N9831 Shows Lack of Trastuzumab Benefit In HER2-Positive Breast Cancer Patients with High TILs

Researchers question the need for trastuzumab therapy in human epidermal growth factor 2–positive breast cancer patients with high baseline levels of tumour-infiltrating lymphocytes

medwireNews: High diagnostic levels of stromal tumour-infiltrating lymphocytes (TILs) are not associated with improved relapse-free survival (RFS) in women with early human epidermal growth factor 2 (HER2)-positive breast cancer treated with concurrent chemotherapy and trastuzumab , suggests research.

These findings are contradictory to previous research, which has demonstrated an association between elevated levels of stromal TILs and increased benefit of adjuvant trastuzumab therapy, the researchers point out in JAMA Oncology.

Indeed, findings from the NeoALTTO phase III trial, published in a previous issue of the same journal and also reported on OncologyPro , showed that pretherapeutic TIL levels were associated with improved response to treatment in HER2-positive breast cancer patients, regardless of the anti-HER2 agent given.

The current analysis of the phase III N9831 adjuvant trial included 489 women from the chemotherapy alone arm of the trial and 456 women from the chemotherapy plus concurrent trastuzumab arm who were followed-up for a median of 4.4 years.

Among women treated with doxorubicincyclophosphamide followed by weekly paclitaxel , 10-year RFS estimates were 90.9% for those with baseline tumour stromal TIL levels of at least 60% and 64.5% for patients with levels below this cutoff, a significant difference.

But the 10-year RFS estimates for patients given doxorubicin–cyclophosphamide followed by weekly paclitaxel plus trastuzumab and then by trastuzumab alone were 80.0% and 81.0% in patients with high and low levels of TILs, respectively, and the difference was not significant.

The study authors report a significant interaction between the treatment arm and the so-called lymphocyte-predominant breast cancer status (LPBC; defined as tumours with 60% or higher TIL levels). Thus, LPBC patients did not derive additional benefit from trastuzumab treatment, while non-LPBC patients did, with hazard ratios (HRs) of 2.43 and 0.49, respectively.

Moreover, in a multivariate analysis, LPBC status was significantly associated with RFS in the chemotherapy alone arm (HR=0.19), but not in the chemotherapy plus trastuzumab arm (HR=1.01).

In light of the observed significant interaction between LPBC status and trastuzumab therapy benefit, researcher Edith Perez, from Mayo Clinic in Jacksonville, Florida, USA, and team question the need for trastuzumab treatment in women with HER2-positive disease who have high diagnostic levels of stromal TILs.

However, they caution that their results should only be considered hypothesis generating limited as they are by “the small numbers of patients, limited number of events, and the exploratory nature of the study”.


Perez EA, Ballman KV, Tenner KS, et al. Association of Stromal Tumor-Infiltrating Lymphocytes With Recurrence-Free Survival in the N9831 Adjuvant Trial in Patients With Early-Stage HER2-Positive Breast Cancer.JAMA Oncol 2015; Advance online publication 15 October. doi:10.1001/jamaoncol.2015.3239

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