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. 2023 Sep 9;9(1):75.
doi: 10.1038/s41523-023-00580-9.

High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: the randomized phase III NeoTN trial

Sonja Vliek #  1   2 , Florentine S Hilbers #  1 , Erik van Werkhoven  3   4 , Ingrid Mandjes  3 , Rob Kessels  3 , Sieta Kleiterp  1 , Esther H Lips  1 , Lennart Mulder  1 , Mutamba T Kayembe  3 , Claudette E Loo  5 , Nicola S Russell  6 , Marie-Jeanne T F D Vrancken Peeters  7   8 , Marjo J Holtkamp  9 , Margaret Schot  9 , Joke W Baars  9 , Aafke H Honkoop  10 , Annelie J E Vulink  11 , Alex L T Imholz  12 , Suzan Vrijaldenhoven  13 , Franchette W P J van den Berkmortel  14 , Jetske M Meerum Terwogt  15 , Jolanda G Schrama  16 , Philomeen Kuijer  16 , Judith R Kroep  17 , Annemieke van der Padt-Pruijsten  18 , Jelle Wesseling  1   17   19 , Gabe S Sonke  9 , Kenneth G A Gilhuijs  20 , Agnes Jager  21 , Petra Nederlof  22 , Sabine C Linn  23   24   25
Affiliations

High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: the randomized phase III NeoTN trial

Sonja Vliek et al. NPJ Breast Cancer. .

Abstract

Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution (p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23-1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III (n = 35; HR 0.16; 95% CI 0.03-0.75), but not stage II (n = 86; HR 1.00; 95% CI 0.30-3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24-87%), 71% (95% CI 48-100%) and 88% (95% CI 74-100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069.

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Conflict of interest statement

The authors declare that they have no financial or non-financial interest in the subject matter or materials discussed in this manuscript. S.C.L. does have a pending patent application for a BRCA-like ovarian cancer classifier.

Figures

Fig. 1
Fig. 1. CONSORT diagram.
*Three ineligible patients were randomized by mistake: two patients with a tumor that showed a sporadic-like profile, but that at the same time was positive for BRCA1 promoter hyper-methylation were randomized to the conventional chemotherapy arm. One received ddAC-only, the other ddAC-CP. One patient was found to be metastatic at baseline and was randomized to the high-dose arm. These patients remained part of the ITT analysis.
Fig. 2
Fig. 2. Locoregional response.
a Neoadjuvant Response Index (NRI) by chemotherapy arm, b pathological complete response (pCR) rate by disease stage, stratified by treatment arm.
Fig. 3
Fig. 3. Recurrence-free and overall survival.
a Recurrence-free survival (RFS) by treatment arm and b Overall survival by treatment arm for high-dose (HD) chemotherapy vs. conventional (Conv.) chemotherapy.
Fig. 4
Fig. 4. Forest plot recurrence-free survival.
Recurrence-free survival hazard ratios (HR) for high-dose (HD) chemotherapy vs. conventional (Conv.) chemotherapy for various patient subgroups.
See this image and copyright information in PMC

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