Defining Breast Cancer Intrinsic Subtypes by Quantitative Receptor Expression

被引：139

作者：

Cheang, Maggie C. U. ^{[1
,3
]}

Martin, Miguel ^{[4
]}

Nielsen, Torsten O. ^{[5
]}

Prat, Aleix ^{[6
]}

Voduc, David ^{[7
]}

Rodriguez-Lescure, Alvaro ^{[8
]}

Ruiz, Amparo ^{[9
]}

Chia, Stephen ^{[7
]}

Shepherd, Lois ^{[10
]}

Ruiz-Borrego, Manuel ^{[11
]}

Calvo, Lourdes ^{[12
]}

Alba, Emilio ^{[13
]}

Carrasco, Eva ^{[14
]}

Caballero, Rosalia ^{[14
]}

Tu, Dongsheng ^{[10
]}

Pritchard, Kathleen I. ^{[15
]}

Levine, Mark N. ^{[16
]}

Bramwell, Vivien H. ^{[17
]}

Parker, Joel ^{[1
,2
]}

Bernard, Philip S. ^{[18
]}

Ellis, Matthew J. ^{[19
]}

Perou, Charles M. ^{[1
,2
]}

Di Leo, Angelo ^{[20
]}

Carey, Lisa A. ^{[1
]}

机构：

[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[3] Inst Canc Res, Clin Trials & Stat Unit, London SW3 6JB, England

[4] Univ Complutense Madrid, Fac Med, Inst Invest Sanitaria Hosp Univ Gregorio Maranon, Med Oncol Serv, Madrid, Spain

[5] Univ British Columbia, Dept Pathol, Vancouver, BC, Canada

[6] Vall dHebron Inst Oncol, Translat Genom Unit, Barcelona, Spain

[7] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada

[8] Hosp Gen Univ Elche, Dept Med Oncol, Alicante, Spain

[9] Inst Valenciano Oncol, Dept Med Oncol, Valencia, Spain

[10] Natl Canc Inst Canada, Clin Trials Grp, Kingston, ON, Canada

[11] Hosp Univ Virgen del Rocio, Dept Med Oncol, Seville, Spain

[12] Complejo Hosp Univ A Coruna, Dept Med Oncol, Coruna, Spain

[13] Hosp Univ Virgen de la Victoria, Dept Med Oncol, Malaga, Spain

[14] GEICAM, Madrid, Spain

[15] Univ Toronto, Sunnybrook Odette Canc Ctr, Toronto, ON, Canada

[16] McMaster Univ, Hamilton, ON, Canada

[17] Univ Calgary, Tom Baker Canc Ctr, Dept Oncol, Calgary, AB, Canada

[18] Univ Utah, Hlth Sci Ctr, Dept Pathol, Salt Lake City, UT 84132 USA

[19] Washington Univ, Dept Med, St Louis, MO USA

[20] Ist Toscani Tumori, Dept Oncol, Florence, SC USA

来源：

ONCOLOGIST | 2015年 / 20卷 / 05期

关键词：

Breast cancer; Intrinsic subtypes; Receptor expression; MOLECULAR CHARACTERIZATION; CLINICAL ONCOLOGY/COLLEGE; PROGESTERONE-RECEPTORS; ADJUVANT CHEMOTHERAPY; PREMENOPAUSAL WOMEN; AMERICAN SOCIETY; GENE-EXPRESSION; ESTROGEN; TRIAL; PREDICTOR;

D O I：

10.1634/theoncologist.2014-0372

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose. To determine intrinsic breast cancer subtypes represented within categories defined by quantitative hormone receptor (HR) and HER2 expression. Methods. We merged 1,557 cases from three randomized phase III trials into a single data set. These breast tumors were centrally reviewed in each trial for quantitative ER, PR, and HER2 expression by immunohistochemistry (IHC) stain and by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), with intrinsic subtyping by research-based PAM50RT-qPCR assay. Results. Among 283 HER2-negative tumors with <1% HR expression by IHC, 207 (73%) were basal-like; other subtypes, particularly HER2-enriched (48, 17%), were present. Among the 1,298 HER2-negative tumors, borderline HR (1%-9% staining) was uncommon (n = 39), and these tumors were heterogeneous: 17 (44%) luminal A/B, 12 (31%) HER2-enriched, and only 7 (18%) basal-like. Including them in the definition of triple-negative breast cancer significantly diminished enrichment for basal-like cancer (p < .05). Among 106 HER2-positive tumors with <1% HR expression by IHC, the HER2-enriched subtype was the most frequent (87, 82%), whereas among 127 HER2-positive tumors with strong HR (>10%) expression, only 69 (54%) were HER2-enriched and 55 (43%) were luminal (39 luminal B, 16 luminal A). Quantitative HR expression by RT-qPCR gave similar results. Regardless of methodology, basal-like cases seldom expressed ER/ESR1 or PR/PGR and were associated with the lowest expression level of HER2/ERBB2 relative to other subtypes. Conclusion. Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. For identifying basal-like breast cancer, the optimal HRIHC cut point was <1%, matching the American Society of Clinical Oncology and College of American Pathologists guidelines. Tumors with borderlineHRstaining are molecularly diverse and may require additional assays to clarify underlying biology.

引用

页码：474 / 482

页数：9

共 36 条

[1] Prognosis of early breast cancer by immunohistochemistry defined intrinsic sub-types in patients treated with adjuvant chemotherapy in the NEAT/BR9601 trial [J].

Ali, Alaa M. ;

Provenzano, Elena ;

Bartlett, John M. S. ;

Abraham, Jean ;

Driver, Kristy ;

Munro, Alison F. ;

Twelves, Christopher ;

Poole, Christopher J. ;

Hiller, Louise ;

Dunn, Janet A. ;

Earl, Helena M. ;

Caldas, Carlos ;

Pharoah, Paul D. .

INTERNATIONAL JOURNAL OF CANCER, 2013, 133 (06) :1470-1478

[2] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[3] A randomized placebo-controlled study of tamoxifen after adjuvant chemotherapy in premenopausal women with early breast cancer (National Cancer Institute of Canada-Clinical Trials Group Trial, MA.12) [J].

Bramwell, V. H. C. ;

Pritchard, K. I. ;

Tu, D. ;

Tonkin, K. ;

Vachhrajani, H. ;

Vandenberg, T. A. ;

Robert, J. ;

Arnold, A. ;

O'Reilly, S. E. ;

Graham, B. ;

Shepherd, L. .

ANNALS OF ONCOLOGY, 2010, 21 (02) :283-290

[4]

Carey LA, 2014, J CLIN ONCOL S, V32, p506a

[5] Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study [J].

Carey, Lisa A. ;

Perou, Charles M. ;

Livasy, Chad A. ;

Dressler, Lynn G. ;

Cowan, David ;

Conway, Kathleen ;

Karaca, Gamze ;

Troester, Melissa A. ;

Tse, Chiu Kit ;

Edmiston, Sharon ;

Deming, Sandra L. ;

Geradts, Joseph ;

Cheang, Maggie C. U. ;

Nielsen, Torsten O. ;

Moorman, Patricia G. ;

Earp, H. Shelton ;

Millikan, Robert C. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2006, 295 (21) :2492-2502

[6]

Carey LA, 2013, J CLIN ONCOL, V31

[7] Effect of continuous statistically standardized measures of estrogen and progesterone receptors on disease-free survival in NCIC CTG MA.12 Trial and BC Cohort [J].

Chapman, Judith-Anne W. ;

Nielsen, Torsten O. ;

Ellis, Matthew J. ;

Bernard, Phillip ;

Chia, Stephen ;

Gelmon, Karen A. ;

Pritchard, Kathleen I. ;

Le Maitre, Aurelie ;

Goss, Paul E. ;

Leung, Samuel ;

Shepherd, Lois E. ;

Bramwell, Vivien H. C. .

BREAST CANCER RESEARCH, 2013, 15 (04)

[8] Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial [J].

Cheang, Maggie C. U. ;

Voduc, K. David ;

Tu, Dongsheng ;

Jiang, Shan ;

Leung, Samuel ;

Chia, Stephen K. ;

Shepherd, Lois E. ;

Levine, Mark N. ;

Pritchard, Kathleen I. ;

Davies, Sherri ;

Stijleman, Inge J. ;

Davis, Carole ;

Ebbert, Mark T. W. ;

Parker, Joel S. ;

Ellis, Matthew J. ;

Bernard, Philip S. ;

Perou, Charles M. ;

Nielsen, Torsten O. .

CLINICAL CANCER RESEARCH, 2012, 18 (08) :2402-2412

[9] A 50-Gene Intrinsic Subtype Classifier for Prognosis and Prediction of Benefit from Adjuvant Tamoxifen [J].

Chia, Stephen K. ;

Bramwell, Vivien H. ;

Tu, Dongsheng ;

Shepherd, Lois E. ;

Jiang, Shan ;

Vickery, Tammi ;

Mardis, Elaine ;

Leung, Samuel ;

Ung, Karen ;

Pritchard, Kathleen I. ;

Parker, Joel S. ;

Bernard, Philip S. ;

Perou, Charles M. ;

Ellis, Matthew J. ;

Nielsen, Torsten O. .

CLINICAL CANCER RESEARCH, 2012, 18 (16) :4465-4472

[10] Comparison of PAM50 Risk of Recurrence Score With Oncotype DX and IHC4 for Predicting Risk of Distant Recurrence After Endocrine Therapy [J].

Dowsett, Mitch ;

Sestak, Ivana ;

Lopez-Knowles, Elena ;

Sidhu, Kalvinder ;

Dunbier, Anita K. ;

Cowens, J. Wayne ;

Ferree, Sean ;

Storhoff, James ;

Schaper, Carl ;

Cuzick, Jack .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (22) :2783-+

← 1 2 3 4 →