Optimizing neoadjuvant systemic treatment in HER2 positive breast cancer - the TRAIN-2 study

Upfront trastuzumab treatment is beneficial to patients with HER2 positive
breast cancer. The potential synergistic cardiotoxicity of trastuzumab and
anthracyclines has lead to the development of non-anthracycline containing
regimens, which have shown high pathologic complete response rates.
Anthracyclines remain very active in HER2 positive breast cancer, however, and
increasing evidence now supports safe combination of trastuzumab and
epirubicin. Therefore, the addition of epirubicine to a non-anthracycline
containing regimen may further improve outcome for patients with HER2 positive
breast cancer.
Several reports confirmed benefit of dual HER2 blockade by adding pertuzumab to
a trastuzumab containing neo-adjuvant regimen. The results of the combined
treatment in the Neosphere study, however, are similar to what we found in a
phase II trial using a weekly paclitaxel, trastuzumab, carboplatin combination
with pCR rates of approximately 45%. Adding pertuzumab to this regimen is
likely to also increase the high pCR rate and to add substantial benefit to
patients.

To compare the efficacy of six cycles neoadjuvant PTC plus pertuzumab preceded
by either three cycles of FEC-T plus pertuzumab or three cycles of PTC plus
pertuzumab in HER2 positive breast cancer
Secondary objectives
• To describe the safety of the various regimens
• To identify prognostic and predictive biomarkers for pCR

Randomized multicenter national phase III study. Randomisation:
3 cycles PTC regimen (trastuzumab 6 mg/kg (loading dose 8 mg/kg) in 250 ml NaCl
0,0%; carboplatin AUC=6 in 250 ml NaCl 0,0%; paclitaxel 80 mg/m2 in 250 ml NaCl
0,0% or dextrose 5%). PTC day 1, P day 8 of each cycle.
Plus pertuzumab 420 mg (loading dose 840 mg) on day 1 of each cycle.
Or
3 cycles FEC-T regimen (5-FU 500 mg/kg in 100 ml NaCl 0,0%); epirubicine 90
mg/m2, i.v. bolus injection; cyclophosphamide 500 mg/m2 in 100 ml NaCl 0,0%);
trastuzumab 6 mg/kg (loading dose 8 mg/kg) in 250 ml NaCl 0,0%. FEC-T all
components only day 1 of each cycle..
Plus pertuzumab 420 mg (loading dose 840 mg) on day 1 of each course.

After these 3 randomized cycles 3 all participants will be treated with 6 PTC
cycles plus pertuzumab.
The endpoint (pCR) will be assessed at surgery (<6 weeks after the last
administration of chemotherapy).
Follow-up after surgery acc. to Dutch guidelines.
394 patients.
Independent DSMB.

Treatment with 9 cycles PTC plus pertuzumab or 3 cycles FEC-T plus pertuzumab,
followed by 6 cycles PTC plus pertuzumab

Risks: Adverse events of combination chemotherapy.
Burden:
There is no neo-adjuvant standard regimen for HER2 positive tumors. Most
regimens are based on those that are used as standard in the adjuvant setting,
such as 4x AC folowed by 12x paclitaxel + trastuzumab or 3x FEC followed by 3x
docetaxel + trastuzumab. These regimen are comparable in terms of duration and
burden with the regimens used in this study.
No extra visits.
Before the start of neoadjuvant systemic therapy a tumor biopsy is taken to
determine the characteristics of the tumor. Based on these characteristics (and
characteristics of the patiënt and his wishes) the choice for systemic therapy
is made.
3 additional tumor biopsies for translational research before the start of the
study (optional)
10 ml blood at baseline, for translational research (optional).
Sentinel node procedure conform standard.
Hematology and biochemistry prior to every cycle, not different from standard.
Imaging conform standard.
Ejection fraction assessment every 3 months, not different from standard.