Journal Article
. 2019 Feb; 175(2):287-295.
doi: 10.1007/s10549-019-05142-x.

Systemic treatment and radiotherapy, breast cancer subtypes, and survival after long-term clinical follow-up

Sherry X Yang 1 Eric C Polley 2 
Affiliations
  • PMID: 30746635
  •     42 References
  •     6 citations

Abstract

Background: It remains unclear whether breast cancer subtypes are associated with clinical outcome in patients without any treatment including systemic and radiation therapy as an independent entity. Understanding the survival profiles among subtypes by treatment status could impact optimal selection of treatments.

Methods: Patients were diagnosed with invasive breast cancer from the community hospitals across four geographical regions of the United States. Expression of hormone receptor (HR) and HER2 in tumor specimens from 1169 patients was centrally determined by immunohistochemistry and fluorescence in situ; breast cancer was classified into HR+/HER2-, HR+/HER2+, triple-negative, and HER2+ subtypes. Overall survival (OS) at a median follow-up of about 15 years among subtypes in untreated patients and those with systemic treatments and radiotherapy was analyzed by Kaplan-Meier method and multivariable analysis adjusting for age, tumor size and grade, number of positive nodes, stage and breast cancer subtypes.

Results: Without treatment, breast cancer subtypes were not associated with OS (P = 0.983) and remained insignificant for prognosis by multivariable analysis after adjusting for confounders. This contrasted with a significant survival difference across the subtypes in patients with conventional therapies (P < 0.0001). Compared with HR+/HER2- subtype, triple-negative subtype (HR 1.5, 95% CI 1.11-2.04; P = 0.009) and HER2+ subtype (HR 2.18, 95% CI 1.48-3.28; P = 0.0001) were significantly associated with worse survival by multivariable analyses.

Conclusion: Breast cancer subtypes are not associated with survival in untreated patient population and, in contrast, significantly associated with prognosis in patients with conventional therapy. The data provide evidence of treatment-associated differential outcomes among breast cancer subtypes.

Keywords: Breast cancer subtypes; HER2; Hormone receptor (HR); Overall survival; Radiotherapy; Systemic treatment; Triple-negative breast cancer.

Molecular portraits of human breast tumours.
C M Perou, T Sørlie, +15 authors, D Botstein.
Nature, 2000 Aug 30; 406(6797). PMID: 10963602
Highly Cited.
The Cooperative Breast Cancer Tissue Resource: archival tissue for the investigation of tumor markers.
A G Glass, H Donis-Keller, +5 authors, Cooperative Breast Cancer Tissue Resource.
Clin Cancer Res, 2001 Jul 13; 7(7). PMID: 11448894
Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
T Sørlie, C M Perou, +14 authors, A L Børresen-Dale.
Proc Natl Acad Sci U S A, 2001 Sep 13; 98(19). PMID: 11553815    Free PMC article.
Highly Cited.
Gene expression profiling predicts clinical outcome of breast cancer.
Laura J van 't Veer, Hongyue Dai, +13 authors, Stephen H Friend.
Nature, 2002 Feb 02; 415(6871). PMID: 11823860
Highly Cited.
A gene-expression signature as a predictor of survival in breast cancer.
Marc J van de Vijver, Yudong D He, +18 authors, René Bernards.
N Engl J Med, 2002 Dec 20; 347(25). PMID: 12490681
Highly Cited.
Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer.
Yixin Wang, Jan G M Klijn, +11 authors, John A Foekens.
Lancet, 2005 Feb 22; 365(9460). PMID: 15721472
Highly Cited.
Molecular classification and molecular forecasting of breast cancer: ready for clinical application?
James D Brenton, Lisa A Carey, Ahmed Ashour Ahmed, Carlos Caldas.
J Clin Oncol, 2005 Sep 08; 23(29). PMID: 16145060
Highly Cited. Review.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study.
Lisa A Carey, Charles M Perou, +14 authors, Robert C Millikan.
JAMA, 2006 Jun 08; 295(21). PMID: 16757721
Highly Cited.
REporting recommendations for tumor MARKer prognostic studies (REMARK).
Lisa M McShane, Douglas G Altman, +4 authors, Statistics Subcommittee of NCI-EORTC Working Group on Cancer Diagnostics.
Breast Cancer Res Treat, 2006 Aug 26; 100(2). PMID: 16932852
Highly Cited.
Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.
Sherene Loi, Benjamin Haibe-Kains, +14 authors, Christos Sotiriou.
J Clin Oncol, 2007 Apr 03; 25(10). PMID: 17401012
Highly Cited.
The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes.
Lisa A Carey, E Claire Dees, +7 authors, Charles M Perou.
Clin Cancer Res, 2007 Apr 18; 13(8). PMID: 17438091
Highly Cited.
Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy.
Paul L Nguyen, Alphonse G Taghian, +7 authors, Jay R Harris.
J Clin Oncol, 2008 Apr 17; 26(14). PMID: 18413639
Highly Cited.
Supervised risk predictor of breast cancer based on intrinsic subtypes.
Joel S Parker, Michael Mullins, +17 authors, Philip S Bernard.
J Clin Oncol, 2009 Feb 11; 27(8). PMID: 19204204    Free PMC article.
Highly Cited.
Systemic effects of local radiotherapy.
Silvia C Formenti, Sandra Demaria.
Lancet Oncol, 2009 Jul 04; 10(7). PMID: 19573801    Free PMC article.
Highly Cited. Review.
American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.
M Elizabeth H Hammond, Daniel F Hayes, +29 authors, Antonio C Wolff.
J Clin Oncol, 2010 Apr 21; 28(16). PMID: 20404251    Free PMC article.
Highly Cited. Systematic Review.
Akt phosphorylation at Ser473 predicts benefit of paclitaxel chemotherapy in node-positive breast cancer.
Sherry X Yang, Joseph P Costantino, +7 authors, Sandra M Swain.
J Clin Oncol, 2010 May 19; 28(18). PMID: 20479407    Free PMC article.
A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer.
Torsten O Nielsen, Joel S Parker, +12 authors, Matthew J Ellis.
Clin Cancer Res, 2010 Sep 15; 16(21). PMID: 20837693    Free PMC article.
Highly Cited.
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.
A Goldhirsch, W C Wood, +4 authors, Panel members.
Ann Oncol, 2011 Jun 29; 22(8). PMID: 21709140    Free PMC article.
Highly Cited.
Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), C Davies, +11 authors, R Peto.
Lancet, 2011 Aug 02; 378(9793). PMID: 21802721    Free PMC article.
Highly Cited.
Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), S Darby, +13 authors, R Peto.
Lancet, 2011 Oct 25; 378(9804). PMID: 22019144    Free PMC article.
Highly Cited. Review.
Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), R Peto, +15 authors, K Pritchard.
Lancet, 2011 Dec 14; 379(9814). PMID: 22152853    Free PMC article.
Highly Cited.
A 50-gene intrinsic subtype classifier for prognosis and prediction of benefit from adjuvant tamoxifen.
Stephen K Chia, Vivien H Bramwell, +12 authors, Torsten O Nielsen.
Clin Cancer Res, 2012 Jun 20; 18(16). PMID: 22711706    Free PMC article.
Highly Cited.
Breast cancer subtypes: response to radiotherapy and potential radiosensitisation.
F E Langlands, K Horgan, D D Dodwell, L Smith.
Br J Radiol, 2013 Feb 09; 86(1023). PMID: 23392193    Free PMC article.
Review.
Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy.
Mitch Dowsett, Ivana Sestak, +7 authors, Jack Cuzick.
J Clin Oncol, 2013 Jul 03; 31(22). PMID: 23816962
Highly Cited.
Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients.
M J Engstrøm, S Opdahl, +5 authors, A M Bofin.
Breast Cancer Res Treat, 2013 Aug 01; 140(3). PMID: 23901018    Free PMC article.
Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer.
D J Slamon, W Godolphin, +7 authors, A Ullrich.
Science, 1989 May 12; 244(4905). PMID: 2470152
Highly Cited.
US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status.
Nadia Howlader, Sean F Altekruse, +4 authors, Kathleen A Cronin.
J Natl Cancer Inst, 2014 Apr 30; 106(5). PMID: 24777111    Free PMC article.
Highly Cited.
Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial.
Katherine L Pogue-Geile, Nan Song, +13 authors, Soonmyung Paik.
J Clin Oncol, 2015 Jan 07; 33(12). PMID: 25559813    Free PMC article.
Clinical implications of the intrinsic molecular subtypes of breast cancer.
Aleix Prat, Estela Pineda, +7 authors, Montserrat Muñoz.
Breast, 2015 Aug 09; 24 Suppl 2. PMID: 26253814
Highly Cited. Review.
Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V.
Marco Colleoni, Zhuoxin Sun, +8 authors, Aron Goldhirsch.
J Clin Oncol, 2016 Jan 21; 34(9). PMID: 26786933    Free PMC article.
Highly Cited.
Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology.
William J Gradishar, Benjamin O Anderson, +28 authors, Rashmi Kumar.
J Natl Compr Canc Netw, 2016 Mar 10; 14(3). PMID: 26957618
Highly Cited.
New insights on PI3K/AKT pathway alterations and clinical outcomes in breast cancer.
Sherry X Yang, Eric Polley, Stanley Lipkowitz.
Cancer Treat Rev, 2016 Mar 21; 45. PMID: 26995633    Free PMC article.
Highly Cited. Review.
Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients.
Tina Gruosso, Virginie Mieulet, +8 authors, Fatima Mechta-Grigoriou.
EMBO Mol Med, 2016 Mar 24; 8(5). PMID: 27006338    Free PMC article.
Association of γH2AX at Diagnosis with Chemotherapy Outcome in Patients with Breast Cancer.
Sherry X Yang, Eric C Polley, Dat Nguyen.
Theranostics, 2017 Apr 07; 7(4). PMID: 28382166    Free PMC article.
Response to Radiotherapy After Breast-Conserving Surgery in Different Breast Cancer Subtypes in the Swedish Breast Cancer Group 91 Radiotherapy Randomized Clinical Trial.
Martin Sjöström, Dan Lundstedt, +8 authors, Per Karlsson.
J Clin Oncol, 2017 Aug 02; 35(28). PMID: 28759347
Systematic review and meta-analysis of the efficacy of breast conservation therapy followed by radiotherapy in four breast cancer subtypes.
Xin-Bin Pan, Rou-Jun Chen, +2 authors, Xiao-Dong Zhu.
Oncotarget, 2017 Sep 17; 8(34). PMID: 28915682    Free PMC article.
20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years.
Hongchao Pan, Richard Gray, +9 authors, EBCTCG.
N Engl J Med, 2017 Nov 09; 377(19). PMID: 29117498    Free PMC article.
Highly Cited.
Cancer statistics, 2018.
Rebecca L Siegel, Kimberly D Miller, Ahmedin Jemal.
CA Cancer J Clin, 2018 Jan 10; 68(1). PMID: 29313949
Highly Cited.
Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.
Antonio C Wolff, M Elizabeth Hale Hammond, +14 authors, Mitchell Dowsett.
J Clin Oncol, 2018 May 31; 36(20). PMID: 29846122
Highly Cited.
Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
Joseph A Sparano, Robert J Gray, +27 authors, George W Sledge.
N Engl J Med, 2018 Jun 05; 379(2). PMID: 29860917    Free PMC article.
Highly Cited.
Hormone receptors: their role in predicting prognosis and response to endocrine therapy.
W L McGuire.
Semin Oncol, 1978 Dec 01; 5(4). PMID: 734443
Highly Cited.
Association of Independent Prognostic Factors and Treatment Modality With Survival and Recurrence Outcomes in Breast Cancer.
Dat Nguyen, John Yu, William C Reinhold, Sherry X Yang.
JAMA Netw Open, 2020 Jul 10; 3(7). PMID: 32644137    Free PMC article.
A DNA Methylation-Based Panel for the Prognosis and Dagnosis of Patients With Breast Cancer and Its Mechanisms.
Xiao-Ping Liu, Jinxuan Hou, +3 authors, Sheng Li.
Front Mol Biosci, 2020 Aug 01; 7. PMID: 32733914    Free PMC article.
The Hypoxic Response Expression as a Survival Biomarkers in Treatment-Naive Advanced Breast Cancer.
Irwan Gunawan, Mochammad Hatta, Andi Fachruddin Benyamin, Andi Asadul Islam.
Asian Pac J Cancer Prev, 2020 Mar 28; 21(3). PMID: 32212787    Free PMC article.
Risk of recurrence among patients with HR-positive, HER2-negative, early breast cancer receiving adjuvant endocrine therapy: A systematic review and meta-analysis.
Elizabeth M Salvo, Abril Oliva Ramirez, +4 authors, Imtiaz A Samjoo.
Breast, 2021 Mar 08; 57. PMID: 33677313    Free PMC article.
KIN17 promotes tumor metastasis by activating EMT signaling in luminal-A breast cancer.
Qiyuan Huang, Kashif Rafiq Zahid, +9 authors, Tao Zeng.
Thorac Cancer, 2021 May 20; 12(13). PMID: 34008927    Free PMC article.
The association between molecular type and prognosis of patients with stage IV breast cancer: an observational study based on SEER database.
Lingmi Hou, Mengxue Qiu, +6 authors, Hongwei Yang.
Gland Surg, 2021 Jul 17; 10(6). PMID: 34268073    Free PMC article.