Abstract S5-04: Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer

Abstract

Background: BCIRG-006 was study designed to assess the relative efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of early HER2+ breast cancer. We present the final, protocol-specified analysis of the long-term results from this trial that was initially developed to determine how to maximize adjuvant treatment efficacy and safety in these patients. Material & Methods: Between April, 2001 and March, 2004, we randomized 3,222 HER2+ operable breast cancer patients with axillary lymph node-positive or high risk node-negative disease, to either standard AC (60/600mg/m2 q3wk x 4) followed by T (100mg/m2 q3wk x 4) (AC-T) or two trastuzumab-based regimens. The trastuzumab-based regimens were AC followed by T (100mg/m2 q3wk x 4) and trastuzumab (H) x 1 year (AC-TH), or TCarbo (75mg/m2/AUC6 q3wk x 6) and H x 1 year (TCH). Patients were prospectively stratified by number of positive nodes (0, 1-3 vs ≥4) and hormone receptor status and those with ER and/or PR positive disease received hormone-directed therapy for 5yrs post chemotherapy. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety, with extensive cardiac evaluation (symptomatic events and asymptomatic, sustained LVEF declines). Results: Baseline characteristics of the study population were well balanced in the three study arms. At a median follow-up of 10.3 years, a persistent significant DFS benefit is seen in both trastuzumab-containing arms compared to AC-T with only 10 DFS events separating the two trastuzumab-based regimens: AC-TH (HR=0.70, 95%CI [0.60, 0.83]; p<0.001)) and TCH (HR=0.76, 95% CI [0.65, 0.90]; p<0.001). At this final analysis, the DFS HRs for AC-TH and TCH are closer than those observed in any prior protocol-directed study analyses (at 5 years follow-up the HRs were 0.64 and 0.75 for AC-TH and TCH respectively). Also, an OS benefit was observed in both AC-TH (HR=0.64, 95% CI [0.52, 0.79]; p<0.001)) and TCH (HR=0.76, 95% CI [0.62, 0.93]; p=0.0081). Importantly, TCH has significantly lower symptomatic CHF events by five-fold compared to AC-TH; 21 (2.0%) for AC-TH vs. 4 (0.4%) for TCH; p=0.0005. The AC-T control arm had 8 (0.8%) symptomatic CHF events. The incidence of patients with a relative LVEF decline >10% is doubled in the AC-TH compared to TCH regimens (206 vs 97; p<0.0001). Discussion: The long-term 10 years final results of the BCIRG 006 trial confirm the significant benefit of trastuzumab in the adjuvant treatment of HER2+ breast cancers, no significant efficacy difference between AC-TH and TCH as well as a significant symptomatic and asymptomatic cardiac safety benefit in the non-anthracycline, TCH trastuzumab-based regimen. Citation Format: Slamon DJ, Eiermann W, Robert NJ, Giermek J, Martin M, Jasiowka M, Mackey JR, Chan A, Liu M-C, Pinter T, Valero V, Falkson C, Fornander T, Shiftan TA, Bensfia S, Hitier S, Xu N, Bée-Munteanu V, Drevot P, Press MF, Crown J, On Behalf of the BCIRG-006 Investigators. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-04.

Neoadjuvant Chemotherapy with Docetaxel, Carboplatin and Weekly Trastuzumab Is Active in HER2-Positive Early Breast Cancer: Results after a Median Follow-Up of over 4 Years

“…The rate of symptomatic congestive heart failure events was 5-fold lower following TCH (n = 4; 0.4%) compared to AC-TH (n = 21; 2.0%) (p = 0.0005). The number of patients suffering from a left ventricular ejection fraction decline of > 10% after AC-TH (n = 206) was double that after TCH (n = 97) (p < 0.0001) [14]. These data led to the establishment of TCH as 1 of the standards in the adjuvant treatment of HER2-positive breast cancer.…”

Trastuzumab as adjuvant treatment for early stage HER2-positive breast cancer — a 10 year history

“…Similar results were obtained within a long observation period (median observation period: 10.3 years) of the patients from the BCIRG 006 study. A significant improvement of survival periods was observed (DFS and OS) in both study arms with combined therapy in comparison with chemotherapy alone [19]. In the arm with anthracyclines, for the disease free survival (ACAEDct+T) the obtained HR value was 0.70 (95%CI 0.60-0.83, p < 0.001), whilst in the arm without anthracyclines (DCbT) -HR 0.76 (95% CI 0.65-0.90, p < 0.001), and the rates were slightly lower than in the previous analysis (then it was 0.61 and 0.67 respectively, Table III, Figure 3a and 3b).…”

“…Figure 3a. Long-term study results: BCIRG 006 -DFS [19] Trastuzumab was added into the treatment immediately with taxoids (after 4 cycles of anthracyclines) or at the moment of initiation of adjuvant chemotherapy in the arm without anthracyclines (BCIRG 006 study), after 3 AC chemotherapy cycles (American trials) or after the completion of chemo-and, alternatively, also radiotherapy (the HERA study). The above studies did not evaluate the immediate combination of trastuzumab with anthracyclines, as such combinations were evaluated in the neoadjuvant treatment.…”

15. Internationale St.-Gallen-Konsensus-Konferenz: Behandlung des frühen Mammakarzinoms

“…Das TCHRegime ist eine wirksame Therapieoption mit Vorteilen bei der kardialen Verträg-lichkeit gegenüber den anthrazyklin-/ taxanbasierten Regimen. Die aktuellen Zehnjahresdaten der BCIRG-006-Studie unterstreichen dies [21,22] …”