Association between Molecular Subtypes and Survival in Patients with Breast Cancer

• Mehmet Fuat Eren

  Department of Radiation Oncology, Cumhuriyet University School of Medicine, Sivas, Turkey

• Ayfer Ay Eren

  Department of Radiation Oncology, Cumhuriyet University School of Medicine, Sivas, Turkey

• Birsen Yücel

  Department of Radiation Oncology, Cumhuriyet University School of Medicine, Sivas, Turkey

• Seher Bahar

  Department of Radiation Oncology, Cumhuriyet University School of Medicine, Sivas, Turkey

• Ahmet Cinkaya

  Department of Radiation Oncology, Dumlupınar University School of Medicine, Kutahya, Turkey

• Rayna K. Matsuno

  Department of Radiation Medicine and Applied Science, University of California School of Medicine, San Diego, USA

• Nuran Beşe

  Acıbadem Maslak Hospital Breast Health Unit, Istanbul, Turkey

 Background: Aim of this study is to classify intrinsic subtypes and evaluate the differences in clinical/pathological characteristics and survival outcomes among the molecular types.

Patients and Methods: Breast cancer subtypes were classified according to the 2013 St. Gallen Consensus. Five molecular subtypes were determined, Luminal A, Luminal B-like HER2 negative, Luminal B-like HER2 positive, HER2 positive, and triple negative. Data was obtained from the records of patients with invasive breast cancer retrospectively. The differences in clinical/pathological parameters, overall survival and disease-free survival among the molecular subtypes were analyzed. The Kaplan-Meier method, log-rank test and Cox regression tests were used to compare groups.

Results: The median follow-up period is 48 months. The Luminal B-HER2 negative was the most prevalent type (26.6%). Patient demographics, tumor characteristics and survival data were analyzed. The Luminal A and Luminal B-HER2 negative subtypes had significantly higher overall survival and disease-free survival rates. Multivariate Cox analysis revealed that tumor stage, more than 3 positive axillary lymph node involvement, and breast cancer subtype as significant factors for overall survival and disease-free survival (p<0.05). Triple Negative subtype had a higher relative hazard of local recurrence and distant metastasis (HR=2.69, 95% CI=1.47; 4.95).

Conclusions: Breast cancer subtype has significant impact on overall survival and disease-free survival rates. While Luminal A and luminal B HER2 negative subtypes have better outcome, triple negative and HER2- subtypes remain poor.

Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, et al. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin 2012; 62: 220-41. https://doi.org/10.3322/caac.21149

Ferlay J, Soerjomataram I, Ervik M, Dikshit R, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No 11

Coleman MP, Quaresma M, Berrino F, Lutz JM, De Angelis R, Capocaccia R, Baili P, Rachet B, Gatta G, Hakulinen T, Micheli A, Sant M, Weir HK, Elwood JM, Tsukuma H, Koifman S, E Silva GA, Francisci S, Santaquilani M, Verdecchia A, Storm HH, Young JL. CONCORD Working Group. Cancersurvival in fivecontinents: a worldwide population-based study (CONCORD). Lancet Oncol 2008; 9(8): 730-56. https://doi.org/10.1016/S1470-2045(08)70179-7

Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol 2009; 20(8): 1319-1329. https://doi.org/10.1093/annonc/mdp322

Rafiq S, Tapper W, Collins A, Khan S, Politopoulos I, Gerty S, et al. Identification of inherited genetic variations influencing prognosis in early-onset breast cancer. Cancer Res 2013; 73: 1883-1891. https://doi.org/10.1158/0008-5472.CAN-12-3377

Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D. Molecular portraits of human breast tumors. Nature 2000; 406: 747-752. https://doi.org/10.1038/35021093

Van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002; 347(25): 1999-2009. https://doi.org/10.1056/NEJMoa021967

Sørlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003; 100(14): 8418-8423. https://doi.org/10.1073/pnas.0932692100

Herschkowitz JI, Simin K, Weigman VJ, et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 2007; 8(5): R76. https://doi.org/10.1186/gb-2007-8-5-r76

Kittaneh M, Montero AJ, Gluck S. Molecular profiling for breast cancer: a comprehensive review. Biomark Cancer 2013; 5: 61-70.

Sorlie T, Perou CM, Tibshirani R, et al. Gene expressionpatterns of breast carcinomas distinguish tumor subclasses withclinical implications. Proc Natl Acad Sci USA 2001; 98: 10869-74. https://doi.org/10.1073/pnas.191367098

Cuzick J, Dowsett M, Pineda S, Wale C, Salter J, Quinn E, et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol 2011; 29: 4273-8. https://doi.org/10.1200/JCO.2010.31.2835

Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22(8): 1736-1747. https://doi.org/10.1093/annonc/mdr304

Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013; 24: 2206-23. https://doi.org/10.1093/annonc/mdt303

Millikan RC, Newman B, Tse CK, et al. Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 2008; 109: 123-139. https://doi.org/10.1007/s10549-007-9632-6

Phipps AI, Buist DS, Malone KE, et al. Reproductive history and risk of threebreast cancer subtypes defined by three biomarkers. Cancer Causes Control 2011; 22: 399-405. https://doi.org/10.1007/s10552-010-9709-0

Aebi S, Sun Z, Braun D, et al. Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: long-term follow up on IBCSG Trial IX. Ann Oncol 2011

Sørlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lønning PE, Brown PO, Børresen-Dale A and Botstein D. Repeated observation of breast tumor subtypes in independent gene expression data sets. PNAS 2003; 100: 8418-8423. https://doi.org/10.1073/pnas.0932692100

Park S, Koo JS, Kim, Park HS, Lee JS, Lee JS, Kim SI, Park BW. Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry. Breast (Edinburgh, Scotland) 2012; 21(1): 50-57. https://doi.org/10.1016/j.breast.2011.07.008

Nguyen PL, Taghian AG, Katz MS, Niemierko A, AbiRaad RF, Boon WL, et al. Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast conserving therapy. J Clin Oncol 2008; 26: 2373-8. https://doi.org/10.1200/JCO.2007.14.4287

Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13: 4429-34. https://doi.org/10.1158/1078-0432.CCR-06-3045

Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol 2010; 28: 1684-91. https://doi.org/10.1200/JCO.2009.24.9284

Zhang C, Wang S, Israel HP, Yan SX, Horowitz DP, Crockford S, Gidea-Addeo D, Clifford Chao KS, Kalinsky K, Connolly EP: Higher locoregional recurrence rate for triple-negative breast cancer following neoadjuvant chemotherapy, surgery and radiotherapy. Springerplus 2015; 4: 386. https://doi.org/10.1186/s40064-015-1116-2

O’Brien KM, Cole SR, Tse CK, Perou CM, Carey LA, Foulkes WD, Dressler LG, Geradts J and Millikan RC. Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study. Clin Cancer Res 2010; 16: 6100-6110. https://doi.org/10.1158/1078-0432.CCR-10-1533

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