Download Path SDL 37: Carcinoma of the Breast – BONUS Material: Invasive

Path SDL 37: Carcinoma of the Breast – BONUS Material:
 Invasive (Infiltrating) Ductal Carcinoma:
 Recently developed techniques that examine the DNA, RNA, and proteins of carcinomas globally have provided
a framework for NEW MOLECULAR CLASSIFICATIONS for infiltrating ductal carcinomas.
 Gene expression profiling, which can measure the relative quantities of mRNA for essentially every gene, has
identified five major patterns of gene expression in the “invasive carcinoma, NST” group:
A. Luminal A
B. Luminal B
C. Normal
D. Basal-like
E. HER2 positive
 These molecular classes correlate with prognosis and response to therapy, and thus have taken on clinical
importance.
A. "Luminal A" (40% to 55% of NST cancers):
 This is the largest group and consists of cancers that are ER positive and HER2/neu negative.
 THE GENE SIGNATURE IS DOMINATED BY THE DOZENS OF GENES UNDER THE CONTROL OF ER.
 These show increased transcription of genes thought to be characteristic of normal luminal cells.
 The majority are well- or moderately differentiated, and most occur in postmenopausal women.
 These cancers are generally slow growing and respond well to hormonal treatments.
 Conversely, only a small number will respond to standard chemotherapy.
Gene expression portraits of breast
carcinomas. Alterations in DNA, messenger
RNA (mRNA), and protein expression identify
breast cancer subtypes previously recognized
by morphology (e.g., lobular carcinomas) and
define new subtypes ("luminal A," "HER2/neu
positive," and "basal-like").
(Array data courtesy of Dr. Andrea Richardson,
Brigham and Women's Hospital, Boston, MA,
as modified from Signoretti S et al.: Oncogenic
role of the ubiquitin ligase subunit skp2 in
human breast cancer. J Clin Invest 110:633,
2002.)
B. "Luminal B" (15 - 20% of NST cancers):
 This group of cancers also expresses ER but is generally of higher grade, has a higher proliferative rate,
and often overexpresses HER2/neu.
 They compose a major group of ER-positive cancers that are more likely to have lymph node
metastases, and that may respond to chemotherapy.
C. “Normal breast-like" (6 -10% of NST cancers):
 This is a small group of usually well-differentiated ER-positive, HER2/neu-negative cancers characterized
by the similarity of their gene expression pattern to normal tissue.
 It is not yet clear whether or not this is a specific tumor expression pattern.
D. "Basal-like" (13% to 25% of NST cancers):
 THESE CANCERS ARE NOTABLE FOR THE ABSENCE OF ER, PR, AND HER2/NEU (TRIPLE-NEGATIVE) AND
THE EXPRESSION OF MARKERS TYPICAL OF MYOEPITHELIAL CELLS (e.g., basal keratins, P-cadherin, p63,
or laminin), progenitor cells, or putative stem cells (e.g., cytokeratins 5 and 6).
 Members of this group include MEDULLARY CARCINOMAS, METAPLASTIC CARCINOMAS (E.G., SPINDLE
CELL CARCINOMAS OR MATRIX-PRODUCING CARCINOMAS), AND CARCINOMAS WITH A CENTRAL
FIBROTIC FOCUS.
 Many carcinomas arising in women with BRCA1 mutations are of this type.
 There is also an increased incidence in certain ethnic populations and in young women.
 These cancers are generally high grade, associated with an aggressive course, and a poor prognosis.
E. HER2 positive (7% to 12% of NST cancers):
 THIS GROUP COMPRISES ER-NEGATIVE CARCINOMAS THAT OVEREXPRESS HER2/NEU PROTEIN.
 In over 90% of HER2/neu positive cancers, overexpression is due to amplification of the segment of
DNA on 17q21 that includes the HER2/NEU gene and varying numbers of adjacent genes.
 These cancers are usually poorly differentiated, have a high proliferation rate, and are associated with a
high frequency of brain metastasis.