Abstract
Introduction
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Although TNBC accounts for approximately 15% of all breast cancers, it contributes disproportionately to all breast cancer-related mortality (approximately 40%). Its molecular aggressiveness, genetic diversity, genomic instability, and biological heterogeneity make relapsed, multidrug-resistant, and metastatic TNBC particularly challenging to treat. TNBC patients experience 40-50% relapse and 22% mortality rates in general. Before 2021, chemotherapy was the mainstay of standard-of-care (SOC) treatment in both neoadjuvant and adjuvant settings. On July 26, 2021, the FDA approved pembrolizumab (Keytruda), an immune checkpoint inhibitor, in combination with chemotherapy as a new SOC regimen to treat high-risk early-stage TNBC in the neoadjuvant setting. Despite remarkable improvements in pathological complete response (pCR) rates with immuno-oncology (IO) therapy, patients with similar clinicopathological characteristics, including tumor-node-metastasis (TNM) stage and residual cancer burden (RCB), still experience different clinical outcomes. Historically, pCR has been used as an important and reliable prognostic marker to predict event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) in TNBC. Whether the prognostic significance of pCR remains equivalent post-IO-therapy warrants further investigation.
Methods
We reviewed landmark findings from the KEYNOTE-522 and I-SPY 2 clinical trials and related high-profile publications from 2020 through 2025. We also reviewed all the clinical prognostic markers recognized or utilized by NCI, NCCN, and FDA in the evaluation and management of TNBC. The pCR and long-term survival rates reported in KEYNOTE-522 and I-SPY 2 were extracted and compared to evaluate the relationship between pCR rate and survival benefit following neoadjuvant IO-therapy in TNBC.
Results
The results from KEYNOTE-522 and I-SPY 2 demonstrate marked increases in the pCR rates following IO-therapy, with the reported pCR rates increasing from approximately 40–45% with conventional chemotherapy to approximately 60–65% with IO-therapy. This represents an approximately 40–50% percentage-point absolute increase in the pCR rate. In contrast, improvements in 3/5-year survival rate appear comparatively modest. In KEYNOTE-522, the EFS rate increased from 76.8% to 84.5%, representing a 7.7-percentage-point absolute increase. Thus, the magnitude of improvement in pCR was substantially greater than the corresponding improvement in EFS/PFS/OS. This apparent discordance raises the question that the prognostic relationship between pCR and survival may differ following the new IO-therapy when compared with conventional neoadjuvant chemotherapy (NACT).
Conclusion
The new IO-therapy has produced a substantial increase in pCR rates in early-stage TNBC, whereas the corresponding improvement in 5-year survival rate appears comparatively limited/modest. These findings suggest that an increase in pCR does not necessarily translate into a proportional improvement in patient survival following IO-therapy. We propose the concept of “pseudo-pCR” to describe the discrepancies in which the pCR rate following IO-therapy may overestimate its traditional prognostic value in predicting survival benefit in TNBC. Since pCR may become discordant and incongruent with survival benefit post-IO therapy, this “pseudo-pCR” concept is hypothesis-generating and requires further investigation and integrated analyses of tumor/TME/TIME biology, host immune response, residual disease burden, new molecular biomarkers, and long-term clinical outcomes.