New Meta-Analysis: Complete Response to Neoadjuvant Therapy in Breast Cancer Predictor of Long-Term Benefit

Audrey Andrews

March 2013, Highlights - Clinical Research


A new meta-analysis confirmed that patients with breast cancer who achieve a pathologic complete response (pCR) to neoadjuvant therapy have a more favorable outcome than those who do not.

Patients who achieved a pCR had a 52% reduction in the probability of an event and a 64% reduction in the probability of death (P <.001 for both), as was shown in the meta-analysis of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC).

“pCR is a proposed surrogate end point for predicting long-term clinical benefit on end points such as disease-free survival, event-free survival [EFS], or overall survival [OS]. A meta-analysis has been needed to establish the magnitude of pCR improvement on a trial level that results in improved disease-free survival,” said lead investigator Patricia Cortazar, MD, Clinical Team Leader for the Breast Oncology Group of the US Food and Drug Administration.

The analysis included 12 neoadjuvant randomized controlled trials in which pCR was clearly defined, all the necessary data were collected, and data on EFS and OS with long-term follow-up were available.

The studies used various definitions of pCR, including:

  • ypT0ypN0: absence of invasive cancer in the breast and axillary nodes, and absence of ductal carcinoma in situ (DCIS)
  • ypT0/isypN0: absence of invasive cancer in the breast and axillary nodes; DCIS is allowed
  • ypT0/is: absence of invasive cancer in the breast; DCIS is allowed regardless of nodal involvement.

Major Findings

The analysis showed that pCR was positively associated with more favorable long-term outcomes, including EFS and OS. The more favorable outcomes after pCR occurred regardless of whether DCIS was present or absent. For consistency, a standard pCR definition should be used in future trials, preferably ypT0ypN0 or ypT0/isypN0.

By breast subtype, a larger association with EFS was observed in patients with aggressive tumor subtypes; the association was smaller in patients with less aggressive tumors.

The magnitude of pCR improvement that predicts long-term clinical benefit (ie, EFS and OS improvement) could not be established, possibly as a result of low pCR rates, heterogeneous populations, and the lack of targeted therapies in most trials.

Larger pCR differences between treatment arms are needed to translate into long-term outcome and may vary according to breast cancer subtype.

Overall, the percentage of patients achieving a pCR was 13% by using the ypT0ypN0 definition, 18% by ypT0/isypN0, and 22% by ypT0/is. Eradication of tumor from the breast and from the lymph nodes was better associated with improved EFS and with OS than with eradication from the breast alone.

Patients who achieved a pCR had a 52% reduction in the probability of an event and a 64% reduction in the probability of death.

The achievement of pCR was variable by tumor subtype, being infrequent in patients with low-grade hormone receptor (HR)-positive tumors (7%) and more frequent among high-grade HR-positive (16%), triple-negative (34%), HR-positive and HER2-positive (30%), and HR-negative and HER2-positive (50%) tumors.

“Patients with more aggressive tumor subtypes who achieved pCRs had greater EFS compared with patients who did not achieve pCRs,” Dr Cortazar noted.

Among HER2-positive patients, the achievement of pCR was associated with significant reductions in risk; within certain subgroups, this was enhanced with treatment with trastuz­umab (Herceptin). In HER2-positive and HER2-negative patients, hazard ratios associated with pCR were 0.35 without trastuzumab and 0.15 (P <.001 for both) with trastuzumab.

In addition, the triple-negative subgroup greatly benefited from attaining a pCR, with a hazard ratio of 0.24 (P <.001), Dr Cortazar added.

Of note, the magnitude of pCR improvement in the randomized trials did not predict the EFS and OS effects. “This meta-analysis did not establish the magnitude of increase in pCR rate needed to predict the superiority of one regimen over another in terms of EFS or OS,” she said. “The absolute magnitude of improvement in pCR rate needed to impact long-term outcome may be greater than the observed difference in these trials, and may vary according to breast cancer subtype.”