Triple-negative breast cancer

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Triple-negative breast cancer (sometimes abbreviated TNBC) refers to any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) and Her2/neu.[1] This makes it more difficult to treat since most chemotherapies target one of the three receptors, so triple-negative cancers often require combinatorial therapies (see below). Triple negative is sometimes used as a surrogate term for basal-like; however, more detailed classification may provide better guidance for treatment and better estimates for prognosis.[2]

Triple-negative breast cancers comprise a very heterogeneous group of cancers. There is conflicting information over prognosis for the various subtypes but it appears that the Nottingham prognostic index is valid and hence general prognosis is rather similar with other breast cancer of same stage, except that more aggressive treatment is required.[3] Some types of triple-negative breast cancer are known to be more aggressive with poor prognosis, while other types have prognosis very similar or better than hormone receptor positive breast cancers.[4] Pooled data of all triple-negative subtypes suggest that with optimal treatment 20-year survival rates are very close to those of hormone positive cancer.[2]

Triple-negative breast cancers have a relapse pattern that is very different from hormone-positive breast cancers: the risk of relapse is much higher for the first 3–5 years but drops sharply and substantially below that of hormone-positive breast cancers after that. This relapse pattern has been recognized for all types of triple-negative cancers for which sufficient data exists although the absolute relapse and survival rates differ across subtypes.[2][4]

Classification[edit]

Triple-negative breast cancers (TNBC) are sometimes classified into "basal-type" and other cancers; however, there is no standard classification scheme. Basal type cancers are frequently defined by cytokeratin 5/6 and EGFR staining. However, no clear criteria or cutoff values have been standardized yet.[2] About 75% of basal-type breast cancers are triple negative.

Some TNBC overexpresses epidermal growth factor receptor (EGFR).[5][6] Some TNBC over expresses transmembrane glycoprotein NMB (GPNMB).

Upon histologic examination, triple-negative breast tumors mostly fall into the categories of secretory cell carcinoma or adenoid cystic types (both considered less aggressive); medullary cancers and grade 3 invasive ductal carcinomas with no specific subtype; and highly aggressive metastatic cancers.[2] Medullary TNBC in younger women are frequently BRCA1-related.

Rare forms of triple-negative breast cancer are apocrine and squamous carcinoma. Inflammatory breast cancer is also frequently triple negative.

Many proteins such as Caveolin 1/2, Survivin are researched as possible classification or prognostic factors.

Treatment[edit]

Standard treatment is surgery with adjuvant chemotherapy and radiotherapy. As a variation neoadjuvant chemotherapy is very frequently used for triple-negative breast cancers. This allows for a higher rate of breast-conserving surgeries and by evaluating the response to the chemotherapy gives important clues about the individual responsiveness of the particular cancer to chemotherapy.

TNBCs are generally very susceptible to chemotherapy. In some cases, however, early complete response does not correlate with overall survival. This makes it particularly complicated to find the optimal chemotherapy. Adding a taxane to the chemotherapy appears to improve outcome substantially.[2]

BRCA1-related triple-negative breast cancer appear to be particularly susceptible to chemotherapy including platinum-based agents and taxanes.

Epidemiology[edit]

Triple-negative breast cancer accounts for approximately 15%-25% of all breast cancer cases. The overall proportion of TNBC is very similar in all age groups. Younger women have a higher rate of basal or BRCA related TNBC while older women have a higher proportion of apocrine, normal-like and rare subtypes including neuroendocrine TNBC.[2]

Among younger women, African American and Hispanic women have a higher risk of TNBC,[7] with African Americans facing worse prognosis than other ethnic groups.[8]

In 2009, a case-control study of 187 triple-negative breast cancer patients described a 2.5 increased risk for triple-negative breast cancer in women who used oral contraceptives (OCs) for more than one year compared to women who used OCs for less than one year or never.[9] The increased risk for triple-negative breast cancer was 4.2 among women 40 years of age or younger who used OCs for more than one year, while there was no increased risk for women between the ages of 41 and 45. Also, as duration of OC use increased, triple-negative breast cancer risk increased.

Research directions[edit]

Angiogenesis and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown efficacy. Treatment modalities are not sufficiently established for normal use, and it is unclear in which stage they are best used and which patients would profit.

PARP inhibitors had shown some promise in early trials[10] but failed in some later trials.[11] A novel antibody-drug conjugate known as Glembatumumab vedotin (CDX-011), which targets the protein GPNMB, has also shown encouraging results in recent clinical trials.[12]

Triple-negative breast cancers have, on average, significantly higher fluorine-18 fluorodeoxyglucose (FDG) uptake (measured by the SUVmax values) compared with uptake in ER+/PR+/HER2- tumors using fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET).[13] It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology.

A number of new strategies are currently being tested in clinical trials,[14] including the PARP inhibitor BSI 201,[10] NK012,[15] and the GPNMB targeted CDX-011.

The widely used diabetes drug, metformin, holds promise for the treatment of triple-negative breast cancer.[16] In addition metformin may influence cancer cells through indirect (insulin-mediated) effects, or it may directly affect cell proliferation and apoptosis of cancer cells. Epidemiologic and preclinical lab studies indicate that metformin has anti-tumor effects, via at least two mechanisms, both involving activation of the AMP-activated protein kinase (AMPK). A large-scale phase III trial of metformin in the adjuvant breast cancer setting is being planned.[17]

See also[edit]

References[edit]

  1. ^ article; NEJM
  2. ^ a b c d e f g Hudis, C. A.; Gianni, L. (2011). "Triple-Negative Breast Cancer: An Unmet Medical Need". The Oncologist 16: 1–11. doi:10.1634/theoncologist.2011-S1-01. PMID 21278435.  edit
  3. ^ Albergaria, A.; Ricardo, S.; Milanezi, F.; Carneiro, V. T.; Amendoeira, I.; Vieira, D.; Cameselle-Teijeiro, J.; Schmitt, F. (2011). "Nottingham Prognostic Index in Triple-Negative Breast Cancer: A reliable prognostic tool?". BMC Cancer 11: 299. doi:10.1186/1471-2407-11-299. PMC 3151231. PMID 21762477.  edit
  4. ^ a b Cheang, M. C. U.; Voduc, D.; Bajdik, C.; Leung, S.; McKinney, S.; Chia, S. K.; Perou, C. M.; Nielsen, T. O. (2008). "Basal-Like Breast Cancer Defined by Five Biomarkers Has Superior Prognostic Value than Triple-Negative Phenotype". Clinical Cancer Research 14 (5): 1368–1376. doi:10.1158/1078-0432.CCR-07-1658. PMID 18316557.  edit
  5. ^ Feb 2009 Breast Cancer Watch
  6. ^ Anders (2008). "Understanding and Treating Triple-Negative Breast Cancer". 
  7. ^ Reynolds, Sharon (2007-07-24). "Spotlight: Triple-Negative Breast Cancer Disproportionately Affects African American and Hispanic Women". National Cancer Institute. Retrieved 2008-10-13. 
  8. ^ Chustecka, Zosia (2007-03-19). "Survival Disadvantage Seen for Triple-Negative Breast Cancer". Medscape Medical News. Retrieved 2008-10-13. 
  9. ^ Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, Malone KE (2009). "Risk Factors for Triple-Negative Breast Cancer in Women Under Age 45". Cancer Epidemiology, Biomarkers & Prevention 18 (4): 1157–1166. doi:10.1158/1055-9965.EPI-08-1005. PMC 2754710. PMID 19336554. 
  10. ^ a b "SABCS: PARP Inhibitor Data Called 'Spectacular' "; Dec 2009
  11. ^ Guha, M. (2011). "PARP inhibitors stumble in breast cancer". Nature Biotechnology 29 (5): 373–374. doi:10.1038/nbt0511-373. PMID 21552220.  edit
  12. ^ Burris (2009). "A Phase I/II Study of CR011-vcMMAE (CDX-011), an Antibody-Drug Conjugate,in Patients with Locally Advanced or Metastatic Breast Cancer". 
  13. ^ Basu S, Chen W, Tchou J, Mavi A, Cermik T, Czerniecki B, Schnall M, Alavi A (2008). "Comparison of triple-negative and estrogen receptor-positive/progesterone receptor-positive/HER2-negative breast carcinoma using quantitative fluorine-18 fluorodeoxyglucose/positron emission tomography imaging parameters: a potentially useful method for disease characterization". Cancer 112 (5): 995–1000. doi:10.1002/cncr.23226. PMID 18098228. 
  14. ^ Anders C; Carey, LA (2008). "Understanding and Treating Triple-Negative Breast Cancer". Oncology 22 (11): 1233–9; discussion 1239–40, 1243. PMC 2868264. PMID 18980022. 
  15. ^ "A Study of NK012 in Patients With Advanced, Metastatic Triple Negative Breast Cancer". 
  16. ^ Jiralerspong S, Gonzalez-Angulo AM, Hung MC (2009). "Expanding the arsenal: metformin for the treatment of triple-negative breast cancer?". Cell Cycle 8 (13): 2031–40. doi:10.4161/cc.8.17.9502. PMID 19440038. 
  17. ^ Goodwin PJ, Ligibel JA, Stambolic V (2009). "Metformin in breast cancer: time for action". American Society of Clinical Oncology 27 (20): 3271–3273. doi:10.1200/JCO.2009.22.1630. PMID 19487373. 

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