PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance)

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Abstract

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99–1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS ( P < 0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P < 0.0001), but no association with treatment benefit was seen ( P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline- and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

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Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer

Maggie C. U. Cheang, Stephen Chia, David Voduc … (2009)

Background Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival. Methods Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan–Meier curves and multivariable Cox regression. Results Gene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor–positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer–specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal–HER2 subtypes. Conclusion Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.

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Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype.

Maggie C. U. Cheang, David Voduc, Chris Bajdik … (2008)

Basal-like breast cancer is associated with high grade, poor prognosis, and younger patient age. Clinically, a triple-negative phenotype definition [estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER)-2, all negative] is commonly used to identify such cases. EGFR and cytokeratin 5/6 are readily available positive markers of basal-like breast cancer applicable to standard pathology specimens. This study directly compares the prognostic significance between three- and five-biomarker surrogate panels to define intrinsic breast cancer subtypes, using a large clinically annotated series of breast tumors. Four thousand forty-six invasive breast cancers were assembled into tissue microarrays. All had staging, pathology, treatment, and outcome information; median follow-up was 12.5 years. Cox regression analyses and likelihood ratio tests compared the prognostic significance for breast cancer death-specific survival (BCSS) of the two immunohistochemical panels. Among 3,744 interpretable cases, 17% were basal using the triple-negative definition (10-year BCSS, 6 7%) and 9% were basal using the five-marker method (10-year BCSS, 62%). Likelihood ratio tests of multivariable Cox models including standard clinical variables show that the five-marker panel is significantly more prognostic than the three-marker panel. The poor prognosis of triple-negative phenotype is conferred almost entirely by those tumors positive for basal markers. Among triple-negative patients treated with adjuvant anthracycline-based chemotherapy, the additional positive basal markers identified a cohort of patients with significantly worse outcome. The expanded surrogate immunopanel of estrogen receptor, progesterone receptor, human HER-2, EGFR, and cytokeratin 5/6 provides a more specific definition of basal-like breast cancer that better predicts breast cancer survival.

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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, Samuel Leung … (2010)

To compare clinical, immunohistochemical (IHC), and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor (ER)-positive breast cancers from patients uniformly treated with adjuvant tamoxifen. Quantitative real-time reverse transcription-PCR (qRT-PCR) assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median follow-up, 11.7 years) and IHC [ER, progesterone receptor (PR), HER2, and Ki67] data. Performance of predefined intrinsic subtype and risk-of-relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell's C-index was used to compare fixed models trained in independent data sets, including proliferation signatures. Despite clinical ER positivity, 10% of cases were assigned to nonluminal subtypes. qRT-PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease-specific survival over the first 5 years of follow-up, relative to the most common luminal A subtype, are 1.99 [95% confidence interval (CI), 1.09-3.64] for luminal B, 3.65 (95% CI, 1.64-8.16) for HER2-enriched subtype, and 17.71 (95% CI, 1.71-183.33) for the basal-like subtype. For node-negative disease, PAM50 qRT-PCR-based risk assignment weighted for tumor size and proliferation identifies a group with >95% 10-year survival without chemotherapy. In node-positive disease, PAM50-based prognostic models were also superior. The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin-fixed, paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and IHC using standard cut points. ©2010 AACR.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101674891

Journal ID (pubmed-jr-id): 44777

Journal ID (nlm-ta): NPJ Breast Cancer

Journal ID (iso-abbrev): NPJ Breast Cancer

Title: NPJ breast cancer

ISSN (Electronic): 2374-4677

Publication date Nihms-submitted: 15 April 2017

Publication date (Electronic): 6 January 2016

Publication date (Print): 2016

Publication date PMC-release: 07 July 2017

Volume: 2

Electronic Location Identifier: 15023

Affiliations

[1 ]Department of Oncology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

[2 ]Department of Biostatistics and Bioinformatics, Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC, USA

[3 ]The Genome Institute, Washington University, St. Louis, MO, USA

[4 ]Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

[5 ]Alliance for Clinical Trials in Oncology, University of Chicago, Chicago, IL, USA

[6 ]Department of Pathology, Washington University, St. Louis, MO, USA

[7 ]Department of Pathology, New York University Medical Center, New York, NY, USA

[8 ]Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

[9 ]Department of Medicine, Mayo Clinic, Jacksonville, FL, USA

[10 ]The Angeles Clinic and Research Institute, Santa Monica, CA, USA

[11 ]Department of Medical Oncology, Hofstra North Shore-LIJ School of Medicine, ProHEALTH Care Associates, Lake Success, NY, USA

[12 ]Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

[13 ]Department of Medicine, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

[14 ]Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

[15 ]Department of Pathology, Huntsman Cancer Center, University of Utah, Salt Lake City, UT, USA

[16 ]Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, USA

[17 ]Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

[18 ]Department of Medical Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

[19 ]Department of Biostatistics and Computational Biology, Alliance Statistics and Data Center, Dana Farber Cancer Institute, Boston, MA, USA

Author notes

Correspondence: MC Liu ( liu.minetta@ 123456mayo.edu )

Article

Manuscript ID: NIHMS829888

DOI: 10.1038/npjbcancer.2015.23

PMC ID: 5501351

PubMed ID: 28691057

SO-VID: 878a4327-fabc-45bc-a255-4078b778bfe1

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PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance)

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Most cited references 17

Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer

Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype.

A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer.

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