Elevated tumor mutation burden and immunogenic activity in patients with hormone receptor‑negative or human epidermal growth factor receptor 2‑positive breast cancer

Xu,Junnan; Bao,Hua; Wu,Xue; Wang,Xiaonan; Shao,Yang  W.; Sun,Tao

doi:10.3892/ol.2019.10287

Elevated tumor mutation burden and immunogenic activity in patients with hormone receptor‑negative or human epidermal growth factor receptor 2‑positive breast cancer

Authors:
- Junnan Xu
- Hua Bao
- Xue Wu
- Xiaonan Wang
- Yang W. Shao
- Tao Sun
View Affiliations

Affiliations: Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Key Laboratory of Liaoning Breast Cancer Research, Shenyang, Liaoning 110042, P.R. China, Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, ON M5G 1L7, Canada, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu 210032, P.R. China
Published online on: April 30, 2019 https://doi.org/10.3892/ol.2019.10287
Pages: 449-455
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Immunotherapy has been found to be efficient in a variety of cancers and, therefore, may be a promising strategy for breast cancer (BC), particularly due to the limited therapeutic options currently available for triple‑negative BC (TNBC). However, heterogeneity of tumor mutation burden (TMB), immune gene expression and mismatch repair (MMR) gene activity across BC subtypes has not been well characterized. In the present study, a comprehensive analysis of TMB, expression levels of immune cell type marker genes, and expression levels of MMR‑associated genes was performed. A total of 5 MMR‑associated genes, including MLH1, MLH3, MSH2, MSH6 and PMS2, were analyzed. Patients that harbored at least two MMR genes with expression levels in the lower 10% percentile across the cohort were considered as potentially aberrant (lost expression). Hormone receptor (HR)‑negative BC is associated with a higher TMB and immune gene expression compared with HR‑positive BC [TMB, estrogen receptor (ER)‑negative vs. ER‑negative, 55 vs. 32, respectively; P=4.1x10‑13; progesterone receptor (PR)‑negative vs. PR‑positive, 53 vs. 31, respectively; P<2.2x10‑16]. By contrast, human epidermal growth factor receptor 2 (HER2)‑negative BC tended to have a lower TMB and decreased immune gene expression compared with HER2‑positive BC (TMB, HER2‑negative vs. HER2‑positive, 36 vs. 48, respectively; P=0.02). Furthermore, aberrant expression of MMR genes was found to be more common in HR‑negative compared with HR‑positive BC (P<0.001). Significantly higher expression levels of each immune marker gene of four major immune cell types were found in patients who were HR‑negative compared with patients who were HR‑positive (P<0.001). The findings of the present study suggest that HR‑negative or HER2‑positive BC exhibits elevated TMB and immunogenic activity, and immunotherapeutic options are recommended.

View Figures

View References

1	DeSantis CE, Ma J, Goding Sauer A, Newman LA and Jemal A: Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin. 67:439–448. 2017. View Article : Google Scholar : PubMed/NCBI
2	Effi AB, Aman NA, Koui BS, Koffi KD, Traore ZC and Kouyate M: Breast cancer molecular subtypes defined by ER/PR and HER2 status: Association with clinicopathologic parameters in ivorian patients. Asian Pac J Cancer Prev. 17:1973–1978. 2016. View Article : Google Scholar : PubMed/NCBI
3	Dunnwald LK, Rossing MA and Li CI: Hormone receptor status, tumor characteristics, and prognosis: A prospective cohort of breast cancer patients. Breast Cancer Res. 9:R62007. View Article : Google Scholar : PubMed/NCBI
4	Davis SL, Eckhardt SG, Tentler JJ and Diamond JR: Triple-negative breast cancer: Bridging the gap from cancer genomics to predictive biomarkers. Ther Adv Med Oncol. 6:88–100. 2014. View Article : Google Scholar : PubMed/NCBI
5	Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, et al: Pembrolizumab in patients with advanced triple-negative breast cancer: Phase Ib KEYNOTE-012 study. J Clin Oncol. 34:2460–2467. 2016. View Article : Google Scholar : PubMed/NCBI
6	Hartman ZC, Poage GM, den Hollander P, Tsimelzon A, Hill J, Panupinthu N, Zhang Y, Mazumdar A, Hilsenbeck SG, Mills GB and Brown PH: Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Res. 73:3470–3480. 2013. View Article : Google Scholar : PubMed/NCBI
7	Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, Cescon DW, Iwata H, Campone M, Nanda R, et al: Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: Cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 30:397–404. 2019. View Article : Google Scholar : PubMed/NCBI
8	Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong A, et al: Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: Cohort B of the phase II KEYNOTE-086 study. Ann Oncol. 30:405–411. 2019. View Article : Google Scholar : PubMed/NCBI
9	Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Diéras V, Hegg R, Im SA, Shaw Wright G, et al: Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 379:2108–2121. 2018. View Article : Google Scholar : PubMed/NCBI
10	Criscitiello C and Curigliano G: Immunotherapy of breast cancer. Prog Tumor Res. 42:30–43. 2015. View Article : Google Scholar : PubMed/NCBI
11	Rummel SK, Lovejoy L, Shriver CD and Ellsworth RE: Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer. Breast Cancer Res Treat. 164:593–601. 2017. View Article : Google Scholar : PubMed/NCBI
12	Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, Schrock A, Campbell B, Shlien A, Chmielecki J, et al: Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9:342017. View Article : Google Scholar : PubMed/NCBI
13	Tomczak K, Czerwińska P and Wiznerowicz M: The cancer genome atlas (TCGA): An immeasurable source of knowledge. Contemp Oncol (Pozn). 19:A68–A77. 2015.PubMed/NCBI
14	Boland CR and Goel A: Microsatellite instability in colorectal cancer. Gastroenterology. 138:2073–2087, e2073. 2010. View Article : Google Scholar : PubMed/NCBI
15	Rooney MS, Shukla SA, Wu CJ, Getz G and Hacohen N: Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 160:48–61. 2015. View Article : Google Scholar : PubMed/NCBI
16	Danaher P, Warren S, Dennis L, D'Amico L, White A, Disis ML, Geller MA, Odunsi K, Beechem J and Fling SP: Gene expression markers of Tumor Infiltrating Leukocytes. J Immunother Cancer. 5:182017. View Article : Google Scholar : PubMed/NCBI
17	Low SK, Zembutsu H and Nakamura Y: Breast cancer: The translation of big genomic data to cancer precision medicine. Cancer Sci. 109:497–506. 2018. View Article : Google Scholar : PubMed/NCBI
18	Kraya AA, Maxwell KN, Wubbenhorst B, Wenz BM, Pluta J, Rech AJ, Dorfman LM, Lunceford N, Barrett A, Mitra N, et al: Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer. Clin Cancer Res. pii:clincanres.0468.2018. 2019.
19	Stovgaard ES, Nielsen D, Hogdall E and Balslev E: Triple negative breast cancer-prognostic role of immune-related factors: A systematic review. Acta Oncol. 57:74–82. 2018. View Article : Google Scholar : PubMed/NCBI
20	Yang J, Xu J, E Y and Sun T: Predictive and prognostic value of circulating blood lymphocyte subsets in metastatic breast cancer. Cancer Med. 8:492–500. 2019. View Article : Google Scholar : PubMed/NCBI
21	Xu J, Jiang L, Cao H, Jia Y, Wu S, Jiang C and Sun T: Predictive value of CD4⁺/CD8⁺ ratio in patients with breast cancer receiving recombinant human thrombopoietin. J Interferon Cytokine Res. 38:213–220. 2018. View Article : Google Scholar : PubMed/NCBI
22	McGrail DJ, Federico L, Li Y, Dai H, Lu Y, Mills GB, Yi S, Lin SY and Sahni N: Multi-omics analysis reveals neoantigen-independent immune cell infiltration in copy-number driven cancers. Nat Commun. 9:13172018. View Article : Google Scholar : PubMed/NCBI
23	Shaw JA, Guttery DS, Hills A, Fernandez-Garcia D, Page K, Rosales BM, Goddard KS, Hastings RK, Luo J, Ogle O, et al: Mutation analysis of cell-free DNA and single circulating tumor cells in metastatic breast cancer patients with high circulating tumor cell counts. Clin Cancer Res. 23:88–96. 2017. View Article : Google Scholar : PubMed/NCBI
24	Bidard FC, Hajage D, Bachelot T, Delaloge S, Brain E, Campone M, Cottu P, Beuzeboc P, Rolland E, Mathiot C and Pierga JY: Assessment of circulating tumor cells and serum markers for progression-free survival prediction in metastatic breast cancer: A prospective observational study. Breast Cancer Res. 14:R292012. View Article : Google Scholar : PubMed/NCBI
25	Xu J, Sun T, Guo X, Wang Y and Jing M: Estrogen receptor-α promoter methylation is a biomarker for outcome prediction of cisplatin resistance in triple-negative breast cancer. Oncol Lett. 15:2855–2862. 2018.PubMed/NCBI
26	Birkbak NJ, Kochupurakkal B, Izarzugaza JM, Eklund AC, Li Y, Liu J, Szallasi Z, Matulonis UA, Richardson AL, Iglehart JD and Wang ZC: Tumor mutation burden forecasts outcome in ovarian cancer with BRCA1 or BRCA2 mutations. PLoS One. 8:e800232013. View Article : Google Scholar : PubMed/NCBI
27	Xu J, Guo X, Jing M and Sun T: Prediction of tumor mutation burden in breast cancer based on the expression of ER, PR, HER-2, and Ki-67. Onco Targets Ther. 11:2269–2275. 2018. View Article : Google Scholar : PubMed/NCBI
28	Win AK, Lindor NM and Jenkins MA: Risk of breast cancer in Lynch syndrome: A systematic review. Breast Cancer Res. 15:R272013. View Article : Google Scholar : PubMed/NCBI
29	Kappil M, Terry MB, Delgado-Cruzata L, Liao Y and Santella RM: Mismatch repair polymorphisms as markers of breast cancer prevalence in the breast cancer family registry. Anticancer Res. 36:4437–4441. 2016. View Article : Google Scholar : PubMed/NCBI
30	Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, et al: Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): A single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 20:371–382. 2019. View Article : Google Scholar : PubMed/NCBI
31	Rugo HS, Delord JP, Im SA, Ott PA, Piha-Paul SA, Bedard PL, Sachdev J, Tourneau CL, van Brummelen EMJ, Varga A, et al: Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Clin Cancer Res. 24:2804–2811. 2018. View Article : Google Scholar : PubMed/NCBI