Triple-negative breast cancer

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) or Her2/neu.[1] This makes it more difficult to treat since most hormone therapies target one of the three receptors, so triple-negative cancers often require combination therapies. 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 are 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 very similar or better prognosis 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.[5]

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.[5][4]

Cause

One known cause of triple negative breast cancer is germline mutations. These are alterations within the heritable lineage that is being passed down to the offspring. 15% of TNBC can be traced back to germline mutations that are within the BRCA1 and BRCA2 genes (Song 2014). These genes were identified as high risk for triple negative due to their high predisposition for cancers of the breasts, ovaries, pancreas, and prostate (Pruss 2014). Changes or mutations in 19p13.1 and MDM4 loci have also been associated with triple negative breast cancer, but not other forms of breast cancer, thus triple negative tumors may be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline alterations (Kristen 2013).

Classification

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 overexpress epidermal growth factor receptor (EGFR)[6][7] or 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

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.

In addition to chemotherapy, an additive called Didox can be added to aid in the reduction of drug resistance and further treatment efforts. Didox is used to inhibit ribonucleotide reductase M2 (RRM2) which contributes to the cells resistance of the chemotherapy treatment resulting in a large number of relapse (Wilson 2016). RRM2 is upregulated within these specific Triple Negative cancer cells leading to a higher rate of drug resistance and inability to slow or stop the tumor progression which leads to more aggressive forms of triple negative breast cancer that are often fatal (Wilson 2016).

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.

Although mutations in single genes were not individually predictive, TNBC tumors bearing mutations in genes involved in the androgen receptor (AR) and FOXA1 pathways were much more sensitive to chemotherapy. Mutations in the AR/FOXA1 pathway provide a novel marker for identifying chemosensitive TNBC patients who may benefit from current standard-of-care chemotherapy regimens. Mutations that lowered the levels of functional BRCA1 or BRCA2 RNA were associated with significantly better survival outcomes. This BRCA deficience signature define a new, highly chemosensitive subtype of TNBC. BRCA-deficient TNBC tumors have a higher rate of clonal mutation burden, defined as more clonal tumors with a higher number of mutations per clone, and are also associated with a higher level of immune activation, which may explain their greater chemosensitivity.[8]

Epidemiology

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,[9] with African Americans facing worse prognosis than other ethnic groups.[10]

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.[11] 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.

Clinical research/trials

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.

By 2009 A number of new strategies for TNBC were being tested in clinical trials,[12] including the PARP inhibitor BSI 201,[13] NK012.[14]

A novel antibody-drug conjugate known as Glembatumumab vedotin (CDX-011), which targets the protein GPNMB, has also shown encouraging clinical trial results in 2009.[15]

PARP inhibitors had shown some promise in early trials[13] but failed in some later trials.[16]

Nov 2013: An accelerated approval Phase II clinical trial (METRIC) investigating glembatumumab vedotin versus capecitabine has begun, expected to enroll 300 patients with GPNMB-expressing metastatic TNBC.[17]

Three early stage trials reported TNBC results in June 2016, for IMMU-132, Vantictumab, and atezolizumab in combination with the chemotherapy nab-paclitaxel.[18]

Pre-clinical research/speculations

Triple-negative breast cancers (TNBC) 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).[19] It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology.

The widely used diabetes drug, metformin, holds promise for the treatment of triple-negative breast cancer.[20] 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 in 2009.[21]

Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study[22]

See also

References

  1. ↑ Foulkes, William D., Ian E. Smith, and Jorge S. Reis-Filho. "Triple-negative breast cancer." New England journal of medicine 363.20 (2010): 1938-1948.
  2. 1 2 3 4 5 Hudis, C. A.; Gianni, L. (2011). "Triple-Negative Breast Cancer: An Unmet Medical Need". The Oncologist. 16: 1–11. PMID 21278435. doi:10.1634/theoncologist.2011-S1-01.
  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. PMC 3151231 Freely accessible. PMID 21762477. doi:10.1186/1471-2407-11-299.
  4. 1 2 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. PMID 18316557. doi:10.1158/1078-0432.CCR-07-1658.
  5. 1 2 Hudis, C. A.; Gianni, L. (2011). "Triple-Negative Breast Cancer: An Unmet Medical Need". The Oncologist. 16: 1–11. PMID 21278435. doi:10.1634/theoncologist.2011-S1-01.
  6. ↑ Feb 2009 Breast Cancer Watch
  7. ↑ Anders (2008). "Understanding and Treating Triple-Negative Breast Cancer".
  8. ↑ Jiang, Tingting; Shi, Weiwei; Wali, Vikram B.; Pongor, Lőrinc S.; Li, Charles; Lau, Rosanna; Győrffy, Balázs; Lifton, Richard P.; Symmans, William F. (2016-12-13). "Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis". PLOS Medicine. 13 (12): e1002193. ISSN 1549-1676. PMC 5154510 Freely accessible. PMID 27959926. doi:10.1371/journal.pmed.1002193.
  9. ↑ Reynolds, Sharon (2007-07-24). "Spotlight: Triple-Negative Breast Cancer Disproportionately Affects African American and Hispanic Women". National Cancer Institute. Retrieved 2008-10-13.
  10. ↑ Chustecka, Zosia (2007-03-19). "Survival Disadvantage Seen for Triple-Negative Breast Cancer". Medscape Medical News. Retrieved 2008-10-13.
  11. ↑ 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. PMC 2754710 Freely accessible. PMID 19336554. doi:10.1158/1055-9965.EPI-08-1005.
  12. ↑ Anders C; Carey, LA (2008). "Understanding and Treating Triple-Negative Breast Cancer". Oncology. 22 (11): 1233–9; discussion 1239–40, 1243. PMC 2868264 Freely accessible. PMID 18980022.
  13. 1 2 "SABCS: PARP Inhibitor Data Called 'Spectacular' "; Dec 2009
  14. ↑ "A Study of NK012 in Patients With Advanced, Metastatic Triple Negative Breast Cancer".
  15. ↑ 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" (PDF).
  16. ↑ Guha, M. (2011). "PARP inhibitors stumble in breast cancer". Nature Biotechnology. 29 (5): 373–374. PMID 21552220. doi:10.1038/nbt0511-373.
  17. ↑ Clinical trial number NCT01997333 for "Study of Glembatumumab Vedotin (CDX-011) in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer (METRIC)" at ClinicalTrials.gov
  18. ↑ Finally, targeted therapies for triple-negative breast cancer. June 2016
  19. ↑ 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. PMID 18098228. doi:10.1002/cncr.23226.
  20. ↑ 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. PMID 19440038. doi:10.4161/cc.8.17.9502.
  21. ↑ Goodwin PJ, Ligibel JA, Stambolic V (2009). "Metformin in breast cancer: time for action". American Society of Clinical Oncology. 27 (20): 3271–3273. PMID 19487373. doi:10.1200/JCO.2009.22.1630.
  22. ↑ Louie, Sharon M.; Grossman, Elizabeth A.; Crawford, Lisa A.; Ding, Lucky; Camarda, Roman; Huffman, Tucker R.; Miyamoto, David K.; Goga, Andrei; Weerapana, Eranthie; Nomura, Daniel (2016-05-19). "GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity". Cell Chemical Biology. 23 (5): 567–578. ISSN 2451-9456. PMID 27185638. doi:10.1016/j.chembiol.2016.03.017.

Alanazi, Ibrahim O., and Zahid Khan. "Understanding EGFR Signaling in Breast Cancer and Breast Cancer Stem Cells: Overexpression and Therapeutic Implications." Asian Pacific Journal of Cancer Prevention 17.2 (2016): 445-453.

Lehmann, Brian D., and Jennifer A. Pietenpol. "Identification and use of biomarkers in treatment strategies for triple‐negative breast cancer subtypes." The Journal of pathology 232.2 (2014): 142-150.

Pruss, Dmitry, et al. "Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes." Breast cancer research and treatment 147.1 (2014): 119-132.

Song, Honglin, et al. "The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population." Human molecular genetics (2014): ddu172.

Stevens, Kristen N., Celine M. Vachon, and Fergus J. Couch. "Genetic susceptibility to triple-negative breast cancer." Cancer research 73.7 (2013): 2025-2030.

Wilson, Elizabeth A., Howard L. Elford, and Jesika S. Faridi. "Successfully targeting triple negative breast cancer using combination therapy of Didox and Doxorubicin with reduced cardiotoxicity." Cancer Research 76.14 Supplement (2016): 4689-4689.

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