Pathology Associates Of Lexington, P.A.
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        Molecular/DNA/Genomic-based Classification
      

[Back to Breast Cancer Index]

Though all types of "expression" are a result of DNA programming, the current molecular classification is pretty much related to patterns of protein & receptor expression or non-expression. Patterns of nucleic acid content of cancer cells are being evaluated. Breast epithelial structures have an inner luminal epithelium and an outer basal or myoepithelial layer6. Current thinking is that breast epithelia derives from ck5+/ck8- stem cells (progenitor cells) to form the luminal glandular cells (ck8+) and the outer myoepithelial cells (SMA+). Normally, the ck5 down-regulates/becomes lost as structures differentiate to ck8 or SMA positivity. Usual ductal  hyperplasia tends to have much ck5 positivity, while d-AH and d-CIS more ck8+ and far less to negative for ck5. Large numbers of breast cancers were studied using DNA micro-array testing, and Perou used this to lead to the below four groups, the thinking being that cancers derive from luminal (duct and lobular) epithelium or myoepithelium (basal); and Sorlie6 used gene expression profiles by micro-array to sort breast cancer into 5 groups. We started to speak of "triple negative" breast cancers (ER, PR, & HER-2 negative) in 2005. The Neilson & Gown criteria for "basal-like" breast cancer are more specific than "triple negative": no ER nuclear positivity, plus HER-2 that is less than 3+, plus either ck5 cytoplasmic positivity (weak or strong) of invasive tumor cells, or EGFR cytoplasmic positivity (weak or strong) of invasive tumor cells. The "basal-like" subtype has a significantly decreased relapse-free survival, indicating poor prognosis.6  EFGR and c-kit status can identify potential therapeutic opportunities. "Luminal" markers are ER, PR, & ck8; basal markers CK5, CK17, EGFR, and vimentin14.

Four breast cancer molecular classes8:

  • HER-2 positive
  • HER-2 negative, ER/PR positive...favorable (on basis of genomic, etc.) type.
  • HER-2 negative, ER/PR positive...unfavorable (on basis of genomic, etc.) type.
  • basal-like ["triple negative"...HER-2 being less than 3+ ]

Data Table From Various Sources

  ER PR HER-2 Ki67
(MIB1) prolif.		 other IHC markers comments

normal-breast-like9

MMN (multiple marker negative)

neg./weak pos. neg./weak pos. neg. low  

27%

better prog. than basal-like but poor response to neo-adjuvant chemo.10. Strong ck8.

luminal A9 high pos. high pos. neg. low  

27%

grade I & sensitive to anti-hormonal TX. FOXA1 expression defines13. Is negatively correlated with OncoType DX risk score & better prognosis12.
luminal B9 lower pos. lower pos. expressed increased  

12%

intermediate prog.

Her-2 amplified9 essentially negative   pos. (amplified) high  

21%

poor prog.
basal-like9... (stem cell ck5/6+; EGFR+;
c-kit+; p53+2).		 neg. neg. neg. for product over-expression or gene amplification6. high

2004 definition is ck5/6+, plus ER+, plus HER-2-, plus EGFR+10;

pos. for ck5/61, 6 and 80-96% specific11 ; or EGFR6; (50% p63 pos.6 and less than 10% of non-basals pos. ).

 

13%

Tend hematogenous spread10. Poorest prognosis. Most likely of mole. types to met to brain9, 10. About 19% of brcas & strongly assoc. with BRCA1 pos6. High proportion are EGFR pos3. Some 80% are ductal, 73% grade 3, 67% ck5/6+ & are triple neg., 75% increased Ki67, 65% EGFR pos4. Often mammaglobin & GCDFP-15 negative 3. So genetically unstable that should be a target for DNA damaging chemo. Tend to "pushing" border & tend lymphocytic host response & are triple neg. & ck5/6+ &/or EGFR pos.9.

References:

  1. PhenoPath 2005 newsletter.
  2. various Googled web sources.
  3. Gown A., personal communication 3/6/05 and later.
  4. Siziopikou KP, et. al., annual meeting abstracts USCAP (2/26-3/4/05), "The Basal Subtype of Breast Carcinomas..." [from Rush U. Med. Ctr., Chicago].
  5. Perou CM, et al, Nature (2000), (London), 406:747-752.
  6. Miller RT, Immunohistochemistry in the Recognition of "Basal-like" or "Basaloid" Breast Carcinoma, ProPath The Focus newsletter, July 2005, @ Immunoportal.com.
  7. Nielson TO, Gown A, et. al., Immunohistochemical and clinical characterization of basal-like subtype of of invasive breast carcinoma, Clin. Cancer Research, 5367-5374,15 August 2004.
  8. articles & editorials, NEJMed 353(16):1654, 20 October 2005 .
  9. David G. Hicks, MD, Director of S. P., Dept. Path. & Lab. Med. @ U. of Rochester Med. Ctr., Rochester, N. Y. & previously @ Cleveland Clinic. Molecular interests. He was a speaker at The Second International Course in Applied Immunohistochemistry and Molecular Pathology (Santa Barbara, Calif. 1/28/08-2/1/08).
  10. Reis-Filho JS & Tutt, ANJ, [from London] "Triple Negative Tumors: a Critical Review", Histopathology 52(1):108-118, January 2008.
  11. Feb. 2008 issue of PhenoPath's "Phenomena" (a 4 March 2008 USCAP poster session "Basal-like...".
  12. Sitiriou C, et. a., "Review: Gene-Expression Signatures in Breast Cancer", NEJMed 360(8):790-800 February 19, 2009.
  13. Badve S, et. al., "Imaging, Diagnosis, Prognosis: FOXA1 Expression in Breast Cancer—Correlation with Luminal Subtype A and Survival", Clinical Cancer Research 13:4415, August 1, 2007.
  14. Diallo-Danebrock R, et. al., "Protein Expression Profiling in High-Risk Breast Cancer Patients Treated with High-Dose or Conventional Dose–Dense Chemotherapy", Clinical Cancer Research 13:488, January 15, 2007.
(posted 26 February 2005; latest addition 1 August 2009)
 
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