In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-10-05-P4-10-05
Abstract:
Purpose: Only limited data are available on predictive markers for use of chemotherapy-free, anti-HER2 combinations in HER2-positive early breast cancer (eBC), in particular within the molecularly distinct HER2+/HR- subgroup. Background: In the ADAPT HER2+/HR- trial, a promising pCR of about 43-45% was found in patients treated by 4 cycles of pertuzumab and trastuzumab with either defined early response (low tumor cellularity or relative Ki-67 decrease ≥30%) or indeterminate early response (e.g. no visible tumor by ultrasound), compared to under 10% in early non-responders. In addition to early response, HER2 protein expression and stromal TIL (s-TIL) dynamics after one cycle of therapy are promising tools for identification of patients with high likelihood of pathological complete response (pCR) after therapy with double anti-HER2 blockade (e.g. by lapatinib+trastuzumab) or T-DM1. Methods: Patients with cT1-cT4c, cN0-3 early HER2+/HR- BC (n=134) were treated with 4 cycles of P+T +/- paclitaxel d1,8,15 q3w. Primary endpoint of the study was pCR (ypT0/is, ypN0). All tumors were HR-negative (ER and PR & lt;1%) and locally HER2 positive, i.e., 2+ with positive FISH or 3+ by immunohistochemistry (IHC). HR and HER2 status were confirmed by central pathology prior to randomization. Tumors were classified as “HER2-low” if HER2-1+ or HER2-2+ by either local or central IHC assessment, otherwise “HER2-high”. s-TILs were measured semi-quantitively according to current international consensus in triplicate at baseline and on-treatment (at cycle 2); the median of the three measurements was taken to define the quantities TIL-0 and TIL-3, respectively. “Lymphocyte-dominant subtype” at baseline and cycle 2 were defined as TIL-0≥40% and TIL-3≥40%, respectively. The present analysis characterizes the predictive impact of early response HER2 protein expression, and s-TILs on pCR under dual anti-HER2 therapy for the first time within a prospective neoadjuvant trial specific to the HER2+/HR- BC subtype. Results: As previously reported, pCR was 34.4% without chemotherapy and 90.5% with chemotherapy. TIL-0 and TIL-3 were available in n=119/134 and n=103/134 patients, respectively. TIL-0 and TIL-3 were not significantly associated with pCR in the whole cohort or within the T+P arm, either modeled as a continuous variable or in terms of binary variables representing lymphocyte-dominant subtype or defined by the respective population medians. HER2-high expression was found in 87% of patients. In the T+P arm, pCR was much higher in HER2-high than HER2-low patients (40.3% vs. 0%, p=.003). In the T+P arm, 24 and 38 of 92 patients were classified as non- and responders, unclassified early response was observed in 30 of 92 patients. pCR in these groups were 8.3% vs. 44.7% vs. 42.9% respectively. Higher baseline TILs were positively associated with early response. Clinically meaningful pCR of 49% after only 4 cycles of chemotherapy-free P+T was seen in those patients with early response after one cycle of therapy and HER2-high classification, compared to 11.8% in the HER2-high/non-responder group). Conclusions: At present, a combination of baseline high HER2 expression with low cellularity after one cycle of neoadjuvant therapy – rather than s-TIL determination (at baseline or in response to therapy) – appears to be a simple and feasible tool for identification of candidates for de-escalated treatment in HER2+/HR- disease. Further research on high-precision determination of HER2-high expression (by immunohistochemistry vs. mRNA-based tools) is strongly needed for optimal patient selection for future chemotherapy de-escalation trials. Citation Format: Oleg Gluz, Cornelia Kolberg-Liedtke, Claudia Biehl, Matthias Christgen, Sherko Kuemmel, Eva-Maria Grischke, Doris Augustin, Michael Braun, Jochem Potenberg, Monika Graeser, Ronald Kates, Rachel Wuerstlein, Friedrich Feuerhake, Ulrike Nitz, Hans Kreipe, Nadia Harbeck, West German Study Group. Predictive value of HER2 expression, early response and tumor infiltrating lymphocytes (TILs) on efficacy of de-escalated pertuzumab+trastuzumab in the neoadjuvant WSG-ADAPT-HER2+/HR- trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-05.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.SABCS19-P4-10-05
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
