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01-11-2018 | Clinical trial

Differences in prognosis and efficacy of chemotherapy by p53 expression in triple-negative breast cancer

Authors: Soo Youn Bae, Seok Jin Nam, Yongsik Jung, Sae Byul Lee, Byung-Woo Park, Woosung Lim, Sung Hoo Jung, Hsien Wen Yang, Seung Pil Jung

Published in: Breast Cancer Research and Treatment | Issue 2/2018

Abstract

Purpose

TP53 mutation is the most common mutation in breast cancer, and it is considered a target marker of triple-negative breast cancer (TNBC). We investigated whether expression of p53 detected by immunochemical staining predicts the chemotherapy response of TNBC.

Methods

A total of 11,393 TNBC patients who had between stage I and stage III enrolled in the Korean Breast Cancer Society Registry database from January 1, 2000 to December 31, 2015. There were 6,331 ‘p53-positive (+) TNBC’ patients and 5062 ‘p53-negative (−) TNBC’ patients.

Results

In univariate analysis, p53(+) TNBC had a worse prognosis than p53(−) TNBC in patients not receiving chemotherapy (P = 0.003). However, there was no difference in prognosis between p53(+) TNBC and p53(−) TNBC for patients receiving chemotherapy. In multivariate analysis adjusted for age and stage, the risk of p53(+) TNBC was 1.84 times higher than that of p53(−) TNBC in the non-chemotherapy group. However, there was no difference between p53(+) TNBC and p53(−) TNBC in patients receiving chemotherapy. In p53(+) TNBC, the risk was 0.6-fold lower when chemotherapy was administered than when chemotherapy was not administered. However, in p53(−) TNBC, there was no risk reduction effect by chemotherapy.

Conclusion

The prognosis of p53(+) TNBC has worse than p53(−) TNBC, but the risk for survival was significantly reduced with chemotherapy. It suggests that p53(+) TNBC would be more sensitive to chemotherapy than p53(−) TNBC.

Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO (2007) Prognostic markers in triple-negative breast cancer. Cancer 109(1):25–32CrossRef

Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, Harris L, Hait W, Toppmeyer D (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24(36):5652–5657CrossRef

Brenton JD, Carey LA, Ahmed AA, Caldas C (2005) Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol 23(29):7350–7360CrossRef

Network CGA (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70CrossRef

Ahn SH, Yoo KY (2006) Chronological changes of clinical characteristics in 31,115 new breast cancer patients among Koreans during 1996–2004. Breast Cancer Res Treat 99(2):209–214CrossRef

Ahn SH, Son BH, Kim SW, Kim SI, Jeong J, Ko SS, Han W (2007) Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea—a report from the Korean Breast Cancer Society. J Clin Oncol 25(17):2360–2368CrossRef

Synnott NC, Bauer MR, Madden S, Murray A, Klinger R, O’Donovan N, O’Connor D, Gallagher WM, Crown J, Fersht AR et al (2018) Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: preclinical investigation with the anti-p53 drug, PK11007. Cancer Lett 414:99–106CrossRef

Duffy MJ, Synnott NC, Crown J (2018) Mutant p53 in breast cancer: potential as a therapeutic target and biomarker. Breast Cancer Res Treat 170(2):213–219CrossRef

Blagosklonny MV (1997) Loss of function and p53 protein stabilization. Oncogene 15(16):1889–1893CrossRef

10.

Thor AD, Moore DH, Edgerton II, Kawasaki SM, Reihsaus ES, Lynch E, Marcus HT, Schwartz JN, Chen L, Mayall LC (1992) BH et al: Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 84(11):845–855CrossRef

11.

Brosh R, Rotter V (2009) When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9(10):701–713CrossRef

12.

Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M (2007) TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26(15):2157–2165CrossRef

13.

Joerger AC, Fersht AR (2016) The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem 85(1):375–404CrossRef

14.

Abdel-Fattah R, Challen C, Griffiths TR, Robinson MC, Neal DE, Lunec J (1998) Alterations of TP53 in microdissected transitional cell carcinoma of the human urinary bladder: high frequency of TP53 accumulation in the absence of detected mutations is associated with poor prognosis. Br J Cancer 77(12):2230–2238CrossRef

15.

George B, Datar RH, Wu L, Cai J, Patten N, Beil SJ, Groshen S, Stein J, Skinner D, Jones PA et al (2007) p53 gene and protein status: the role of p53 alterations in predicting outcome in patients with bladder cancer. J Clin Oncol 25(34):5352–5358CrossRef

16.

Lipponen P, Ji H, Aaltomaa S, Syrjanen S, Syrjanen K (1993) p53 protein expression in breast cancer as related to histopathological characteristics and prognosis. Int J Cancer 55(1):51–56CrossRef

17.

Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bieche I et al (2006) The clinical value of somatic TP53 gene mutations in 1794 patients with breast cancer. Clin Cancer Res 12(4):1157–1167CrossRef

18.

Coates AS, Millar EK, O’Toole SA, Molloy TJ, Viale G, Goldhirsch A, Regan MM, Gelber RD, Sun Z, Castiglione-Gertsch M et al (2012) Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative breast cancer: results from IBCSG Trials VIII and IX. Breast Cancer Res 14(6):R143CrossRef

19.

Lara JF, Thor AD, Dressler LG, Broadwater G, Bleiweiss IJ, Edgerton S, Cowan D, Goldstein LJ, Martino S, Ingle JN et al (2011) p53 Expression in node-positive breast cancer patients: results from the cancer and leukemia group B 9344 Trial (159905). Clin Cancer Res 17(15):5170–5178CrossRef

20.

Fernandez-Cuesta L, Oakman C, Falagan-Lotsch P, Smoth KS, Quinaux E, Buyse M, Dolci MS, Azambuja ED, Hainaut P, Dell’orto P et al (2012) Prognostic and predictive value of TP53 mutations in node-positive breast cancer patients treated with anthracycline- or anthracycline/taxane-based adjuvant therapy: results from the BIG 02-98 phase III trial. Breast Cancer Res 14(3):R70CrossRef

21.

Silwal-Pandit L, Vollan HK, Chin SF, Rueda OM, McKinney S, Osako T, Quigley DA, Kristensen VN, Aparicio S, Borresen-Dale AL et al (2014) TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 20(13):3569–3580CrossRef

22.

Bertheau P, Turpin E, Rickman DS, Espie M, de Reynies A, Feugeas JP, Plassa LF, Soliman H, Varna M, de Roquancourt A et al (2007) Exquisite sensitivity of TP53 mutant and basal breast cancers to a dose-dense epirubicin-cyclophosphamide regimen. PLoS Med 4(3):e90CrossRef

23.

Bertheau P, Plassa F, Espie M, Turpin E, de Roquancourt A, Marty M, Lerebours F, Beuzard Y, Janin A, de The H (2002) Effect of mutated TP53 on response of advanced breast cancers to high-dose chemotherapy. Lancet 360(9336):852–854CrossRef

24.

Lehmann-Che J, Andre F, Desmedt C, Mazouni C, Giacchetti S, Turpin E, Espie M, Plassa LF, Marty M, Bertheau P et al (2010) Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers. The Oncologist 15(3):246–252CrossRef

25.

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

26.

Varna M, Lehmann-Che J, Turpin E, Marangoni E, El-Bouchtaoui M, Jeanne M, Grigoriu C, Ratajczak P, Leboeuf C, Plassa LF et al (2009) p53 dependent cell-cycle arrest triggered by chemotherapy in xenografted breast tumors. Int J Cancer 124(4):991–997CrossRef

27.

Jackson JG, Pant V, Li Q, Chang LL, Quintas-Cardama A, Garza D, Tavana O, Yang P, Manshouri T, Li Y et al (2012) p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21(6):793–806CrossRef

Title: Differences in prognosis and efficacy of chemotherapy by p53 expression in triple-negative breast cancer
Authors: Soo Youn Bae
Seok Jin Nam
Yongsik Jung
Sae Byul Lee
Byung-Woo Park
Woosung Lim
Sung Hoo Jung
Hsien Wen Yang
Seung Pil Jung
Publication date: 01-11-2018
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4928-2

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