Skip to main content
Top
Published in: Breast Cancer Research and Treatment 2/2012

01-09-2012 | Review

Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a meta-analysis

Authors: Aaron M. Drucker, Shenhong Wu, Chau T. Dang, Mario E. Lacouture

Published in: Breast Cancer Research and Treatment | Issue 2/2012

Login to get access

Abstract

Pertuzumab is a novel humanized monoclonal antibody that blocks human epidermal growth factor receptor 2 (HER2) dimerization. It was recently approved by the US FDA for use in combination with trastuzumab and docetaxel for patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Rash is inconsistently reported as a common adverse event in most clinical trials of pertuzumab, at varying incidences. In this study, we have investigated the overall incidence and risk of rash with pertuzumab. Relevant studies were identified from the PubMed database (1966–2012), abstracts presented at the American Society of Clinical Oncology annual conference (2004–2011), and Web of Science database (1998–2012). Eligible studies were prospective phase II–III clinical trials using pertuzumab in cancer patients. Incidence, relative risk (RR), and 95 % confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. Data from a total of 1,726 patients (pertuzumab, n = 1,157; controls, n = 569) with breast, ovarian, and prostate cancers from eight clinical trials were included for analysis. The incidence of all-grade and high-grade rash with pertuzumab were 24.6 % (95 % CI 19.3–30.8 %) and 1.1 % (95 % CI 0.5–2.2 %), respectively. The risk varied with tumor types, as patients with prostate cancer had a lower incidence of rash (13.2 %; 95 % CI 8.0–21.1 %) than those with breast, ovarian, fallopian tube, and peritoneal cancer (P = 0.001). Overall, pertuzumab significantly increased the risk of rash in comparison with controls (RR 1.53; 95 % CI 1.12–2.09; P = 0.007). Pertuzumab is associated with a significant risk of rash, and the incidence varies among different tumor types. Prevention, early recognition, and appropriate treatment of this rash may lead to improvement in patient quality of life, adherence to therapy, and possibly optimize clinical outcomes.
Literature
1.
go back to reference Franklin MC, Carey KD, Vajdos FF et al (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5:317–328PubMedCrossRef Franklin MC, Carey KD, Vajdos FF et al (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5:317–328PubMedCrossRef
2.
go back to reference Baselga J, Cortes J, Kim SB et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109–119PubMedCrossRef Baselga J, Cortes J, Kim SB et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109–119PubMedCrossRef
3.
go back to reference Lacouture ME, Laabs SM, Koehler M et al (2009) Analysis of dermatologic events in patients with cancer treated with lapatinib. Breast Cancer Res Treat 114:485–493PubMedCrossRef Lacouture ME, Laabs SM, Koehler M et al (2009) Analysis of dermatologic events in patients with cancer treated with lapatinib. Breast Cancer Res Treat 114:485–493PubMedCrossRef
4.
go back to reference Jia Y, Lacouture ME, Su X et al (2009) Risk of skin rash associated with erlotinib in cancer patients: a meta-analysis. J Support Oncol 7:211–217PubMed Jia Y, Lacouture ME, Su X et al (2009) Risk of skin rash associated with erlotinib in cancer patients: a meta-analysis. J Support Oncol 7:211–217PubMed
5.
go back to reference Su X, Lacouture ME, Jia Y et al (2009) Risk of high-grade skin rash in cancer patients treated with cetuximab—an antibody against epidermal growth factor receptor: systemic review and meta-analysis. Oncology 77:124–133PubMedCrossRef Su X, Lacouture ME, Jia Y et al (2009) Risk of high-grade skin rash in cancer patients treated with cetuximab—an antibody against epidermal growth factor receptor: systemic review and meta-analysis. Oncology 77:124–133PubMedCrossRef
6.
go back to reference Untch M, Loibl S, Bischoff J et al (2012) Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13:135–144PubMedCrossRef Untch M, Loibl S, Bischoff J et al (2012) Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol 13:135–144PubMedCrossRef
7.
go back to reference Gordon MS, Matei D, Aghajanian C et al (2006) Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 24:4324–4332PubMedCrossRef Gordon MS, Matei D, Aghajanian C et al (2006) Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 24:4324–4332PubMedCrossRef
8.
go back to reference de Bono JS, Bellmunt J, Attard G et al (2007) Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol 25:257–262PubMedCrossRef de Bono JS, Bellmunt J, Attard G et al (2007) Open-label phase II study evaluating the efficacy and safety of two doses of pertuzumab in castrate chemotherapy-naive patients with hormone-refractory prostate cancer. J Clin Oncol 25:257–262PubMedCrossRef
9.
go back to reference Agus DB, Sweeney CJ, Morris MJ et al (2007) Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. J Clin Oncol 25:675–681PubMedCrossRef Agus DB, Sweeney CJ, Morris MJ et al (2007) Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. J Clin Oncol 25:675–681PubMedCrossRef
10.
go back to reference Makhija S, Amler LC, Glenn D et al (2010) Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 28:1215–1223PubMedCrossRef Makhija S, Amler LC, Glenn D et al (2010) Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 28:1215–1223PubMedCrossRef
11.
go back to reference Baselga J, Gelmon KA, Verma S et al (2010) Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 28:1138–1144PubMedCrossRef Baselga J, Gelmon KA, Verma S et al (2010) Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol 28:1138–1144PubMedCrossRef
12.
go back to reference Gianni L, Llado A, Bianchi G et al (2010) Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28:1131–1137PubMedCrossRef Gianni L, Llado A, Bianchi G et al (2010) Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28:1131–1137PubMedCrossRef
13.
go back to reference Gianni L, Pienkowski T, Im YH et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25–32PubMedCrossRef Gianni L, Pienkowski T, Im YH et al (2012) Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 13:25–32PubMedCrossRef
14.
go back to reference Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812PubMedCrossRef Lacouture ME (2006) Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6:803–812PubMedCrossRef
15.
go back to reference Borovicka JH, Calahan C, Gandhi M et al (2011) Economic burden of dermatologic adverse events induced by molecularly targeted cancer agents. Arch Dermatol 147:1403–1409PubMedCrossRef Borovicka JH, Calahan C, Gandhi M et al (2011) Economic burden of dermatologic adverse events induced by molecularly targeted cancer agents. Arch Dermatol 147:1403–1409PubMedCrossRef
16.
go back to reference Nardone B, Nicholson K, Newman M et al (2010) Histopathologic and immunohistochemical characterization of rash to human epidermal growth factor receptor 1 (HER1) and HER1/2 inhibitors in cancer patients. Clin Cancer Res 16:4452–4460PubMedCrossRef Nardone B, Nicholson K, Newman M et al (2010) Histopathologic and immunohistochemical characterization of rash to human epidermal growth factor receptor 1 (HER1) and HER1/2 inhibitors in cancer patients. Clin Cancer Res 16:4452–4460PubMedCrossRef
17.
go back to reference Agus DB, Gordon MS, Taylor C et al (2005) Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23:2534–2543PubMedCrossRef Agus DB, Gordon MS, Taylor C et al (2005) Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23:2534–2543PubMedCrossRef
18.
go back to reference Laux I, Jain A, Singh S et al (2006) Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies. Br J Cancer 94:85–92PubMedCrossRef Laux I, Jain A, Singh S et al (2006) Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies. Br J Cancer 94:85–92PubMedCrossRef
19.
go back to reference Agus DB, Akita RW, Fox WD et al (2002) Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2:127–137PubMedCrossRef Agus DB, Akita RW, Fox WD et al (2002) Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell 2:127–137PubMedCrossRef
20.
go back to reference Cai Z, Zhang G, Zhou Z et al (2008) Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes. Oncogene 27:3870–3874PubMedCrossRef Cai Z, Zhang G, Zhou Z et al (2008) Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes. Oncogene 27:3870–3874PubMedCrossRef
21.
go back to reference Karunagaran D, Tzahar E, Beerli RR et al (1996) ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 15:254–264PubMed Karunagaran D, Tzahar E, Beerli RR et al (1996) ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 15:254–264PubMed
22.
go back to reference Graus-Porta D, Beerli RR, Daly JM et al (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16:1647–1655PubMedCrossRef Graus-Porta D, Beerli RR, Daly JM et al (1997) ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J 16:1647–1655PubMedCrossRef
23.
go back to reference Beerli RR, Hynes NE (1996) Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. J Biol Chem 271:6071–6076PubMedCrossRef Beerli RR, Hynes NE (1996) Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. J Biol Chem 271:6071–6076PubMedCrossRef
24.
go back to reference Forsberg S, Ostman A, Rollman O (2008) Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase. Arch Dermatol Res 300:505–516PubMedCrossRef Forsberg S, Ostman A, Rollman O (2008) Regeneration of human epidermis on acellular dermis is impeded by small-molecule inhibitors of EGF receptor tyrosine kinase. Arch Dermatol Res 300:505–516PubMedCrossRef
25.
go back to reference De Potter IY, Poumay Y, Squillace KA et al (2001) Human EGF receptor (HER) family and heregulin members are differentially expressed in epidermal keratinocytes and modulate differentiation. Exp Cell Res 271:315–328PubMedCrossRef De Potter IY, Poumay Y, Squillace KA et al (2001) Human EGF receptor (HER) family and heregulin members are differentially expressed in epidermal keratinocytes and modulate differentiation. Exp Cell Res 271:315–328PubMedCrossRef
26.
go back to reference Lacouture ME, Anadkat MJ, Bensadoun RJ et al (2011) Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19:1079–1095PubMedCrossRef Lacouture ME, Anadkat MJ, Bensadoun RJ et al (2011) Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 19:1079–1095PubMedCrossRef
27.
go back to reference Lacouture ME, Mitchell EP, Piperdi B et al (2010) Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 28:1351–1357PubMedCrossRef Lacouture ME, Mitchell EP, Piperdi B et al (2010) Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 28:1351–1357PubMedCrossRef
28.
go back to reference Luu M, Lai SE, Patel J et al (2007) Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib. Photodermatol Photoimmunol Photomed 23:42–45PubMedCrossRef Luu M, Lai SE, Patel J et al (2007) Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib. Photodermatol Photoimmunol Photomed 23:42–45PubMedCrossRef
29.
go back to reference Luu M, Boone SL, Patel J et al (2011) Higher severity grade of erlotinib-induced rash is associated with lower skin phototype. Clin Exp Dermatol 36:733–738PubMedCrossRef Luu M, Boone SL, Patel J et al (2011) Higher severity grade of erlotinib-induced rash is associated with lower skin phototype. Clin Exp Dermatol 36:733–738PubMedCrossRef
30.
go back to reference Scope A, Agero AL, Dusza SW et al (2007) Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 25:5390–5396PubMedCrossRef Scope A, Agero AL, Dusza SW et al (2007) Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 25:5390–5396PubMedCrossRef
31.
go back to reference Burtness B, Anadkat M, Basti S et al (2009) NCCN Task Force Report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Cancer Netw 7(Suppl 1):S5–S21 quiz S22-4 Burtness B, Anadkat M, Basti S et al (2009) NCCN Task Force Report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Cancer Netw 7(Suppl 1):S5–S21 quiz S22-4
32.
go back to reference Lacouture ME, Maitland ML, Segaert S et al (2010) A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Support Care Cancer 18:509–522PubMedCrossRef Lacouture ME, Maitland ML, Segaert S et al (2010) A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Support Care Cancer 18:509–522PubMedCrossRef
33.
go back to reference Chen AP, Setser A, Anadkat MJ et al (2012) Grading dermatologic adverse events of cancer treatments: The Common Terminology Criteria for Adverse Events Version 4.0. J Am Acad Dermatol. doi:10.1016/j.jaad.2012.02.010 Chen AP, Setser A, Anadkat MJ et al (2012) Grading dermatologic adverse events of cancer treatments: The Common Terminology Criteria for Adverse Events Version 4.0. J Am Acad Dermatol. doi:10.​1016/​j.​jaad.​2012.​02.​010
34.
go back to reference Edgerly M, Fojo T (2008) Is there room for improvement in adverse event reporting in the era of targeted therapies? J Natl Cancer Inst 100:240–242PubMedCrossRef Edgerly M, Fojo T (2008) Is there room for improvement in adverse event reporting in the era of targeted therapies? J Natl Cancer Inst 100:240–242PubMedCrossRef
35.
go back to reference Joshi SS, Ortiz S, Witherspoon JN et al (2010) Effects of epidermal growth factor receptor inhibitor-induced dermatologic toxicities on quality of life. Cancer 116:3916–3923PubMedCrossRef Joshi SS, Ortiz S, Witherspoon JN et al (2010) Effects of epidermal growth factor receptor inhibitor-induced dermatologic toxicities on quality of life. Cancer 116:3916–3923PubMedCrossRef
36.
go back to reference Boone SL, Rademaker A, Liu D et al (2007) Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 72:152–159PubMedCrossRef Boone SL, Rademaker A, Liu D et al (2007) Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 72:152–159PubMedCrossRef
Metadata
Title
Risk of rash with the anti-HER2 dimerization antibody pertuzumab: a meta-analysis
Authors
Aaron M. Drucker
Shenhong Wu
Chau T. Dang
Mario E. Lacouture
Publication date
01-09-2012
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 2/2012
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-012-2157-7

Other articles of this Issue 2/2012

Breast Cancer Research and Treatment 2/2012 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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