Array ( [0] => {{Short description|Medication}} [1] => {{Distinguish|Trastuzumab emtansine}} [2] => {{Use dmy dates|date=December 2023}} [3] => {{cs1 config |name-list-style=vanc |display-authors=6}} [4] => {{Drugbox [5] => | Verifiedfields = changed [6] => | verifiedrevid = 470612477 [7] => | type = mab [8] => | image = Trastuzumab Fab-HER2 complex 1N8Z.png [9] => | width = [10] => | alt = [11] => | caption = Trastuzumab [[Fab region]] (cyan) binding HER2/neu (gold) [12] => [13] => [14] => | mab_type = mab [15] => | source = zu/o [16] => | target = [[HER2/neu]] [17] => [18] => [19] => | pronounce = [20] => | tradename = Herceptin, Herceptin SC, others [21] => | Drugs.com = {{drugs.com|monograph|trastuzumab}} [22] => | MedlinePlus = [23] => | DailyMedID = Trastuzumab [24] => | pregnancy_AU = D [25] => | pregnancy_AU_comment = [26] => | pregnancy_category= [27] => | routes_of_administration = [[Intravenous]], [[Subcutaneous injection|subcutaneous]] [28] => | class = [[Antineoplastic agent]] [29] => | ATC_prefix = L01 [30] => | ATC_suffix = FD01 [31] => | ATC_supplemental = [32] => | biosimilars = trastuzumab-anns,{{cite web | title=Kanjinti- trastuzumab-anns injection, powder, lyophilized, for solution; Kanjinti- trastuzumab-anns kit | website=DailyMed | date=13 October 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9a94f5b2-b84e-4987-8ea1-c4346db5a5fa | access-date=11 December 2023 | archive-date=5 December 2021 | archive-url=https://web.archive.org/web/20211205115531/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9a94f5b2-b84e-4987-8ea1-c4346db5a5fa | url-status=live }} trastuzumab-dkst, trastuzumab-dttb,{{cite web | title=Ontruzant- trastuzumab injection, powder, lyophilized, for solution; Ontruzant- ontruzant kit | website=DailyMed | date=31 January 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ce2a2492-85e3-4b0a-872a-047f44e4203d | access-date=11 December 2023 | archive-date=13 August 2022 | archive-url=https://web.archive.org/web/20220813064908/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ce2a2492-85e3-4b0a-872a-047f44e4203d | url-status=live }} trastuzumab-pkrb, trastuzumab-qyyp,{{cite web | title=Trazimera- trastuzumab-qyyp kit; Trazimera- trastuzumab-qyyp injection, powder, lyophilized, for solution | website=DailyMed | date=14 February 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9c5e894-27d2-4245-a653-df986fed3c56 | access-date=11 December 2023 | archive-date=7 December 2022 | archive-url=https://web.archive.org/web/20221207054300/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9c5e894-27d2-4245-a653-df986fed3c56 | url-status=live }} trastuzumab-strf,https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761346Orig1s000lbl.pdf Hercessi, Herzuma, Herwenda, Kanjinti, Ogivri,{{cite web | title=Ogivri- trastuzumab kit; Ogivri- trastuzumab injection, powder, lyophilized, for solution | website=DailyMed | date=8 February 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b7938e6-14c7-4a65-9605-967542ecfb8f | access-date=11 December 2023 | archive-date=7 December 2022 | archive-url=https://web.archive.org/web/20221207234134/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6b7938e6-14c7-4a65-9605-967542ecfb8f | url-status=live }}{{cite web | title=Ogivri- trastuzumab kit; Ogivri- trastuzumab injection, powder, lyophilized, for solution | website=DailyMed | date=28 July 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6465b44-a6dd-f99c-d009-6851cf05169c | access-date=11 December 2023 | archive-date=10 March 2024 | archive-url=https://web.archive.org/web/20240310064336/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6465b44-a6dd-f99c-d009-6851cf05169c | url-status=live }} Ontruzant, Trastucip, Trazimera, Tuzucip, Zercepac [33] => [34] => [35] => | legal_AU = S4 [36] => | legal_AU_comment = {{cite web |url=https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropherce10315 |title=Herceptin (trastuzumab) powder for injection| date = 7 May 2021 | work = Roche Products Pty Limited |access-date=8 January 2023 |archive-date=8 March 2023 |archive-url=https://web.archive.org/web/20230308180216/https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropherce10315 |url-status=live }}{{cite web | title = Trastuzumab | date = 7 April 2022 | work = Roche Products Pty Limited | url = https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=rophersc10315 | archive-url = https://web.archive.org/web/20230108233204/https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=rophersc10315 | archive-date=8 January 2023 }}{{cite web | title=Trastucip and Tuzucip APMDS | website=Therapeutic Goods Administration (TGA) | date=29 July 2022 | url=https://www.tga.gov.au/resources/auspmd/trastucip-and-tuzucip | access-date=2 August 2022 | archive-date=30 July 2022 | archive-url=https://web.archive.org/web/20220730084120/https://www.tga.gov.au/apm-summary/trastucip-and-tuzucip | url-status=live }} [37] => | legal_BR = [38] => | legal_BR_comment = [39] => | legal_CA = Rx-only [40] => | legal_CA_comment = / Schedule D{{cite web | title=Summary Basis of Decision - Ontruzant | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00591&lang=en | access-date=6 August 2022 | archive-date=6 August 2022 | archive-url=https://web.archive.org/web/20220806061607/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00591&lang=en | url-status=live }} [41] => | legal_DE = [42] => | legal_DE_comment = [43] => | legal_NZ = [44] => | legal_NZ_comment = [45] => | legal_UK = [46] => | legal_UK_comment = [47] => | legal_US = Rx-only [48] => | legal_US_comment = [49] => | legal_EU = Rx-only [50] => | legal_EU_comment = {{cite web | title=Herwenda EPAR | website=European Medicines Agency | date=15 November 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/herwenda | access-date=11 December 2023 | archive-date=3 December 2023 | archive-url=https://web.archive.org/web/20231203211712/http://www.ema.europa.eu/en/medicines/human/EPAR/herwenda | url-status=live }}{{cite web | title=Herwenda Product information | website=Union Register of medicinal products | date=16 November 2023 | url=https://ec.europa.eu/health/documents/community-register/html/h1762.htm | access-date=11 December 2023 | archive-date=26 November 2023 | archive-url=https://web.archive.org/web/20231126162548/https://ec.europa.eu/health/documents/community-register/html/h1762.htm | url-status=live }} [51] => | legal_UN = [52] => | legal_UN_comment = [53] => | legal_status = [54] => [55] => [56] => | bioavailability = [57] => | protein_bound = [58] => | metabolism = Unknown, possibly reticuloendothelial system [59] => | metabolites = [60] => | onset = [61] => | elimination_half-life = 2-12 days [62] => | duration_of_action = [63] => | excretion = [64] => [65] => [66] => | CAS_number_Ref = {{cascite|correct|??}} [67] => | CAS_number = 180288-69-1 [68] => | CAS_supplemental = [69] => | PubChem = [70] => | PubChemSubstance = 46507516 [71] => | IUPHAR_ligand = [72] => | DrugBank_Ref = {{drugbankcite|correct|drugbank}} [73] => | DrugBank = DB00072 [74] => | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} [75] => | ChemSpiderID = none [76] => | UNII_Ref = {{fdacite|correct|FDA}} [77] => | UNII = P188ANX8CK [78] => | KEGG_Ref = {{keggcite|correct|kegg}} [79] => | KEGG = D03257 [80] => | ChEBI = [81] => | ChEMBL_Ref = {{ebicite|changed|EBI}} [82] => | ChEMBL = 1201585 [83] => | NIAID_ChemDB = [84] => | PDB_ligand = [85] => | synonyms = [86] => [87] => [88] => | IUPAC_name = [89] => | C=6470 | H=10012 | N=1726 | O=2013 | S=42 [90] => | SMILES = [91] => | StdInChI = [92] => | StdInChI_comment = [93] => | StdInChIKey = [94] => | density = [95] => | density_notes = [96] => | melting_point = [97] => | melting_high = [98] => | melting_notes = [99] => | boiling_point = [100] => | boiling_notes = [101] => | solubility = [102] => | sol_units = [103] => | specific_rotation = [104] => }} [105] => [106] => [107] => '''Trastuzumab''', sold under the brand name '''Herceptin''' among others, is a [[monoclonal antibody]] used to treat [[breast cancer]] and [[stomach cancer]].{{cite web|title=Trastuzumab|url=https://www.drugs.com/monograph/trastuzumab.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221162802/https://www.drugs.com/monograph/trastuzumab.html|archive-date=21 December 2016}}{{cite web | title=Herceptin- trastuzumab kit Herceptin- trastuzumab injection, powder, lyophilized, for solution | website=DailyMed | date=30 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=492dbdb2-077e-4064-bff3-372d6af0a7a2 | access-date=28 July 2020 | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804153434/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=492dbdb2-077e-4064-bff3-372d6af0a7a2 | url-status=live }}{{cite press release |title=FDA approves first biosimilar for the treatment of certain breast and stomach cancers |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treatment-certain-breast-and-stomach-cancers |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=18 February 2020 |date=10 September 2019 |archive-date=15 December 2019 |archive-url=https://web.archive.org/web/20191215091513/https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treatment-certain-breast-and-stomach-cancers |url-status=live }} It is specifically used for cancer that is [[HER2 receptor positive]]. It may be used by itself or together with other [[chemotherapy medication]]. Trastuzumab is given by [[intravenous infusion|slow injection into a vein]] and [[Subcutaneous injection|injection just under the skin]].{{cite book|title=British national formulary : BNF 69|date=2015|publisher=British Medical Association|isbn=978-0-85711-156-2|page=626|edition=69}} [108] => [109] => [110] => Common side effects include fever, infection, cough, headache, trouble sleeping, and rash. Other severe side effects include [[heart failure]], [[allergic reactions]], and [[lung disease]]. Use during [[pregnancy]] may harm the baby.{{cite web|title=Trastuzumab Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/trastuzumab.html|website=Drugs.com | archive-url=https://web.archive.org/web/20191203180757/https://www.drugs.com/pregnancy/trastuzumab.html | archive-date=3 December 2019 | url-status=live | access-date=3 December 2019 }} Trastuzumab works by binding to the [[HER2 receptor]] and slowing down cell replication. [111] => [112] => [113] => Trastuzumab was approved for medical use in the United States in September 1998, and in the European Union in August 2000.{{cite web | title=Trastuzumab Product Approval Information - Licensing Action 9/25/98 | website=U.S. [[Food and Drug Administration]] (FDA) | date=18 December 2015 | url=https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080591.htm | archive-url=https://web.archive.org/web/20170128163102/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ucm080591.htm | archive-date=28 January 2017 | url-status=dead | access-date=3 December 2019}} {{PD-notice}}{{cite web | title=Herceptin EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/herceptin | access-date=28 July 2020 | archive-date=28 July 2020 | archive-url=https://web.archive.org/web/20200728160341/https://www.ema.europa.eu/en/medicines/human/EPAR/herceptin | url-status=live }} It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }} [114] => [115] => ==Medical uses== [116] => The safety and efficacy of trastuzumab-containing combination therapies (with chemotherapy, hormone blockers, or [[lapatinib]]) for the treatment of metastatic breast cancer.{{clarify|date=December 2019}} The overall hazard ratios (HR) for overall survival and progression free survival were 0.82 and 0.61, respectively.{{clarify|date=December 2019}} It was difficult to accurately ascertain the true impact of trastuzumab on survival, as in three of the seven trials, over half of the patients in the control arm were allowed to cross-over and receive trastuzumab after their cancer began to progress.{{cite journal | vauthors = Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja L, D'Amico R | title = Trastuzumab-containing regimens for metastatic breast cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 6 | pages = CD006242 | date = June 2014 | pmid = 24919460 | pmc = 6464904 | doi = 10.1002/14651858.CD006242.pub2 | url = https://air.unimi.it/bitstream/2434/237345/2/CD006242.pdf | access-date = 9 June 2018 | url-status = live | archive-url = https://web.archive.org/web/20210829093518/https://air.unimi.it/retrieve/handle/2434/237345/316843/CD006242.pdf | archive-date = 29 August 2021 }} Thus, this analysis likely underestimates the true survival benefit associated with trastuzumab treatment in this population.{{cite journal | vauthors = Wilcken N | title = Treating metastatic breast cancer: the evidence for targeted therapy | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = ED000083 | date = June 2014 | volume = 2014 | pmid = 25032250 | doi = 10.1002/14651858.ED000083 | veditors = Tovey D | doi-access = | pmc = 10845883 }} [117] => [118] => In early-stage HER2-positive breast cancer, trastuzumab-containing regimens improved overall survival ([[Hazard ratio]] (HR) = 0.66) and disease-free survival (HR = 0.60). Increased risk of heart failure (RR = 5.11) and decline in left ventricular ejection fraction ([[relative risk]] RR = 1.83) were seen in these trials as well. Two trials involving shorter term treatment with trastuzumab did not differ in efficacy from longer trials, but produced less cardiac toxicity.{{cite journal | vauthors = Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, D'Amico R | title = Trastuzumab containing regimens for early breast cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 4 | pages = CD006243 | date = April 2012 | pmid = 22513938 | pmc = 6718210 | doi = 10.1002/14651858.CD006243.pub2 }} [119] => [120] => The original studies of trastuzumab showed that it improved overall survival in late-stage (metastatic) HER2-positive breast cancer from 20.3 to 25.1 months. In early-stage HER2-positive breast cancer, it reduces the risk of cancer returning after surgery. The absolute reduction in the risk of cancer returning within three years was 9.5%, and the absolute reduction in the risk of death within 3 years was reduced by 3%. However, it increases serious heart problems by an absolute risk of 2.1%, though the problems may resolve if treatment is stopped.{{cite journal | vauthors = Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, D'Amico R | title = Trastuzumab containing regimens for early breast cancer | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 4 | pages = CD006243 | date = April 2012 | pmid = 22513938 | pmc = 6718210 | doi = 10.1002/14651858.CD006243.pub2 }} [121] => [122] => Trastuzumab has had a "major impact in the treatment of HER2-positive metastatic breast cancer."{{cite journal | vauthors = Tan AR, Swain SM | title = Ongoing adjuvant trials with trastuzumab in breast cancer | journal = Seminars in Oncology | volume = 30 | issue = 5 Suppl 16 | pages = 54–64 | date = October 2003 | pmid = 14613027 | doi = 10.1053/j.seminoncol.2003.08.008 | author2-link = Sandra M. Swain }} The combination of trastuzumab with chemotherapy has been shown to increase both survival and response rate, in comparison to trastuzumab alone.{{cite journal | vauthors = Nahta R, Esteva FJ | title = HER-2-targeted therapy: lessons learned and future directions | journal = Clinical Cancer Research | volume = 9 | issue = 14 | pages = 5078–5084 | date = November 2003 | pmid = 14613984 }} [123] => [124] => It is possible to determine the "erbB2 status" of a tumor, which can be used to predict efficacy of treatment with trastuzumab. If it is determined that a tumor is overexpressing the erbB2 oncogene and the patient has no significant pre-existing heart disease, then a patient is eligible for treatment with trastuzumab.{{cite journal | vauthors = Yu D, Hung MC | title = Overexpression of ErbB2 in cancer and ErbB2-targeting strategies | journal = Oncogene | volume = 19 | issue = 53 | pages = 6115–6121 | date = December 2000 | pmid = 11156524 | doi = 10.1038/sj.onc.1203972 | doi-access = free }} It is surprising that although trastuzumab has great affinity for HER2 and high doses can be administered (because of its low toxicity), 70% of HER2+ patients do not respond to treatment. In fact resistance to the treatment develops rapidly, in virtually all patients. A mechanism of resistance involves failure to downregulate p27 (Kip1) {{cite journal | vauthors = Le XF, Pruefer F, Bast RC | title = HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways | journal = Cell Cycle | volume = 4 | issue = 1 | pages = 87–95 | date = January 2005 | pmid = 15611642 | doi = 10.4161/cc.4.1.1360 | doi-access = free }} as well as suppressing p27 translocation to the nucleus in breast cancer, enabling cdk2 to induce cell proliferation. [125] => [126] => In May 2021, the FDA approved [[pembrolizumab]] in combination with trastuzumab, [[fluoropyrimidine]]- and [[Platinum-based antineoplastic|platinum-containing]] chemotherapy for the first-line treatment of people with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.{{cite web | title=FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer | website=U.S. [[Food and Drug Administration]] (FDA) | date=5 May 2021 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer | access-date=5 May 2021 | archive-date=5 May 2021 | archive-url=https://web.archive.org/web/20210505194245/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer | url-status=live }} {{PD-notice}} [127] => [128] => ===Duration of treatment=== [129] => The optimal duration of add-on trastuzumab treatment after surgery for early breast cancer is unknown. One year of treatment is generally accepted based on clinical trial evidence that demonstrated the superiority of one-year treatment over none.{{cite journal | vauthors = Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N | title = Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1673–1684 | date = October 2005 | pmid = 16236738 | doi = 10.1056/NEJMoa052122 | s2cid = 9534884 | doi-access = free }}{{cite journal | vauthors = Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD | title = Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer | journal = The New England Journal of Medicine | volume = 353 | issue = 16 | pages = 1659–1672 | date = October 2005 | pmid = 16236737 | doi = 10.1056/NEJMoa052306 | hdl-access = free | s2cid = 25624974 | hdl = 10722/251817 }} However, a small Finnish trial also showed similar improvement with nine weeks of treatment over no therapy.{{cite journal | vauthors = Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J | title = Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer | journal = The New England Journal of Medicine | volume = 354 | issue = 8 | pages = 809–820 | date = February 2006 | pmid = 16495393 | doi = 10.1056/NEJMoa053028 | s2cid = 25832514 | doi-access = free }} Because of the lack of direct head-to-head comparison in clinical trials, it is unknown whether a shorter duration of treatment may be just as effective (with fewer side effects) than the accepted practice of treatment for one year. Debate about treatment duration has become a relevant issue for many public health policy makers because administering trastuzumab for a year is very expensive. Consequently, some countries with a taxpayer-funded public health system, such as New Zealand, chose to fund limited adjuvant therapy.{{cite journal | vauthors = Metcalfe S, Evans J, Priest G | title = PHARMAC funding of 9-week concurrent trastuzumab (Herceptin) for HER2-positive early breast cancer | journal = The New Zealand Medical Journal | volume = 120 | issue = 1256 | pages = U2593 | date = June 2007 | pmid = 17589560 }} However, subsequently New Zealand has revised its policy and now funds trastuzumab treatment for up to 12 months.{{cite web |url=http://www.beehive.govt.nz/release/12-month-herceptin-treatment-now-available |title=12-month Herceptin treatment now available |publisher=New Zealand Government |access-date=2 May 2017 |url-status=live |archive-url=https://web.archive.org/web/20170120122328/https://www.beehive.govt.nz/release/12-month-herceptin-treatment-now-available |archive-date=20 January 2017 }} [130] => [131] => ==Adverse effects== [132] => [133] => Some of the common side effects of trastuzumab are flu-like symptoms (such as fever, chills and mild pain), [[nausea]] and [[diarrhea]].{{cite web|title=Breast Cancer Care Trastuzumab factsheet|url=http://www2.breastcancercare.org.uk/sites/default/files/bcc41_trastuzumab_2011.pdf|publisher=Breast Cancer Care|access-date=22 October 2013|url-status=live|archive-url=https://web.archive.org/web/20131023061716/http://www2.breastcancercare.org.uk/sites/default/files/bcc41_trastuzumab_2011.pdf|archive-date=23 October 2013}} [134] => [135] => One of the more serious complications of trastuzumab is its effect on the heart, although this is rare. In 2–7% of cases,{{cite journal | vauthors = Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D | title = Cardiac dysfunction in the trastuzumab clinical trials experience | journal = Journal of Clinical Oncology | volume = 20 | issue = 5 | pages = 1215–1221 | date = March 2002 | pmid = 11870163 | doi = 10.1200/JCO.20.5.1215 }} trastuzumab is associated with cardiac dysfunction, which includes [[congestive heart failure]]. As a result, regular cardiac screening with either a [[MUGA scan]] or [[echocardiography]] is commonly undertaken during the trastuzumab treatment period. The decline in ejection fraction appears to be reversible.{{cite journal | vauthors = van Hasselt JG, Boekhout AH, Beijnen JH, Schellens JH, Huitema AD | title = Population pharmacokinetic-pharmacodynamic analysis of trastuzumab-associated cardiotoxicity | journal = Clinical Pharmacology and Therapeutics | volume = 90 | issue = 1 | pages = 126–132 | date = July 2011 | pmid = 21633346 | doi = 10.1038/clpt.2011.74 | s2cid = 27190873 }} [136] => [137] => Trastuzumab downregulates [[neuregulin-1]] (NRG-1), which is essential for the activation of cell survival pathways in [[cardiomyocyte]]s and the maintenance of cardiac function. NRG-1 activates the MAPK pathway and the [[PI3K/AKT pathway]] as well as focal adhesion kinases (FAK). These are all significant for the function and structure of cardiomyocytes. Trastuzumab can therefore lead to cardiac dysfunction.{{cite journal | vauthors = Zeglinski M, Ludke A, Jassal DS, Singal PK | title = Trastuzumab-induced cardiac dysfunction: A 'dual-hit' | journal = Experimental and Clinical Cardiology | volume = 16 | issue = 3 | pages = 70–4 | date = 2011 | pmid = 22065936 | pmc = 3209542 | doi = | url = }} [138] => [139] => Trastuzumab may harm a developing fetus.{{cite web|title=Breast Cancer Care Trastuzumab factsheet|url=http://www2.breastcancercare.org.uk/sites/default/files/bcc41_trastuzumab_2011.pdf|access-date=22 October 2013|url-status=live|archive-url=https://web.archive.org/web/20131023061716/http://www2.breastcancercare.org.uk/sites/default/files/bcc41_trastuzumab_2011.pdf|archive-date=23 October 2013}}{{dead link|date=December 2023}}{{Unreliable medical source|date=December 2023}} [140] => [141] => ==Mechanism of action== [142] => {{Cleanup section|reason=Capitalization, syntax and tone.|date=October 2016}} [143] => [144] => The ''[[HER2/neu|HER2]]'' gene (also known as ''HER2/neu'' and ''ErbB2'' gene) is amplified in 20–30% of early-stage [[breast cancer]]s. Trastuzumab is a monoclonal antibody targeting HER2, inducing an immune-mediated response that causes internalization and recycling of HER2. It may also upregulate cell cycle inhibitors such as [[P21|p21Waf1]] and [[CDKN1B|p27Kip1]].{{cite journal | vauthors = Bange J, Zwick E, Ullrich A | title = Molecular targets for breast cancer therapy and prevention | journal = Nature Medicine | volume = 7 | issue = 5 | pages = 548–552 | date = May 2001 | pmid = 11329054 | doi = 10.1038/87872 | s2cid = 6010551 }} [145] => [146] => The HER2 pathway promotes cell growth and division when it is functioning normally; however, when it is overexpressed, cell growth accelerates beyond its normal limits. In some types of cancer, the pathway is exploited to promote rapid cell growth and proliferation and hence tumor formation.{{cite web|url=http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/breastcancer_htmlcourse/page3|title=Targeted Therapies for Breast Cancer Tutorial|website=National Cancer Institute|access-date=19 April 2011|url-status=live|archive-url=https://web.archive.org/web/20110329143648/http://www.cancer.gov/cancertopics/understandingcancer/targetedtherapies/breastcancer_htmlcourse/page3|archive-date=29 March 2011}} The EGF pathway includes the receptors [[HER1]] (EGFR), HER2, [[HER3]], and [[HER4]]; the binding of ligands (e.g. EGF etc.) to HER receptors is required to activate the pathway. The pathway initiates the [[Mitogen-activated protein kinase|MAP kinase]] pathway as well as the PI3 kinase/AKT pathway, which in turn activates the NF-κB pathway.{{cite journal | vauthors = Feldman AM, Koch WJ, Force TL | title = Developing strategies to link basic cardiovascular sciences with clinical drug development: another opportunity for translational sciences | journal = Clinical Pharmacology and Therapeutics | volume = 81 | issue = 6 | pages = 887–892 | date = June 2007 | pmid = 17392727 | doi = 10.1038/sj.clpt.6100160 | s2cid = 34778864 }} In cancer cells the HER2 protein can be expressed up to 100 times more than in normal cells (2 million versus 20,000 per cell).{{cite web| vauthors = Winer E |title=HER2 Disease in the Metastatic and Adjuvant Settings|url=http://www.medscape.org/viewarticle/557474|website=Medscape Education|access-date=20 April 2011|url-status=live|archive-url=https://web.archive.org/web/20110410233213/http://www.medscape.org/viewarticle/557474|archive-date=10 April 2011}} [147] => [148] => The HER receptors are proteins that are embedded in the cell membrane and communicate molecular signals from outside the cell (molecules called [[Epidermal growth factor|EGFs]]) to inside the cell, and turn genes on and off. The [[HER2/neu|HER]] (human epidermal growth factor receptor) protein, binds to human epidermal growth factor, and stimulates cell proliferation. In some cancers, notably certain types of breast cancer, HER2 is over-expressed and causes cancer cells to reproduce uncontrollably.{{cite journal | vauthors = Hudis CA | title = Trastuzumab--mechanism of action and use in clinical practice | journal = The New England Journal of Medicine | volume = 357 | issue = 1 | pages = 39–51 | date = July 2007 | pmid = 17611206 | doi = 10.1056/NEJMra043186 }} [149] => [150] => HER2 is localized at the cell surface, and carries signals from outside the cell to the inside. Signaling compounds called [[mitogens]] (specifically EGF in this case) arrive at the cell membrane, and bind to the extracellular domain of the HER family of receptors. Those bound proteins then link ([[protein dimer|dimerize]]), activating the receptor. HER2 sends a signal from its intracellular domain, activating several different biochemical pathways. These include the [[PI3K]]/[[AKT|Akt]] pathway and the [[Mitogen-activated protein kinase|MAPK]] pathway. Signals on these pathways promote cell proliferation and the growth of blood vessels to nourish the tumor ([[angiogenesis]]).{{cite journal | vauthors = Ménard S, Pupa SM, Campiglio M, Tagliabue E | title = Biologic and therapeutic role of HER2 in cancer | journal = Oncogene | volume = 22 | issue = 42 | pages = 6570–6578 | date = September 2003 | pmid = 14528282 | doi = 10.1038/sj.onc.1206779 | doi-access = free }} ERBB2 is the preferred dimerization partner for the other family members and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. It has been reported that Trastuzumab induces the formation of [[complementarity-determining regions]] (CDRs) leading to surface redistribution of ERBB2 and [[Epidermal growth factor receptor|EGFR]] in CDRs and that the ERBB2-dependent [[MAPK]] phosphorylation and EGFR/ERBB1 expression are both required for CDR formation. CDR formation requires activation of both the protein regulator of actin polymerization [[N-WASP]], mediated by ERK1/2, and of the actin-depolymerizing protein [[cofilin]], mediated by EGFR/ERBB1. Furthermore, this latter event may be inhibited by the negative [[cell motility]] regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation. [151] => [152] => Normal cell division—[[mitosis]]—has checkpoints that keep cell division under control. Some of the proteins that control this cycle are called [[Cyclin-dependent kinases|cdk2]] (CDKs). Overexpression of HER2 sidesteps these checkpoints, causing cells to proliferate in an uncontrolled fashion.{{cite journal | vauthors = Kute T, Lack CM, Willingham M, Bishwokama B, Williams H, Barrett K, Mitchell T, Vaughn JP | title = Development of Herceptin resistance in breast cancer cells | journal = Cytometry. Part A | volume = 57 | issue = 2 | pages = 86–93 | date = February 2004 | pmid = 14750129 | doi = 10.1002/cyto.a.10095 | s2cid = 40236173 | doi-access = free }} [153] => [154] => Trastuzumab binds to domain IV of the{{cite journal | vauthors = Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Leahy DJ | title = Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab | journal = Nature | volume = 421 | issue = 6924 | pages = 756–760 | date = February 2003 | pmid = 12610629 | doi = 10.1038/nature01392 | s2cid = 2311471 | bibcode = 2003Natur.421..756C }} extracellular segment of the HER2/neu receptor. Monoclonal antibodies that bind to this region have been shown to reverse the phenotype of HER2/neu expressing tumor cells.{{cite journal | vauthors = Drebin JA, Stern DF, Link VC, Weinberg RA, Greene MI | title = Monoclonal antibodies identify a cell-surface antigen associated with an activated cellular oncogene | journal = Nature | volume = 312 | issue = 5994 | pages = 545–548 | date = December 1984 | pmid = 6504162 | doi = 10.1038/312545a0 | s2cid = 4357211 | bibcode = 1984Natur.312..545D }} Cells treated with trastuzumab undergo arrest during the G1 phase of the [[cell cycle]] so there is reduced proliferation. It has been suggested that trastuzumab does not alter HER-2 expression, but downregulates activation of AKT. In addition, trastuzumab suppresses [[angiogenesis]] both by induction of antiangiogenic factors and repression of proangiogenic factors. It is thought that a contribution to the unregulated growth observed in cancer could be due to proteolytic cleavage of HER2/neu that results in the release of the extracellular domain. One of the most relevant proteins that trastuzumab activates is the tumor suppressor p27 (kip1), also known as [[CDKN1B]]. Trastuzumab has been shown to inhibit HER2/neu ectodomain cleavage in breast cancer cells.{{cite book | vauthors = Albanell J, Codony J, Rovira A, Mellado B, Gascón P | title=New Trends in Cancer for the 21stCentury | chapter=Mechanism of Action of Anti-Her2 Monoclonal Antibodies: Scientific Update on Trastuzumab and 2c4 | year=2003 | volume=532 | pages=253–268 | pmid=12908564 | doi=10.1007/978-1-4615-0081-0_21 | series=Advances in Experimental Medicine and Biology | isbn=978-0-306-47762-1}} [155] => [156] => Experiments in laboratory animals indicate that antibodies, including trastuzumab, when bound to a cell, induce immune cells to kill that cell, and that such [[antibody-dependent cell-mediated cytotoxicity]] is another important mechanism of action.{{cite journal | vauthors = Clynes RA, Towers TL, Presta LG, Ravetch JV | title = Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets | journal = Nature Medicine | volume = 6 | issue = 4 | pages = 443–446 | date = April 2000 | pmid = 10742152 | doi = 10.1038/74704 | s2cid = 20629632 }} [157] => [158] => ==Predicting response== [159] => Trastuzumab inhibits the effects of overexpression of HER2. If the breast cancer does not overexpress HER2, trastuzumab will have no beneficial effect (and may cause harm). Doctors use laboratory tests to discover whether HER2 is overexpressed. In the routine [[clinical laboratory]], the most commonly employed methods for this are [[immunohistochemistry]] (IHC) and either silver, chromogenic or fluorescent [[in situ hybridisation]] (SISH/CISH/FISH). HER2 amplification can be detected by [[Virtual Karyotype|virtual karyotyping]] of formalin-fixed paraffin embedded tumor. Virtual karyotyping has the added advantage of assessing copy number changes throughout the genome, in addition to detecting HER-2 amplification (but not overexpression). Numerous [[Polymerase chain reaction|PCR]]-based methodologies have also been described in the literature.{{cite journal | vauthors = Jennings BA, Hadfield JE, Worsley SD, Girling A, Willis G | title = A differential PCR assay for the detection of c-erbB 2 amplification used in a prospective study of breast cancer | journal = Molecular Pathology | volume = 50 | issue = 5 | pages = 254–256 | date = October 1997 | pmid = 9497915 | pmc = 379641 | doi = 10.1136/mp.50.5.254 }} It is also possible to estimate ''HER2'' copy number from microarray data.{{cite journal | vauthors = Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Gräf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerød A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Børresen-Dale AL, Brenton JD, Tavaré S, Caldas C, Aparicio S | title = The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups | journal = Nature | volume = 486 | issue = 7403 | pages = 346–352 | date = April 2012 | pmid = 22522925 | pmc = 3440846 | doi = 10.1038/nature10983 | bibcode = 2012Natur.486..346. }} [160] => [161] => There are two FDA-approved commercial kits available for HER2 IHC; Dako HercepTest{{cite web |url=http://www.dakousa.com/index/prod_search/prod_baseproducts.htm?productareaid=1&productgroupid=3&productsubgroupid=1003000 |title=Product groups |access-date=24 June 2008 |url-status=live |archive-url=https://web.archive.org/web/20090523140046/http://www.dakousa.com/index/prod_search/prod_baseproducts.htm?productareaid=1&productgroupid=3&productsubgroupid=1003000 |archive-date=23 May 2009 }} and [[Ventana Medical Systems|Ventana]] Pathway.{{cite web |url=http://www.ventanamed.com/ |title=ventanamed.com |publisher=ventanamed.com |date=25 May 2012 |access-date=16 June 2013 |url-status=live |archive-url=https://web.archive.org/web/20111127211754/http://www.ventanamed.com/ |archive-date=27 November 2011 }} [162] => [163] => [[Fluorescent in situ hybridization]] (FISH) is viewed as being the "gold standard" technique in identifying patients who would benefit from trastuzumab, but it is expensive and requires fluorescence microscopy and an image capture system. The main expense involved with CISH is in the purchase of FDA-approved kits, and as it is not a fluorescent technique it does not require specialist microscopy and slides may be kept permanently. Comparative studies of CISH and FISH have shown that these two techniques show excellent correlation. The lack of a separate chromosome 17 probe on the same section is an issue with regards to acceptance of CISH. As of June 2011 Roche has obtained FDA approval for the INFORM HER2 Dual ISH DNA Probe cocktail {{cite web |url=http://www.bioportfolio.com/news/article/711287/Ventana-Medical-Systems-Inc-Receives-Fda-Approval-For-The-First-Fully-Automated.html |title=Ventana Medical Systems, Inc. Receives FDA Approval for the First Fully Automated Diagnostic Assay for HER2 Gene Status Determination in Breast Cancer Patients |publisher=BioPortfolio.com |date=14 June 2011 |access-date=6 January 2013 |url-status=dead |archive-url=https://web.archive.org/web/20120325110438/http://www.bioportfolio.com/news/article/711287/Ventana-Medical-Systems-Inc-Receives-Fda-Approval-For-The-First-Fully-Automated.html |archive-date=25 March 2012 }} developed by [[Ventana Medical Systems]]. The DDISH (Dual-chromagen/Dual-hapten In-situ hybridization) cocktail uses both HER2 and Chromosome 17 hybridization probes for chromagenic visualization on the same tissue section. The detection can be achieved by using a combination of ultraView SISH(silver in-situ hybridization) and ultraView Red ISH for deposition of distinct chromgenic precipitates at the site of DNP or DIG labeled probes.{{cite web |url=http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=70&abstractID=40271 |title=Dual color dual hapten HER2 genotyping for breast biopsy specimens (DDISH): Concordance with fluorescence in situ hybridization (FISH) |publisher=ASCO |date=6 October 2009 |access-date=6 January 2013 |url-status=live |archive-url=https://web.archive.org/web/20120323004623/http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=70&abstractID=40271 |archive-date=23 March 2012 }} [164] => [165] => == Resistance == [166] => One of the challenges in the treatment of breast cancer patients by herceptin is our understanding towards herceptin resistance. In the last decade, several assays have been performed to understand the mechanism of Herceptin resistance with/without supplementary drugs. Recently, all this information has been collected and compiled in form of a database HerceptinR.{{cite journal | vauthors = Ahmad S, Gupta S, Kumar R, Varshney GC, Raghava GP | title = Herceptin resistance database for understanding mechanism of resistance in breast cancer patients | journal = Scientific Reports | volume = 4 | pages = 4483 | date = March 2014 | pmid = 24670875 | pmc = 3967150 | doi = 10.1038/srep04483 | bibcode = 2014NatSR...4E4483A }} [167] => [168] => ==History== [169] => The drug was first discovered by scientists including [[Axel Ullrich]] and [[H. Michael Shepard]] at Genentech, Inc. in South San Francisco, CA.{{cite web |url=http://www.cancer.ucla.edu/ |title=cancer.ucla.edu |publisher=cancer.ucla.edu |access-date=16 June 2013 |url-status=live |archive-url=https://web.archive.org/web/20130611071654/http://www.cancer.ucla.edu/ |archive-date=11 June 2013 }} Earlier discovery about the ''neu'' oncogene by [[Robert Weinberg (biologist)|Robert Weinberg]]'s lab {{cite journal | vauthors = Schechter AL, Stern DF, Vaidyanathan L, Decker SJ, Drebin JA, Greene MI, Weinberg RA | title = The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen | journal = Nature | volume = 312 | issue = 5994 | pages = 513–516 | date = December 1984 | pmid = 6095109 | doi = 10.1038/312513a0 | s2cid = 4357655 | bibcode = 1984Natur.312..513S }} and the monoclonal antibody recognizing the oncogenic receptor by Mark Greene's lab {{cite journal | vauthors = Drebin JA, Link VC, Weinberg RA, Greene MI | title = Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 23 | pages = 9129–9133 | date = December 1986 | pmid = 3466178 | pmc = 387088 | doi = 10.1073/pnas.83.23.9129 | doi-access = free | bibcode = 1986PNAS...83.9129D }} also contributed to the establishment of HER2 targeted therapies. Dr. [[Dennis Slamon]] subsequently worked on trastuzumab's development. A book about Dr. Slamon's work was made into a television film called ''[[Living Proof (2008 film)|Living Proof]]'', that premiered in 2008. [[Genentech]] developed trastuzumab jointly with [[UCLA]], beginning the first clinical trial with 15 women in 1992.{{cite web |url=http://www.gene.com/media/press-releases/4763/1998-09-25/biotechnology-breakthrough-in-breast-can |title=Biotechnology Breakthrough In Breast Cancer Wins FDA Approval |publisher=[[Genentech]] |date=25 September 1998 |access-date=30 May 2016 |url-status=live |archive-url=https://web.archive.org/web/20160701223424/http://www.gene.com/media/press-releases/4763/1998-09-25/biotechnology-breakthrough-in-breast-can |archive-date=1 July 2016 }} By 1996, clinical trials had expanded to over 900 women, but due to pressure from advocates based on early success, Genentech worked with the FDA to begin a lottery system allowing 100 women each quarter access to the medication outside the trials.{{cite news |title=Drug Is Shown to Shrink Tumors in Breast Cancer Characterized by Gene Defect |url=https://www.nytimes.com/1998/05/18/us/drug-is-shown-to-shrink-tumors-in-breast-cancer-characterized-by-gene-defect.html |work=[[The New York Times]] | vauthors = Altman L |access-date=30 May 2016 |date=18 May 1998 |url-status=live |archive-url=https://web.archive.org/web/20160630214956/http://www.nytimes.com/1998/05/18/us/drug-is-shown-to-shrink-tumors-in-breast-cancer-characterized-by-gene-defect.html?pagewanted=all |archive-date=30 June 2016 }} Herceptin was [[Fast track (FDA)|Fast-tracked]] by the FDA and gained approval in September 1998. [170] => [171] => Biocon Ltd and its partner [[Mylan]] obtained regulatory approval to sell a biosimilar in 2014, but Roche contested the legality of the approval; that litigation ended in 2016, and Biocon and Mylan each introduced their own branded biosimilars.{{cite news| vauthors = Palmer E |title=Mylan and Biocon finally win right to sell Herceptin biosim in India even as they have taken it to U.S. and EU|url=http://www.fiercepharma.com/pharma/mylan-and-biocon-finally-win-right-to-sell-herceptin-biosim-india-even-as-they-have-taken-it|work=FiercePharma|date=3 March 2017|url-status=live|archive-url=https://web.archive.org/web/20170908112222/http://www.fiercepharma.com/pharma/mylan-and-biocon-finally-win-right-to-sell-herceptin-biosim-india-even-as-they-have-taken-it|archive-date=8 September 2017}} [172] => [173] => ==Society and culture== [174] => ===Economics=== [175] => Trastuzumab costs about {{US$|70,000}} for a full course of treatment.{{cite journal | vauthors = Fleck LM | title = The costs of caring: Who pays? Who profits? Who panders? | journal = The Hastings Center Report | volume = 36 | issue = 3 | pages = 13–17 | year = 2006 | pmid = 16776017 | doi = 10.1353/hcr.2006.0040 | s2cid = 7873442 }} [176] => [177] => Australia has negotiated a lower price of A$50,000 per course of treatment.{{cite web | publisher = Australian Government, Dept of Health and Ageing | title = Listing of Herceptin on PBS | date = 1 October 2006 | url = http://www.health.gov.au/internet/main/publishing.nsf/Content/herceptin-govtdecision.htm | url-status = dead | archive-url = https://web.archive.org/web/20090912045429/http://www.health.gov.au/internet/main/publishing.nsf/Content/herceptin-govtdecision.htm | archive-date = 12 September 2009 | access-date = 6 August 2009 }} [178] => [179] => Since October 2006, trastuzumab has been made available for Australian women and men with early-stage breast cancer via the [[Pharmaceutical Benefits Scheme]]. This is estimated to cost the country over A$470 million for 4–5 years supply of the drug.Australian Government, Dept of Health and Ageing "Listing of Herceptin on PBS", 1 October 2006. {{cite web |url=http://www.pbs.gov.au/info/news/2006/10/listing-of-herceptin |title=Pharmaceutical Benefits Scheme (PBS) | Listing of Herceptin on the PBS |access-date=20 October 2013 |url-status=live |archive-url=https://web.archive.org/web/20131023114913/http://www.pbs.gov.au/info/news/2006/10/listing-of-herceptin |archive-date=23 October 2013 }} [180] => [181] => Roche has agreed{{when|date=December 2019}} with [[Emcure]] in India to make an affordable version of this cancer drug available to the Indian market.{{cite news | url=http://articles.economictimes.indiatimes.com/2012-03-02/news/31117087_1_emcure-pharmaceuticals-anti-hiv-drugs-emcure-signs-deal | work=The Times Of India | title=Emcure signs deal to manufacture Roche's anti-cancer drugs | date=2 March 2012 | access-date=12 April 2012 | archive-date=2 April 2015 | archive-url=https://web.archive.org/web/20150402170456/http://articles.economictimes.indiatimes.com/2012-03-02/news/31117087_1_emcure-pharmaceuticals-anti-hiv-drugs-emcure-signs-deal | url-status=live }} [182] => [183] => Roche has changed the brand name of the drug and has re-introduced an affordable version of the same in the Indian market.{{when|date=December 2019}} The new drug named Herclon would cost approximately RS75,000 INR ({{US$}}1,200) {{clarify|reason=Per month?|date=August 2017}} in the Indian market.{{cite news | vauthors = Rajagopla D |date=26 November 2015 |title=Swiss drugmaker Roche launches costliest cancer drugs in India |work=The Economic Times |url=https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/swiss-drugmaker-roche-launches-costliest-cancer-drugs-in-india/articleshow/49927222.cms |access-date=4 February 2023 |issn=0013-0389 |archive-date=4 February 2023 |archive-url=https://web.archive.org/web/20230204125531/https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/swiss-drugmaker-roche-launches-costliest-cancer-drugs-in-india/articleshow/49927222.cms |url-status=live }} [184] => [185] => On 16 September 2014, Genentech notified hospitals in the United States that, as of October, trastuzumab could only be purchased through their selected [[specialty drugs]] distributors not through the usual general line wholesalers. By being forced to purchase through specialty pharmacies, hospitals lost rebates from the big wholesalers and the ability to negotiate cost-minus discounts with their wholesalers.{{cite magazine | url=http://time.com/3541484/cancer-drug-price-hikes/ | title=Hospitals Furious at Cancer-Drug Price Hikes | magazine=[[Time (magazine)|Time]] | date=27 October 2014 | access-date=26 October 2015 | author=Saporito, Bill | url-status=live | archive-url=https://web.archive.org/web/20151020062334/http://time.com/3541484/cancer-drug-price-hikes/ | archive-date=20 October 2015 }} [186] => [187] => ===Biosimilars=== [188] => {{see also|Biosimilars}} [189] => [190] => By 2014, around 20 companies, particularly from [[emerging market]]s, were developing [[biosimilar]] versions of trastuzumab [191] => after Roche/Genentech's patents expired in 2014 in Europe, and in 2019 in the United States.{{cite journal | vauthors = Challener C | title=Monoclonal Antibodies Key to Unlocking the Biosimilars Market | journal=BioPharm International | series=BioPharm International-04-01-2014 | date=1 April 2014 | volume=27 | issue=4 | url=http://www.biopharminternational.com/monoclonal-antibodies-key-unlocking-biosimilars-market | archive-url=https://web.archive.org/web/20160301220108/http://www.biopharminternational.com/monoclonal-antibodies-key-unlocking-biosimilars-market | archive-date=1 March 2016 | url-status=live | access-date=13 March 2023 | page=}} [192] => [193] => In January 2015, BIOCAD{{clarify|date=December 2019}} announced the first trastuzumab biosimilar approved by the [[Ministry of Health of the Russian Federation]]. Iran also approved its own version of the monoclonal antibody in January 2016, as [[AryoGen|AryoTrust]], and announced its readiness to export the drug to other countries in the Middle-East and Central Asia when [[Sanctions against Iran|trade sanctions]] were lifted.{{cite web|title=Trastuzumab - Drugs.com|url=https://www.drugs.com/international/trastuzumab.html|website=www.drugs.com|access-date=21 December 2016|url-status=live|archive-url=https://web.archive.org/web/20170407085909/https://www.drugs.com/international/trastuzumab.html|archive-date=7 April 2017}}{{cite web | vauthors = Feldges D | title=Brustkrebspräparat Herceptin im Fokus: Iraner kopieren Roche | website=Neue Zürcher Zeitung | date=18 February 2016 | url= http://www.nzz.ch/wirtschaft/kommentare/iraner-kopieren-roche-1.18697650 | archive-url= https://web.archive.org/web/20160302060434/http://www.nzz.ch/wirtschaft/kommentare/iraner-kopieren-roche-1.18697650 | archive-date=2 March 2016 | url-status=unfit | language=de | access-date=13 March 2023}} [194] => [195] => In 2016, the investigational biosimilar MYL-1401O showed comparable efficacy and safety to the Herceptin branded trastuzumab.{{cite web | title=Biosimilar Matches Trastuzumab in Metastatic HER2-Positive Breast Cancer | website=Cancer Network | date=3 June 2016 | url=http://www.cancernetwork.com/asco-2016-breast-cancer/biosimilar-matches-trastuzumab-metastatic-her2-positive-breast-cancer | archive-url=https://web.archive.org/web/20160611224312/http://www.cancernetwork.com/asco-2016-breast-cancer/biosimilar-matches-trastuzumab-metastatic-her2-positive-breast-cancer | archive-date=11 June 2016 | url-status=dead | access-date=13 March 2023}} Trastuzumab-dkst (Ogivri, Mylan GmbH) was approved in the United States in December 2017, to "treat people with breast cancer or gastric or gastroesophageal junction adenocarcinoma whose tumors overexpress the HER-2 gene."{{cite web | title=FDA approves Ogivri as a biosimilar to Herceptin | website=U.S. [[Food and Drug Administration]] (FDA) | date=1 December 2017 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ogivri-biosimilar-herceptin | archive-url=https://web.archive.org/web/20191203044428/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ogivri-biosimilar-herceptin | archive-date=3 December 2019 | url-status=live | access-date=2 December 2019}} {{PD-notice}}{{cite web |url=https://www.healio.com/hematology-oncology/breast-cancer/news/online/%7B08a199fb-ea5a-4aac-b6ef-36bb547ef9e6%7D/fda-approves-ogivri-first-biosimilar-for-certain-breast-stomach-cancers?m_bt=2863263984850 |title=FDA approves Ogivri, first biosimilar for certain breast, stomach cancers. December 2017 |access-date=26 December 2017 |archive-date=29 August 2021 |archive-url=https://web.archive.org/web/20210829093511/https://www.healio.com/news/hematology-oncology/20171201/fda-approves-ogivri-first-biosimilar-for-certain-breast-stomach-cancers?m_bt=2863263984850 |url-status=live }} Ogivri was approved for medical use in the European Union in December 2018.{{cite web | title=Ogivri EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ogivri | access-date=28 July 2020 | archive-date=24 March 2020 | archive-url=https://web.archive.org/web/20200324053621/https://www.ema.europa.eu/en/medicines/human/EPAR/ogivri | url-status=live }} [196] => [197] => In November 2017, the European Commission approved Ontruzant, a biosimilar-trastuzumab from [[Samsung Bioepis]] Co., Ltd, for the treatment of early breast cancer, metastatic breast cancer and metastatic gastric cancer.{{cite web | title=Ontruzant EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ontruzant | access-date=28 July 2020 | archive-date=4 August 2020 | archive-url=https://web.archive.org/web/20200804092326/https://www.ema.europa.eu/en/medicines/human/EPAR/ontruzant | url-status=live }} Ontruzant is the first trastuzumab biosimilar to receive regulatory approval in Europe.{{cite web |url=http://www.samsungbioepis.com/en/newsroom/detail/Samsung-Bioepis-Receives-Regulatory-Approval.html |title=Samsung Bioepis Receives Regulatory Approval for Europe's First Trastuzumab Biosimilar. Nov 2017 |access-date=18 January 2018 |archive-date=4 June 2018 |archive-url=https://web.archive.org/web/20180604235558/http://www.samsungbioepis.com/en/newsroom/detail/Samsung-Bioepis-Receives-Regulatory-Approval.html |url-status=live }} [198] => [199] => Herzuma was approved for medical use in the European Union in February 2018.{{cite web | title=Herzuma EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/herzuma | access-date=28 July 2020 | archive-date=8 November 2020 | archive-url=https://web.archive.org/web/20201108115519/https://www.ema.europa.eu/en/medicines/human/EPAR/herzuma | url-status=live }} Herzuma, a trastuzumab biosimilar, was approved in the United States in December 2018.{{cite web | title=Drug Approval Package: Herzuma | website=U.S. [[Food and Drug Administration]] (FDA) | date=7 February 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761091Orig1s000TOC.cfm | access-date=28 July 2020 | archive-date=18 December 2019 | archive-url=https://web.archive.org/web/20191218045010/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761091Orig1s000TOC.cfm | url-status=live }}{{cite web | title=Herzuma- trastuzumab kit; Herzuma- trastuzumab injection, powder, lyophilized, for solution | website=DailyMed | date=6 February 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae71c003-883a-4cd8-ad50-e8cc9a54e971 | access-date=11 December 2023 | archive-date=16 May 2021 | archive-url=https://web.archive.org/web/20210516180117/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae71c003-883a-4cd8-ad50-e8cc9a54e971 | url-status=live }}{{cite press release | title=FDA approves Herzuma as a biosimilar to Herceptin | website=U.S. [[Food and Drug Administration]] (FDA) | date=18 December 2018 | url=https://www.fda.gov/drugs/fda-approves-herzuma-biosimilar-herceptin | archive-url=https://web.archive.org/web/20191213011107/https://www.fda.gov/drugs/fda-approves-herzuma-biosimilar-herceptin | archive-date=13 December 2019 | url-status=live | access-date=12 December 2019}} {{PD-notice}} The approval was based on comparisons of extensive structural and functional product characterization, animal data, human pharmacokinetic, clinical immunogenicity, and other clinical data demonstrating that Herzuma is biosimilar to US Herceptin. Herzuma has been approved as a biosimilar, not as an interchangeable product. [200] => [201] => Kanjinti was approved for medical use in the European Union in May 2018.{{cite web | title=Kanjinti EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/kanjinti | access-date=28 July 2020 | archive-date=31 October 2020 | archive-url=https://web.archive.org/web/20201031025524/https://www.ema.europa.eu/en/medicines/human/EPAR/kanjinti | url-status=live }} [202] => [203] => Trazimera was approved for medical use in the European Union in July 2018.{{cite web | title=Trazimera EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/trazimera | access-date=28 July 2020 | archive-date=28 July 2020 | archive-url=https://web.archive.org/web/20200728155022/https://www.ema.europa.eu/en/medicines/human/EPAR/trazimera | url-status=live }} [204] => [205] => Ogivri was approved for medical use in Canada in May 2019.{{cite web | title=Summary Basis of Decision (SBD) for Ogivri | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00448&lang=en | access-date=29 May 2022 | archive-date=31 May 2022 | archive-url=https://web.archive.org/web/20220531055108/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00448&lang=en | url-status=live }} [206] => [207] => Trazimera was approved for medical use in Canada in August 2019.{{cite web | title=Summary Basis of Decision (SBD) for Trazimera | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00462&lang=en | access-date=29 May 2022 | archive-date=31 May 2022 | archive-url=https://web.archive.org/web/20220531050119/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00462&lang=en | url-status=live }} [208] => [209] => Herzuma was approved for medical use in Canada in September 2019.{{cite web | title=Summary Basis of Decision (SBD) for Herzuma | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00473&lang=en | access-date=29 May 2022 | archive-date=30 May 2022 | archive-url=https://web.archive.org/web/20220530222522/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00473&lang=en | url-status=live }} [210] => [211] => Kanjinti was approved for medical use in Canada in February 2020.{{cite web | title=Summary Basis of Decision (SBD) for Kanjinti | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00480&lang=en | access-date=29 May 2022 | archive-date=30 May 2022 | archive-url=https://web.archive.org/web/20220530221007/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00480&lang=en | url-status=live }} [212] => [213] => Zercepac was approved for medical use in the European Union in July 2020.{{cite web | title=Zercepac EPAR | website=[[European Medicines Agency]] (EMA) | date=26 May 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/zercepac | access-date=28 July 2020 | archive-date=28 July 2020 | archive-url=https://web.archive.org/web/20200728160454/https://www.ema.europa.eu/en/medicines/human/EPAR/zercepac | url-status=live }} [214] => [215] => Trastucip and Tuzucip were approved for medical use in Australia in July 2022. [216] => [217] => In September 2023, the [[Committee for Medicinal Products for Human Use]] (CHMP) of the [[European Medicines Agency]] adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Herwenda, intended for the treatment of HER2-positive breast and gastric cancer. The applicant for this medicinal product is Sandoz GmbH.{{cite web | title=Herwenda: Pending EC decision | website=European Medicines Agency | date=15 September 2023 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/herwenda | access-date=21 September 2023 | archive-date=21 September 2023 | archive-url=https://web.archive.org/web/20230921023011/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/herwenda | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Herwenda was approved for medical use in November 2023. [218] => [219] => Trastuzumab-strf (Hercessi) was approved for medical use in the United States in April 2024. [220] => [221] => ===Related conjugates === [222] => Trastuzumab is also a component of some [[antibody-drug conjugate]]s, such as [[trastuzumab emtansine]],{{cite web | title=FDA approves ado-trastuzumab emtansine for early breast cancer | website=U.S. Food and Drug Administration | date=3 May 2019 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ado-trastuzumab-emtansine-early-breast-cancer | access-date=11 December 2023 | archive-date=28 September 2019 | archive-url=https://web.archive.org/web/20190928075144/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ado-trastuzumab-emtansine-early-breast-cancer | url-status=live }} and [[trastuzumab deruxtecan]].{{cite press release | title=FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies | website=U.S.[[Food and Drug Administration]] (FDA) | date=20 December 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available | archive-url=https://web.archive.org/web/20191220192916/https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available | archive-date=20 December 2019 | url-status=live | access-date=20 December 2019}}{{cite web | title=FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer | website=U.S. Food and Drug Administration | date=4 May 2022 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer | access-date=11 December 2023 | archive-date=4 May 2022 | archive-url=https://web.archive.org/web/20220504234609/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer | url-status=live }} [223] => [224] => == References == [225] => {{Reflist}} [226] => [227] => == Further reading == [228] => * {{cite book | vauthors = Bazell R |title=Her-2: the making of Herceptin, a revolutionary treatment for breast cancer |date=1998 |publisher=Random House |location=New York |isbn=0-679-45702-X |edition=1st}} [229] => * {{cite news | vauthors=Boseley S | title=The selling of a wonder drug | website=[[The Guardian]] | date=29 March 2006 | url=http://www.theguardian.com/science/2006/mar/29/medicineandhealth.health | access-date=13 December 2019 | archive-date=13 December 2019 | archive-url=https://web.archive.org/web/20191213020446/https://www.theguardian.com/science/2006/mar/29/medicineandhealth.health | url-status=live }} [230] => * {{cite journal | vauthors = Dent S, Verma S, Latreille J, Rayson D, Clemons M, Mackey J, Verma S, Lemieux J, Provencher L, Chia S, Wang B, Pritchard K | title = The role of HER2-targeted therapies in women with HER2-overexpressing metastatic breast cancer | journal = Current Oncology | volume = 16 | issue = 4 | pages = 25–35 | date = August 2009 | pmid = 19672422 | pmc = 2722050 | doi = 10.3747/co.v16i4.469 }} [231] => * {{cite book | title=Medical Genetics Summaries | chapter=Trastuzumab (Herceptin) Therapy and ERBB2 (HER2) Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK310376/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=[[National Center for Biotechnology Information]] (NCBI) | year=2015 | pmid=28520362 | id=Bookshelf ID: NBK310376 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ | access-date=5 February 2020 | archive-date=26 October 2020 | archive-url=https://web.archive.org/web/20201026145821/https://www.ncbi.nlm.nih.gov/books/NBK61999/ | url-status=live }} [232] => [233] => == External links == [234] => {{Wiktionary}} [235] => * {{cite web | title=Trastuzumab | website=National Cancer Institute | date=5 October 2006 | url=https://www.cancer.gov/about-cancer/treatment/drugs/trastuzumab }} [236] => [237] => {{Extracellular chemotherapeutic agents}} [238] => {{Monoclonals for tumors}} [239] => {{Growth factor receptor modulators}} [240] => {{Portal bar | Medicine}} [241] => {{Authority control}} [242] => [243] => [[Category:Drugs developed by Genentech]] [244] => [[Category:Drugs developed by Hoffmann-La Roche]] [245] => [[Category:Immunology]] [246] => [[Category:Drugs developed by Merck & Co.]] [247] => [[Category:Monoclonal antibodies for tumors]] [248] => [[Category:Wikipedia medicine articles ready to translate]] [249] => [[Category:Specialty drugs]] [250] => [[Category:World Health Organization essential medicines]] [] => )
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Trastuzumab

Trastuzumab, also known as Herceptin, is a monoclonal antibody used in the treatment of certain types of breast and gastric cancers that overexpress the protein HER2/neu. It was the first FDA-approved targeted therapy for HER2-positive breast cancer and has since become a standard treatment option.

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It was the first FDA-approved targeted therapy for HER2-positive breast cancer and has since become a standard treatment option. Trastuzumab works by inhibiting HER2 signaling pathways, leading to cell growth arrest and increased sensitivity to chemotherapy. The drug is administered through intravenous infusion and is often combined with chemotherapy drugs. Trastuzumab has been shown to significantly improve patient survival rates and has become an important component of multimodal cancer treatments. However, it can have side effects such as cardiac toxicity and infusion-related reactions. Ongoing research is focused on improving the efficacy and safety of trastuzumab and exploring its use in other types of cancer. Overall, trastuzumab has revolutionized the treatment of HER2-positive breast and gastric cancers and continues to be an integral part of targeted cancer therapy.

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