SAN ANTONIO -- Response-guided neoadjuvant chemotherapy demonstrated a survival advantage over standard therapy in patients with newly diagnosed breast cancer, results of a large, randomized trial showed.
Adapting therapy to interim response was associated with a 29% improvement in disease-free survival (DFS) and a 21% improvement in overall survival compared with standard therapy.
Analysis of the data showed that the benefits were limited to patients with luminal tumors, according to a report here at the San Antonio Breast Cancer Symposium. Patients with HER2-positive or triple-negative breast cancer did no better with experimental therapy than with standard therapy.
"This treatment effect could not be predicted by pathologic complete response as [luminal] tumors have lower pathologic complete response rates and their prognosis does not depend on pathologic complete response," said Gunter von Minckwitz, MD, of the German Breast Group in Neu-Isenburg.
"Patients with HER2-positive or triple-negative tumors did not benefit from response-guided treatment, as pathologic complete response is highly prognostic in these subgroups. Lack of treatment effect on pathologic complete response rate corresponds to lack of long-term treatment."
Early response to neoadjuvant chemotherapy identifies chemosensitive tumors that have a high likelihood of pathologic complete response at surgery. Investigators in the German GeparTrio study sought to determine whether information about early tumor response could be used to develop more individualized treatment strategies.
Specifically, investigators wanted to determine whether extended chemotherapy, as guided by interim tumor response, could lead to further increases in the rate of pathologic complete response.
The study involved 2,072 patients with operable or locally advanced breast cancer. All patients received two cycles of neoadjuvant chemotherapy with docetaxel (Taxotere), doxorubicin, and cyclophosphamide (Cytoxan), collectively known as TAC, and were randomized to subsequent therapy on the basis of interim assessment of tumor response.
Patients who responded (≥50% tumor shrinkage) to the initial two cycles of chemotherapy were randomized to receive four or six additional cycles of TAC. Patients with nonresponding tumors were randomized to four cycles of TAC or four cycles of vinorelbine-capecitabine (Navelbine-Xeloda) chemotherapy.
The primary objective of the trial was to determine whether either experimental therapy (TAC x 8 or vinorelbine-capecitabine) could improve the pathologic complete response rate compared with the standard six cycles of TAC. Secondary endpoints included DFS and overall survival.
Subsequently, 1,344 patients met criteria for objective response after the initial two cycles of TAC.
As previously reported, the rates of pathologic complete response differed between responders and nonresponders but not between randomized therapies (J Natl Cancer Inst 2008; 100: 542-551, 552-562).
Von Minckwitz reported results of secondary outcomes after a median follow-up of 62 months. About 17% of the patients were younger than 40, 55% had nodal involvement, 35% had hormone receptor-negative tumors, and 30% had HER2-positive tumors.
The analysis showed that patients who received either experimental therapy had significant improvement in DFS, reflected in a hazard ratio of 0.71 (P<0.001) and in overall survival (HR 0.79, P=0.048).
Additional analyses showed that patients with objective responses had a 22% improvement in DFS with TAC x 8 (P=0.026), and patients with nonresponding tumors had a 41% improvement in DFS with the Navelbine-capecitabine therapy (P=0.001). These analyses did not show a significant difference in overall survival.
Examination phenotype data showed that about two-thirds of the patients had luminal tumors, 11% had HER2-positive nonluminal tumors, and 22% had triple-negative tumors.
Substantially fewer pathologic complete responses occurred in luminal-type tumors (5% to about 18%, depending on subtype) versus almost 30% for HER2-positive tumors and more than 35% for triple-negative tumors.
Pathologic complete response correlated significantly with DFS in patients who had the following:
- HER2-positive tumors (P<0.0001)
- Triple-negative tumors (P<0.0001)
- Luminal B subtype (HER2-negative) tumors (P=0.004)
Pathologic complete response did not predict DFS for patients with luminal A tumors (P=0.66) or luminal B (HER2-positive) tumors (P=0.67).
"Adapting neoadjuvant chemotherapy according to interim response leads to better disease-free survival and overall survival and represents therefore a unique advantage over adjuvant treatment," von Minckwitz said.
"These phenotypes are usually considered less chemosensitive, and pathologic complete response is not a prognostic factor," he added. "This might explain why the observed survival advantages could not be predicted by pathologic complete response."
Von Minckwitz disclosed relationships with sanofi-aventis and Roche. Other investigators disclosed relationships with Roche, Amgen, sanofi-aventis, AstraZeneca, and Novartis.
- Reviewed by Dori F. Zaleznik, MD Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner