New data for prognostic markers in early breast cancer as well as further analyses of the Phase 3 studies TAILORx and KATHERINE were presented at the ESMO Congress 2019 in Barcelona. Wolfgang Janni, from the Ulm University Women's Hospital, summarised the findings in a highlight session at the ESMO Congress.
It is known that more tumor-infiltrating lymphocytes (TIL) can be detected in patients with triple-negative and HER2-positive breast cancer, that high TIL values predict response to neoadjuvant chemotherapy and that TILs have prognostic significance in patients with early triple-negative and HER2-positive breast cancer. In a recently published analysis, Sherene Loi, from the Peter MacCallum Cancer Centre, Melbourne, Australia, was able to show with data from 2,148 patients from nine studies that the combination of TIL and nodal status could possibly identify women with triple-negative breast cancer who have such a good prognosis that chemotherapy could be de-escalated or even omitted1.
The next logical step was to carry out an analysis of women who had not yet been treated. Park and his colleagues at ESMO presented such an analysis2. The pooled analysis included data from 518 patients from four cohorts. Compared to the analysis of pretreated women, the prognosis of untreated women was worse. While the 5-year survival of treated women was 30% 95% for TILs ≥, it was 88% for untreated women in the analysis presented at ESMO. The analysis also showed that the effect of TILs on prognosis was independent of nodal status. If only a very early stage 1 tumor is considered, TILs ≥ 30% achieved a 10-year survival of 98%. However, Janni would not do without chemotherapy in such cases.
A US-based working group dealt with the predictive and prognostic value of B-cell gene expression signatures and the B-cell receptor (BCR) repertoire. They analyzed data from the Phase 3 study CALGB-40601 (Alliance), which investigated the neoadjuvant administration of paclitaxel and trastuzumab without and with lapatinib in women with HER2-positive breast cancer. The pathologic response rate was not significantly improved by lapatinib. In the subanalysis, the diversity of the B cell receptors was examined and the distribution of the IgG signature was examined. Two B-cell and two IgG signatures were associated with a higher pathological response rate and a better outcome. “Other TILs" may be available. However, according to Janni, the treatment investigated in the Alliance study is not a therapeutic standard.
The results of the TAILORx study were presented for the first time at the president's meeting at ASCO 2018. The four-arm study investigated whether the 21-gene expression test (Oncotype DX) in women with hormone receptor-positive, HER2 negative and lymph node-negative breast cancer could measure the likely benefit of chemotherapy and the risk of distant recurrence in the first ten years after diagnosis. The 21 gene expression test provides a recurrence score (RS) between 0 and 100. Now the group of authors around Joseph A. Sparano presented an update on the outcome of high-risk women with an RS between 26 and 100 who had been treated with chemotherapy and endocrine therapy4. In parallel, the results were published in JAMA Oncology5. After five years, 93.0% were without remote metastasis recurrence, 91.0% had no local or distant metastases. A comparison with the NASBP-20 data showed that chemotherapy plus endocrine therapy achieved significantly better results than endocrine therapy alone. However, Janni pointed out that caution should be exercised when interpreting these data, as they compare two independent studies. The large difference between the two therapy regimens would, however, have been a clear indication that additional chemotherapy would be useful for high-risk patients, although he did not consider this finding to be major novelty.
In an update of the KATHERINE study, Michael Untch and colleagues investigated the influence of trastuzumab therapy or trastuzumab emtansine (T-DM1) on peripheral neuropathy, thrombocytopenia and CNS relapses6,7.
Peripheral neuropathy was comparable in the two arms at the start of the study (baseline or BL) with 22.7% (T-DM1) and 21.4% (T) respectively. Under T-DM1 therapy, peripheral neuropathy was more frequent regardless of BL neuropathy than under trastuzumab. Regardless of therapy, neuropathy lasted longer in women with BL neuropathy and disappeared less frequently than in women without BL neuropathy. The type of taxane used in neoadjuvant therapy had no influence on the incidence of neuropathy. If the patients had received platinum-containing neoadjuvant therapy, thrombocytopenia in the T-DM1 arm was more frequent. However, the duration of thrombocytopenia and its disappearance were independent of previous platinum treatment. However, Janni considers these findings less relevant in view of the significantly better efficacy of T-DM1.
Sources:
1. Loi S, et al. Tumor-Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers. J Clin Oncol 2019.
2. Park JH, et al. Prognostic value of tumor-infiltrating lymphocytes (TILs) in patients with early-stage triple-negative breast cancers (TNBC) in the absence of chemotherapy. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 1750.
3. Fernandez-Martinez A, et al. Predictive and prognostic value of B-cell gene-expression signatures and B-cell receptor repertoire in HER2+ breast cancer: A correlative analysis of the CALGB 40601 clinical trial (Alliance). ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 1740.
4. Sparano JA, et al. Clinical outcomes by chemotherapy regimen in patients with RS 26-100 in TAILORx. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, LBA 18.
5. Sparano JA, et al. Clinical outcomes in early breast cancer with a high 21-gene recurrence score of 26 to 100 assigned to adjuvant chemotherapy plus endocrine therapy. A secondary analysis of the TAILORx randomized clinical trial. JAMA Oncol. Published online on September 30, 2019.
6. Untch M, et al. Peripheral neuropathy, thrombocytopenia and central nervous system recurrence: An update of the phase III KATHERINE trial of post-neoadjuvant trastuzumab emtansine or trastuzumab in patients with residual invasive HER2-positive breast cancer. ESMO 2019 Annual Meeting, September 27 to October 1, 2019, Barcelona, LBA 19.
7. Von Minckwitz G, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380:617-628.