Top

Published in:

01-10-2018 | Clinical trial

Pharmacometabolomics reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced peripheral neuropathy

Authors: Yihan Sun, Jae Hyun Kim, Kiran Vangipuram, Daniel F. Hayes, Ellen M. L. Smith, Larisa Yeomans, N. Lynn Henry, Kathleen A. Stringer, Daniel L. Hertz

Published in: Breast Cancer Research and Treatment | Issue 3/2018

Abstract

Purpose

Approximately 25% of breast cancer patients experience treatment delays or discontinuation due to paclitaxel-induced peripheral neuropathy (PN). Currently, there are no predictive biomarkers of PN. Pharmacometabolomics is an informative tool for biomarker discovery of drug toxicity. We conducted a secondary whole blood pharmacometabolomics analysis to assess the association between pretreatment metabolome, early treatment-induced metabolic changes, and the development of PN.

Methods

Whole blood samples were collected pre-treatment (BL), just before the end of the first paclitaxel infusion (EOI), and 24 h after the first infusion (24H) from sixty patients with breast cancer receiving (80 mg/m²) weekly treatment. Neuropathy was assessed at BL and prior to each infusion using the sensory subscale (CIPN8) of the EORTC CIPN20 questionnaire. Blood metabolites were quantified from 1-D-¹H-nuclear magnetic resonance spectra using Chenomx® software. Metabolite concentrations were normalized in preparation for Pearson correlation and one-way repeated measures ANOVA with multiple comparisons corrected by false discovery rate (FDR).

Results

Pretreatment histidine, phenylalanine, and threonine concentrations were inversely associated with maximum change in CIPN8 (ΔCIPN8) (p < 0.02; FDR ≤ 25%). Paclitaxel caused a significant change in concentrations of 2-hydroxybutyrate, 3-hydroxybutyrate, pyruvate, o-acetylcarnitine, and several amino acids from BL to EOI and/or 24H (p < 0.05; FDR ≤ 25%), although these changes were not associated with ΔCIPN8.

Conclusions

Whole blood metabolomics is a feasible approach to identify potential biomarker candidates of paclitaxel-induced PN. The findings suggest that pretreatment concentrations of histidine, phenylalanine, and threonine may be predictive of the severity of future PN and paclitaxel-induced metabolic changes may be related to disruption of energy homeostasis.

Available only for authorised users

Speck RM, Sammel MD, Farrar JT, Hennessy S, Mao JJ, Stineman MG, DeMichele A (2013) Impact of chemotherapy-induced peripheral neuropathy on treatment delivery in nonmetastatic breast cancer. J Oncol Pract 9:e234–e240. https://doi.org/10.1200/JOP.2012.000863 CrossRefPubMed

Hershman DL, Weimer LH, Wang A, Kranwinkel G, Brafman L, Fuentes D, Awad D, Crew KD (2011) Association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors treated with adjuvant paclitaxel chemotherapy. Breast Cancer Res Treat 125:767–774. https://doi.org/10.1007/s10549-010-1278-0 CrossRefPubMed

Han Y, Smith MT (2013) Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN). Front Pharmacol 4 DEC:1–16. https://doi.org/10.3389/fphar.2013.00156 CrossRef

Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith M, Lou Smith T, Terstriep S, Wagner-Johnston N, Bak K, Loprinzi CL (2014) Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American society of clinical oncology clinical practice guideline. J Clin Oncol 32:1941–1967. https://doi.org/10.1200/JCO.2013.54.0914 CrossRefPubMed

Travis LB, Fossa SD, Sesso HD, Frisina RD, Herrmann DN, Beard CJ, Feldman DR, Pagliaro LC, Miller RC, Vaughn DJ, Einhorn LH, Cox NJ, Dolan ME (2014) Chemotherapy-induced peripheral neurotoxicity and ototoxicity: new paradigms for translational genomics. J Natl Cancer Inst https://doi.org/10.1093/jnci/dju044 CrossRefPubMedPubMedCentral

Joerger M, von Pawel J, Kraff S, Fischer JR, Eberhardt W, Gauler TC, Mueller L, Reinmuth N, Reck M, Kimmich M, Mayer F, Kopp HG, Behringer DM, Ko YD, Hilger RA, Roessler M, Kloft C, Henrich A, Moritz B, Miller MC, Salamone SJ, Jaehde U (2016) Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). Ann Oncol 27:1895–1902. https://doi.org/10.1093/annonc/mdw290 CrossRefPubMed

Bianchi G, Vitali G, Caraceni A, Ravaglia S, Capri G, Cundari S, Zanna C, Gianni L (2005) Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-l-carnitine. Eur J Cancer 41:1746–1750. https://doi.org/10.1016/j.ejca.2005.04.028 CrossRefPubMed

Hershman DL, Unger JM, Crew KD, Minasian LM, Awad D, Moinpour CM, Hansen L, Lew DL, Greenlee H, Fehrenbacher L, Wade JL, Wong SF, Hortobagyi GN, Meyskens FL, Albain KS (2013) Randomized double-blind placebo-controlled trial of acetyl-l-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol 31:2627–2633. https://doi.org/10.1200/JCO.2012.44.8738 CrossRefPubMedPubMedCentral

Smyth JF, Bowman A, Perren T, Wilkinson P, Prescott RJ, Quinn KJ, Tedeschi M (1997) Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial. Ann Oncol 8:569–573CrossRefPubMed

10.

Colombo N, Bini S, Miceli D, Bogliun G, Marzorati L, Cavaletti G, Parmigiani F, Venturino P, Tedeschi M, Frattola L, Buratti C, Mangioni C (1995) Weekly cisplatin ± glutathione in relapsed ovarian carcinoma. Int J Gynecol Cancer 5:81–86. https://doi.org/10.1046/j.1525-1438.1995.05020081.x CrossRefPubMed

11.

Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, Beretta GD, Ubiali E, Catalano G (2002) neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 20:3478–3483. https://doi.org/10.1200/JCO.2002.07.061 CrossRefPubMed

12.

Wang W-S, Lin J-K, Lin T-C, Chen W-S, Jiang J-K, Wang H-S, Chiou T-J, Liu J-H, Yen C-C, Chen P-M (2007) Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist 12:312–319. https://doi.org/10.1634/theoncologist.12-3-312 CrossRefPubMed

13.

Vahdat L, Papadopoulos K, Lange D, Leuin S, Kaufman E, Donovan D, Frederick D, Bagiella E, Tiersten A, Nichols G, Garrett T, Savage D, Antman K, Hesdorffer CS, Balmaceda C (2001) Reduction of paclitaxel-induced peripheral neuropathy with glutamine. Clin Cancer Res 7:1192–1197PubMed

14.

Subblefield MD, Vahdat LT, Balmaceda CM, Troxel AB, Hesdorffer CS, Gooch CL (2005) Glutamine as a neuroprotective agent in high-dose paclitaxel-induced peripheral neuropathy: a clinical and electrophysiologic study. Clin Oncol 17:271–276. https://doi.org/10.1016/j.clon.2004.11.014 CrossRef

15.

Zirpoli GR, McCann SE, Sucheston-Campbell LE, Hershman DL, Ciupak G, Davis W, Unger JM, Moore HCF, Stewart JA, Isaacs C, Hobday TJ, Salim M, Hortobagyi GN, Gralow JR, Budd GT, Albain KS, Ambrosone CB (2017) Supplement use and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221): the DELCaP study. JNCI 109:1–8. https://doi.org/10.1093/jnci/djx098 CrossRef

16.

Chopra K, Tiwari V (2012) Alcoholic neuropathy: possible mechanisms and future treatment possibilities. Br J Clin Pharmacol 73:348–362. https://doi.org/10.1111/j.1365-2125.2011.04111.x CrossRefPubMed

17.

Kaddurah-Daouk R, Weinshilboum RM (2014) Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology. Clin Pharmacol Ther 95:154–167. https://doi.org/10.1038/clpt.2013.217 CrossRefPubMed

18.

Kwon HN, Kim M, Wen H, Kang S, Yang H, Choi M-J, Lee HS, Choi D, Park IS, Suh YJ, Hong S, Park S (2011) Predicting idiopathic toxicity of cisplatin by a pharmacometabonomic approach. Kidney Int 79:529–537. https://doi.org/10.1038/ki.2010.440 CrossRefPubMed

19.

Keun HC, Sidhu J, Pchejetski D, Lewis JS, Marconell H, Patterson M, Bloom SR, Amber V, Coombes RC, Stebbing J (2009) Serum molecular signatures of weight change during early breast cancer chemotherapy. Clin Cancer Res 15:6716–6723. https://doi.org/10.1158/1078-0432.CCR-09-1452 CrossRefPubMed

20.

Backshall A, Sharma R, Clarke SJ, Keun HC (2011) Pharmacometabonomic profiling as a predictor of toxicity in patients with inoperable colorectal cancer treated with capecitabine. Clin Cancer Res 17:3019–3028. https://doi.org/10.1158/1078-0432.CCR-10-2474 CrossRefPubMed

21.

Hertz DL, Kidwell KM, Vangipuram K, Li F, Pai MP, Burness M, Griggs JJ, Schott AF, Poznak C, Van Hayes DF, Smith EML, Henry NL (2018) Paclitaxel plasma concentration after the first infusion predicts treatment-limiting peripheral neuropathy. Clin Cancer Res https://doi.org/10.1158/1078-0432.CCR-18-0656 PubMedCrossRef

22.

Smith EML, Barton DL, Qin R, Steen PD, Aaronson NK, Loprinzi CL (2013) Assessing patient-reported peripheral neuropathy: the reliability and validity of the European Organization for Research and Treatment of Cancer QLQ-CIPN20 Questionnaire. Qual Life Res 22:2787–2799. https://doi.org/10.1007/s11136-013-0379-8 CrossRef

23.

Postma TJ, Aaronson NK, Heimans JJ, Muller MJ, Hildebrand JG, Delattre JY, Hoang-Xuan K, Lantéri-Minet M, Grant R, Huddart R, Moynihan C, Maher J, Lucey R (2005) The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20. Eur J Cancer 41:1135–1139. https://doi.org/10.1016/j.ejca.2005.02.012 CrossRefPubMed

24.

Fayers P, Aaronson NK, Bjordal KCD, Grønvold M (2001) EORTC QLQ-C30 scoring manual, 3rd edn, EORTC Quality of Life Group, Brussels

25.

Hertz DL, Kidwell KM, Vangipuram K, Sun D, Henry NL (2018) Abstract P6-11-03: association of systemic paclitaxel concentrations with severity and progression of paclitaxel-induced peripheral neuropathy. Cancer Res https://doi.org/10.1158/1538-7445.SABCS17-P6-11-03 CrossRef

26.

Nagana Gowda GA, Raftery D (2017) Whole blood metabolomics by1H NMR spectroscopy provides a new opportunity to evaluate coenzymes and antioxidants. Anal Chem 89:4620–4627. https://doi.org/10.1021/acs.analchem.7b00171 CrossRefPubMed

27.

Lacy P, McKay RT, Finkel M, Karnovsky A, Woehler S, Lewis MJ, Chang D, Stringer KA (2014) Signal intensities derived from different NMR probes and parameters contribute to variations in quantification of metabolites. PLoS ONE 9:1–10. https://doi.org/10.1371/journal.pone.0085732 CrossRef

28.

Trexel J, Yoon GS, Keswani RK, McHugh C, Yeomans L, Vitvitsky V, Banerjee R, Sud S, Sun Y, Rosania GR, Stringer KA (2017) Macrophage-mediated clofazimine sequestration is accompanied by a shift in host energy metabolism. J Pharm Sci 106:1162–1174. https://doi.org/10.1016/j.xphs.2016.12.009 CrossRefPubMed

29.

Xia J, Sinelnikov IV, Han B, Wishart DS (2015) MetaboAnalyst 3.0-making metabolomics more meaningful. Nucleic Acids Res 43:W251–W257. https://doi.org/10.1093/nar/gkv380 CrossRefPubMedPubMedCentral

30.

Storey JD (2003) The positive false discovery rate: a Bayesian interpretation and the q-value. Ann Stat 31:2013–2035. https://doi.org/10.1214/aos/1074290335 CrossRef

31.

Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci 100:9440–9445. https://doi.org/10.1073/pnas.1530509100 CrossRefPubMed

32.

Dunnet C (1955) A multiple comparison procedure for comparing several treatments with a control. J Am Stat Assoc 50:1096–1121CrossRef

33.

Gao J, Tarcea VG, Karnovsky A, Mirel BR, Weymouth TE, Beecher CW, Cavalcoli JD, Athey BD, Omenn GS, Burant CF, Jagadish HV (2010) Metscape: a Cytoscape plug-in for visualizing and interpreting metabolomic data in the context of human metabolic networks. Bioinformatics 26:971–973. https://doi.org/10.1093/bioinformatics/btq048 CrossRefPubMedPubMedCentral

34.

Cirillo M, Venturini M, Ciccarelli L, Coati F, Bortolami O, Verlato G (2009) Clinician versus nurse symptom reporting using the National Cancer Institute—Common Terminology Criteria for Adverse Events during chemotherapy: results of a comparison based on patient’s self-reported questionnaire. Ann Oncol 20:1929–1935. https://doi.org/10.1093/annonc/mdp287 CrossRefPubMed

35.

Le-Rademacher J, Kanwar R, Seisler D, Pachman DR, Qin R, Abyzov A, Ruddy KJ, Banck MS, Lavoie Smith EM, Dorsey SG, Aaronson NK, Sloan J, Loprinzi CL, Beutler AS (2017) Patient-reported (EORTC QLQ-CIPN20) versus physician-reported (CTCAE) quantification of oxaliplatin- and paclitaxel/carboplatin-induced peripheral neuropathy in NCCTG/Alliance clinical trials. Support Care Cancer 25:3537–3544. https://doi.org/10.1007/s00520-017-3780-y CrossRefPubMed

36.

Bennett BK, Park SB, Lin CSY, Friedlander ML, Kiernan MC, Goldstein D (2012) Impact of oxaliplatin-induced neuropathy: a patient perspective. Support Care Cancer 20:2959–2967. https://doi.org/10.1007/s00520-012-1428-5 CrossRefPubMed

37.

Huang L, Adachi N, Nagaro T, Liu K, Arai T (2007) Histaminergic involvement in neuropathic pain produced by partial ligation of the sciatic nerve in rats. Reg Anesth Pain Med 32:124–129. https://doi.org/10.1016/j.rapm.2006.11.009 CrossRefPubMed

38.

Farshid AA, Tamaddonfard E, Najafi S (2015) Effects of histidine and n-acetylcysteine on experimental lesions induced by doxorubicin in sciatic nerve of rats. Drug Chem Toxicol 38:436–441. https://doi.org/10.3109/01480545.2014.981753 CrossRefPubMed

39.

Yu J, Lou GD, Yue JX, Tang YY, Hou WW, Shou WT, Ohtsu H, Zhang SH, Chen Z (2013) Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy. Neurosci Bull 29:261–269. https://doi.org/10.1007/s12264-013-1316-0 CrossRefPubMedPubMedCentral

40.

Zhou G, Shoji H, Yamada S, Matsuishi T (1997) Decreased beta-phenylethylamine in CSF in Parkinson’s disease. J Neurol Neurosurg Psychiatry 63:754–758CrossRefPubMedPubMedCentral

41.

Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR (2007) Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev 17:91–101. https://doi.org/10.1007/s11065-007-9021-2 CrossRefPubMed

42.

Boehm G, Cervantes H, Georgi G, Jelinek J, Sawatzki G, Wermuth B, Colombo J-P (1998) Effect of increasing dietary threonine intakes on amino acid metabolism of the central nervous system and peripheral tissues in growing rats. Pediatr Res 44:900CrossRefPubMed

43.

Gall WE, Beebe K, Lawton KA, Adam KP, Mitchell MW, Nakhle PJ, Ryals JA, Milburn MV, Nannipieri M, Camastra S, Natali A, Ferrannini E (2010) Α-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population. PLoS ONE https://doi.org/10.1371/journal.pone.0010883 CrossRefPubMedPubMedCentral

44.

Xiao WH, Zheng H, Zheng FY, Nuydens R, Meert TF, Bennett GJ (2011) Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat. Neuroscience 199:461–469. https://doi.org/10.1016/j.neuroscience.2011.10.010 CrossRefPubMedPubMedCentral

45.

Flatters SJL, Bennett GJ (2006) Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 122:245–257. https://doi.org/10.1016/j.pain.2006.01.037 CrossRefPubMedPubMedCentral

46.

Zhang H, Li Y, De Carvalho-Barbosa M, Kavelaars A, Heijnen CJ, Albrecht PJ, Dougherty PM (2016) Dorsal root ganglion infiltration by macrophages contributes to paclitaxel chemotherapy induced peripheral neuropathy HHS Public Access. J Pain 17:775–786. https://doi.org/10.1016/j.jpain.2016.02.011 CrossRefPubMedPubMedCentral

47.

Duggett NA, Griffiths LA, Flatters SJL (2017) Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons. Pain 158:1499–1508. https://doi.org/10.1097/j.pain.0000000000000939 CrossRefPubMedPubMedCentral

48.

Sucheston-Campbell LE, Clay-Gilmour AI, Barlow WE, Budd GT, Stram DO, Haiman CA, Sheng X, Yan L, Zirpoli G, Yao S, Jiang C, Owzar K, Hershman D, Albain KS, Hayes DF, Moore HC, Hobday TJ, Stewart JA, Rizvi A, Isaacs C, Salim M, Gralow JR, Hortobagyi GN, Livingston RB, Kroetz DL, Ambrosone CB (2018) Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci. Pharmacogenet Genom 28: 49–55CrossRef

49.

Schneider BP, Li L, Radovich M, Shen F, Miller KD, Flockhart DA, Jiang G, Vance G, Gardner L, Vatta M, Bai S, Lai D, Koller D, Zhao F, O’Neill A, Smith M, Lou Railey E, White C, Partridge A, Sparano J, Davidson NE, Foroud T, Sledge GW (2015) Genome-wide association studies for taxane-induced peripheral neuropathy in ECOG-5103 and ECOG-1199. Clin Cancer Res 21:5082–5091. https://doi.org/10.1158/1078-0432.CCR-15-0586 CrossRefPubMedPubMedCentral

50.

Baldwin RM, Owzar K, Zembutsu H, Chhibber A, Kubo M, Jiang C, Watson D, Eclov RJ, Mefford J, McLeod HL, Friedman PN, Hudis CA, Winer EP, Jorgenson EM, Witte JS, Shulman LN, Nakamura Y, Ratain MJ, Kroetz DL (2012) A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101. Clin Cancer Res 18:5099–5109. https://doi.org/10.1158/1078-0432.CCR-12-1590 CrossRefPubMedPubMedCentral

51.

Chen EI, Crew KD, Trivedi M, Awad D, Maurer M, Kalinsky K, Koller A, Patel P, Kim Kim J, Hershman DL. Chen EI, Crew KD, Trivedi M et al (2015) Identifying predictors of taxane-induced P1. Identifying predictors of taxane-induced peripheral neuropathy using mass spectrometry-based proteomics technology. PLoS ONE 10(12):e0145816. https://doi.org/10.1371/journal.pone.0 CrossRefPubMedPubMedCentral

52.

Budd GT, Barlow WE, Moore HCF, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN (2015) SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol 33:58–64. https://doi.org/10.1200/JCO.2014.56.3296 CrossRefPubMed

53.

Lu W, Su X, Klein MS, Lewis IA, Fiehn O, Rabinowitz JD (2017) Metabolite measurement: pitfalls to avoid and practices to follow. Annu Rev Biochem 86:277–304. https://doi.org/10.1146/annurev-biochem-061516-044952 CrossRefPubMedPubMedCentral

54.

Koulman A, Lane GA, Harrison SJ, Volmer DA (2009) From differentiating metabolites to biomarkers. Anal Bioanal Chem 394:663–670. https://doi.org/10.1007/s00216-009-2690-3 CrossRefPubMedPubMedCentral

55.

Ioannidis JPA, Bossuyt PMM (2017) Waste, leaks, and failures in the biomarker pipeline. Clin Chem 63:963–972. https://doi.org/10.1373/clinchem.2016.254649 CrossRefPubMed

Title: Pharmacometabolomics reveals a role for histidine, phenylalanine, and threonine in the development of paclitaxel-induced peripheral neuropathy
Authors: Yihan Sun
Jae Hyun Kim
Kiran Vangipuram
Daniel F. Hayes
Ellen M. L. Smith
Larisa Yeomans
N. Lynn Henry
Kathleen A. Stringer
Daniel L. Hertz
Publication date: 01-10-2018
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-4862-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2018

Correction to: Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence, characteristics, and prevention with scalp cooling

Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancer

Optimal vascular access strategies for patients receiving chemotherapy for early-stage breast cancer: a systematic review

Thyroid hormone receptor beta-1 expression in early breast cancer: a validation study

Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence, characteristics, and prevention with scalp cooling

Efficacy and safety of fulvestrant in postmenopausal patients with hormone receptor-positive advanced breast cancer: a systematic literature review and meta-analysis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer