Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients.
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Breast Neoplasms
/ drug therapy
Capecitabine
/ therapeutic use
Chemotherapy, Adjuvant
Cyclophosphamide
/ adverse effects
Disease-Free Survival
Docetaxel
/ therapeutic use
Epirubicin
/ adverse effects
Female
Homologous Recombination
Humans
Triple Negative Breast Neoplasms
/ drug therapy
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
14
07
2021
accepted:
17
01
2022
revised:
16
12
2021
pubmed:
7
2
2022
medline:
14
5
2022
entrez:
6
2
2022
Statut:
ppublish
Résumé
The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial. Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm. For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08-0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24-1.81) (P-interaction = 0.17). Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.
Sections du résumé
BACKGROUND
The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial.
METHODS
Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm.
RESULTS
For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08-0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24-1.81) (P-interaction = 0.17).
CONCLUSION
Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.
Identifiants
pubmed: 35124703
doi: 10.1038/s41416-022-01711-y
pii: 10.1038/s41416-022-01711-y
pmc: PMC9090783
doi:
Substances chimiques
Docetaxel
15H5577CQD
Epirubicin
3Z8479ZZ5X
Capecitabine
6804DJ8Z9U
Cyclophosphamide
8N3DW7272P
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1401-1409Informations de copyright
© 2022. The Author(s).
Références
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13:4429–34.
pubmed: 17671126
doi: 10.1158/1078-0432.CCR-06-3045
Hudis CA, Gianni L. Triple-negative breast cancer: an unmet medical need. Oncologist. 2011;16:1–11.
pubmed: 21278435
doi: 10.1634/theoncologist.2011-S1-01
Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382:810–21.
pubmed: 32101663
doi: 10.1056/NEJMoa1910549
Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6:676–84.
pubmed: 32053137
doi: 10.1001/jamaoncol.2019.6650
Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376:2147–59.
pubmed: 28564564
doi: 10.1056/NEJMoa1612645
van Mackelenbergh M, Seither F, Möbus V, O’Shaugnessy J, Martin M, Joensuu H, et al. Abstract GS1-07: Effects of capecitabine as part of neo-/adjuvant chemotherapy. A meta-analysis of individual patient data from 12 randomized trials including 15,457 patients. Cancer Res. 2020;80:GS1-07–GS1-.
doi: 10.1158/1538-7445.SABCS19-GS1-07
Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, et al. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012;30:11–8.
pubmed: 22105826
doi: 10.1200/JCO.2011.35.4639
Burstein HJ, Curigliano G, Loibl S, Dubsky P, Gnant M, Poortmans P, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann Oncol. 2019;30:1541–57.
pubmed: 31373601
doi: 10.1093/annonc/mdz235
Denduluri N, Chavez-MacGregor M, Telli ML, Eisen A, Graff SL, Hassett MJ, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36:2433–43.
pubmed: 29787356
doi: 10.1200/JCO.2018.78.8604
Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30:1194–220.
pubmed: 31161190
doi: 10.1093/annonc/mdz173
Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3:330–8.
pubmed: 12724731
doi: 10.1038/nrc1074
Asleh K, Brauer HA, Sullivan A, Lauttia S, Lindman H, Nielsen TO, et al. Predictive biomarkers for adjuvant capecitabine benefit in early-stage triple-negative breast cancer in the FinXX clinical trial. Clin Cancer Res. 2020;26:2603–14.
pubmed: 32005747
doi: 10.1158/1078-0432.CCR-19-1945
Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, et al. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384:2394–405.
Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16:110–20.
pubmed: 26775620
doi: 10.1038/nrc.2015.21
Vollebergh MA, Lips EH, Nederlof PM, Wessels LF, Schmidt MK, van Beers EH, et al. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann Oncol. 2011;22:1561–70.
pubmed: 21135055
doi: 10.1093/annonc/mdq624
Severson TM, Wolf DM, Yau C, Peeters J, Wehkam D, Schouten PC, et al. The BRCA1ness signature is associated significantly with response to PARP inhibitor treatment versus control in the I-SPY 2 randomized neoadjuvant setting. Breast Cancer Res. 2017;19:99.
pubmed: 28851423
pmcid: 5574249
doi: 10.1186/s13058-017-0861-2
den Brok WD, Schrader KA, Sun S, Tinker AV, Zhao EY, Aparicio S, et al. Homologous recombination deficiency in breast cancer: a clinical review. JCO Precis Oncol. 2017;1:1–13.
Pellegrino B, Mateo J, Serra V, Balmaña J. Controversies in oncology: are genomic tests quantifying homologous recombination repair deficiency (HRD) useful for treatment decision making? ESMO Open. 2019;4:e000480.
pubmed: 31231558
pmcid: 6555601
doi: 10.1136/esmoopen-2018-000480
Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33:304–11.
pubmed: 25452441
doi: 10.1200/JCO.2014.57.1414
Robertson L, Hanson H, Seal S, Warren-Perry M, Hughes D, Howell I, et al. BRCA1 testing should be offered to individuals with triple-negative breast cancer diagnosed below 50 years. Br J Cancer. 2012;106:1234–8.
pubmed: 22333603
pmcid: 3304410
doi: 10.1038/bjc.2012.31
Hartman A-R, Kaldate RR, Sailer LM, Painter L, Grier CE, Endsley RR, et al. Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer. 2012;118:2787–95.
pubmed: 22614657
doi: 10.1002/cncr.26576
Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res. 2011;17:1082–9.
pubmed: 21233401
pmcid: 3048924
doi: 10.1158/1078-0432.CCR-10-2560
Rummel S, Varner E, Shriver CD, Ellsworth RE. Evaluation of BRCA1 mutations in an unselected patient population with triple-negative breast cancer. Breast Cancer Res Treat. 2013;137:119–25.
pubmed: 23192404
doi: 10.1007/s10549-012-2348-2
Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4:814–9.
pubmed: 15510162
doi: 10.1038/nrc1457
Tung NM, Garber JE. BRCA1/2 testing: therapeutic implications for breast cancer management. Br J Cancer. 2018;119:141–52.
pubmed: 29867226
pmcid: 6048046
doi: 10.1038/s41416-018-0127-5
Joosse SA, van Beers EH, Tielen IH, Horlings H, Peterse JL, Hoogerbrugge N, et al. Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH. Breast Cancer Res Treat. 2009;116:479–89.
pubmed: 18704682
doi: 10.1007/s10549-008-0117-z
Joosse SA, Brandwijk KIM, Devilee P, Wesseling J, Hogervorst FBL, Verhoef S, et al. Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH. Breast Cancer Res Treat. 2012;132:379–89.
pubmed: 20614180
doi: 10.1007/s10549-010-1016-7
Vollebergh MA, Lips EH, Nederlof PM, Wessels LF, Wesseling J, Vd Vijver MJ, et al. Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy. Breast Cancer Res. 2014;16:R47.
pubmed: 24887359
pmcid: 4076636
doi: 10.1186/bcr3655
Schouten PC, Marme F, Aulmann S, Sinn HP, van Essen HF, Ylstra B, et al. Breast cancers with a BRCA1-like DNA copy number profile recur less often than expected after high-dose alkylating chemotherapy. Clin Cancer Res. 2015;21:763–70.
pubmed: 25480832
doi: 10.1158/1078-0432.CCR-14-1894
Schouten PC, Gluz O, Harbeck N, Mohrmann S, Diallo-Danebrock R, Pelz E, et al. BRCA1-like profile predicts benefit of tandem high dose epirubicin-cyclophospamide-thiotepa in high risk breast cancer patients randomized in the WSG-AM01 trial. Int J Cancer. 2016;139:882–9.
pubmed: 26946057
doi: 10.1002/ijc.30078
Lluch A, Barrios CH, Torrecillas L, Ruiz-Borrego M, Bines J, Segalla J, et al. Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01). J Clin Oncol. 2020;38:203–13.
pubmed: 31804894
doi: 10.1200/JCO.19.00904
O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002;20:2812–23.
pubmed: 12065558
doi: 10.1200/JCO.2002.09.002
Filho OM, Stover DG, Asad S, Ansell PJ, Watson M, Loibl S, et al. Association of immunophenotype with pathologic complete response to neoadjuvant chemotherapy for triple-negative breast cancer: a secondary analysis of the BrighTNess phase 3 randomized clinical trial. JAMA Oncol. 2021;7:603–8.
pubmed: 33599688
doi: 10.1001/jamaoncol.2020.7310
Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, et al. Adjuvant capecitabine in combination with docetaxel, epirubicin, and cyclophosphamide for early breast cancer: the randomized clinical FinXX trial. JAMA Oncol. 2017;3:793–800.
pubmed: 28253390
pmcid: 5824321
doi: 10.1001/jamaoncol.2016.6120
Li H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv. https://arxiv.org/pdf/1303.3997.pdf (2013).
Quinlan AR, Hall IM. BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 2010;26:841–2.
pubmed: 20110278
pmcid: 2832824
doi: 10.1093/bioinformatics/btq033
Amemiya HM, Kundaje A, Boyle AP. The ENCODE blacklist: identification of problematic regions of the genome. Sci Rep. 2019;9:9354.
pubmed: 31249361
pmcid: 6597582
doi: 10.1038/s41598-019-45839-z
De Boo LW, Opdam M, Kluin RJC, Schouten PC, Steenis C, Brugman W, et al. Sequence Read Archive (SRA) BioProject number PRJNA647428. https://www.ncbi.nlm.nih.gov/Traces/study1/?acc=PRJNA647428& . (2021).
Schouten PC, Grigoriadis A, Kuilman T, Mirza H, Watkins JA, Cooke SA, et al. Robust BRCA1-like classification of copy number profiles of samples repeated across different datasets and platforms. Mol Oncol. 2015;9:1274–86.
pubmed: 25825120
pmcid: 5528812
doi: 10.1016/j.molonc.2015.03.002
van Rossum AGJ, Schouten PC, Weber KE, Nekljudova V, Denkert C, Solbach C, et al. BRCA1-like profile is not significantly associated with survival benefit of non-myeloablative intensified chemotherapy in the GAIN randomized controlled trial. Breast Cancer Res Treat. 2017;166:775–85.
pubmed: 28822007
doi: 10.1007/s10549-017-4444-9
Brauer HA, Mashadi-Hossein A, Buckingham W, Danaher P, Ferree S Gene expression signature development to decode breast cancer heterogeneity. J Clin Oncol. 2018;36:e24243-e.
Morningside Healthcare Ltd. Capecitabine 500mg Film-coated Tablets - summary of product characteristics (SPC). https://www.medicines.org.uk/emc/product/11498/smpc (2021)
Iwaizumi M, Tseng-Rogenski S, Carethers JM. DNA mismatch repair proficiency executing 5-fluorouracil cytotoxicity in colorectal cancer cells. Cancer Biol Ther. 2011;12:756–64.
pubmed: 21814034
pmcid: 3367669
doi: 10.4161/cbt.12.8.17169
Huehls AM, Huntoon CJ, Joshi PM, Baehr CA, Wagner JM, Wang X, et al. Genomically incorporated 5-fluorouracil that escapes UNG-initiated base excision repair blocks DNA replication and activates homologous recombination. Mol Pharmacol. 2016;89:53–62.
pubmed: 26494862
pmcid: 4702102
doi: 10.1124/mol.115.100164
Alli E, Sharma VB, Hartman AR, Lin PS, McPherson L, Ford JM. Enhanced sensitivity to cisplatin and gemcitabine in Brca1-deficient murine mammary epithelial cells. BMC Pharmacol. 2011;11:7.
pubmed: 21771338
pmcid: 3146825
doi: 10.1186/1471-2210-11-7
Quinn JE, Kennedy RD, Mullan PB, Gilmore PM, Carty M, Johnston PG, et al. BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res. 2003;63:6221–8.
pubmed: 14559807
Mayer IA, Zhao F, Arteaga CL, Symmans WF, Park BH, Burnette BL, et al. Randomized phase III postoperative trial of platinum-based chemotherapy versus capecitabine in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: ECOG-ACRIN EA1131. J Clin Oncol. 2021;39:2539–51.
pubmed: 34092112
doi: 10.1200/JCO.21.00976
Severson TM, Peeters J, Majewski I, Michaut M, Bosma A, Schouten PC, et al. BRCA1-like signature in triple negative breast cancer: molecular and clinical characterization reveals subgroups with therapeutic potential. Mol Oncol. 2015;9:1528–38.
pubmed: 26004083
pmcid: 5528786
doi: 10.1016/j.molonc.2015.04.011
Lips EH, Mulder L, Oonk A, van der Kolk LE, Hogervorst FBL, Imholz ALT, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer. 2013;108:2172–7.
pubmed: 23558900
pmcid: 3670471
doi: 10.1038/bjc.2013.144
Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst. 2009;101:1446–52.
pubmed: 19815849
pmcid: 2782246
doi: 10.1093/jnci/djp335
Lokich JJ, Ahlgren JD, Gullo JJ, Philips JA, Fryer JG. A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study. J Clin Oncol. 1989;7:425–32.
pubmed: 2926468
doi: 10.1200/JCO.1989.7.4.425
Rugo HS, Olopade OI, DeMichele A, Yau C, van ‘t Veer LJ, Buxton MB, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375:23–34.
pubmed: 27406347
pmcid: 5259561
doi: 10.1056/NEJMoa1513749
Loibl S, O’Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018;19:497–509.
pubmed: 29501363
doi: 10.1016/S1470-2045(18)30111-6
Fasching PA, Link T, Hauke J, Seither F, Jackisch C, Klare P, et al. Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Ann Oncol. 2021;32:49–57.
Drost R, Bouwman P, Rottenberg S, Boon U, Schut E, Klarenbeek S, et al. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell. 2011;20:797–809.
pubmed: 22172724
doi: 10.1016/j.ccr.2011.11.014
Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008;68:2581–6.
pubmed: 18413725
pmcid: 2674369
doi: 10.1158/0008-5472.CAN-08-0088
Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 2008;451:1116–20.
pubmed: 18264087
pmcid: 2577037
doi: 10.1038/nature06633
Barber LJ, Sandhu S, Chen L, Campbell J, Kozarewa I, Fenwick K, et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J Pathol. 2013;229:422–9.
pubmed: 23165508
doi: 10.1002/path.4140
de Boo LW, Jóźwiak K, Joensuu H, Lindman H, Lauttia S, Opdam M, et al. Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency status among early-stage TNBC patients in the FinXX trial. Research Square. https://doi.org/10.21203/rs.3.rs-125140/v1 .