Genomic Patterns Resembling BRCA1- and BRCA2-mutated Breast Cancers Predict Benefit of Intensified Carboplatin-based Chemotherapy

Overview

Journal Breast Cancer Res

Specialty Oncology

Date 2014 Jun 3

PMID 24887359

Citations 52

Authors

Marieke A Vollebergh

Esther H Lips

Petra M Nederlof

Lodewyk F A Wessels

Jelle Wesseling

Marc J Vd Vijver

Elisabeth G E de Vries

Harm van Tinteren

Jos Jonkers

Michael Hauptmann

Sjoerd Rodenhuis

Sabine C Linn

Affiliations

Soon will be listed here.

Abstract

Introduction: BRCA-mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1-mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non-BRCA-mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2-mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy.

Methods: Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1- and/or BRCA2-mutated breast cancers were defined as having a BRCA-likeCGH status, others as non-BCRA-likeCGH. Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy.

Results: Among patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-likeCGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-likeCGH tumors were ER-positive.

Conclusions: Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-likeCGH patients) and those without benefit (non-BRCA-likeCGH patients).

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References

Lehmann-Che J, Andre F, Desmedt C, Mazouni C, Giacchetti S, Turpin E . Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers. Oncologist. 2010; 15(3):246-52. PMC: 3227956. DOI: 10.1634/theoncologist.2009-0243. View

Moebus V, Jackisch C, Lueck H, du Bois A, Thomssen C, Kurbacher C . Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol. 2010; 28(17):2874-80. DOI: 10.1200/JCO.2009.24.7643. View

Lakhani S, van de Vijver M, Jacquemier J, Anderson T, Osin P, McGuffog L . The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002; 20(9):2310-8. DOI: 10.1200/JCO.2002.09.023. View

Rodenhuis S, Bontenbal M, Van Hoesel Q, Smit W, Nooij M, Voest E . Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer. Ann Oncol. 2006; 17(4):588-96. DOI: 10.1093/annonc/mdl001. View

Rottenberg S, Jaspers J, Kersbergen A, van der Burg E, Nygren A, Zander S . High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008; 105(44):17079-84. PMC: 2579381. DOI: 10.1073/pnas.0806092105. View

Lips E, Mulder L, Hannemann J, Laddach N, Vrancken Peeters M, van de Vijver M . Indicators of homologous recombination deficiency in breast cancer and association with response to neoadjuvant chemotherapy. Ann Oncol. 2010; 22(4):870-876. DOI: 10.1093/annonc/mdq468. View

Bertheau P, Turpin E, Rickman D, Espie M, De Reynies A, Feugeas J . Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicin-cyclophosphamide regimen. PLoS Med. 2007; 4(3):e90. PMC: 1831731. DOI: 10.1371/journal.pmed.0040090. View

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron J, Nobel A . Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003; 100(14):8418-23. PMC: 166244. DOI: 10.1073/pnas.0932692100. View

Kriege M, Jager A, Hooning M, Huijskens E, Blom J, van Deurzen C . The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer. 2011; 118(4):899-907. DOI: 10.1002/cncr.26351. View

10.

Berry D, Ueno N, Johnson M, Lei X, Caputo J, Rodenhuis S . High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials. J Clin Oncol. 2011; 29(24):3214-23. PMC: 4322115. DOI: 10.1200/JCO.2010.32.5910. View

11.

Khanna K, Jackson S . DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001; 27(3):247-54. DOI: 10.1038/85798. View

12.

Tutt A, Robson M, Garber J, Domchek S, Audeh M, Weitzel J . Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010; 376(9737):235-44. DOI: 10.1016/S0140-6736(10)60892-6. View

13.

J van t Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M . Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415(6871):530-6. DOI: 10.1038/415530a. View

14.

Sargent D, Conley B, Allegra C, Collette L . Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol. 2005; 23(9):2020-7. DOI: 10.1200/JCO.2005.01.112. View

15.

Farquhar C, Marjoribanks J, Lethaby A, Basser R . High dose chemotherapy for poor prognosis breast cancer: systematic review and meta-analysis. Cancer Treat Rev. 2007; 33(4):325-37. DOI: 10.1016/j.ctrv.2007.01.007. View

16.

Konstantinopoulos P, Spentzos D, Karlan B, Taniguchi T, Fountzilas E, Francoeur N . Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010; 28(22):3555-61. PMC: 2917311. DOI: 10.1200/JCO.2009.27.5719. View

17.

van Beers E, Joosse S, Ligtenberg M, Fles R, Hogervorst F, Verhoef S . A multiplex PCR predictor for aCGH success of FFPE samples. Br J Cancer. 2005; 94(2):333-7. PMC: 2361127. DOI: 10.1038/sj.bjc.6602889. View

18.

Farmer H, McCabe N, Lord C, Tutt A, Johnson D, Richardson T . Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434(7035):917-21. DOI: 10.1038/nature03445. View

19.

Fong P, Boss D, Yap T, Tutt A, Wu P, Mergui-Roelvink M . Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009; 361(2):123-34. DOI: 10.1056/NEJMoa0900212. View

20.

Fisher B, Anderson S, DeCillis A, Dimitrov N, Atkins J, Fehrenbacher L . Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol. 1999; 17(11):3374-88. DOI: 10.1200/JCO.1999.17.11.3374. View