nach oben

Erschienen in:

03.05.2018 | Clinical trial

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients

verfasst von: Marius Wunderle, Paul Gass, Lothar Häberle, Vivien M. Flesch, Claudia Rauh, Mayada R. Bani, Carolin C. Hack, Michael G. Schrauder, Sebastian M. Jud, Julius Emons, Ramona Erber, Arif B. Ekici, Juliane Hoyer, Georgia Vasileiou, Cornelia Kraus, Andre Reis, Arndt Hartmann, Michael P. Lux, Matthias W. Beckmann, Peter A. Fasching, Alexander Hein

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose

BRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy.

Methods

Breast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival.

Results

Among 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as “ypT0; ypN0” was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26–4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status.

Conclusions

BRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.

Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P et al (2014) Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384(9938):164–172CrossRefPubMed

von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J et al (2012) Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30(15):1796–1804CrossRef

Cortesi L, Masini C, Cirilli C, Medici V, Marchi I, Cavazzini G, Pasini G, Turchetti D, Federico M (2010) Favourable ten-year overall survival in a Caucasian population with high probability of hereditary breast cancer. BMC Cancer 10:90CrossRefPubMedPubMedCentral

Arun B, Bayraktar S, Liu DD, Gutierrez Barrera AM, Atchley D, Pusztai L, Litton JK, Valero V, Meric-Bernstam F, Hortobagyi GN et al (2011) Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol 29(28):3739–3746CrossRefPubMedPubMedCentral

Rennert G, Bisland-Naggan S, Barnett-Griness O, Bar-Joseph N, Zhang S, Rennert HS, Narod SA (2007) Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. New Engl J Med 357(2):115–123CrossRefPubMed

Copson ER, Maishman TC, Tapper WJ, Cutress RI, Greville-Heygate S, Altman DG, Eccles B, Gerty S, Durcan LT, Jones L et al (2018) Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol 19(2):169–180CrossRefPubMedPubMedCentral

Zhong Q, Peng HL, Zhao X, Zhang L, Hwang WT (2015) Effects of BRCA1- and BRCA2-related mutations on ovarian and breast cancer survival: a meta-analysis. Clin Cancer Res 21(1):211–220CrossRefPubMed

Goodwin PJ, Phillips KA, West DW, Ennis M, Hopper JL, John EM, O’Malley FP, Milne RL, Andrulis IL, Friedlander ML et al (2012) Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol 30(1):19–26CrossRefPubMed

Huzarski T, Byrski T, Gronwald J, Gorski B, Domagala P, Cybulski C, Oszurek O, Szwiec M, Gugala K, Stawicka M et al (2013) Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol 31(26):3191–3196CrossRefPubMed

10.

van den Broek AJ, Schmidt MK, van ‘t Veer LJ, Tollenaar RA, van Leeuwen FE (2015) Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what’s the evidence? A systematic review with meta-analysis. PLoS ONE 10(3):e0120189CrossRefPubMedPubMedCentral

11.

Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, Mierzwa T, Szwiec M, Wisniowski R, Siolek M et al (2010) Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 28(3):375–379CrossRefPubMed

12.

Byrski T, Huzarski T, Dent R, Gronwald J, Zuziak D, Cybulski C, Kladny J, Gorski B, Lubinski J, Narod SA (2009) Response to neoadjuvant therapy with cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 115(2):359–363CrossRefPubMed

13.

Byrski T, Huzarski T, Dent R, Marczyk E, Jasiowka M, Gronwald J, Jakubowicz J, Cybulski C, Wisniowski R, Godlewski D et al (2014) Pathologic complete response to neoadjuvant cisplatin in BRCA1-positive breast cancer patients. Breast Cancer Res Treat 147(2):401–405CrossRefPubMed

14.

Paluch-Shimon S, Friedman E, Berger R, Papa M, Dadiani M, Friedman N, Shabtai M, Zippel D, Gutman M, Golan T et al (2016) Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers. Breast Cancer Res Treat 157(1):157–165CrossRefPubMed

15.

Beckmann MW, Brucker C, Hanf V, Rauh C, Bani MR, Knob S, Petsch S, Schick S, Fasching PA, Hartmann A et al (2011) Quality assured health care in certified breast centers and improvement of the prognosis of breast cancer patients. Onkologie 34(7):362–367CrossRefPubMed

16.

Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ (2009) Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol 20(8):1319–1329CrossRefPubMedPubMedCentral

17.

Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M et al (2010) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch Pathol Lab Med 134(6):907–922PubMedPubMedCentral

18.

Fasching PA, Heusinger K, Haberle L, Niklos M, Hein A, Bayer CM, Rauh C, Schulz-Wendtland R, Bani MR, Schrauder M et al (2011) Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment. BMC Cancer 11:486CrossRefPubMedPubMedCentral

19.

Meindl A, Ditsch N, Kast K, Rhiem K, Schmutzler RK (2011) Hereditary breast and ovarian cancer: new genes, new treatments, new concepts. Dtsch Arztebl Int 108(19):323–330PubMedPubMedCentral

20.

Li H (2014) Toward better understanding of artifacts in variant calling from high-coverage samples. Bioinformatics 30(20):2843–2851CrossRefPubMedPubMedCentral

21.

Szabo C, Masiello A, Ryan JF, Brody LC (2000) The breast cancer information core: database design, structure, and scope. Hum Mutat 16(2):123–131CrossRefPubMed

22.

Haberle L, Fasching PA, Brehm B, Heusinger K, Jud SM, Loehberg CR, Hack CC, Preuss C, Lux MP, Hartmann A et al (2016) Mammographic density is the main correlate of tumors detected on ultrasound but not on mammography. Int J Cancer 139(9):1967–1974CrossRefPubMed

23.

Burghaus S, Haberle L, Schrauder MG, Heusinger K, Thiel FC, Hein A, Wachter D, Strehl J, Hartmann A, Ekici AB et al (2015) Endometriosis as a risk factor for ovarian or endometrial cancer - results of a hospital-based case-control study. BMC Cancer 15:751CrossRefPubMedPubMedCentral

24.

Salmen J, Neugebauer J, Fasching PA, Haeberle L, Huober J, Wockel A, Rauh C, Schuetz F, Weissenbacher T, Kost B et al (2014) Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies. Breast Cancer Res Treat 148(1):143–151CrossRefPubMed

25.

Hahnen E, Lederer B, Hauke J, Loibl S, Krober S, Schneeweiss A, Denkert C, Fasching PA, Blohmer JU, Jackisch C et al (2017) Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: Secondary analysis of the GeparSixto randomized clinical trial. JAMA Oncol 3(10):1378–1385CrossRefPubMed

26.

Fasching PA, Loibl S, Eidtmann H, Tesch H, Untch M, Hilfrich J, Schem C, Rezai M, Gerber B, Costa SD et al. (2016) BRCA mutations, therapy response and prognosis in the neoadjuvant GeparQuinto study. AACR Cancer Res 76 (4 Suppl): S5-06CrossRef

27.

Lux MP, Janni W, Hartkopf AD, Nabieva N, Taran FA, Overkamp F, Kolberg HC, Hadji P, Tesch H, Ettl J et al (2017) Update breast cancer 2017—implementation of novel therapies. Geburtshilfe Frauenheilkd 77(12):1281–1290CrossRefPubMedPubMedCentral

28.

Fasching PA, Blohmer JU, Burchardi N, Costa SD, Denkert C, Hanusch C, Huober JB, Von Minckwitz G, Paepke S, Schneeweiss A et al. (2016) A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients with HER2-negative early breast cancer and homologous recombination deficiency (HRD). GeparOLA. J Clin Oncol 34(15 Suppl):TPS1096CrossRef

29.

Schneeweiss A, Jackisch C, Schmatloch S, Aktas B, Denkert C, Schem C, Wiebringhaus H, Kümmel S, Rhiem K, Warm M et al. (2018) Survival analysis of the prospectively randomized phase III GeparSepto trial comparing neoadjuvant chemotherapy with weekly nab-paclitaxel with solvent-based paclitaxel followed by anthracycline–cyclophosphamide for patients with early breast cancer—GBG69. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium, AACR, Dec 5–9 2017, San Antonio, TX

30.

von Minckwitz G, Blohmer JU, Costa SD, Denkert C, Eidtmann H, Eiermann W, Gerber B, Hanusch C, Hilfrich J, Huober J et al (2013) Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol 31(29):3623–3630CrossRef

31.

von Minckwitz G, Hahnen E, Fasching PA, Hauke J, Schneeweiss A, Salat C, Rezai M, Blohmer JU, Zahm DM, Jackisch C (2014) Pathological complete response (pCR) rates after carboplatin-containing neoadjuvant chemotherapy in patients with germline BRCA (g BRCA) mutation and triple-negative breast cancer (TNBC): results from GeparSixto. Int J Clin Oncol 32:5s

32.

Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921CrossRefPubMed

33.

Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, Ramus SJ, Spurdle A, Robson M, Sherman M et al (2012) Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev 21(1):134–147CrossRefPubMed

34.

Timms KM, Abkevich V, Hughes E, Neff C, Reid J, Morris B, Kalva S, Potter J, Tran TV, Chen J et al (2014) Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res 16(6):475CrossRefPubMedPubMedCentral

35.

Zhang J, Powell SN (2005) The role of the BRCA1 tumor suppressor in DNA double-strand break repair. Mol Cancer Res 3(10):531–539CrossRefPubMed

36.

Narod SA, Huzarski T, Gronwald J, Byrski T, Marczyk E, Cybulski C, Szwiec M, Wisniowski R, Birkenfeld B, Kilar E et al. (2017) Predictors of survival for breast cancer patients with a BRCA1 mutation. Breast Cancer Res Treat 168(2), 513–521CrossRefPubMed

37.

Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, Juul N, Leong CO, Calogrias D, Buraimoh A et al (2010) Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol 28(7):1145–1153CrossRefPubMedPubMedCentral

38.

Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER et al (2015) Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol 33(1):13–21CrossRefPubMed

39.

von Minckwitz G, Timms K, Untch M, Elkin EP, Hahnen E, Fasching PA, Schneeweiss A, Salat CT, Rezai M, Blohmer J-U et al (2017) Homologous repair deficiency (HRD) as measure to predict the effect of carboplatin on survival in the neoadjuvant phase II trial GeparSixto in triple-negative early breast cancer. AACR Cancer Res 77 (4 Suppl):P1-09-02CrossRef

40.

Gluz O, Nitz U, Liedtke C, Christgen M, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C et al (2017) Comparison of neoadjuvant Nab-Paclitaxel + carboplatin vs nab-paclitaxel + gemcitabine in triple-negative breast cancer: randomized WSG-ADAPT-TN trial results. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djx258 CrossRef

41.

von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, Blohmer JU, Jackisch C, Paepke S, Gerber B et al (2014) Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol 15(7):747–756CrossRef

42.

Von Minckwitz G, Loibl S, Schneeweiss A (2015) Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). In: San Antonio Breast Cancer Symposium, San Antonio, Dec 9 2015

43.

Curigliano G, Burstein HJ, E PW, Gnant M, Dubsky P, Loibl S, Colleoni M, Regan MM, Piccart-Gebhart M, Senn HJ et al. (2017) De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the primary therapy of early breast cancer 2017. Ann Oncol 28(8):1700–1712PubMedCrossRef

44.

Hurvitz SA, Martin M, Symmans WF, Jung KH, Huang CS, Thompson AM, Harbeck N, Valero V, Stroyakovskiy D, Wildiers H et al (2018) Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol 19(1):115–126CrossRefPubMed

Titel: BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients
verfasst von: Marius Wunderle
Paul Gass
Lothar Häberle
Vivien M. Flesch
Claudia Rauh
Mayada R. Bani
Carolin C. Hack
Michael G. Schrauder
Sebastian M. Jud
Julius Emons
Ramona Erber
Arif B. Ekici
Juliane Hoyer
Georgia Vasileiou
Cornelia Kraus
Andre Reis
Arndt Hartmann
Michael P. Lux
Matthias W. Beckmann
Peter A. Fasching
Alexander Hein
Publikationsdatum: 03.05.2018
Verlag: Springer US
Erschienen in: Breast Cancer Research and Treatment / Ausgabe 1/2018
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4797-8

Springer Medizin

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients