Olaparib monotherapy as primary treatment in unselected triple negative breast cancer
Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved..
BACKGROUND: The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure.
PATIENTS AND METHODS: In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples.
RESULTS: The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response.
CONCLUSION: Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624973.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:32 |
|---|---|
| Enthalten in: |
Annals of oncology : official journal of the European Society for Medical Oncology - 32(2021), 2 vom: 10. Feb., Seite 240-249 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Eikesdal, H P [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 08.02.2021 Date Revised 31.05.2022 published: Print-Electronic ClinicalTrials.gov: NCT02624973 Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.annonc.2020.11.009 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM31809083X |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM31809083X | ||
| 003 | DE-627 | ||
| 005 | 20231225164629.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.annonc.2020.11.009 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1060.xml |
| 035 | |a (DE-627)NLM31809083X | ||
| 035 | |a (NLM)33242536 | ||
| 035 | |a (PII)S0923-7534(20)43164-3 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Eikesdal, H P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Olaparib monotherapy as primary treatment in unselected triple negative breast cancer |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.02.2021 | ||
| 500 | |a Date Revised 31.05.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02624973 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved. | ||
| 520 | |a BACKGROUND: The antitumor efficacy of PARP inhibitors (PARPi) for breast cancer patients harboring germline BRCA1/2 (gBRCA1/2) mutations is well established. While PARPi monotherapy was ineffective in patients with metastatic triple negative breast cancer (TNBC) wild type for BRCA1/2, we hypothesized that PARPi may be effective in primary TNBCs without previous chemotherapy exposure | ||
| 520 | |a PATIENTS AND METHODS: In the phase II PETREMAC trial, patients with primary TNBC >2 cm received olaparib for up to 10 weeks before chemotherapy. Tumor biopsies collected before and after olaparib underwent targeted DNA sequencing (360 genes) and BRCA1 methylation analyses. In addition, BRCAness (multiplex ligation-dependent probe amplification), PAM50 gene expression, RAD51 foci, tumor-infiltrating lymphocytes (TILs) and PD-L1 analyses were performed on pretreatment samples | ||
| 520 | |a RESULTS: The median pretreatment tumor diameter was 60 mm (range 25-112 mm). Eighteen out of 32 patients obtained an objective response (OR) to olaparib (56.3%). Somatic or germline mutations affecting homologous recombination (HR) were observed in 10/18 responders [OR 55.6%, 95% confidence interval (CI) 33.7-75.4] contrasting 1/14 non-responders (OR 7.1%; CI 1.3-31.5, P = 0.008). Among tumors without HR mutations, 6/8 responders versus 3/13 non-responders revealed BRCA1 hypermethylation (P = 0.03). Thus, 16/18 responders (88.9%, CI 67.2-96.9), in contrast to 4/14 non-responders (28.6%, CI 11.7-54.7, P = 0.0008), carried HR mutations and/or BRCA1 methylation. Excluding one gPALB2 and four gBRCA1/2 mutation carriers, 12/14 responders (85.7%, CI 60.1-96.0) versus 3/13 non-responders (23.1%, CI 8.2-50.3, P = 0.002) carried somatic HR mutations and/or BRCA1 methylation. In contrast to BRCAness signature or basal-like subtype, low RAD51 scores, high TIL or high PD-L1 expression all correlated to olaparib response | ||
| 520 | |a CONCLUSION: Olaparib yielded a high clinical response rate in treatment-naïve TNBCs revealing HR deficiency, beyond germline HR mutations | ||
| 520 | |a TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624973 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a PARP inhibitor | |
| 650 | 4 | |a homologous recombination deficiency | |
| 650 | 4 | |a neoadjuvant therapy | |
| 650 | 4 | |a olaparib | |
| 650 | 4 | |a prediction | |
| 650 | 4 | |a triple negative breast cancer | |
| 650 | 7 | |a BRCA1 Protein |2 NLM | |
| 650 | 7 | |a Phthalazines |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
| 650 | 7 | |a olaparib |2 NLM | |
| 650 | 7 | |a WOH1JD9AR8 |2 NLM | |
| 700 | 1 | |a Yndestad, S |e verfasserin |4 aut | |
| 700 | 1 | |a Elzawahry, A |e verfasserin |4 aut | |
| 700 | 1 | |a Llop-Guevara, A |e verfasserin |4 aut | |
| 700 | 1 | |a Gilje, B |e verfasserin |4 aut | |
| 700 | 1 | |a Blix, E S |e verfasserin |4 aut | |
| 700 | 1 | |a Espelid, H |e verfasserin |4 aut | |
| 700 | 1 | |a Lundgren, S |e verfasserin |4 aut | |
| 700 | 1 | |a Geisler, J |e verfasserin |4 aut | |
| 700 | 1 | |a Vagstad, G |e verfasserin |4 aut | |
| 700 | 1 | |a Venizelos, A |e verfasserin |4 aut | |
| 700 | 1 | |a Minsaas, L |e verfasserin |4 aut | |
| 700 | 1 | |a Leirvaag, B |e verfasserin |4 aut | |
| 700 | 1 | |a Gudlaugsson, E G |e verfasserin |4 aut | |
| 700 | 1 | |a Vintermyr, O K |e verfasserin |4 aut | |
| 700 | 1 | |a Aase, H S |e verfasserin |4 aut | |
| 700 | 1 | |a Aas, T |e verfasserin |4 aut | |
| 700 | 1 | |a Balmaña, J |e verfasserin |4 aut | |
| 700 | 1 | |a Serra, V |e verfasserin |4 aut | |
| 700 | 1 | |a Janssen, E A M |e verfasserin |4 aut | |
| 700 | 1 | |a Knappskog, S |e verfasserin |4 aut | |
| 700 | 1 | |a Lønning, P E |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Annals of oncology : official journal of the European Society for Medical Oncology |d 1990 |g 32(2021), 2 vom: 10. Feb., Seite 240-249 |w (DE-627)NLM012606308 |x 1569-8041 |7 nnns |
| 773 | 1 | 8 | |g volume:32 |g year:2021 |g number:2 |g day:10 |g month:02 |g pages:240-249 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.annonc.2020.11.009 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 32 |j 2021 |e 2 |b 10 |c 02 |h 240-249 | ||