur vival, this was truncated at 5 years. Mitotic index and combined grade as a ssessed by both pathologists showed significant associations with survival. High combined histologic grade was predictive for response to cyclophospha mide/methotrexate/5-fluorouracil (CMF) with survival differences at 5 years of 30% in the treated high-grade patients over the un-treated patients. Ov erall, it is clear that pathologists can have close agreement in assignment of combined histologic grades, with highly significant prediction in univa riate and borderline significance in multivariate analysis in prognosticati on of time to recurrence as well as survival. Thus, stratification used in these trials was highly prognostic as hoped, leaving a role for histologic grading in these relatively large tumors, more powerful than S-phase analys is in this series. In the subgroups of high-risk patients randomized betwee n CMF and observation, there was a suggestion that the high-combined-grade group was predictive of treatment efficacy. We conclude that a combined his tologic grade with defined criteria may be reliably assigned by practiced p athologists using readily available criteria, and that the measure may be o f use in prognostication and prediction of therapeutic responsiveness when done in a technically ideal fashion.