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Triple-negative breast cancer

January 30, 2023

Triple-negative breast cancer (TNBC) is any breast cancer that lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e. the tumor is negative on all three tests giving the name triple-negative).[1] Triple-negative is sometimes used as a surrogate term for basal-like.[2]

Triple-negative breast cancer comprises 15–20% of all breast cancer cases[3] and affects more young women or women with a mutation in the BRCA1 gene than other breast cancers.[4] Triple-negative breast cancers comprise a very heterogeneous group of cancers. TNBC is the most challenging breast cancer type to treat.[5] Hormone therapy that is used for other breast cancers does not work for TNBC.[6] In its early stages, the cancer is typically treated through surgery, radiation and chemotherapy. In later stages where surgery is not possible or the cancer has spread from the initial localised area, treatment is limited to chemotherapy and in some cases further targeted therapy.[6]

Triple-negative breast cancers have a relapse pattern that is very different from hormone-positive breast cancers where 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.[2][7]

Risk factors

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 has shown that, among younger women, African American and Hispanic women have a higher risk of TNBC,[8] with African Americans facing worse prognosis than other ethnic groups.[9]

One known risk factor for 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.[10] 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.[11]

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.[12] 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.

Classification

Breast cancer classification is used to assess the tumor to decide on treatment and prognosis. Classification can be performed using molecular, immunohistochemical, and clinical characteristics.[13] One of the important classification types is receptor status, because it identifies those cancers that have specific targeted treatments available. Breast cancer tumors have traditionally been classed using immunohistochemistry as one of four types:[13]

  • eostrogen receptor positive
  • progesterone receptor positive
  • HER2 overexpression positive
  • triple-negative

There are targeted therapies for estrogen and progesterone receptor cancers and more recently HER2 receptor cancers but there are no targeted therapies for TNBC as a whole.[13]

The threshold level for hormone receptor positivity was changed in 2010 and now requires more than 1% positive tumor nuclei are found in the tumor sample.[14]

Newer techniques for categorising breast cancer are based on gene expression in the tumor which classifies breast cancer into:[15][16]

  • luminal A (HR+/HER2-) 68%
  • luminal B (HR+/HER2+) 10%
  • HER2 overexpressing (HR-/HER2+) 4%
  • basal-like (HR-/HER2-) 10%

with 7% of unknown subtype. HR indicates hormone receptor and +/- indicates status whether positive or negative.

The basal-like subtype has many overlapping features to TNBC and in addition to being receptor negative, has increased expression of basal cytokeratins.[15] 85% of basal-like tumors are TNBC.[13]

Subtypes are used to try to define better treatments or a more accurate prognosis. However, there is no standard classification for TNBC subtypes.[13] Although TNBC has a variety of different subtypes that may vary depending on how they are determined, to date the disease is still uniformly treated with chemotherapy although they may have additional targeted treatments.[13] One of the popular subtype classification for TNBC is:[13][14][17]

  • basal-like 1 (BL1) 35%
  • basal-like 2 (BL2) 22%
  • mesenchymal (M) 25%
  • luminal androgen receptor (LAR) 16%

Most of TNBC is invasive carcinoma of no special type. The following rarer breast tumors have a higher proportion of being TNBC:[18]

Prognosis

TNBC is more likely to recur within the first five years after treatment than other breast cancers. However, after five years the chance of recurrence is much less than for other breast cancers. [19] The risk of recurrence peaks at three years from diagnosis and reduces after that.[20]

Cancer survival is typically based on 5-year survival rates which is the survival rate compared to women without breast cancer and is based on the stage when the cancer is first diagnosed. These statistics do not apply if the cancer returns after treatment.[6]

Survival rates for Triple-negative breast cancer from time of diagnosis[6]
stage 5-year survival
Localised 91%
Regional 65%
Distant 12%
All stages 77%

Approximately 25% of those with localised disease will relapse with distant metastasis also known as stage IV.[20] Median survival from diagnosis of metastasis is around 12 months.[20] Metastasis in TNBC is different from other breast cancers with a tendency to spread to the brain and other organs such as lungs and liver and there is less of a tendency to spread to bones.[20]

Treatment

Early stage disease

Standard treatment is surgery with adjuvant chemotherapy and radiotherapy.

Surgery is primarily used for early stage disease and may be either a lumpectomy or a mastectomy. Studies have found that the overall survival for lumpectomy and radiotherapy was the same or higher than for a mastectomy for TNBC patients.[21]

Neoadjuvant chemotherapy (before surgery) 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.

Early stage TNBC is generally very susceptible to chemotherapy and can lead to a pathological complete response (pCR) i.e. no detectable cancer cells in the breast or lymph nodes.[22] Although this does not always translate into overall survival.

Chemotherapy used to treat early stage cancers are:[22]

  • anthracyclines
  • alkalating agents such as cisplatin and carboplatin. These are particularly effective with BRCA positive cases. These agents cause DNA damage which is unable to be repaired when there are BRCA defects leading to cell death.
  • taxanes

Late stage disease

Late stage disease is known as metastatic TNBC (mTNBC).

Treatment depends on whether the tumour tests positive for the programmed death cell ligand 1 (PD-L1) protein or BRCA gene mutation. Also known as immunotherapy the presence of PD-L1 on cancer cells mates with an associate PD-1 receptor on the bodies own immune killer T cells which prevents the T cell from further attacking the cancer cell. By blocking these receptors the T-cells can attack both cancer cells and healthy cells.

The following treatment is recommended by the American Society of Clinical Oncology (ASCO) for metastatic TNBC:[23]

  • mTNBC +PD-L1: 1st line: offered chemo + immune checkpoint inhibitor
  • mTNBC -PD-L1: 1st line: single-agent chemo; 3rd line: sacituzumab govitecan
  • mTNBC +BRCA: patients previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease should be offered PARP inhibitor rather than chemotherapy.

Sacituzumab govitecan (Trodelvy ) is an anti-Trop-2 antibody linked to SN-38, developed by Immunomedics Inc. (now Gilead Sciences). It was approved by the FDA on 22 April 2020 for the treatment of metastatic TNBC.[24] Sacituzumab govitecan had previously received FDA priority review, breakthrough therapy, and fast track designations.[24]

Clinical trials

Angiogenesis and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown efficacy.[25] 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,[26] including the PARP inhibitor BSI 201,[27] NK012.[28]

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.[29]

PARP inhibitors had shown some promise in early trials[27] but failed in some later trials.[30]

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.[31]

Three early stage trials reported TNBC results in June 2016, for IMMU-132, Vantictumab, and atezolizumab in combination with the chemotherapy nab-paclitaxel.[32]

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.[33][34]

Research

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).[35] 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.[36] 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.[37]

Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study.[38]

See also

References

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  2. ^ a b c 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. S2CID 22362118.
  3. ^ Sporikova Z, Koudelakova V, Trojanec R, Hajduch M (October 2018). "Genetic Markers in Triple-Negative Breast Cancer". Clinical Breast Cancer. 18 (5): e841–e850. doi:10.1016/j.clbc.2018.07.023. PMID 30146351. S2CID 52091594.
  4. ^ "Old drugs bring new hope to a cancer that lacks precision therapy". www.uchicagomedicine.org. Retrieved 2022-02-23.
  5. ^ Garrido-Castro AC, Lin NU, Polyak K (2019). "Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment". Cancer Discovery. 9 (2): 176–198. doi:10.1158/2159-8290.CD-18-1177. PMC 6387871. PMID 30679171.
  6. ^ a b c d "Triple-negative Breast Cancer". Retrieved 22 Feb 2022.
  7. ^ 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.
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  12. ^ 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.
  13. ^ a b c d e f g Ensenyat-Mendez M, Llinàs-Arias P, Orozco JI, Íñiguez-Muñoz S, Salomon MP, Sesé B, DiNome ML, Marzese DM (16 Jun 2021). "Current Triple-Negative Breast Cancer Subtypes: Dissecting the Most Aggressive Form of Breast Cancer". Frontiers in Oncology. 11 (681476): 681476. doi:10.3389/fonc.2021.681476. PMC 8242253. PMID 34221999.
  14. ^ a b Nunnery SE, Mayer IA, Balko JM (1 Jan 2021). "Triple-Negative Breast Cancer: Breast Tumors With an Identity Crisis". Cancer Journal. 27 (1): 2–7. doi:10.1097/PPO.0000000000000494. PMC 8109153. PMID 33475287.
  15. ^ a b Ovcaricek T, Frkovic SG, Matos E, Mozina B, Borstnar S (Mar 2011). "Triple negative breast cancer - prognostic factors and survival". Radiology and Oncology. 45 (1): 46–52. doi:10.2478/v10019-010-0054-4. PMC 3423721. PMID 22933934.
  16. ^ "Cancer Stat Facts: Female Breast Cancer Subtypes". Retrieved 1 Mar 2022.
  17. ^ Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA (16 Jun 2016). "Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection". PLOS ONE. 11 (6): e0157368. Bibcode:2016PLoSO..1157368L. doi:10.1371/journal.pone.0157368. PMC 4911051. PMID 27310713.
  18. ^ Plasilova ML, Hayse B, Killelea BK, Horowitz NR, Chagpar AB, Lannin DR (Aug 2016). "Features of triple-negative breast cancer: Analysis of 38,813 cases from the national cancer database". Medicine (Baltimore). 95 (35): e4614. doi:10.1097/MD.0000000000004614. PMC 5008562. PMID 27583878.
  19. ^ "10 Triple Negative Breast Cancer Survival Statistics". 15 July 2014. Retrieved 22 Feb 2022.
  20. ^ a b c d O'Reilly D, Al Sendi M, Kelly CM (24 Mar 2021). "Overview of recent advances in metastatic triple negative breast cancer". World Journal of Clinical Oncology. 12 (3): 164–182. doi:10.5306/wjco.v12.i3.164. PMC 7968109. PMID 33767972.
  21. ^ Guo L, Xie G, Wang R, Yang L, Sun L, Xu M, Yang W, Chung MC (19 June 2021). "Local treatment for triple-negative breast cancer patients undergoing chemotherapy: breast-conserving surgery or total mastectomy?". BMC Cancer. 21 (1): 717. doi:10.1186/s12885-021-08429-9. PMC 8214797. PMID 34147061.
  22. ^ a b Bergin A, Loi S (2 Aug 2019). "Triple-negative breast cancer: recent treatment advances". F1000Research. 8: 1342. doi:10.12688/f1000research.18888.1. PMC 6681627. PMID 31448088.
  23. ^ Moy B, Rumble RB, Come SE, Davidson NE, Di Leo A, Gralow JR, Hortobagyi GN, Yee D, Smith IE, Chavez-MacGregor M, Nanda R, McArthur HL, Spring L, Reeder-Hayes KE, Ruddy KJ, Unger PS, Vinayak S, Irvin WJ Jr, Armaghani A, Danso MA, Dickson N, Turner SS, Perkins CL, Carey LA (10 Dec 2021). "Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update". Journal of Clinical Oncology. 39 (35): 3938–3958. doi:10.1200/JCO.21.01374. PMID 34324366. S2CID 236515507.
  24. ^ a b 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.
  25. ^ 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. PMID 22517820.
  26. ^ 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.
  27. ^ a b "SABCS: PARP Inhibitor Data Called 'Spectacular' "; Dec 2009
  28. ^ "A Study of NK012 in Patients With Advanced, Metastatic Triple Negative Breast Cancer". 12 February 2015.
  29. ^ 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).
  30. ^ 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.
  31. ^ 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
  32. ^ Finally, targeted therapies for triple-negative breast cancer. June 2016
  33. ^ "Study of Leronlimab (PRO 140) Combined With Carboplatin in Patients With CCR5+ mTNBC". 13 January 2022.
  34. ^ First Patient in CytoDyn's Triple-Negative Metastatic Breast Cancer Trial Shows Significant Reduction in Circulating Tumor Cells (CTC) and Reduced Tumor Size
  35. ^ 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.
  36. ^ 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.
  37. ^ 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.
  38. ^ 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

  • Lehmann BD, Pietenpol JA (January 2014). "Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes". The Journal of Pathology. 232 (2): 142–50. doi:10.1002/path.4280. PMC 4090031. PMID 24114677.

External links

  • The Official Triple Negative Breast Cancer Foundation Site

January 30, 2023
triple, negative, breast, cancer, tnbc, breast, cancer, that, lacks, shows, levels, estrogen, receptor, progesterone, receptor, human, epidermal, growth, factor, receptor, her2, overexpression, gene, amplification, tumor, negative, three, tests, giving, name, . Triple negative breast cancer TNBC is any breast cancer that lacks or shows low levels of estrogen receptor ER progesterone receptor PR and human epidermal growth factor receptor 2 HER2 overexpression and or gene amplification i e the tumor is negative on all three tests giving the name triple negative 1 Triple negative is sometimes used as a surrogate term for basal like 2 Triple negative breast cancer comprises 15 20 of all breast cancer cases 3 and affects more young women or women with a mutation in the BRCA1 gene than other breast cancers 4 Triple negative breast cancers comprise a very heterogeneous group of cancers TNBC is the most challenging breast cancer type to treat 5 Hormone therapy that is used for other breast cancers does not work for TNBC 6 In its early stages the cancer is typically treated through surgery radiation and chemotherapy In later stages where surgery is not possible or the cancer has spread from the initial localised area treatment is limited to chemotherapy and in some cases further targeted therapy 6 Triple negative breast cancers have a relapse pattern that is very different from hormone positive breast cancers where 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 2 7 Contents 1 Risk factors 2 Classification 3 Prognosis 4 Treatment 4 1 Early stage disease 4 2 Late stage disease 5 Clinical trials 6 Research 7 See also 8 References 8 1 Further reading 9 External linksRisk factors EditTriple 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 has shown that among younger women African American and Hispanic women have a higher risk of TNBC 8 with African Americans facing worse prognosis than other ethnic groups 9 One known risk factor for 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 10 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 11 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 12 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 Classification EditBreast cancer classification is used to assess the tumor to decide on treatment and prognosis Classification can be performed using molecular immunohistochemical and clinical characteristics 13 One of the important classification types is receptor status because it identifies those cancers that have specific targeted treatments available Breast cancer tumors have traditionally been classed using immunohistochemistry as one of four types 13 eostrogen receptor positive progesterone receptor positive HER2 overexpression positive triple negativeThere are targeted therapies for estrogen and progesterone receptor cancers and more recently HER2 receptor cancers but there are no targeted therapies for TNBC as a whole 13 The threshold level for hormone receptor positivity was changed in 2010 and now requires more than 1 positive tumor nuclei are found in the tumor sample 14 Newer techniques for categorising breast cancer are based on gene expression in the tumor which classifies breast cancer into 15 16 luminal A HR HER2 68 luminal B HR HER2 10 HER2 overexpressing HR HER2 4 basal like HR HER2 10 with 7 of unknown subtype HR indicates hormone receptor and indicates status whether positive or negative The basal like subtype has many overlapping features to TNBC and in addition to being receptor negative has increased expression of basal cytokeratins 15 85 of basal like tumors are TNBC 13 Subtypes are used to try to define better treatments or a more accurate prognosis However there is no standard classification for TNBC subtypes 13 Although TNBC has a variety of different subtypes that may vary depending on how they are determined to date the disease is still uniformly treated with chemotherapy although they may have additional targeted treatments 13 One of the popular subtype classification for TNBC is 13 14 17 basal like 1 BL1 35 basal like 2 BL2 22 mesenchymal M 25 luminal androgen receptor LAR 16 Most of TNBC is invasive carcinoma of no special type The following rarer breast tumors have a higher proportion of being TNBC 18 adenoid cystic carcinoma 78 2 are TNBC metaplastic 76 2 are TNBC medullary carcinoma 60 5 are TNBC apocrine adenocarcinoma 56 7 are TNBC inflammatory 25 9 are TNBCPrognosis EditTNBC is more likely to recur within the first five years after treatment than other breast cancers However after five years the chance of recurrence is much less than for other breast cancers 19 The risk of recurrence peaks at three years from diagnosis and reduces after that 20 Cancer survival is typically based on 5 year survival rates which is the survival rate compared to women without breast cancer and is based on the stage when the cancer is first diagnosed These statistics do not apply if the cancer returns after treatment 6 Survival rates for Triple negative breast cancer from time of diagnosis 6 stage 5 year survivalLocalised 91 Regional 65 Distant 12 All stages 77 Approximately 25 of those with localised disease will relapse with distant metastasis also known as stage IV 20 Median survival from diagnosis of metastasis is around 12 months 20 Metastasis in TNBC is different from other breast cancers with a tendency to spread to the brain and other organs such as lungs and liver and there is less of a tendency to spread to bones 20 Treatment EditEarly stage disease Edit Standard treatment is surgery with adjuvant chemotherapy and radiotherapy Surgery is primarily used for early stage disease and may be either a lumpectomy or a mastectomy Studies have found that the overall survival for lumpectomy and radiotherapy was the same or higher than for a mastectomy for TNBC patients 21 Neoadjuvant chemotherapy before surgery 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 Early stage TNBC is generally very susceptible to chemotherapy and can lead to a pathological complete response pCR i e no detectable cancer cells in the breast or lymph nodes 22 Although this does not always translate into overall survival Chemotherapy used to treat early stage cancers are 22 anthracyclines alkalating agents such as cisplatin and carboplatin These are particularly effective with BRCA positive cases These agents cause DNA damage which is unable to be repaired when there are BRCA defects leading to cell death taxanesLate stage disease Edit Late stage disease is known as metastatic TNBC mTNBC Treatment depends on whether the tumour tests positive for the programmed death cell ligand 1 PD L1 protein or BRCA gene mutation Also known as immunotherapy the presence of PD L1 on cancer cells mates with an associate PD 1 receptor on the bodies own immune killer T cells which prevents the T cell from further attacking the cancer cell By blocking these receptors the T cells can attack both cancer cells and healthy cells The following treatment is recommended by the American Society of Clinical Oncology ASCO for metastatic TNBC 23 mTNBC PD L1 1st line offered chemo immune checkpoint inhibitor mTNBC PD L1 1st line single agent chemo 3rd line sacituzumab govitecan mTNBC BRCA patients previously treated with chemotherapy in the neoadjuvant adjuvant or metastatic disease should be offered PARP inhibitor rather than chemotherapy Sacituzumab govitecan Trodelvy is an anti Trop 2 antibody linked to SN 38 developed by Immunomedics Inc now Gilead Sciences It was approved by the FDA on 22 April 2020 for the treatment of metastatic TNBC 24 Sacituzumab govitecan had previously received FDA priority review breakthrough therapy and fast track designations 24 Clinical trials EditThis section needs to be updated Please help update this article to reflect recent events or newly available information February 2016 Angiogenesis and EGFR HER 1 inhibitors are frequently tested in experimental settings and have shown efficacy 25 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 26 including the PARP inhibitor BSI 201 27 NK012 28 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 29 PARP inhibitors had shown some promise in early trials 27 but failed in some later trials 30 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 31 Three early stage trials reported TNBC results in June 2016 for IMMU 132 Vantictumab and atezolizumab in combination with the chemotherapy nab paclitaxel 32 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 naive 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 33 34 Research EditThis section needs to be updated Please help update this article to reflect recent events or newly available information September 2018 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 35 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 36 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 37 Triple negative breast cancer cells rely on glutathione S transferase Pi1 and an inhibitor LAS17 shows encouraging results in a pre clinical study 38 See also EditTriple Negative Breast Cancer FoundationReferences Edit 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 a b c 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 S2CID 22362118 Sporikova Z Koudelakova V Trojanec R Hajduch M October 2018 Genetic Markers in Triple Negative Breast Cancer Clinical Breast Cancer 18 5 e841 e850 doi 10 1016 j clbc 2018 07 023 PMID 30146351 S2CID 52091594 Old drugs bring new hope to a cancer that lacks precision therapy www uchicagomedicine org Retrieved 2022 02 23 Garrido Castro AC Lin NU Polyak K 2019 Insights into Molecular Classifications of Triple Negative Breast Cancer Improving Patient Selection for Treatment Cancer Discovery 9 2 176 198 doi 10 1158 2159 8290 CD 18 1177 PMC 6387871 PMID 30679171 a b c d Triple negative Breast Cancer Retrieved 22 Feb 2022 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 Reynolds Sharon 2007 07 24 Spotlight Triple Negative Breast Cancer Disproportionately Affects African American and Hispanic Women National Cancer Institute Retrieved 2008 10 13 Chustecka Zosia 2007 03 19 Survival Disadvantage Seen for Triple Negative Breast Cancer Medscape Medical News Retrieved 2008 10 13 Pruss D Morris B Hughes E Eggington JM Esterling L Robinson BS et al August 2014 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 1 119 32 doi 10 1007 s10549 014 3065 9 PMID 25085752 S2CID 21438028 Stevens KN Vachon CM Couch FJ 2013 Genetic susceptibility to triple negative breast cancer Cancer Research 73 7 2025 2030 doi 10 1158 0008 5472 CAN 12 1699 PMC 3654815 PMID 23536562 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 amp Prevention 18 4 1157 66 doi 10 1158 1055 9965 EPI 08 1005 PMC 2754710 PMID 19336554 a b c d e f g Ensenyat Mendez M Llinas Arias P Orozco JI Iniguez Munoz S Salomon MP Sese B DiNome ML Marzese DM 16 Jun 2021 Current Triple Negative Breast Cancer Subtypes Dissecting the Most Aggressive Form of Breast Cancer Frontiers in Oncology 11 681476 681476 doi 10 3389 fonc 2021 681476 PMC 8242253 PMID 34221999 a b Nunnery SE Mayer IA Balko JM 1 Jan 2021 Triple Negative Breast Cancer Breast Tumors With an Identity Crisis Cancer Journal 27 1 2 7 doi 10 1097 PPO 0000000000000494 PMC 8109153 PMID 33475287 a b Ovcaricek T Frkovic SG Matos E Mozina B Borstnar S Mar 2011 Triple negative breast cancer prognostic factors and survival Radiology and Oncology 45 1 46 52 doi 10 2478 v10019 010 0054 4 PMC 3423721 PMID 22933934 Cancer Stat Facts Female Breast Cancer Subtypes Retrieved 1 Mar 2022 Lehmann BD Jovanovic B Chen X Estrada MV Johnson KN Shyr Y Moses HL Sanders ME Pietenpol JA 16 Jun 2016 Refinement of Triple Negative Breast Cancer Molecular Subtypes Implications for Neoadjuvant Chemotherapy Selection PLOS ONE 11 6 e0157368 Bibcode 2016PLoSO 1157368L doi 10 1371 journal pone 0157368 PMC 4911051 PMID 27310713 Plasilova ML Hayse B Killelea BK Horowitz NR Chagpar AB Lannin DR Aug 2016 Features of triple negative breast cancer Analysis of 38 813 cases from the national cancer database Medicine Baltimore 95 35 e4614 doi 10 1097 MD 0000000000004614 PMC 5008562 PMID 27583878 10 Triple Negative Breast Cancer Survival Statistics 15 July 2014 Retrieved 22 Feb 2022 a b c d O Reilly D Al Sendi M Kelly CM 24 Mar 2021 Overview of recent advances in metastatic triple negative breast cancer World Journal of Clinical Oncology 12 3 164 182 doi 10 5306 wjco v12 i3 164 PMC 7968109 PMID 33767972 Guo L Xie G Wang R Yang L Sun L Xu M Yang W Chung MC 19 June 2021 Local treatment for triple negative breast cancer patients undergoing chemotherapy breast conserving surgery or total mastectomy BMC Cancer 21 1 717 doi 10 1186 s12885 021 08429 9 PMC 8214797 PMID 34147061 a b Bergin A Loi S 2 Aug 2019 Triple negative breast cancer recent treatment advances F1000Research 8 1342 doi 10 12688 f1000research 18888 1 PMC 6681627 PMID 31448088 Moy B Rumble RB Come SE Davidson NE Di Leo A Gralow JR Hortobagyi GN Yee D Smith IE Chavez MacGregor M Nanda R McArthur HL Spring L Reeder Hayes KE Ruddy KJ Unger PS Vinayak S Irvin WJ Jr Armaghani A Danso MA Dickson N Turner SS Perkins CL Carey LA 10 Dec 2021 Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2 Negative Metastatic Breast Cancer That is Either Endocrine Pretreated or Hormone Receptor Negative ASCO Guideline Update Journal of Clinical Oncology 39 35 3938 3958 doi 10 1200 JCO 21 01374 PMID 34324366 S2CID 236515507 a b 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 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 PMID 22517820 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 a b SABCS PARP Inhibitor Data Called Spectacular Dec 2009 A Study of NK012 in Patients With Advanced Metastatic Triple Negative Breast Cancer 12 February 2015 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 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 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 Finally targeted therapies for triple negative breast cancer June 2016 Study of Leronlimab PRO 140 Combined With Carboplatin in Patients With CCR5 mTNBC 13 January 2022 First Patient in CytoDyn s Triple Negative Metastatic Breast Cancer Trial Shows Significant Reduction in Circulating Tumor Cells CTC and Reduced Tumor Size 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 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 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 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 Edit Lehmann BD Pietenpol JA January 2014 Identification and use of biomarkers in treatment strategies for triple negative breast cancer subtypes The Journal of Pathology 232 2 142 50 doi 10 1002 path 4280 PMC 4090031 PMID 24114677 External links EditThe Official Triple Negative Breast Cancer Foundation Site Retrieved from https en wikipedia org w index php title Triple negative breast cancer amp oldid 1136162664, wikipedia, wiki, book, books, library,

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