medwireNews: Long-term follow-up of the TRAIN-2 study shows that patients with stage II or III HER2-positive breast cancer who receive neoadjuvant chemotherapy and dual HER2-blockade derive no survival benefit from the addition of anthracyclines.
“Importantly, anthracyclines increase the risk of febrile neutropenia, cardiac toxicity, and chemotherapy-associated leukemia,” Anna van der Voort, from The Netherlands Cancer Institute in Amsterdam, reported at the virtual 2020 ASCO Annual Meeting.
“Therefore, a neoadjuvant anthracycline-free regimen with dual HER2-blockade should be considered in all stage II and III HER2-positive breast cancer patients.”
Primary analysis of the phase 3 study found the pathologic complete response rate was 68% among the 219 patients randomly assigned to receive nine 21-day cycles of neoadjuvant chemotherapy with paclitaxel 80 mg/m2 (days 1 and 8) and carboplatin (area under curve = 6 mg/mL per min).
This was not significantly different from the rate of 67% observed among the 219 patients assigned to receive three cycles of the anthracycline-containing regimen of 5-fluoruoracil 500 mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 500 mg/m2 followed by six cycles of paclitaxel and carboplatin.
Of note, patients in both arms also received dual HER-2 blockade with trastuzumab 6 mg/kg (loading dose 8 mg/kg) and pertuzumab 420 mg (loading dose 840 mg).
The current analysis, with a median follow-up of 49 months, revealed no significant difference between the two arms in event-free-survival (EFS), defined as time from randomization to disease progression resulting in inoperability, recurrence, secondary primary malignancies, or death.
There were 21 EFS events among the patients who did not receive anthracyclines and 23 events among those who did. Van der Voort and co-investigators calculated that the 3-years EFS rates were 93.5% and 92.7%, respectively.
Subgroup analysis showed similar results regardless of hormone receptor status, age, tumor size, nodal status, and grade, suggesting there is “no evidence that higher-risk patients require anthracyclines,” van der Voort remarked.
There was also no significant difference between the two groups in overall survival (OS), with eight deaths in the anthracycline-free arm and nine in the anthracycline-containing arm and estimated 3-year OS rates of 98.2% and 97.7%, respectively.
Of note, significantly more patients in the non-anthracycline group completed a full year of trastuzumab treatment than in the anthracycline group (97 vs 89%), which van der Voort attributed to a higher rate of cardiotoxicity with the latter regimen.
Indeed, the proportion of patients with left ventricular ejection fraction decline of at least 10% and an absolute value below 50% was 3.2% in the group that did not receive anthracyclines and 8.6% in the group that did, a statistically significant difference.
Patients in the non-anthracycline arm also had significantly lower rates of grade 3 or higher febrile neutropenia (1 vs 10%) and hypokalemia (4 vs 9%) than those in the anthracycline arm.
In addition, two patients in the anthracycline arm developed chemotherapy-associated acute leukemia, compared with no cases in the anthracycline-free arm.
Van der Voort concluded: “In this era of dual HER2-blockade, further research should focus on de-escalating cytotoxic treatment in patients who achieve early and complete responses to neoadjuvant treatment.”
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