Neoadjuvant HER2 Blockade Plus Systemic Chemotherapy Best For Achieving Breast Cancer pCR

The use of neoadjuvant trastuzumab emtansine instead of docetaxel, carboplatin and trastuzumab, both given alongside pertuzumab, is not supported for patients with stage II–III HER2-positive breast cancer

medwireNews: A phase III trial has found no improvement in the pathological complete response (pCR) rate with a treatment regimen that includes HER2-targeted chemotherapy in lieu of the traditional systemic chemotherapy element of the currently used HER2 inhibition-based neoadjuvant approach for patients with HER2-positive breast cancer.

Sara Hurvitz, from the University of California Los Angeles in the USA, and fellow KRISTINE investigators used the antibody–drug conjugate trastuzumab emtansine as it is “not associated with typical chemotherapy side-effects because of the targeted delivery of the chemotherapy to HER2-overexpressing cells.”

pCR – defined as the absence of any residual invasive cancer in the resected breast specimen and all sampled ipsilateral lymph nodes – was achieved by 44.4% of 223 patients with stage II–III operable breast cancer who were randomly assigned to receive trastuzumab emtansine 3.6 mg/kg plus pertuzumab at a loading dose of 840 mg and a maintenance dose of 420 mg for six cycles of 21 days each.

This was significantly lower than the 55.7% rate achieved by their 221 counterparts given the same number of cycles of docetaxel (75 mg/m2), carboplatin (area under the concentration–time curve of 6 mg/mL per min) and trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance doses) alongside the same dose of pertuzumab.

Furthermore, among those with noninflammatory disease, a smaller proportion of patients in the trastuzumab emtansine than the control group subsequently received breast conserving surgery, at 42% of 218 versus 53% of 213.

However, the combination of trastuzumab emtansine and pertuzumab appeared to have a more favourable toxicity profile, with a lower incidence of grade 3–4 toxicities and serious adverse events than in the control treatment arm, at rates of 13% versus 64% and 5% versus 29%, respectively.

And the median time to deterioration in health-related quality of life (HRQoL) – as assessed by the EORTC quality of life questionnaire (QLQ)-C30 and the QLQ-modified breast cancer module (BR23) – was longer in trastuzumab emtansine-treated patients than those given the control regimen (4.6 vs 3.0 months), as was the median time to worsening in physical function (4.9 vs 2.8 months).

“Collectively, these results support the neoadjuvant systemic chemotherapy regimen of docetaxel, carboplatin, and trastuzumab plus pertuzumab remaining as the standard of care, although less intensive therapeutic options, including therapy based on trastuzumab emtansine plus pertuzumab or the adjuvant paclitaxel and trastuzumab regimen, might be a suitable treatment option for patients unlikely to tolerate systemic taxane-based chemotherapy”, the study authors conclude in The Lancet Oncology.

Writing in a related comment, Joseph Gligorov, from Sorbonne Université in Paris, France, says that “[i]f pathological complete response is a valid surrogate marker for survival, then we could conclude that the combination of trastuzumab emtansine plus pertuzumab is not effective in this setting and should not be pursued further”.

But he adds that “[a]ssumptions about the differences in pathological complete response should not obscure the goal of any therapeutic trial: improving care,” and “we should be careful about our conclusions until any survival data are available.”


Hurvitz SA, Martin M, Symmans WF, et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol; Advance online publication 23 November 2017. doi:  

Gligorov J. Early HER2-positive breast cancers: time for a new revolution? Lancet Oncol; Advance online publication 23 November 2017. doi:

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