With the advent of next-generation sequencing and other technologies, a highly diverse and heterogeneous molecular landscape underlying TNBC has been revealed, and multiple molecular subclassifications have been established. 2, 3 Distant failure is a seminal event in the natural history of TNBC, with a 5-year overall survival (OS) rate of approximately 25% and median survival of 24 months in women with metastatic disease. 1 This is driven primarily by an increased propensity for distant failure compared with other subtypes of breast cancer, particularly within the first 5 years of diagnosis. As a group, patients with this subtype of breast cancer have a relatively worse prognosis than women with non-TNBC. Triple-negative breast cancer (TNBC) is an often-used surrogate for the basal subtype of breast cancer defined by the lack of estrogen receptor (ER) and progesterone receptor (PR) expression and HER2 gene amplification. In patients with residual disease after NAC, pathologic lymph node positivity and lymphovascular space invasion predicted worse FFDM. Conclusions: Lack of pCR after NAC resulted in worse overall survival and FFDM, despite trimodality therapy. Patients with a greater number of factors had worse FFDM 5-year FFDM was 76.5% for patients with no factors (n=38) versus 54.9% and 27.5% for patients with 1 (n=44) and 2 factors (n=26), respectively ( P<.001). Factors independently predicting FFDM in patients without pCR were pathologic nodal positivity (hazard ratio, 3.08 95% CI, 1.54–6.14 P=.001) and lymphovascular space invasion (hazard ratio, 1.91 95% CI, 1.07–3.43 P=.030). Five-year FFDM was 98% and 55% in patients with and without pCR, respectively ( P<.001). After NAC, 108 had residual disease (pCR, 29%). Results: We identified 153 patients with median follow-up of 4.0 years (range, 0.5–14.0 years). In patients without pCR, univariate and multivariable Cox analyses were used to determine factors predictive of distant metastasis. Freedom from distant metastasis (FFDM) was compared between patients with and without pCR using the Kaplan-Meier method. Methods: Women with TNBC treated with NAC, surgery, and radiation therapy in 2000 through 2013 were reviewed. This study investigated factors predictive of distant metastasis in TNBC without pCR after NAC. However, most patients do not experience pCR, and other risk factors for distant metastasis after NAC are poorly characterized. The main focus of the guidance is to discuss the use of pathological complete response (pCR) in high-risk early-stage breast cancer as a potential endpoint to support approval under the accelerated approval regulations (21 CFR part 314, subpart H, for new drug applications and 21 CFR part 601, subpart E, for biologics license applications).Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) predicts decreased distant metastasis. This guidance is intended to assist sponsors in designing trials to support marketing approval of drugs and biological products for the treatment of high-risk early-stage breast cancer in the neoadjuvant (preoperative) setting.
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