Cheang Maggie C U, Martin Miguel, Nielsen Torsten O, Prat Aleix, Voduc David, Rodriguez-Lescure Alvaro, Ruiz Amparo, Chia Stephen, Shepherd Lois, Ruiz-Borrego Manuel, Calvo Lourdes, Alba Emilio, Carrasco Eva, Caballero Rosalia, Tu Dongsheng, Pritchard Kathleen I, Levine Mark N, Bramwell Vivien H, Parker Joel, Bernard Philip S, Ellis Matthew J, Perou Charles M, Di Leo Angelo, Carey Lisa A
Lineberger Comprehensive Cancer Center and Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA; Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, United Kingdom; Servicio de Oncología Médica, Instituto de Investigacion Sanitaria Hospital Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; Translation Genomics Unit, Vall d´Hebron Institute of Oncology, Barcelona, Spain; British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Department of Medical Oncology, Hospital General Universitario de Elche, Alicante, Spain; Department of Medical Oncology, Instituto Valenciano de Oncologia, Valencia, Spain; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; Department of Medical Oncology, Hospital Universitario Virgen del Rocio, Seville, Spain; Department of Medical Oncology, Complejo Hospitalario Universitario A Coruña, Coruña, Spain; Department of Medical Oncology, Hospital Universitario Virgen de la Victoria, Málaga, Spain; GEICAM, Madrid, Spain; Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada; McMaster University, Hamilton, Ontario, Canada; Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada; Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA; Department of Medicine, Washington University, St. Louis, Missouri, USA; Department of Oncology, Hospital of Prato, Istituto Toscani Tumori, Florence, Italy.
Lineberger Comprehensive Cancer Center and Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA; Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, United Kingdom; Servicio de Oncología Médica, Instituto de Investigacion Sanitaria Hospital Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; Translation Genomics Unit, Vall d´Hebron Institute of Oncology, Barcelona, Spain; British Columbia Cancer Agency, Vancouver, British Columbia, Canada; Department of Medical Oncology, Hospital General Universitario de Elche, Alicante, Spain; Department of Medical Oncology, Instituto Valenciano de Oncologia, Valencia, Spain; National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada; Department of Medical Oncology, Hospital Universitario Virgen del Rocio, Seville, Spain; Department of Medical Oncology, Complejo Hospitalario Universitario A Coruña, Coruña, Spain; Department of Medical Oncology, Hospital Universitario Virgen de la Victoria, Málaga, Spain; GEICAM, Madrid, Spain; Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada; McMaster University, Hamilton, Ontario, Canada; Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada; Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA; Department of Medicine, Washington University, St. Louis, Missouri, USA; Department of Oncology, Hospital of Prato, Istituto Toscani Tumori, Florence, Italy
Oncologist. 2015 May;20(5):474-82. doi: 10.1634/theoncologist.2014-0372. Epub 2015 Apr 23.
To determine intrinsic breast cancer subtypes represented within categories defined by quantitative hormone receptor (HR) and HER2 expression.
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 PAM50 RT-qPCR assay.
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.
Significant discordance remains between clinical assay-defined subsets and intrinsic subtype. For identifying basal-like breast cancer, the optimal HR IHC cut point was <1%, matching the American Society of Clinical Oncology and College of American Pathologists guidelines. Tumors with borderline HR staining are molecularly diverse and may require additional assays to clarify underlying biology.
确定在由定量激素受体（HR）和HER2表达定义的类别中所代表的原发性乳腺癌亚型。
我们将来自三项随机III期试验的1557例病例合并为一个数据集。在每项试验中，通过免疫组织化学（IHC）染色和逆转录定量聚合酶链反应（RT-qPCR）对这些乳腺肿瘤进行集中审查，以检测定量雌激素受体（ER）、孕激素受体（PR）和HER2表达，并通过基于研究的PAM50 RT-qPCR检测进行内在亚型分类。
在283例通过IHC检测HR表达<1%的HER2阴性肿瘤中，207例（73%）为基底样型；存在其他亚型，尤其是HER2富集型（48例，17%）。在1298例HER2阴性肿瘤中，HR临界值（1%-9%染色）不常见（n = 39），且这些肿瘤具有异质性：17例（44%）为腔面A/B型，12例（31%）为HER2富集型，仅7例（18%）为基底样型。将它们纳入三阴性乳腺癌的定义中会显著降低基底样癌的富集度（p < 0.05）。在106例通过IHC检测HR表达<1%的HER2阳性肿瘤中，HER2富集型亚型最为常见（87例，82%），而在127例HR强阳性（>10%）表达的HER2阳性肿瘤中，只有69例（54%）为HER2富集型，55例（43%）为腔面型（39例腔面B型，16例腔面A型）。通过RT-qPCR进行的定量HR表达给出了相似的结果。无论采用何种方法，基底样病例很少表达ER/ESR1或PR/PGR，并且相对于其他亚型，其HER2/ERBB2表达水平最低。
临床检测定义的亚组与内在亚型之间仍存在显著不一致。为了识别基底样乳腺癌，最佳的HR IHC切点为<1%，符合美国临床肿瘤学会和美国病理学家学会的指南。HR染色临界的肿瘤在分子水平上具有多样性，可能需要额外的检测来阐明其潜在生物学特性。
