Triple-negative breast cancer

Triple-negative breast cancer (sometimes abbreviated TNBC) is any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2).[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 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 very similar or better prognosis than hormone receptor positive breast cancers.[4] Among breast cancer patients, 15–20% of women have been diagnosed as triple-negative and TNBC affects more young women or women with a mutation in the BRCA1 gene than other breast cancers.[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 afterwards. This relapse pattern has been recognized for all types of triple-negative cancers for which sufficient data exist, although the absolute relapse and survival rates differ across subtypes.[2][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. Due to their high disposition for cancers of the breast, ovaries, pancreas, and prostate, the BRCA1 and BRCA2 genes were identified as high risk for triple-negative (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.

TNBCs have been classified using an integrative analysis of cancer genomics data (DNA copy number, DNA methylation, and mRNA) and PPI data from a prognostic point of view, and several key subnetworks (i.e. ubiquitin/proteasome, complement system, metabolism-related Warburg effect, ER-Golgi-cell surface trafficking, transcription) significantly related to patient survival have been identified.[8]

Treatment

Standard treatment is surgery with adjuvant chemotherapy and radiotherapy. As a variation, neoadjuvant chemotherapy is very frequently used for triple-negative breast cancers as they are more susceptible to platinum-based regimen, allowing for a higher rate of breast-conserving surgeries. Important details on the individual responsiveness of particular cancers can be gained from evaluating the response to this form of chemotherapy. However, the improvement in breast conservation is only 10–15% and the clues to individual responsiveness have conclusively proven to make an improvement in outcomes.

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.[9]

Trodelvy (sacituzumab govitecan), an anti-Trop-2 antibody linked to SN-38, developed by Immunomedics Inc. (now Gilead Sciences), was approved by the FDA on 22 April 2020 for the treatment of metastatic TNBC.[10] Trodelvy had previously received FDA priority review, breakthrough therapy, and fast track designations.[10]

Epidemiology

Triple-negative breast cancer accounts for approximately 15–20% 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]

A study in the US says that, among younger women, African American and Hispanic women have a higher risk of TNBC,[11] with African Americans facing worse prognosis than other ethnic groups.[12]

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.[13] 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.[14] 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,[7] including the PARP inhibitor BSI 201,[15] NK012.[16]

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.[17]

PARP inhibitors had shown some promise in early trials[15] but failed in some later trials.[18]

An accelerated approval Phase II clinical trial (METRIC) investigating glembatumumab vedotin versus capecitabine began in November 2013, expected to enroll 300 patients with GPNMB-expressing metastatic TNBC.[19]

Three early stage trials reported TNBC results in June 2016, for IMMU-132, Vantictumab, and atezolizumab in combination with the chemotherapy nab-paclitaxel.[20]

In 2019, CytoDyn initiated a Phase 1b/2 trial with its humanized monoclonal antibody, leronlimab (PRO 140), in combination with chemotherapy following strong results in animal murine models. Among other mechanisms of action, leronlimab is believed to inhibit metastasis by inhibiting the CCR5 receptor on cell surfaces, which is commonly expressed in triple-negative breast cancer. On November 11, 2019, CytoDyn reported that the first TNBC patient injected under its naïve protocol (not previously treated for triple-negative breast cancer) demonstrated significantly reduced levels of circulating tumor cells (CTCs) and decreased tumor size at two-week and five-week observation intervals compared to baseline observations. CTCs are a potential surrogate endpoint in oncology trials, with reduced levels suggesting long-term clinical benefit.[21][22]

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).[23] 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.[24] 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.[25]

Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study.[26]

See also

  • Triple Negative Breast Cancer Foundation

References

  1. ↑ Foulkes WD, Smith IE, Reis-Filho JS (November 2010). "Triple-negative breast cancer". The New England Journal of Medicine. 363 (20): 1938–48. doi:10.1056/Nejmra1001389. PMID 21067385. S2CID 205115843.
  2. 1 2 3 4 5 6 Hudis CA, Gianni L (2011). "Triple-negative breast cancer: an unmet medical need". The Oncologist. 16 Suppl 1: 1–11. doi:10.1634/theoncologist.2011-S1-01. PMID 21278435.
  3. ↑ Albergaria A, Ricardo S, Milanezi F, Carneiro V, Amendoeira I, Vieira D, et al. (July 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.
  4. 1 2 Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. (March 2008). "Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype". Clinical Cancer Research. 14 (5): 1368–76. doi:10.1158/1078-0432.CCR-07-1658. PMID 18316557.
  5. ↑ "Old drugs bring new hope to triple negative breast cancer - UChicago Medicine". www.uchicagomedicine.org. Retrieved 2019-05-07.
  6. ↑ Feb 2009 Breast Cancer Watch
  7. 1 2 Anders C, Carey LA (October 2008). "Understanding and treating triple-negative breast cancer". Oncology. 22 (11): 1233–9, discussion 1239–40, 1243. PMC 2868264. PMID 18980022.
  8. ↑ Zhang F, Ren C, Zhao H, Yang L, Su F, Zhou MM, et al. (November 2016). "Identification of novel prognostic indicators for triple-negative breast cancer patients through integrative analysis of cancer genomics data and protein interactome data". Oncotarget. 7 (44): 71620–71634. doi:10.18632/oncotarget.12287. PMC 5342106. PMID 27690302.
  9. ↑ Jiang T, Shi W, Wali VB, Pongor LS, Li C, Lau R, et al. (December 2016). "Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis". PLOS Medicine. 13 (12): e1002193. doi:10.1371/journal.pmed.1002193. PMC 5154510. PMID 27959926.
  10. 1 2 Commissioner, Office of the (2020-04-22). "FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments". FDA. Retrieved 2020-11-19.
  11. ↑ Reynolds, Sharon (2007-07-24). "Spotlight: Triple-Negative Breast Cancer Disproportionately Affects African American and Hispanic Women". National Cancer Institute. Retrieved 2008-10-13.
  12. ↑ Chustecka, Zosia (2007-03-19). "Survival Disadvantage Seen for Triple-Negative Breast Cancer". Medscape Medical News. Retrieved 2008-10-13.
  13. ↑ Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, Malone KE (April 2009). "Risk factors for triple-negative breast cancer in women under the age of 45 years". Cancer Epidemiology, Biomarkers & Prevention. 18 (4): 1157–66. doi:10.1158/1055-9965.EPI-08-1005. PMC 2754710. PMID 19336554.
  14. ↑ Gelmon, K.; Dent, R.; Mackey, J. R.; Laing, K.; McLeod, D.; Verma, S. (1 September 2012). "Targeting triple-negative breast cancer: optimising therapeutic outcomes". Annals of Oncology. 23 (9): 2223–2234. doi:10.1093/annonc/mds067.
  15. 1 2 "SABCS: PARP Inhibitor Data Called 'Spectacular' "; Dec 2009
  16. ↑ "A Study of NK012 in Patients With Advanced, Metastatic Triple Negative Breast Cancer".
  17. ↑ 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).
  18. ↑ Guha M (May 2011). "PARP inhibitors stumble in breast cancer". Nature Biotechnology. 29 (5): 373–4. doi:10.1038/nbt0511-373. PMID 21552220. S2CID 205267931.
  19. ↑ 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
  20. ↑ Finally, targeted therapies for triple-negative breast cancer. June 2016
  21. ↑ "Study of Leronlimab (PRO 140) Combined With Carboplatin in Patients With CCR5+ mTNBC".
  22. ↑ First Patient in CytoDyn's Triple-Negative Metastatic Breast Cancer Trial Shows Significant Reduction in Circulating Tumor Cells (CTC) and Reduced Tumor Size
  23. ↑ Basu S, Chen W, Tchou J, Mavi A, Cermik T, Czerniecki B, et al. (March 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. S2CID 22106575. Archived from the original on 2013-01-05.
  24. ↑ Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, Thor AD (July 2009). "Metformin induces unique biological and molecular responses in triple negative breast cancer cells". Cell Cycle. 8 (13): 2031–40. doi:10.4161/cc.8.17.9502. PMID 19440038.
  25. ↑ Goodwin PJ, Ligibel JA, Stambolic V (July 2009). "Metformin in breast cancer: time for action". Journal of Clinical Oncology. 27 (20): 3271–3. doi:10.1200/JCO.2009.22.1630. PMID 19487373.
  26. ↑ Louie SM, Grossman EA, Crawford LA, Ding L, Camarda R, Huffman TR, et al. (May 2016). "GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity". Cell Chemical Biology. 23 (5): 567–578. doi:10.1016/j.chembiol.2016.03.017. PMC 4876719. PMID 27185638.

Further reading

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