Triple-negative breast cancer: Difference between revisions
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{{short description|Type of breast cancer lacking certain gene expressions}} |
{{short description|Type of breast cancer lacking certain gene expressions}} |
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'''Triple-negative breast cancer''' ('''TNBC''') is any [[breast cancer]] that lacks or |
'''Triple-negative breast cancer''' ('''TNBC''') is any [[breast cancer]] that either lacks or shows low levels of [[estrogen receptor]] (ER), [[progesterone receptor]] (PR) and [[HER2/neu|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'').<ref>{{cite journal | vauthors = Foulkes WD, Smith IE, Reis-Filho JS | title = Triple-negative breast cancer | journal = The New England Journal of Medicine | volume = 363 | issue = 20 | pages = 1938–48 | date = November 2010 | pmid = 21067385 | doi = 10.1056/Nejmra1001389 | s2cid = 205115843 }}</ref> Triple-negative is sometimes used as a surrogate term for [[Basal-like carcinoma|basal-like]].<ref name="Hudis_2011_2">{{cite journal | vauthors = Hudis CA, Gianni L | title = Triple-negative breast cancer: an unmet medical need | journal = The Oncologist | volume = 16 | pages = 1–11 | year = 2011 | issue = Suppl 1 | pmid = 21278435 | doi = 10.1634/theoncologist.2011-S1-01 | s2cid = 22362118 }}</ref> |
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Triple-negative breast |
Triple-negative breast cancer comprises 15–20% of all breast cancer cases<ref>{{cite journal |vauthors=Sporikova Z, Koudelakova V, Trojanec R, Hajduch M |title=Genetic Markers in Triple-Negative Breast Cancer |journal=Clinical Breast Cancer |date=October 2018|volume=18 |issue=5 |pages=e841–e850 |doi=10.1016/j.clbc.2018.07.023 |pmid=30146351|s2cid=52091594 |doi-access=free }}</ref> and affects more young women or women with a mutation in the [[BRCA1]] gene than other breast cancers.<ref>{{Cite web|url=https://www.uchicagomedicine.org/forefront/cancer-articles/2019/march/old-drugs-bring-new-hope-to-a-cancer-that-lacks-precision-therapy|title=Old drugs bring new hope to a cancer that lacks precision therapy |website=www.uchicagomedicine.org|language=en|access-date=2022-02-23}}</ref> Triple-negative breast cancers comprise a very heterogeneous group of cancers. |
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⚫ | TNBC is the most challenging breast cancer type to treat.<ref name="castro19">{{cite journal |journal = Cancer Discovery |date = 2019 |volume = 9 |issue = 2 |pages=176–198 |doi= 10.1158/2159-8290.CD-18-1177 |pmid=30679171 |title=Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment |vauthors = Garrido-Castro AC, Lin NU, Polyak K|pmc = 6387871 }}</ref> Hormone therapy that is used for other breast cancers does not work for TNBC.<ref name="cancer22"/> 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.<ref name="cancer22"/> |
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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.<ref name=Hudis_2011_2/><ref name=Cheang_2008>{{cite journal | vauthors = Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO | display-authors = 6 | title = Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype | journal = Clinical Cancer Research | volume = 14 | issue = 5 | pages = 1368–76 | date = March 2008 | pmid = 18316557 | doi = 10.1158/1078-0432.CCR-07-1658 | doi-access = free }}</ref> |
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⚫ | TNBC is the most challenging breast cancer type to treat.<ref name="castro19">{{cite journal |journal = Cancer |
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== Risk factors == |
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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.<ref name=Hudis_2011_2/><ref name=Cheang_2008/> |
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==Cause== |
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⚫ | One known |
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⚫ | A study in the US has shown that, among younger women, African American and Hispanic women have a higher risk of TNBC,<ref name = nci>{{cite web | url = http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_072407/page7 | title = Spotlight: Triple-Negative Breast Cancer Disproportionately Affects African American and Hispanic Women | access-date = 2008-10-13 | last = Reynolds | first = Sharon | date = 2007-07-24 | publisher = National Cancer Institute | archive-date = 2010-12-21 | archive-url = https://web.archive.org/web/20101221152946/http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_072407/page7 | url-status = dead }}</ref> with African Americans facing worse prognosis when diagnosed later than other ethnic groups.<ref name = medscape>{{cite web | url = http://www.medscape.com/viewarticle/554234 | title = Survival Disadvantage Seen for Triple-Negative Breast Cancer | access-date=2008-10-13 | last= Chustecka | first= Zosia | date= 2007-03-19 | publisher= Medscape Medical News}}</ref> |
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⚫ | One known risk factor for triple-negative breast cancer is [[germline mutation]]s. 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.<ref name="pruss14">{{cite journal | vauthors = Pruss D, Morris B, Hughes E, Eggington JM, Esterling L, Robinson BS, van Kan A, Fernandes PH, Roa BB, Gutin A, Wenstrup RJ, Bowles KR | display-authors = 6 | title = Development and validation of a new algorithm for the reclassification of genetic variants identified in the BRCA1 and BRCA2 genes | journal = Breast Cancer Research and Treatment | volume = 147 | issue = 1 | pages = 119–32 | date = August 2014 | pmid = 25085752 | doi = 10.1007/s10549-014-3065-9 | s2cid = 21438028 }}</ref> 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.<ref name="stevens13">{{cite journal |vauthors=Stevens KN, Vachon CM, Couch FJ |title=Genetic susceptibility to triple-negative breast cancer |journal=Cancer Research |volume=73 |issue=7 |date=2013 |pages=2025–2030 |doi=10.1158/0008-5472.CAN-12-1699 |pmid=23536562|pmc=3654815 }}</ref> |
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⚫ | 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.<ref>{{cite journal | vauthors = Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, Malone KE | title = Risk factors for triple-negative breast cancer in women under the age of 45 years | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 18 | issue = 4 | pages = 1157–66 | date = April 2009 | pmid = 19336554 | pmc = 2754710 | doi = 10.1158/1055-9965.EPI-08-1005 | url = }}</ref> 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. |
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==Classification== |
==Classification== |
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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 [[Epidermal growth factor receptor|EGFR]] staining. However, no clear criteria or cutoff values have been standardized yet.<ref name="Hudis_2011_2"/> About 75% of basal-type breast cancers are triple-negative. <!-- watch for confusion "basal type" versus "basal-like" --> |
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[[Breast cancer classification]] is used to assess the tumor to decide on treatment and prognosis. Classification can be performed using [[molecular oncology|molecular]], [[immunohistochemistry|immunohistochemical]], and clinical characteristics.<ref name=mendez21/> 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:<ref name=mendez21>{{cite journal |vauthors=Ensenyat-Mendez M, Llinàs-Arias P, Orozco JI, Íñiguez-Muñoz S, Salomon MP, Sesé B, DiNome ML, Marzese DM |title=Current Triple-Negative Breast Cancer Subtypes: Dissecting the Most Aggressive Form of Breast Cancer |journal=Frontiers in Oncology |date=16 Jun 2021 |volume=11 |number=681476 |page=681476 |doi=10.3389/fonc.2021.681476 |pmid=34221999 |pmc=8242253|doi-access=free }}</ref> |
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Some TNBC overexpress [[epidermal growth factor receptor]] (EGFR)<ref>Feb 2009 Breast Cancer Watch</ref><ref name=Anders2008>{{cite journal | vauthors = Anders C, Carey LA | title = Understanding and treating triple-negative breast cancer | journal = Oncology | volume = 22 | issue = 11 | pages = 1233–9; discussion 1239–40, 1243 | date = October 2008 | pmid = 18980022 | pmc = 2868264 | url = http://www.cancernetwork.com/display/article/10165/1340727 }}</ref> or [[transmembrane glycoprotein NMB]] (GPNMB). |
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* estrogen receptor positive |
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* progesterone receptor positive |
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* HER2 overexpression positive |
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* triple-negative |
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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.<ref name=mendez21/> |
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Upon histologic examination, triple-negative breast tumors mostly fall into the categories of ''[[Secretory component|secretory]] cell carcinoma'' or ''[[Adenoid cystic carcinoma|adenoid cystic types]]'' (both considered less aggressive); ''[[Medullary carcinoma|medullary cancers]]'' and grade 3 invasive ''[[ductal carcinoma]]s'' with no specific subtype; and highly aggressive ''[[metastatic]] cancers''.<ref name="Hudis_2011_2"/> Medullary TNBC in younger women are frequently ''[[BRCA1]]''-related. |
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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.<ref name=nunnery21>{{cite journal |vauthors=Nunnery SE, Mayer IA, Balko JM |title=Triple-Negative Breast Cancer: Breast Tumors With an Identity Crisis |journal=Cancer Journal |date=1 Jan 2021 |volume=27 |issue=1 |pages=2–7 |doi=10.1097/PPO.0000000000000494 |pmid=33475287 |pmc=8109153}}</ref> |
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Rare forms of triple-negative breast cancer are ''[[Apocrine gland carcinoma|apocrine]]'' and ''[[Squamous-cell carcinoma|squamous carcinoma]]''. ''[[Inflammatory breast cancer]]'' is also frequently triple-negative. |
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Newer techniques for categorising breast cancer are based on gene expression in the tumor which classifies breast cancer into:<ref name=ovcaricek11>{{cite journal |vauthors=Ovcaricek T, Frkovic SG, Matos E, Mozina B, Borstnar S |title=Triple negative breast cancer - prognostic factors and survival |journal=Radiology and Oncology |date= Mar 2011 |volume=45 |issue=1 |pages=46–52 | doi= 10.2478/v10019-010-0054-4 |pmid=22933934 |pmc=3423721}}</ref><ref>{{cite web |url=https://seer.cancer.gov/statfacts/html/breast-subtypes.html |title=Cancer Stat Facts: Female Breast Cancer Subtypes |access-date=1 Mar 2022}}</ref> |
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Many proteins such as [[Caveolin]] 1/2, [[Survivin]] are researched as possible classification or prognostic factors. |
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* luminal A (HR+/HER2-) 68% |
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* luminal B (HR+/HER2+) 10% |
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* HER2 overexpressing (HR-/HER2+) 4% |
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* basal-like (HR-/HER2-) 10% |
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with 7% of unknown subtype. HR indicates ''hormone receptor'' and +/- indicates status whether positive or negative. |
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The basal-like subtype has many overlapping features to TNBC and in addition to being receptor negative, has increased expression of basal cytokeratins.<ref name=ovcaricek11/> 85% of basal-like tumors are TNBC.<ref name=mendez21/> |
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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.<ref>{{cite journal | vauthors = Zhang F, Ren C, Zhao H, Yang L, Su F, Zhou MM, Han J, Sobie EA, Walsh MJ | display-authors = 6 | title = Identification of novel prognostic indicators for triple-negative breast cancer patients through integrative analysis of cancer genomics data and protein interactome data | journal = Oncotarget | volume = 7 | issue = 44 | pages = 71620–71634 | date = November 2016 | pmid = 27690302 | pmc = 5342106 | doi = 10.18632/oncotarget.12287 }}</ref> |
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Subtypes are used to try to define better treatments or a more accurate prognosis. However, there is no standard classification for TNBC subtypes.<ref name=mendez21/> 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.<ref name=mendez21/> One of the popular subtype classification for TNBC is:<ref name=mendez21/><ref name=nunnery21/><ref name=lehmann16>{{cite journal |vauthors=Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA |title=Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection |journal=PLOS ONE |date=16 Jun 2016|volume=11 |issue=6 |pages=e0157368 |doi=10.1371/journal.pone.0157368 |pmid=27310713 |pmc=4911051|bibcode=2016PLoSO..1157368L |doi-access=free }}</ref> |
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* basal-like 1 (BL1) 35% |
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* basal-like 2 (BL2) 22% |
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* mesenchymal (M) 25% |
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* luminal androgen receptor (LAR) 16% |
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Most of TNBC is [[invasive carcinoma of no special type]]. The following rarer breast tumors have a higher proportion of being TNBC:<ref name=pasilova16>{{cite journal |vauthors=Plasilova ML, Hayse B, Killelea BK, Horowitz NR, Chagpar AB, Lannin DR |title=Features of triple-negative breast cancer: Analysis of 38,813 cases from the national cancer database|journal=Medicine (Baltimore)|date=Aug 2016 |volume=95 |issue=35 |pages=e4614|doi=10.1097/MD.0000000000004614 |pmid=27583878 |pmc=5008562}}</ref> |
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*[[adenoid cystic carcinoma]] 78.2% are TNBC |
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*[[metaplastic]] 76.2% are TNBC |
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*[[medullary carcinoma]] 60.5% are TNBC |
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*[[apocrine adenocarcinoma]] 56.7% are TNBC |
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*[[inflammatory breast cancer|inflammatory]] 25.9% are TNBC |
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== Prognosis == |
== Prognosis == |
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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. <ref =""health22">{{cite web |title=10 Triple Negative Breast Cancer Survival Statistics |url=https://healthresearchfunding.org/triple-negative-breast-cancer-survival-statistics/ |access-date=22 Feb 2022}}</ref> The risk of recurrence peaks at three years from diagnosis and reduces after that.<ref name="oreilly21">{{cite journal |title=Overview of recent advances in metastatic triple negative breast cancer |vauthors=O'Reilly D,Al Sendi M,Kelly CM |journal=World Journal of Clinical Oncology |volume=12 |issue=3 |date=24 Mar 2021 |pages=164–182 |pmid=33767972 |doi= 10.5306/wjco.v12.i3.164}}</ref> |
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. <ref =""health22">{{cite web |title=10 Triple Negative Breast Cancer Survival Statistics |date=15 July 2014 |url=https://healthresearchfunding.org/triple-negative-breast-cancer-survival-statistics/ |access-date=22 Feb 2022}}</ref> The risk of recurrence peaks at three years from diagnosis and reduces after that.<ref name="oreilly21">{{cite journal |title=Overview of recent advances in metastatic triple negative breast cancer |vauthors=O'Reilly D,Al Sendi M,Kelly CM |journal=World Journal of Clinical Oncology |volume=12 |issue=3 |date=24 Mar 2021 |pages=164–182 |pmid=33767972 |doi= 10.5306/wjco.v12.i3.164|pmc=7968109 |doi-access=free }}</ref> |
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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.<ref name="cancer22"> |
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.<ref name="cancer22">{{cite web |title=Triple-negative Breast Cancer |url=https://www.cancer.org/cancer/breast-cancer/about/types-of-breast-cancer/triple-negative.html |access-date=22 Feb 2022}}</ref> |
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Approximately 25% of those with localised disease will relapse with distant metastasis also known as stage IV.<ref name="oreilly21"/> Median survival from diagnosis of metastasis is around 12 months.<ref name="oreilly21"/> 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 |
Approximately 25% of those with localised disease will relapse with distant metastasis also known as stage IV.<ref name="oreilly21"/> Median survival from diagnosis of metastasis is around 12 months.<ref name="oreilly21"/> Metastasis in TNBC is different from other breast cancers, with a tendency to spread to the brain and other organs such as the lungs and liver and less of a tendency to spread to the bones.<ref name="oreilly21"/> |
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==Treatment== |
==Treatment== |
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=== Early stage disease === |
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Standard treatment is surgery with [[adjuvant therapy|adjuvant]] chemotherapy and radiotherapy. |
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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.<ref name=guo21>{{cite journal |vauthors=Guo L, Xie G, Wang R, Yang L, Sun L, Xu M, Yang W, Chung MC |title=Local treatment for triple-negative breast cancer patients undergoing chemotherapy: breast-conserving surgery or total mastectomy? |journal= BMC Cancer |date= 19 June 2021 |volume=21 |issue=1 |page=717 |doi= 10.1186/s12885-021-08429-9 |pmid=34147061 |pmc=8214797 |doi-access=free }}</ref> |
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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.<ref name="Hudis_2011_2"/> |
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⚫ | [[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. |
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''BRCA1''-related triple-negative breast cancer appear to be particularly susceptible to chemotherapy, including platinum-based agents and taxanes. |
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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.<ref name=bergin19>{{cite journal |vauthors=Bergin A, Loi S |title=Triple-negative breast cancer: recent treatment advances |date=2 Aug 2019 |volume=8 |journal= F1000Research|page=1342 |doi=10.12688/f1000research.18888.1 |pmid=31448088 |pmc=6681627 |doi-access=free }}</ref> Although this does not always translate into overall survival. |
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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.<ref>{{cite journal | vauthors = Jiang T, Shi W, Wali VB, Pongor LS, Li C, Lau R, Győrffy B, Lifton RP, Symmans WF, Pusztai L, Hatzis C | display-authors = 6 | title = Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis | journal = PLOS Medicine | volume = 13 | issue = 12 | pages = e1002193 | date = December 2016 | pmid = 27959926 | pmc = 5154510 | doi = 10.1371/journal.pmed.1002193 }}</ref> |
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Chemotherapy used to treat early stage cancers are:<ref name=bergin19/> |
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* [[anthracycline]]s |
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* 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. |
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* [[taxanes]] |
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=== Late stage disease === |
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==Epidemiology== |
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Late stage disease is known as ''metastatic TNBC'' (mTNBC). |
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⚫ | A study in the US has shown that, among younger women, African American and Hispanic women have a higher risk of TNBC,<ref name = nci>{{cite web | url = http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_072407/page7 | title = Spotlight: Triple-Negative Breast Cancer Disproportionately Affects African American and Hispanic Women | access-date |
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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. |
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⚫ | 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.<ref>{{cite journal | vauthors = Dolle JM, Daling JR, White E, Brinton LA, Doody DR, Porter PL, Malone KE | title = Risk factors for triple-negative breast cancer in women under the age of 45 years | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 18 | issue = 4 | pages = 1157–66 | date = April 2009 | pmid = 19336554 | pmc = 2754710 | doi = 10.1158/1055-9965.EPI-08-1005 | url = }}</ref> 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. |
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The following treatment is recommended by the American Society of Clinical Oncology (ASCO) for metastatic TNBC:<ref name=asco21>{{cite journal |vauthors=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 |title=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=Journal of Clinical Oncology |date=10 Dec 2021 |volume=39 |issue=35 |pages=3938–3958 |doi=10.1200/JCO.21.01374 |pmid=34324366|s2cid=236515507 |doi-access=free }}</ref> |
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* mTNBC +PD-L1: 1st line: offered chemo + immune checkpoint inhibitor |
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* mTNBC -PD-L1: 1st line: single-agent chemo; 3rd line: sacituzumab govitecan |
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* mTNBC +BRCA: patients previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic disease should be offered PARP inhibitor rather than chemotherapy. |
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⚫ | [[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.<ref name="Commissioner">{{Cite web|last=Commissioner|first=Office of the|date=2020-04-22|title=FDA Approves New Therapy for Triple Negative Breast Cancer That Has Spread, Not Responded to Other Treatments|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-triple-negative-breast-cancer-has-spread-not-responded-other-treatments|access-date=2020-11-19|website=FDA|language=en}}</ref> Sacituzumab govitecan had previously received FDA [[priority review]], [[breakthrough therapy]], and [[Fast track (FDA)|fast track]] designations.<ref name="Commissioner"/> |
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==Clinical |
==Clinical trials== |
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{{update section|date=February 2016}} |
{{update section|date=February 2016}} |
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[[Angiogenesis]] and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown efficacy.<ref>{{cite journal |last1=Gelmon |first1=K. |last2=Dent |first2=R. |last3=Mackey |first3=J. R. |last4=Laing |first4=K. |last5=McLeod |first5=D. |last6=Verma |first6=S. |title=Targeting triple-negative breast cancer: optimising therapeutic outcomes |journal=Annals of Oncology |date=1 September 2012 |volume=23 |issue=9 |pages=2223–2234 |doi=10.1093/annonc/mds067}}</ref> 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. |
[[Angiogenesis]] and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown efficacy.<ref>{{cite journal |last1=Gelmon |first1=K. |last2=Dent |first2=R. |last3=Mackey |first3=J. R. |last4=Laing |first4=K. |last5=McLeod |first5=D. |last6=Verma |first6=S. |title=Targeting triple-negative breast cancer: optimising therapeutic outcomes |journal=Annals of Oncology |date=1 September 2012 |volume=23 |issue=9 |pages=2223–2234 |doi=10.1093/annonc/mds067|pmid=22517820 |doi-access=free }}</ref> 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. |
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By 2009 |
By 2009 a number of new strategies for TNBC were being tested in clinical trials,<ref name=Anders2008>{{cite journal | vauthors = Anders C, Carey LA | title = Understanding and treating triple-negative breast cancer | journal = Oncology | volume = 22 | issue = 11 | pages = 1233–9; discussion 1239–40, 1243 | date = October 2008 | pmid = 18980022 | pmc = 2868264 | url = http://www.cancernetwork.com/display/article/10165/1340727 }}</ref> including the [[PARP inhibitor]] [[BSI 201]],<ref name=Dec2009>[http://www.medpagetoday.com/MeetingCoverage/SABCS/17496 "SABCS: PARP Inhibitor Data Called 'Spectacular' "]; Dec 2009</ref> [[NK012]].<ref>{{cite web |url=http://clinicaltrials.gov/ct2/show/NCT00951054 |title=A Study of NK012 in Patients With Advanced, Metastatic Triple Negative Breast Cancer |date=12 February 2015 }}</ref> |
||
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.<ref name=Burris_2009>{{cite web | url=http://www.celldextherapeutics.com/pdf/SABCS%202009_CDX011%20breast_FINAL.pdf |title=A Phase I/II Study of CR011-vcMMAE (CDX-011), an Antibody-Drug Conjugate, in Patients with Locally Advanced or Metastatic Breast Cancer|author=Burris |year=2009 }}</ref> |
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.<ref name=Burris_2009>{{cite web | url=http://www.celldextherapeutics.com/pdf/SABCS%202009_CDX011%20breast_FINAL.pdf |title=A Phase I/II Study of CR011-vcMMAE (CDX-011), an Antibody-Drug Conjugate, in Patients with Locally Advanced or Metastatic Breast Cancer|author=Burris |year=2009 }}</ref> |
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Three early stage trials reported TNBC results in June 2016, for [[IMMU-132]], [[Vantictumab]], and [[atezolizumab]] in combination with the chemotherapy [[nab-paclitaxel]].<ref name=2016-1b>[http://medicalxpress.com/news/2016-06-therapies-triple-negative-breast-cancer.html Finally, targeted therapies for triple-negative breast cancer. June 2016]</ref> |
Three early stage trials reported TNBC results in June 2016, for [[IMMU-132]], [[Vantictumab]], and [[atezolizumab]] in combination with the chemotherapy [[nab-paclitaxel]].<ref name=2016-1b>[http://medicalxpress.com/news/2016-06-therapies-triple-negative-breast-cancer.html Finally, targeted therapies for triple-negative breast cancer. June 2016]</ref> |
||
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. |
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.<ref>{{cite web |url=https://clinicaltrials.gov/ct2/show/NCT03838367?term=leronlimab&draw=2&rank=1 |title=Study of Leronlimab (PRO 140) Combined With Carboplatin in Patients With CCR5+ mTNBC |date=13 January 2022 }}</ref><ref>{{citation |url=https://www.cytodyn.com/newsroom/press-releases/detail/359/first-patient-in-cytodyns-triple-negative-metastatic |title=First Patient in CytoDyn's Triple-Negative Metastatic Breast Cancer Trial Shows Significant Reduction in Circulating Tumor Cells (CTC) and Reduced Tumor Size }}</ref> |
||
{{as of|2022}} a combination of [[ostarine]], a [[selective androgen receptor modulator]], and [[sabizabulin]] is under investigation in a phase II trial.<ref>{{cite web |title=FDA Grants Fast Track Designation to Enobosarm in AR+, ER+, HER2- Metastatic Breast Cancer |url=https://www.cancernetwork.com/view/fda-grants-fast-track-designation-to-enobosarm-in-ar-er-her2--metastatic-breast-cancer |website=Cancer Network |access-date=27 August 2023 |language=en |date=10 January 2022}}</ref> |
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==Pre-clinical research/speculations== |
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== Research== |
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{{Update section|date=September 2018}} |
{{Update section|date=September 2018}} |
||
<!-- approx chronological --> |
<!-- approx chronological --> |
||
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]]).<ref name = "Basu S 2008">{{cite journal | vauthors = Basu S, Chen W, Tchou J, Mavi A, Cermik T, Czerniecki B, Schnall M, Alavi A | display-authors = 6 | title = 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 | journal = Cancer | volume = 112 | issue = 5 | pages = 995–1000 | date = March 2008 | pmid = 18098228 | doi = 10.1002/cncr.23226 | s2cid = 22106575 | |
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]]).<ref name = "Basu S 2008">{{cite journal | vauthors = Basu S, Chen W, Tchou J, Mavi A, Cermik T, Czerniecki B, Schnall M, Alavi A | display-authors = 6 | title = 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 | journal = Cancer | volume = 112 | issue = 5 | pages = 995–1000 | date = March 2008 | pmid = 18098228 | doi = 10.1002/cncr.23226 | s2cid = 22106575 | doi-access = free }}</ref> It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology. [[Galectin-1]] in TNBC is a beta-galactosidase-binding protein that shields cancer cells from the effects of radiotherapy by suppressing anti-tumor doxorubicin-induced apoptosis, and since this immunosuppression mechanism is higher in TNBC than in other cancer, Gal-1 has shown promise as a therapeutic marker of TNBC.<ref>{{cite journal |last1=Nam |first1=KeeSoo |last2=Son |first2 = Seog-ho |last3=Oh |first3=Sunhwa |display-authors=2 |title=Binding of galectin-1 to integrin β1 potentiates drug resistance by promoting survivin expression in breast cancer cells |journal=Oncotarget |date=March 15, 2017 |volume=8 |issue=22 |pages=35804–35823 |doi=10.18632/oncotarget.16208 |pmid=28415760 |doi-access=free |pmc=5482619 }}</ref> |
||
It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology. |
|||
Another therapeutic marker of TNBC examines T-regulatory cells (Treg) and the presence of CCR2-positive Treg causing a decrease in CD8-positive cytotoxic T-cell activation resulting in promotion of tumor growth and metastasis as the tumor microenvironment is infiltrated with Treg.<ref>{{cite journal |last1=Malla |first1=Rama Rao |last2=Vasudevaraju |first2=Padmaraju |last3=Vempati |first3=Rahul Kumar |last4=Rakshmitha |first4=Marni |last5=Merchant |first5=Neha |last6=Nagaraju |first6=Ganji Purnachandra |title=Regulatory T cells: Their role in triple-negative breast cancer progression and metastasis |journal=Cancer |date=January 2022 |volume=128 |issue=6 |pages=1171–1183 |doi=10.1002/cncr.34084 |pmid=34990009 |s2cid=245772158 |url=https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.34084 |access-date=14 November 2023}}</ref> |
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The widely used diabetes drug |
The widely used diabetes drug [[metformin]] holds promise for the treatment of triple-negative breast cancer.<ref name = Jiralerspong>{{cite journal | vauthors = Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, Thor AD | title = Metformin induces unique biological and molecular responses in triple negative breast cancer cells | journal = Cell Cycle | volume = 8 | issue = 13 | pages = 2031–40 | date = July 2009 | pmid = 19440038 | doi = 10.4161/cc.8.17.9502 | doi-access = free }}</ref> 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.<ref name = "Goodwin PJ">{{cite journal | vauthors = Goodwin PJ, Ligibel JA, Stambolic V | title = Metformin in breast cancer: time for action | journal = Journal of Clinical Oncology | volume = 27 | issue = 20 | pages = 3271–3 | date = July 2009 | pmid = 19487373 | doi = 10.1200/JCO.2009.22.1630 | doi-access = free }}</ref> |
||
Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study.<ref>{{cite journal | vauthors = Louie SM, Grossman EA, Crawford LA, Ding L, Camarda R, Huffman TR, Miyamoto DK, Goga A, Weerapana E, Nomura DK | display-authors = 6 | title = GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity | journal = Cell Chemical Biology | volume = 23 | issue = 5 | pages = 567–578 | date = May 2016 | pmid = 27185638 | pmc = 4876719 | doi = 10.1016/j.chembiol.2016.03.017 }}</ref> |
Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study.<ref>{{cite journal | vauthors = Louie SM, Grossman EA, Crawford LA, Ding L, Camarda R, Huffman TR, Miyamoto DK, Goga A, Weerapana E, Nomura DK | display-authors = 6 | title = GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity | journal = Cell Chemical Biology | volume = 23 | issue = 5 | pages = 567–578 | date = May 2016 | pmid = 27185638 | pmc = 4876719 | doi = 10.1016/j.chembiol.2016.03.017 }}</ref> |
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=== Further reading === |
=== Further reading === |
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{{refbegin|30em}} |
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* {{cite journal | vauthors = Alanazi IO, Khan Z | title = Understanding EGFR Signaling in Breast Cancer and Breast Cancer Stem Cells: Overexpression and Therapeutic Implications | journal = Asian Pacific Journal of Cancer Prevention | volume = 17 | issue = 2 | pages = 445–53 | date = 2016 | pmid = 26925626 | doi = 10.7314/apjcp.2016.17.2.445 | doi-access = free }} |
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* {{cite journal | vauthors = Lehmann BD, Pietenpol JA | title = Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes | journal = The Journal of Pathology | volume = 232 | issue = 2 | pages = 142–50 | date = January 2014 | pmid = 24114677 | pmc = 4090031 | doi = 10.1002/path.4280 }} |
* {{cite journal | vauthors = Lehmann BD, Pietenpol JA | title = Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes | journal = The Journal of Pathology | volume = 232 | issue = 2 | pages = 142–50 | date = January 2014 | pmid = 24114677 | pmc = 4090031 | doi = 10.1002/path.4280 }} |
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* {{cite journal | vauthors = Stevens KN, Vachon CM, Couch FJ | title = Genetic susceptibility to triple-negative breast cancer | journal = Cancer Research | volume = 73 | issue = 7 | pages = 2025–30 | date = April 2013 | pmid = 23536562 | pmc = 3654815 | doi = 10.1158/0008-5472.can-12-1699 }} |
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* {{cite journal | vauthors = Wilson EA, Elford HL, Faridi JS | title = Successfully targeting triple negative breast cancer using combination therapy of Didox and Doxorubicin with reduced cardiotoxicity. | journal = Cancer Research | volume = 76 | issue = 14 Supplement | date = 2016 | pages = 4689 | doi = 10.1158/1538-7445.AM2016-4689 }} |
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{{refend}} |
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== External links == |
== External links == |
Latest revision as of 03:40, 14 June 2024
Triple-negative breast cancer (TNBC) is any breast cancer that either 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
[edit]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 when diagnosed later 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
[edit]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]
- estrogen 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]
- 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 TNBC
Prognosis
[edit]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]
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 the lungs and liver and less of a tendency to spread to the bones.[20]
Treatment
[edit]Early 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.
- taxanes
Late 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
[edit]This section needs to be updated.(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 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]
As of 2022[update] a combination of ostarine, a selective androgen receptor modulator, and sabizabulin is under investigation in a phase II trial.[35]
Research
[edit]This section needs to be updated.(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).[36] It is speculated that enhanced glycolysis in these tumors is probably related to their aggressive biology. Galectin-1 in TNBC is a beta-galactosidase-binding protein that shields cancer cells from the effects of radiotherapy by suppressing anti-tumor doxorubicin-induced apoptosis, and since this immunosuppression mechanism is higher in TNBC than in other cancer, Gal-1 has shown promise as a therapeutic marker of TNBC.[37]
Another therapeutic marker of TNBC examines T-regulatory cells (Treg) and the presence of CCR2-positive Treg causing a decrease in CD8-positive cytotoxic T-cell activation resulting in promotion of tumor growth and metastasis as the tumor microenvironment is infiltrated with Treg.[38]
The widely used diabetes drug metformin holds promise for the treatment of triple-negative breast cancer.[39] 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.[40]
Triple-negative breast cancer cells rely on glutathione-S-transferase Pi1, and an inhibitor (LAS17) shows encouraging results in a pre-clinical study.[41]
See also
[edit]References
[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. Archived from the original on 2010-12-21. 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 & 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, 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.
- ^ 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.
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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.