Lancet (London, England) 2014-07-12
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
ABSTRACT
BACKGROUND
Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS.
METHODS
We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS.
FINDINGS
We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70).
INTERPRETATION
Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.
FUNDING
US Food and Drug Administration.
Related Questions
The GEPAR trials presented at ASCO 2015 showed increased LRR with the omission of RT in patients who had a pCR after neoadjuvant chemotherapy.
New comment by Radiation Oncologist at Varian Medical Systems/Allegheny health network ( August 18, 2023)
More recent Dutch data (Lancet 2022) with tailored RT based on response to chemo for clinical N1 disease showed a low LR recurrence rate for low risk disease (mainly patients ...
New answer by Medical Oncologist at UT Southwestern Medical Center (September 10, 2018)
It's a complicated issue. it is important to keep in mind that TRYPHAENA was a relatively small study with a primary endpoint of cardiac safety. It was not designed to investi...
NCCN recommendations seem to mention these patients as not candidates for preoperative systemic therapy if the invasive carcinoma extension cannot be ...
New answer by Medical Oncologist at University of Iowa Holden Comprehensive Cancer Center (February 27, 2019)
I would say the answer depends on the subtype of Invasive breast cancer. I would be fine considering Neo-adjuvant systemic therapy in the setting of TNBC and Her 2 Positive br...
Patient is a post-menopausal woman with 4 lymph node mets that was strongly ER+/PR+, HER2-negative invasive ductal carcinoma with a high Ki-67 w...
New comment by Medical Oncologist at Alvin & Lois Lapidus Cancer Institute Northwest Hospital ( August 26, 2022)
In reviewing the treatment protocol attached to the NEJM article, it does not appear that path CR for a neoadjuvant patient was an exclusionary criterion. I have a patient lik...