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

S Vliek; FS Hilbers; E van Werkhoven; I Mandjes; R Kessels; S Kleiterp; EH Lips; L Mulder; MT Kayembe; CE Loo; NS Russell; MJTFDV Peeters; MJ Holtkamp; M Schot; JW Baars; AH Honkoop; AJE Vulink; ALT Imholz; S Vrijaldenhoven; FWPJ van den Berkmortel; JMM Terwogt; JG Schrama; P Kuijer; JR Kroep; A van der Padt-pruijsten; J Wesseling; GS Sonke; KGA Gilhuijs; A Jager; P Nederlof; SC Linn

doi:10.1038/s41523-023-00580-9

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

S Vliek, FS Hilbers, E van Werkhoven, I Mandjes, R Kessels, S Kleiterp, EH Lips, L Mulder, MT Kayembe, CE Loo, NS Russell, MJTFDV Peeters, MJ Holtkamp, M Schot, JW Baars, AH Honkoop, AJE Vulink, ALT Imholz, S Vrijaldenhoven, FWPJ van den BerkmortelJMM Terwogt, JG Schrama, P Kuijer, JR Kroep, A van der Padt-pruijsten, J Wesseling, GS Sonke, KGA Gilhuijs, A Jager, P Nederlof, SC Linn

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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.

Original language	English
Article number	75
Number of pages	9
Journal	npj Breast Cancer
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41523-023-00580-9
Publication status	Published - Dec 2023

Bibliographical note

Funding Information:
The authors would like to thank Sjoerd Rodenhuis for his dedication to the NeoTN study. In addition, we would like to thank the patients and their families for participating in this study and all staff of the participating centres for their effort and commitment. This study was supported by The Dutch Cancer Foundation (KWF-Kankerbestrijding) and by the Schumacher Kramer Foundation, Amsterdam. This research was also supported by an institutional grant of the Dutch Cancer Society and of the Dutch Ministry of Health, Welfare and Sport.

Publisher Copyright:
© 2023, Springer Nature Limited.

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Vliek, S., Hilbers, FS., van Werkhoven, E., Mandjes, I., Kessels, R., Kleiterp, S., Lips, EH., Mulder, L., Kayembe, MT., Loo, CE., Russell, NS., Peeters, MJTFDV., Holtkamp, MJ., Schot, M., Baars, JW., Honkoop, AH., Vulink, AJE., Imholz, ALT., Vrijaldenhoven, S., ... Linn, SC. (2023). High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: the randomized phase III NeoTN trial. npj Breast Cancer, 9(1), Article 75. https://doi.org/10.1038/s41523-023-00580-9

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

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.",

author = "S Vliek and FS Hilbers and {van Werkhoven}, E and I Mandjes and R Kessels and S Kleiterp and EH Lips and L Mulder and MT Kayembe and CE Loo and NS Russell and MJTFDV Peeters and MJ Holtkamp and M Schot and JW Baars and AH Honkoop and AJE Vulink and ALT Imholz and S Vrijaldenhoven and {van den Berkmortel}, FWPJ and JMM Terwogt and JG Schrama and P Kuijer and JR Kroep and {van der Padt-pruijsten}, A and J Wesseling and GS Sonke and KGA Gilhuijs and A Jager and P Nederlof and SC Linn",

note = "Funding Information: The authors would like to thank Sjoerd Rodenhuis for his dedication to the NeoTN study. In addition, we would like to thank the patients and their families for participating in this study and all staff of the participating centres for their effort and commitment. This study was supported by The Dutch Cancer Foundation (KWF-Kankerbestrijding) and by the Schumacher Kramer Foundation, Amsterdam. This research was also supported by an institutional grant of the Dutch Cancer Society and of the Dutch Ministry of Health, Welfare and Sport. Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s41523-023-00580-9",

language = "English",

volume = "9",

journal = "npj Breast Cancer",

issn = "2374-4677",

publisher = "Nature Publishing Group",

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Vliek, S, Hilbers, FS, van Werkhoven, E, Mandjes, I, Kessels, R, Kleiterp, S, Lips, EH, Mulder, L, Kayembe, MT, Loo, CE, Russell, NS, Peeters, MJTFDV, Holtkamp, MJ, Schot, M, Baars, JW, Honkoop, AH, Vulink, AJE, Imholz, ALT, Vrijaldenhoven, S, van den Berkmortel, FWPJ, Terwogt, JMM, Schrama, JG, Kuijer, P, Kroep, JR, van der Padt-pruijsten, A, Wesseling, J, Sonke, GS, Gilhuijs, KGA, Jager, A, Nederlof, P & Linn, SC 2023, 'High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: the randomized phase III NeoTN trial', npj Breast Cancer, vol. 9, no. 1, 75. https://doi.org/10.1038/s41523-023-00580-9

TY - JOUR

T1 - High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer

T2 - the randomized phase III NeoTN trial

AU - Vliek, S

AU - Hilbers, FS

AU - van Werkhoven, E

AU - Mandjes, I

AU - Kessels, R

AU - Kleiterp, S

AU - Lips, EH

AU - Mulder, L

AU - Kayembe, MT

AU - Loo, CE

AU - Russell, NS

AU - Peeters, MJTFDV

AU - Holtkamp, MJ

AU - Schot, M

AU - Baars, JW

AU - Honkoop, AH

AU - Vulink, AJE

AU - Imholz, ALT

AU - Vrijaldenhoven, S

AU - van den Berkmortel, FWPJ

AU - Terwogt, JMM

AU - Schrama, JG

AU - Kuijer, P

AU - Kroep, JR

AU - van der Padt-pruijsten, A

AU - Wesseling, J

AU - Sonke, GS

AU - Gilhuijs, KGA

AU - Jager, A

AU - Nederlof, P

AU - Linn, SC

N1 - Funding Information: The authors would like to thank Sjoerd Rodenhuis for his dedication to the NeoTN study. In addition, we would like to thank the patients and their families for participating in this study and all staff of the participating centres for their effort and commitment. This study was supported by The Dutch Cancer Foundation (KWF-Kankerbestrijding) and by the Schumacher Kramer Foundation, Amsterdam. This research was also supported by an institutional grant of the Dutch Cancer Society and of the Dutch Ministry of Health, Welfare and Sport. Publisher Copyright: © 2023, Springer Nature Limited.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

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

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Bibliographical note

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