Clinical trialPhase 3Breast cancer

Adjuvant Trastuzumab in HER2-Positive Breast Cancer

N Engl J Med · 20113222 women

Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. N Engl J Med. 2011. 365:1273-1283

Study type: Clinical trial
Study name: BCIRG-006
Phase: Phase 3
Design: Three-arm randomised trial (Breast Cancer International Research Group)
Sample size: 3222 women
Source: N Engl J Med · 2011
Trial registration: NCT00021255

In plain words

In this large study, women with early-stage HER2-positive breast cancer received one of three treatments. Adding one year of trastuzumab to chemotherapy raised the chance of living without the cancer coming back, and of living longer. The regimen without an anthracycline (TCH) worked about as well as the regimen with an anthracycline, but caused fewer heart problems and carried a lower risk of leukaemia. The final choice of treatment is made with your own doctor.

Key results

75% (AC-T) vs 84% (AC-T plus trastuzumab) vs 81% (TCH)

5-year disease-free survival

After a median follow-up of 65 months and 656 events; both trastuzumab regimens were superior to AC-T

87% (AC-T) vs 92% (AC-T plus trastuzumab) vs 91% (TCH)

Overall survival (estimated)

No significant difference in efficacy (disease-free or overall survival) between the two trastuzumab regimens

Significantly more frequent with AC-T plus trastuzumab than with TCH

Congestive heart failure and cardiac dysfunction

P<0.001

8 cases: 7 in the anthracycline-based arms and 1 in the TCH arm

Acute leukaemia

The TCH case occurred after an anthracycline was given outside the study

Drugs in this study:Carboplatin (Paraplatin)Cyclophosphamide (Endoxan)Docetaxel (Taxotere)Doxorubicin (Adriamycin)Trastuzumab (Herceptin)

Dose and schedule cards

TCH: docetaxel + carboplatin + trastuzumab (BCIRG006)

HER2-positive breast cancer, adjuvant treatment without an anthracyclineCycle length: Every 3 weeksOn the page “Trastuzumab (Herceptin)” · Dose and schedule (FDA label)

HER2-positive breast cancer, adjuvant treatment without an anthracycline

Drug	Dose	Route	Schedule
6 cycles
Docetaxel + carboplatin	75 mg/m² + AUC 6	IV (carboplatin over 30 to 60 minutes)	Day 1 every 3 weeks
With the taxane
Weekly trastuzumab	Initial dose 4 mg/kg, then 2 mg/kg	IV infusion; initial 90 minutes, then 30 minutes	Weekly, 18 weeks
One week after the last weekly dose
Trastuzumab	6 mg/kg	IV infusion over 30 to 90 minutes	Every 3 weeks

Cycle length: Every 3 weeks
Duration: Trastuzumab 52 weeks in total

In the AC then TH arm of the same trial, docetaxel was 100 mg/m² every 3 weeks for 4 cycles and trastuzumab weekly for 12 weeks.

On the page “Trastuzumab (Herceptin)” · Dose and schedule (FDA label)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1AC-T (control arm)

Doxorubicin and cyclophosphamide followed by docetaxel, every 3 weeks.

Doxorubicin 60 mg/m² + cyclophosphamide 600 mg/m² every 3 weeks for 4 cycles, then docetaxel 100 mg/m² every 3 weeks for 4 cycles.

2AC-T plus trastuzumab

The same AC-T regimen plus 52 weeks of trastuzumab.

The same AC-T; weekly trastuzumab given with docetaxel (loading dose 4 mg/kg, then 2 mg/kg weekly), then 6 mg/kg every 3 weeks as a single agent to complete 52 weeks.

3TCH

Docetaxel and carboplatin plus 52 weeks of trastuzumab (an anthracycline-free regimen).

Docetaxel 75 mg/m² + carboplatin AUC 6 (‎30-‎ to 60-minute infusion) every 3 weeks for 6 cycles, with weekly trastuzumab (4 then 2 mg/kg), then 6 mg/kg every 3 weeks to complete 52 weeks.

Source of the regimen details: FDA label for Herceptin (DailyMed, section 14.1, BCIRG006)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Women with early-stage HER2-positive breast cancer.

Endpoints

Primary endpoint: disease-free survival. Secondary endpoints: overall survival and safety.

Safety and side effects

Congestive heart failure and cardiac dysfunction were significantly more frequent with AC-T plus trastuzumab than with TCH (P<0.001). Eight cases of acute leukaemia were reported: seven in the anthracycline-based arms and one in the TCH arm, after the patient had received an anthracycline outside the study. The authors considered TCH to have fewer acute toxic effects and lower risks of cardiotoxicity and leukaemia. Exact rates of grade ≥3 adverse events are not given in the abstract.

Clinical significance and place in guidelines

This trial showed that one year of adjuvant trastuzumab improves disease-free and overall survival in early HER2-positive breast cancer, and that the non-anthracycline TCH regimen, with similar efficacy, has less cardiotoxicity and a lower leukaemia risk than AC-T plus trastuzumab. TCH may therefore be the better option for patients prone to cardiac toxicity. The regimen's place in current guidelines should be checked separately, as the abstract does not address it.

Limitations

The abstract does not state the study's limitations. Drug doses and exact rates of grade ≥3 adverse events are not given in the abstract and must be checked in the full paper. The study reports the protocol-specified analysis at a median follow-up of 65 months, and the direct comparison of the two trastuzumab regimens rests on the absence of a significant difference in efficacy.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.