To investigate the clinicopathological characteristics and prognosis of breast cancer subtypes classified by quantitative estrogen receptor (ER), progesterone receptor (PR), and Her2.
Methods and study design
923 patients with primary breast cancer having a median age of 53 years who were treated at the Cancer Hospital of Fudan University in Shanghai between January 2002 and June 2004 were retrospectively analyzed. Four molecular subtypes were constructed from the immunohistochemical results of quantitative hormone receptor (HR) and Her2 status. HR+ was defined as ER+ and PR+, HR± as ER/PR+ at lower levels or lacking either ER or PR, and HR- as both ER- and PR-. The four subtypes were HR+/Her2-, HR±/Her2-, HR-/Her2- (triple-negative), and Her2+. Clinical and pathological parameters, disease-free survival (DFS), and overall survival (OS) measurements were compared between patients with different molecular subtypes.
Results
The proportions of HR+/Her2-, HR±/Her2-, triple-negative, and Her2+ breast cancer were 36.6% (338/923), 22.9% (211/923), 20.6% (190/923), and 19.9% (194/923). The median follow-up was 49.0 months (4–77 months). In 145 cases disease recurrence or death occurred. In multivariate analysis with the HR+/Her2- subtype taken as the reference category, triple-negative and Her2+ subtypes were associated with increased recurrence and death with a hazard ratio (HR) of 2.05 (95% CI 1.31–3.20; P = 0.002) and 1.89 (95% CI 1.20–2.97, P = 0.006) for DFS and 2.84 (95% CI 1.45–5.55; P = 0.002) and 2.95 (95% CI 1.51–5.77, P = 0.002) for OS, respectively; the HR±/Her2- subtype was marginally associated with poor prognosis with HR 1.51 (95% CI 0.94–2.43; P = 0.088) and 1.90 (95% CI 0.92–3.94; P = 0.084) for DFS and OS, respectively.
Conclusions
Breast cancer subtypes based on quantitative ER, PR, and Her2 may be predictive of prognosis. Patients whose tumors were not HR+/Her2- had a worse outcome in our study.
PotterP.: “Westernizing” women's risks? Breast cancer in lower-income countries. N Engl J Med, 358: 213–216, 2008.
2.
YangL., LiL.D., ChenY.D., ParkinD.M.: Time trends, estimates and projects for breast cancer incidence and mortality in China. Zhonghua Zhong Liu Za Zhi, 28: 438–440, 2006.
3.
JemalA., SiegelR., WardE., MurrayT., XuJ., ThunM.J.: Cancer statistics, 2007. CA Cancer J Clin, 57: 43–66, 2007.
4.
FisherE.R., CostantinoJ., FisherB., RedmondC.: Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol 4). Discriminants for 15-year survival. National Surgical Adjuvant Breast and Bowel Project Investigators. Cancer, 71: 2141–2150, 1993.
5.
HowatJ.M., BarnesD.M., HarrisM., SwindellR.: The association of cytosol oestrogen and progesterone receptors with histological features of breast cancer and early recurrence of disease. Br J Cancer, 47: 629–640, 1983.
6.
PerouC.M., SørlieT., EisenM.B., van de RijnM., JeffreyS.S., ReesC.A., PollackJ.R., RossD.T., JohnsenH., AkslenL.A., FlugeO., PergamenschikovA., WilliamsC., ZhuS.X., LønningP.E., Børresen-DaleA.L., BrownP.O., BotsteinD.: Molecular portraits of human breast tumours. Nature, 406: 747–752, 2000.
7.
SørlieT., PerouC.M., TibshiraniR., AasT., GeislerS., JohnsenH., HastieT., EisenM.B., van de RijnM., JeffreyS.S., ThorsenT., QuistH., MateseJ.C., BrownP.O., BotsteinD., LønningP.E., Børresen-DaleA.L.: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA, 98: 10869–10874, 2001.
8.
SorlieT., TibshiraniR., ParkerJ., HastieT., MarronJ.S., NobelA., DengS., JohnsenH., PesichR., GeislerS., DemeterJ., PerouC.M., LønningP.E., BrownP.O., Børresen-DaleA.L., BotsteinD.: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA, 100: 8418–8423, 2003.
9.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG): Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet, 365: 1687–1717, 2005.
10.
GrannV.R., TroxelA.B., ZojwallaN.J., JacobsonJ.S., HershmanD., NeugutA.I.: Hormone receptor status and survival in a population-based cohort of patients with breast carcinoma. Cancer, 103: 2241–2251, 2005.
GschwindA., FischerO.M., UllrichA.: The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer, 4: 361–370, 2004.
13.
SlamonD.J., ClarkG.M., WongS.G., LevinW.J., UllrichA., McGuireW.L.: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 235: 177–182, 1987.
14.
SlamonD.J., GodolphinW., JonesL.A., HoltJ.A., WongS.G., KeithD.E., LevinW.J., StuartS.G., UdoveJ., UllrichA.: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 244: 707–712, 1989.
15.
HarrisL., FritscheH., MennelR., NortonL., RavdinP., TaubeS., SomerfieldM.R., HayesD.F., BastR.C.Jr.: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol, 25: 5287–5312, 2007.
16.
GoldhirschA., WoodW.C., GelberR.D., CoatesA.S., ThürlimannB., SennH.J.: Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol, 18: 1133–1144, 2007.
17.
ChenS.J., WangL.P., LuH.F., ShenK.W.: Detection of Her-2 mRNA and protein expression in breast cancer tissues by using chromogenic in situ hybridization and immunohistochemistry methods. Tumor, 28: 705–708, 2008.
18.
BearH.D., AndersonS., SmithR.E., GeyerC.E.Jr., MamounasE.P., FisherB., BrownA.M., RobidouxA., MargoleseR., KahlenbergM.S., PaikS., SoranA., WickerhamD.L., WolmarkN.: Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol, 24: 2019–2027, 2006.
19.
BardouV.J., ArpinoG., ElledgeR.M., OsborneC.K., ClarkG.M.: Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol, 21: 1973–1979, 2003.
20.
ElledgeR.M., GreenS., PughR., AllredD.C., ClarkG.M., HillJ., RavdinP., MartinoS., OsborneC.K.: Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: a Southwest Oncology Group Study. Int J Cancer, 89: 111–117, 2000.
21.
The Arimidex, Tamoxifen, Alone or in Combination (ATAC)Trialists' Group, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M: Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol, 9: 45–53, 2008.
22.
YuK.D., DiG.H., WuJ., LuJ.S., ShenK.W., LiuG.Y., ShenZ.Z., ShaoZ.M.: Breast cancer patients with estrogen receptor-negative/progesterone receptor-positive tumors: being younger and getting less benefit from adjuvant tamoxifen treatment. J Cancer Res Clin Oncol, 134: 1347–1354, 2008.
23.
DowsettM., AllredC., KnoxJ., QuinnE., SalterJ., WaleC., CuzickJ., HoughtonJ., WilliamsN., MallonE., BishopH., EllisI., LarsimontD., SasanoH., CarderP., CussacA.L., KnoxF., SpeirsV., ForbesJ., BuzdarA.: Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol, 26: 1059–1065, 2008.
24.
KimM.J., RoJ.Y., AhnS.H., KimH.H., KimS.B., GongG.: Clinicopathologic significance of the basal-like subtype of breast cancer: A comparison with hormone receptor and Her2/neu-overexpressing phenotypes. Hum Pathol, 37: 1217–1226, 2006.
25.
CareyL.A., PerouC.M., LivasyC.A., DresslerL.G., CowanD., ConwayK., KaracaG., TroesterM.A., TseC.K., EdmistonS., DemingS.L., GeradtsJ., CheangM.C., NielsenT.O., MoormanP.G., EarpH.S., MillikanR.C.: Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA, 295: 2492–2502, 2006.
26.
LiedtkeC., MazouniC., HessK.R., AndréF., TordaiA., MejiaJ.A., SymmansW.F., Gonzalez-AnguloA.M., HennessyB., GreenM., CristofanilliM., HortobagyiG.N., PusztaiL.: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol, 26: 1275–1281, 2008.
27.
IrvinW.J.Jr., CareyL.A.: What is triple-negative breast cancer?Eur J Cancer, 44: 2799–2805, 2008.
28.
TanA.R., SwainS.M.: Therapeutic strategies for triple-negative breast cancer. Cancer J, 14: 343–351, 2008.
29.
PritchardK.I., ShepherdL.E., O'MalleyF.P., AndrulisI.L., TuD., BramwellV.H., LevineM.N.; National Cancer Institute of Canada Clinical Trials Group: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med, 354: 2103–2111, 2006.
30.
YamashitaH., NishioM., ToyamaT., SugiuraH., ZhangZ., KobayashiS., IwaseH.: Coexistence of HER2 over-expression and p53 protein accumulation is a strong prognostic molecular marker in breast cancer. Breast Cancer Res, 6: 24–30, 2004.
GossP.E., IngleJ.N., MartinoS., RobertN.J., MussH.B., PiccartM.J., CastiglioneM., TuD., ShepherdL.E., PritchardK.I., LivingstonR.B., DavidsonN.E., NortonL., PerezE.A., AbramsJ.S., TherasseP., PalmerM.J., PaterJ.L.: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med, 349: 1793–1802, 2003.
