Role of trastuzumab in the management of HER2-positive metastatic breast cancer

Figures & data

Figure 1 Mechanisms of action of trastuzumab. A) In vitro, trastuzumab is able to disrupt signaling through PI3K/Akt and MAPK signaling pathways; causes a disruption of the binding of Src to HER2, allowing PTEN to inhibit Akt B); induces apoptosis of target cells and C) cell cycle arrest in G0-G1 phase, via modulating the cyclin-dependent kinase (CDK) inhibitor 27 ^Kip1. D) In vivo, trastuzumab binds the Fcγ receptor on NK cells and triggers the antibody-dependent cell-mediated cytotoxicity (ADCC).

Abbreviations: HER2, human epidermal growth factor receptor 2; NK, natural killer; FcγR, fragment crystallizable region gamma receptor; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless protein; Ras, small GTPase protein; Raf, Mek, and Erk, serine/threonine-protein kinases; Elk, transcription factor; Src, Rous sarcoma tyrosine kinase; PTEN, phosphatase and tensin homolog; PI3K, phosphatidylinositol 3-kinases; Akt, serine/threonine protein kinase; mTor, mammalian target of rapamycin; p27 ^Kip−1, cyclin-dependent kinase inhibitor 1B; Cdk2, cyclin-dependent kinase 2a.

Table 1 Results of the main studies of trastuzumab with chemotherapy in metastatic breast cancer

Author	Study	Drugs	No. of patients	Patient’s characteristics	Main results
Slamon et al^Citation10	Phase III	Taxanes or anthracyclines ± wTrastuzumab	469	Previously untreated HER2+ metastatic BC	mTTP (chemo + trastuzumab versus chemo) 7.4 versus 4.6 months (P = 0.001) OS (chemo + trastuzumab versus chemo) 25.1 versus 20.3 months (P = 0.01)
Marty et al^Citation41	R phase II	Docetaxel 100 mg/m^2 + q3wTrastuzumab versus docetaxel 100 mg/m^2 alone	186	Previously untreated HER2+ metastatic BC	ORR 61% versus 34% (P = 0.0002) OS 32 versus 22 months (P = 0.0325)
Esteva et al^Citation43	Phase II	Docetaxel 35 mg/m^2/w + wTrastuzumab	30	HER2+ metastatic BC	ORR 63% (95% CI = 44%–80%)
Sledge^Citation46	Phase II	Gemcitabine 1200 mg/m^2 days 1,8 q21 + paclitaxel 175 mg/m^2 day 1 q21 + wTrastuzumab	42	Previously untreated HER2+ metastatic BC	ORR 67% mTTP 9 months
Bianchi et al^Citation47	Phase II	Cohort 1: 3 cycles of DT (60/150 mg/m^2) and wTrastuzumab followed by 9 cycles of T (80 mg/m^2) and wTrastuzumab Cohort 2: 3 cycles of DT (60/150 mg/m^2) followed by 9 cycles of T (80 mg/m^2) and wTrastuzumab	Cohort 1: 16 Cohort 2: 16	Previously untreated HER2+ advanced and metastatic BC	ORR (for both cohorts) 87.5% (95% CI = 61.65%–98.45%)
Pegram et al^Citation48*	Phase II	1. Docetaxel 75 mg/m^2 q3wks + cisplatin 75 mg/m^2 q3wks + wTrastuzumab 2. Docetaxel 75 mg/m^2 q3wks + carboplatin AUC6 + wTrastuzumab	1.62 2.62	HER2+ advanced and metastatic BC*	1. ORR 79% (95% CI = 66%–89%) mTTP 9.9 months (95% CI = 8.3–13.1 months) 2. ORR 58% (95% CI = 44%–70%) mTTP 12.7 months (95% CI = 8.6–15.5 months)
Robert et al^Citation51	Phase III	Arm A: 6 cycles of T (175 mg/m^2) q3wks + carboplatin AUC6 q3wks + wTrastuzumab Arm B: 6 cycles of T(175 mg/m^2) q3wks + wTrastuzumab	196	Previously untreated HER2+ metastatic BC	ORR Arm A 52% (95% CI = 42%–62%) ORR Arm B 36% (95% CI = 26%–46%) (P = 0.04) PFS Arm A 10.7 months PFS Arm B 7.1 months HR 0.66 (95% CI = 0.59–0.73) (P = 0.03)
Montemurro et al^Citation58	Phase II	Docetaxel 75 mg/m^2 q3wks + wTrastuzumab	25	Heavily pretreated HER2+ metastatic BC	ORR 70%
Jahanzeb et al^Citation44	Phase II	Vinorelbine 30 mg/m^2/w + wTrastuzumab	40	Previously untreated HER2+ metastatic BC	ORR 78% (95% CI = 62%–90%) mTTP 18 months (95% CI = 13.7–34.2 months)
Burstein et al^Citation45	Phase II	Vinorelbine 25 mg/m^2/w + wTrastuzumab	54	Previously untreated HER2+ metastatic BC	ORR 68% (95% CI = 54%–80%) mTTP 5.6 months (95% CI = 0.46–16 months)
Schaller et al^Citation52	Phase II	Capecitabine 2500 mg/m^2 day 1–14 q21 + wTrastuzumab	27	Heavily pretreated HER2+ metastatic BC	ORR 78% PFS 6.7 months
O’Shaughnessy et al^Citation49	Phase II	Gemcitabine 1200 mg/m^2 days 1,8 q21 + wTrastuzumab	64	HER2+ metastatic BC	ORR 38% (95% CI = 26%–50%) mTTP 5.8 months
Pegram and Slamon^Citation42	Phase I/II	Cisplatin + wTrastuzumab	37	HER2+ metastatic BC	ORR 24.3% mTTP 8.4 months
Chia et al^Citation50	Phase II	PLD 50 mg/m^2 q4wks + wTrastuzumab	30	Previously untreated HER2+ metastatic BC	ORR 38% (95% CI = 21.1%–78.9%) PFS 12 months
Andreopoulou et al^Citation53	Phase II	PLD 50 mg/m^2 q4wks + wTrastuzumab	12	Heavily pretreated HER2+ metastatic BC	The trial closed after 2.5 years for slow accrual
Cortes et al^Citation54	Phase II	Nonpegylated LD 50 mg/m^2 q3wks + paclitaxel 80 mg/m^2/w + wTrastuzumab	69	Previously untreated HER2+ metastatic BC	ORR 98.1% (95% CI = 90.1%–99.9%) mTTP 22.1 months (95% CI = 16.4–46.3 months)
Christodoulou et al^Citation55	Phase II	PLD 30 mg/m^2 q3wks + q3wTrastuzumab	37	HER2+ metastatic BC	ORR 22% PFS 6.5 months (95% CI = 0.8–31.1 months)
Stickeler et al^Citation56	Phase II	PLD 40 mg/m^2 q4wks + wTrastuzumab	16	Previously untreated HER2+ metastatic BC	CBR 50% PFS 9.67 months
Venturini et al^Citation57	Phase II	Nonpegylated LD 50 mg/m^2 q3wks + docetaxel 75 mg/m^2 q3wks + wTrastuzumab	31	Previously untreated HER2+ metastatic BC	ORR 65.5% mTTP 13 months

Notes:

* This study includes two phase II studies: (1) BCIRG101 and (2) UCLA-ORN. In the UCLA-ORN study, patients were previously treated with taxanes.

Abbreviations: wTrastuzumab, trastuzumab loading dose of 4 mg/kg followed by weekly doses of 2 mg/kg; R, randomized; HER2+, HER2 positive; BC, breast cancer; chemo, chemotherapy; mTTP, median time to progression; OS, overall survival; q3wTrastuzumab, trastuzumab loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks; ORR, overall response rate (CR-complete remission + PR-partial remission); w, week; wks, weeks; D, doxorubicin; T, paclitaxel; AUC, area under curve; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; LD, liposomal doxorubicin; CBR, clinical benefit rate (CR + PR + stable disease-SD lasting 6 months or more).

Figure 2 Mechanisms of resistance to trastuzumab. A) Loss of PTEN protein can impair efficacy of trastuzumab; B) mutation of PI3KCA gene sequence C) Overexpression of DARPP-32 and its truncated form t-DARPP, leading to increased phosphorylation of Akt; D) HER2 can dimerize with other tyrosine kinase receptors, such as Met or IGF-1R, activating alternative signaling pathways; E) binding of HER2 with trastuzumab can be prevented by other cellular surface proteins, such as Muc4, F) or by the shedding of the extracellular domain of HER2 mediated by metalloproteinases; G) Fcγ-receptor polymorphisms can impair antibody-dependent cell-mediated cytotoxicity (ADCC) in vivo.

Abbreviations: HER2, human epidermal growth factor receptor 2; NK, natural killer; FcγR, fragment crystallizable region gamma receptor; Src, Rous sarcoma tyrosine kinase; PTEN, phosphatase and tensin homolog; PI3K, phosphatidylinositol 3-kinases; Akt, serine/threonine protein kinase; mTor, mammalian target of rapamycin; DARPP-32, dopamine- and cyclic-AMP-regulated phosphoprotein; t-DARPP, truncated form of dopamine- and cyclic-AMP-regulated phosphoprotein; MMP9, matrix metallopeptidase 9; p95, truncated form of HER2; Muc4, mucin 4; IGF-1R, insulin-like growth factor receptor 1; Met, hepatocyte growth factor receptor.

SlamonDJLeyland-JonesBShakSUse of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2N Engl J Med200134478379211248153

 PubMed Web of Science ®Google Scholar

MartyMCognettiFMaraninchiDRandomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study groupJ Clin Oncol2005234265427415911866

 PubMed Web of Science ®Google Scholar

EstevaFJValeroVBooserDPhase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancerJ Clin Oncol2002201800180811919237

 PubMed Web of Science ®Google Scholar

SledgeGW JrGemcitabine, paclitaxel, and trastuzumab in metastatic breast cancerOncology (Williston Park)200317333514768403

 PubMedGoogle Scholar

BianchiGAlbanellJEiermannWPilot trial of trastuzumab starting with or after the doxorubicin component of a doxorubicin plus paclitaxel regimen for women with HER2-positive advanced breast cancerClin Cancer Res200395944595114676119

 PubMed Web of Science ®Google Scholar

PegramMDPienkowskiTNorthfeltDWResults of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancerJ Natl Cancer Inst20049675976915150304

 PubMed Web of Science ®Google Scholar

RobertNLeyland-JonesBAsmarLRandomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancerJ Clin Oncol2006242786279216782917

 PubMed Web of Science ®Google Scholar

MontemurroFChoaGFaggiuoloRSafety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II studyAm J Clin Oncol200326959712576933

 PubMed Web of Science ®Google Scholar

JahanzebMMortimerJEYunusFPhase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(+) metastatic breast cancerOncologist2002741041712401903

 PubMed Web of Science ®Google Scholar

BursteinHJHarrisLNMarcomPKTrastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithmJ Clin Oncol2003212889289512885806

 PubMed Web of Science ®Google Scholar

SchallerGFuchsIGonschTPhase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanesJ Clin Oncol2007253246325017577021

 PubMed Web of Science ®Google Scholar

O’ShaughnessyJAVukeljaSMarslandTKimmelGRatnamSPippenJEPhase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancerClin Breast Cancer2004514214715245619

 PubMedGoogle Scholar

PegramMDSlamonDJCombination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivitySemin Oncol199926899510482199

 PubMed Web of Science ®Google Scholar

ChiaSClemonsMMartinLAPegylated liposomal doxorubicin and trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trialJ Clin Oncol2006242773277816682726

 PubMed Web of Science ®Google Scholar

AndreopoulouEGaiottiDKimEFeasibility and cardiac safety of pegylated liposomal doxorubicin plus trastuzumab in heavily pretreated patients with recurrent HER2-overexpressing metastatic breast cancerClin Breast Cancer2007769069617919349

 PubMed Web of Science ®Google Scholar

CortesJDiCSClimentMANonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and trastuzumab in HER-2-overexpressing breast cancer: a multicenter phase I/II studyClin Cancer Res20091530731419118059

 PubMed Web of Science ®Google Scholar

ChristodoulouCKostopoulosIKalofonosHPTrastuzumab combined with pegylated liposomal doxorubicin in patients with metastatic breast cancer. Phase II Study of the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluationOncology20097627528519262067

 PubMed Web of Science ®Google Scholar

StickelerEKlarMWatermannDPegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trialBreast Cancer Res Treat200911759159819156515

 PubMed Web of Science ®Google Scholar

VenturiniMBighinCPuglisiFA multicentre Phase II study of non-pegylated liposomal doxorubicin in combination with trastuzumab and docetaxel as first-line therapy in metastatic breast cancerBreast201019533333820185313

 PubMed Web of Science ®Google Scholar