Lancet Oncol. 2018 Nov 06
Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial.
Abstract
Background
The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin-taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab.
Methods
The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II-III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2) every 3 weeks for three cycles followed by paclitaxel (80 mg/m2 on days 1 and 8) and carboplatin (area under the concentration-time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group. Patients in both study groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. The primary endpoint was the proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population. Safety was analysed in patients who received at least one treatment cycle according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT01996267, and follow-up for long-term outcome is ongoing.
Findings
Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16-23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60-73) of 212 patients in the anthracycline group and in 140 (68%, 61-74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0·0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related.
Interpretation
In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results.
Funding
Roche Netherlands.
Related Questions
How do differences in toxicity profile factor into your choice between a T-DXd-based neoadjuvant regimen and ddAC-THP?
I have largely abandoned AC in HER2-positive EBC. Cardiac toxicity is just as unpredictable as ILD, in my opinion, and when it occurs is irreversible. There is also the issue of treatment-refractory MDS/AML with anthracyclines.
Would you consider anthracycline based neoadjuvant therapy for ER negative, HER2 positive inflammatory breast cancer in a premenopausal female given the subset not adequately represented in non-anthracycline regimen trials?
The TRAIN-2 study of non-anthracycline vs. anthracycline-based chemotherapy for HER2 positive disease did include inflammatory breast cancer and found no benefit of anthracycline-based chemotherapy over non-anthracycline based chemo. I would not give anthracycline to a HER2-positive patient just bec...
What alternative regimens would you consider to neoadjuvant TCHP in setting of national carboplatin shortage for locally advanced HER2+ breast cancer?
In TRAIN-2, hospitals were allowed to use split dose carboplatin AUC 3 on days 1, 8 for 9 q3wk cycles and the pCR rates and outcomes were the same as the FEC treated group. That could be an option if you are getting limited carbo resupply on a regular basis. WSG ADAPT THP looked good for ER-HER2+ di...
What alternate neo-adjuvant backbone chemotherapy would you recommend in a patient with ER+ HER2+ clinical stage II breast CA with severe pan-colitis following a cycle of TCHP with docetaxel?
I would switch to weekly paclitaxel and carboplatin with trastuzumab only, but might retry pertuzumab if the patient gets through 6 weeks without recurrent diarrhea. This is actually my preferred version of TCHP (including the pertuzumab), which I find to be better tolerated than the every-3-week do...
How do you manage a HR-/HER2+ breast cancer patient with local progression during neoadjuvant TCHP?
With the robust activity of HER2-targeted agents in the operable setting, this is a highly concerning clinical scenario. I would retest for HER2 on the biopsy specimen and confirm its positivity. Also, I have significantly limited the use of anthracyclines in patients with HER2+ breast cancer - give...
Is it acceptable to use TCHP instead of AC-T + trastuzumab as neoadjuvant chemotherapy for HER2+ inflammatory breast cancer?
Yes. With the Neosphere trial demonstrating an impressive PCR rate for the TCHP regimen, the TRAIN-2 trial showing no difference in outcomes with anthracycline containing vs non-anthracycline regimen and the BCIRG-006 trial long term follow showing that only 7 DFS events separating AC-TH and TCH, I ...
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Does ER+ status impact your choice of neoadjuvant systemic therapy in premenopausal women with cT2N0 HER2+ breast cancer?
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Would you switch to TDM-1 in the adjuvant setting in HER-2 positive breast cancer patients with residual disease after neoadjuvant chemotherapy if neoadjuvant chemotherapy did not include anthracyclines?
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Is there data supporting the omission of carboplatin from neoadjuvant TCHP therapy for HER2-positive breast cancer to reduce toxicity, particularly in light of findings from the KATHERINE study?
While there is no doubt that the inclusion of carboplatin increases the risk of hematologic and gastrointestinal (mainly diarrhea, but also more nausea) toxicities with TCHP, clinical trial results demonstrate that it also increases pathologic complete response (pCR) rates. No version of THP (using ...