triple-negative breast cancer

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.

A study in the US has shown that, among younger women, African American and Hispanic women have a higher risk of TNBC,{{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 }} with African Americans facing worse prognosis when diagnosed later than other ethnic groups.{{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}}

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.{{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 }} 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.{{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 }}

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.{{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 = }} 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.

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. 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:{{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 }}

• 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.

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.{{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}}

Newer techniques for categorising breast cancer are based on gene expression in the tumor which classifies breast cancer into:{{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}}{{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}}

• 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. 85% of basal-like tumors are TNBC.

Subtypes are used to try to define better treatments or a more accurate prognosis. However, there is no standard classification for TNBC subtypes. 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. One of the popular subtype classification for TNBC is:{{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 }}

• 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:{{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}}

• 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

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. {{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}} The risk of recurrence peaks at three years from diagnosis and reduces after that.{{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 }}

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.{{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}}

Approximately 25% of those with localised disease will relapse with distant metastasis also known as stage IV. Median survival from diagnosis of metastasis is around 12 months. 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.

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.{{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 }}

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.{{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 }} Although this does not always translate into overall survival.

Chemotherapy used to treat early stage cancers are:

• anthracyclines
• alkylating 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 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:{{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 }}

• 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.{{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|archive-url=https://web.archive.org/web/20200423093342/https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-triple-negative-breast-cancer-has-spread-not-responded-other-treatments|url-status=dead|archive-date=April 23, 2020|access-date=2020-11-19|website=FDA|language=en}} Sacituzumab govitecan had previously received FDA priority review, breakthrough therapy, and fast track designations.

{{update section|date=February 2016}}

Angiogenesis and EGFR (HER-1) inhibitors are frequently tested in experimental settings and have shown efficacy.{{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 }} 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,{{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 }} including the PARP inhibitor BSI 201,[http://www.medpagetoday.com/MeetingCoverage/SABCS/17496 "SABCS: PARP Inhibitor Data Called 'Spectacular' "]; Dec 2009 NK012.{{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 }}

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.{{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 }}

PARP inhibitors had shown some promise in early trials but failed in some later trials.{{cite journal | vauthors = Guha M | title = PARP inhibitors stumble in breast cancer | journal = Nature Biotechnology | volume = 29 | issue = 5 | pages = 373–4 | date = May 2011 | pmid = 21552220 | doi = 10.1038/nbt0511-373 | s2cid = 205267931 }}

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.{{ClinicalTrialsGov|NCT01997333|Study of Glembatumumab Vedotin (CDX-011) in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer (METRIC)}}

Three early stage trials reported TNBC results in June 2016, for IMMU-132, Vantictumab, and atezolizumab in combination with the chemotherapy nab-paclitaxel.[http://medicalxpress.com/news/2016-06-therapies-triple-negative-breast-cancer.html Finally, targeted therapies for triple-negative breast cancer. June 2016]

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.{{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 }}{{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 }}

{{as of|2022}} a combination of ostarine, a selective androgen receptor modulator, and sabizabulin is under investigation in a phase II trial.{{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}}

{{Update section|date=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).{{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 }} 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.{{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 }}

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.{{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|url-access=subscription }}

The widely used diabetes drug metformin holds promise for the treatment of triple-negative breast cancer.{{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 }} 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.{{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 }}

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

• Triple Negative Breast Cancer Foundation

{{reflist|}}

• {{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 }}

• [http://www.tnbcfoundation.org/ The Official Triple Negative Breast Cancer Foundation Site]
• [http://www.tnbcthrivers.org TNBC Thrivers - TNBC Support for the TNBC Community by the TNBC Community]

Category:Breast cancer