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. 2017 May 1;77(9):2213-2221.
doi: 10.1158/0008-5472.CAN-16-2717. Epub 2017 Mar 1.

Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer

Juan M Cejalvo  1   2 , Eduardo Martínez de Dueñas  3   4 , Patricia Galván  5 , Susana García-Recio  1 , Octavio Burgués Gasión  4   6 , Laia Paré  1 , Silvia Antolín  4   7 , Rosella Martinello  1 , Isabel Blancas  4   8 , Barbara Adamo  1 , Ángel Guerrero-Zotano  4   9 , Montserrat Muñoz  1 , Paolo Nucíforo  5 , María Vidal  1 , Ramón M Pérez  4   10 , José I Chacón López-Muniz  4   11 , Rosalía Caballero  4 , Vicente Peg  12 , Eva Carrasco  4 , Federico Rojo  4   13   14 , Charles M Perou  15 , Javier Cortés  4   16 , Vincenzo Adamo  17 , Joan Albanell  4   18   14 , Roger R Gomis  2   19 , Ana Lluch  4   20   14 , Aleix Prat  21   5
Affiliations

Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer

Juan M Cejalvo et al. Cancer Res. .

Abstract

Biological changes that occur during metastatic progression of breast cancer are still incompletely characterized. In this study, we compared intrinsic molecular subtypes and gene expression in 123 paired primary and metastatic tissues from breast cancer patients. Intrinsic subtype was identified using a PAM50 classifier and χ2 tests determined the differences in variable distribution. The rate of subtype conversion was 0% in basal-like tumors, 23.1% in HER2-enriched (HER2-E) tumors, 30.0% in luminal B tumors, and 55.3% in luminal A tumors. In 40.2% of cases, luminal A tumors converted to luminal B tumors, whereas in 14.3% of cases luminal A and B tumors converted to HER2-E tumors. We identified 47 genes that were expressed differentially in metastatic versus primary disease. Metastatic tumors were enriched for proliferation-related and migration-related genes and diminished for luminal-related genes. Expression of proliferation-related genes were better at predicting overall survival in metastatic disease (OSmet) when analyzed in metastatic tissue rather than primary tissue. In contrast, a basal-like gene expression signature was better at predicting OSmet in primary disease compared with metastatic tissue. We observed correlations between time to tumor relapse and the magnitude of changes of proliferation, luminal B, or HER2-E signatures in metastatic versus primary disease. Although the intrinsic subtype was largely maintained during metastatic progression, luminal/HER2-negative tumors acquired a luminal B or HER2-E profile during metastatic progression, likely reflecting tumor evolution or acquisition of estrogen independence. Overall, our analysis revealed the value of stratifying gene expression by both cancer subtype and tissue type, providing clinicians more refined tools to evaluate prognosis and treatment. Cancer Res; 77(9); 2213-21. ©2017 AACR.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

C.M. Perou is a Board of Directors Member, has ownership interest (including patents), and is a consultant/advisory board member for Bioclassifier LLC. A. Prat is a consultant/advisory board member for NanoString Technologies. No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
Distribution of intrinsic subtype in primary versus metastatic disease.
Figure 2
Figure 2
Gene and signature expression changes between primary and metastasis. P value was obtained after performing a paired t test.
Figure 3
Figure 3
Association of 10 signatures with OSmet when evaluated in primary (A) and metastatic (B) disease. Each signature was evaluated as a continuous variable and was standardized to have a mean of 0 and a SD of 1. The size of the square is inversely proportional to the SE; horizontal bars represent the 95% Cls of HRs. Statistically significant variables are shown in blue. Each gene signature was evaluated in a univariate analysis.
Figure 4
Figure 4
Venn diagram of genes that predict overall survival from the data of recurrence when analyzed in primary versus metastatic disease. Green, genes associated with good prognosis; red, genes associated with poor prognosis.
Figure 5
Figure 5
Correlation between time to tumor recurrence (TTR) and the magnitude of gene/signature expression changes between primary and metastatic disease.
See this image and copyright information in PMC

References

    1. Cardoso F, Costa A, Norton L, Senkus E, Aapro M, André F, et al. ESO-ESMO 2nd International Consensus Guidelines for advanced breast cancer (ABC2) Ann Oncol. 2014;25:1871–88. - PMC - PubMed
    1. O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364:205–14. - PubMed
    1. Baselga J, Campone M, Piccart M, Burris HA, III, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9. - PMC - PubMed
    1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25–35. - PubMed
    1. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109–19. - PMC - PubMed

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