Oncology Nurses

Triple Negative Breast Cancer Pathophysiology

PATHOPHYSIOLOGY OF TRIPLE NEGATIVE BREAST CANCER (TNBC)

TNBC is defined immunohistochemically as a breast cancer that lacks expression of hormone receptors estrogen (ER) and progesterone (PR), and does not over-express human epidermal growth factor receptor 2 (HER2).1,2 Despite this immunohistochemical definition, TNBCs often have radiologic and morphologic features that distinguish them from non-TNBCs.2

On mammographic imaging, features such as irregular shape, spiculated margins, and associated suspicious calcifications are less frequently present in TNBC, with the most common presentation being a mass without associated calcifications2.  Some tumors may be occult on mammography (18% of cases), necessitating ultrasonography for enhanced sensitivity of detection (92%-100%).2 On ultrasound, TNBCs are usually irregular or oval in shape, with mostly microlobulated margins.2 MRI has been reported to yield the highest sensitivity, with highly predictive rim enhancement as a common TNBC feature.2 Both ultrasonography and MRI are associated with a high false-positive rate.2 Despite heightened sensitivity of testing, most TNBCs are not detected early via imaging, but rather as a palpable mass or by patient symptomatology, such as breast pain or nipple discharge.2

Pathologic Features of TNBC

  • TNBC is characteristically high grade, with infiltrating ductal carcinoma as the most common histology.1,2
    • A rare histologic subtype, medullary carcinoma, is generally triple negative.1
    • Metaplastic carcinomas (<1%), an uncommon subgroup of TNBC, is comprised of a diverse group of cancers ranging from squamous to stromal in nature.1,2 This tumor subgroup often expresses EGFR and has a poor prognosis.2
    • Pathologic features of TNBCs can include geographic necrosis, a pushing border of invasion, and a stromal lymphocytic response.3
    • Cellular fibrous proliferation is often demonstrated in triple-negative tumors, as compared to fibrosis with hyalinization in non-TNBCs.2
    • Perilobular lymphocytic infiltrate is commonly observed in breast tissue that is tumor-adjacent.2
  • Although the triple-negative clinical phenotype mostly comprises the basal-like molecular subtype (up to 75%), triple-negative and basal breast cancers are not synonymous, having substantial heterogeneity within TNBCs.1,2
    • For example, in one study of utilizing DNA and RNA profiling of TNBCs, four stable subtypes were identified: luminal androgen receptor, mesenchymal, basal-like immunosuppressed, and basal-like immune-activated.4
    • Basal breast cancer is characterized by the genomic expression of the “basal cluster”, a unique cluster of genes that includes:5-8
      • Epidermal growth factor receptor (EGFR, also called HER1)
      • Basal cytokeratins 5/6
      • c-Kit
      • Low expression of the hormone receptor- and HER2-related genes
    • Separate TNBC subtypes have been characterized by gene expression, including two basal-like subtypes (BL1 and BL2), as well as immunomodulatory, mesenchymal, mesenchymal stem-like, and luminal androgen subtypes.9
    • Additional characterized TNBC subtypes include claudin-low tumors, which contain cells with stem cell properties and epithelial to mesenchymal transition potential and interferon-rich subtypes, with significantly better prognosis over other TNBCs.10-12
    • Gene expression analysis of TNBC has also revealed that there is either mutation or aberrant expression of tumor suppressor gene p53 (TP53) and several DNA repair genes, particularly the breast cancer susceptibility genes (BRCA), which may harbor implications for chemotherapeutic sensitivity to platinum and other directly DNA-damaging agents.13,14

References

  1. Anders CK, Carey LA. ER/PR negative, HER2-negative (triple negative) breast cancer. 2020 UpToDate; Wolters Kluwer. https://www.uptodate.com/contents/er-pr-negative-her2-negative-triple-negative-breast-cancer?sectionName=Molecular%20classification%20of%20TNBC&search=human%20epithelial%20growth%20factor%20receptor%202%20breast%20cancer&topicRef=744&anchor=H493962740&source=see_link#H493962740. Accessed July 2020.
  2. Schmadeka R, et al. Triple-negative breast carcinoma: current and emerging concepts. Am J Clin Pathol. 2014;141:462-477. https://academic.oup.com/ajcp/article/141/4/462/1760538
  3. Livasy CA, Karaca G, Nanda R, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma.. Mod Pathol. 2006;19(2):264.
  4. Tsimelzon A, Poage GM, Covington KR, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Burstein MD,. Clin Cancer Res. 2015 Apr;21(7):1688-98. Epub 2014 Sep 10.
  5. Livasy CA, Karaca G, Nanda R, et al..Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006;19(2):264.
  6. Carey LA, Rugo HS, Marcom PK, et al TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer.. J Clin Oncol. 2008;26S:ASCO #1009.
  7. Korsching E, Packeisen J, Agelopoulos K, et al. Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis.. Lab Invest. 2002;82(11):1525.
  8. Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma.. Clin Cancer Res. 2004;10(16):5367.
  9. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.. J Clin Invest. 2011;121(7):2750.
  10. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer.. Genome Biol. 2007;8(8):R157.
  11. Prat A, Parker JS, Karginova Oet al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer.. Breast Cancer Res. 2010;12(5):R68. Epub 2010 Sep 2.
  12. Sørlie T, Perou CM, Tibshirani R,et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869.
  13. Troester MA, Herschkowitz JI, Oh DS, et al. Gene expression patterns associated with p53 status in breast cancer.. BMC Cancer. 2006;6:276. Epub 2006 Dec 6.
  14. Siddharth S, Sharma D. Racial disparity and triple-negative breast cancer in african-american women: a multifaceted affair between obesity, biology, and socioeconomic status. Cancers (Basel). 2018;10:514. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316530/