A Neoadjuvant, Randomized, Open-Label Phase II Trial of Afatinib Versus Trastuzumab Versus Lapatinib in Patients With Locally Advanced HER2-Positive Breast Cancer

Rimawi, Mothaffar F.; Aleixo, Sabina B.; Rozas, Ashley Alarcon; Neto, João Nunes de Matos; Caleffi, Maira; Figueira, Alicardo Cesar; Souza, Sulene Cunha; Reiriz, André Borba; Gutiérrez, Carolina; Arantes, Heloisa; Uttenreuther-Fischer, Martina; Solca, Flavio; Osborne, C. Kent

doi:10.1016/j.clbc.2014.11.004

Cited by 37 publications

(19 citation statements)

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“…It may also have potential to treat some patients with 421 triple-negative BC, due to its anti-EGFR activity [95]. Afati-422 nib monotherapy may have a higher overall response rate 423 compared to both trastuzumab and lapatinib monotherapy in 424 treatment naïve patients with HER2-positive, locally 425 advanced BC [96]. …”

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confidence: 99%

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

Elster

Collins

Toomey

et al. 2014

Breast Cancer Res Treat

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8 Abstract Approximately 20 % of human breast cancers 9 (BC) overexpress HER2 protein, and HER2-positivity is 10 associated with a worse prognosis. Although HER2-tar-11 geted therapies have significantly improved outcomes for 12 HER2-positive BC patients, resistance to trastuzumab-13 based therapy remains a clinical problem. In order to better 14 understand resistance to HER2-targeted therapies in HER2-15 positive BC, it is necessary to examine HER family sig-16 nalling as a whole. An extensive literature search was 17 carried out to critically assess the current knowledge of 18 HER family signalling in HER2-positive BC and response 19 to HER2-targeted therapy. Known mechanisms of trast-20 uzumab resistance include reduced receptor-antibody 21 binding (MUC4, p95HER2), increased signalling through 22 alternative HER family receptor tyrosine kinases 23 (RTK), altered intracellular signalling involving loss of 24 PTEN, reduced p27kip1, or increased PI3 K/AKT activity 25 and altered signalling via non-HER family RTKs such as 26 IGF1R. Emerging strategies to circumvent resistance to 27 HER2-targeted therapies in HER2-positive BC include co-28 targeting HER2/PI3 K, pan-HER family inhibition, and 29 novel therapies such as T-DM1. There is evidence that 30 immunity plays a key role in the efficacy of HER-targeted 31 therapy, and efforts are being made to exploit the immune 32 system in order to improve the efficacy of current anti-HER 33 therapies. With our rapidly expanding understanding of 34 HER2 signalling mechanisms along with the repertoire of 35 HER family and other targeted therapies, it is likely that the 36 near future holds further dramatic improvements to the 37 prognosis of women with HER2-positive BC. 38 39 Keywords Trastuzumab · HER2 · Breast cancer · 40 PI3 K 41 Introduction 42 BC is the second most common cancer in the world, and the 43 fifth highest cause of cancer mortality worldwide [1]. 20 % of 44 human BC's overexpress HER2, and HER2-positivity is 45 associated with a significantly worse prognosis. HER2 first 46 became targetable in patients with trastuzumab (Herceptin, 47 ™ Genentech/Roche), a monoclonal antibody that has sig-48 nificantly improved outcomes for patients with HER2-49 positive BC, but the efficacy of trastuzumab is limited in 50 some patients by acquired and de novo resistance [2]. 51 HER family signalling 52There are 20 known RTK families: since members of over 53 half of these have been found to be mutated or overex-54 pressed in diseases marked by abnormal proliferation, 55 RTK's have been considered potential targets for cancer 56 therapy. HER2, a type 1 transmembrane protein RTK, and 57 an oncogenic driver of the growth of HER2-positive BC, is 58 associated with a shorter time to relapse and decreased 59 overall survival (OS 44Author Proof 26] evidence shows that lapatinib is effective against 151 trastuzumab-resistant HER2-positive BC, and it is cur-152 rently used as subsequent therapy for patients with disease 153 that has progressed on trastuzumab. Lapatinib inhibits 15...

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confidence: 99%

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

Elster

Collins

Toomey

et al. 2014

Breast Cancer Res Treat

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“…Joyfully, about the mutant mechanism, researchers newly reported a case that a breast cancer patient harboring an activating EGFR mutation clinically benefiting from EGFR-targeted treatment (Ali et al, 2014). The immune way ADCC (Nahta, 2012) multiple mAbs HER2 internalization (Ben-Kasu et al, 2009) anti-HER2 vaccine Peptide-based/DNA-based/ anti-idiotypic (Cao et al, 2013;Tagliabue and Campiglio, 2014) Trastuzumab mitogenic signaling (Schroeder et al, 2014;Kawajiri et al, 2015) ADCC 188Re-labeled HYNIC-trastuzuma radioactivity dose-dependent fashion (Luo et al, 2015) 64Cu-DOTA-trastuzumab metastatic breast cancer (Mortimer et al, 2014) Trastuzumab resistance Upregulation of HER3 (Nahta, 2012;Brady et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015) miRNAs (miRNA-21, miR-7, miR-200c) (Bai et al, 2014;Chen and Bourguignon, 2014;Huynh and Jones, 2014; H E R 2 c o p y n u m b e r / dimerization status Interaction between HER2 and other ERBB (Lee et al, 2015) autophagy (Yeh et al, 2014) Anthracyclines HER2/TOP2A (Fountzilas et al, 2012) S-222611 ERBB family dimmers (Spicer et al, 2015) NCT Increase pCR rates (Shinde et al, 2015) Flotillin reduction of ErbB2-ErbB3 (Asp and Pust, 2014) CC apoptosis/ proliferation (Khan et al, 2015) Taspase1 Cyclins E, A, and B (Dong et al, 2014) Combined therapy Trastuzumab, carboplatin, paclitaxel (Shinde et al, 2015) Trastuzumab, MK-2206 (Hudis et al, 2013) Trastuzumab, lapatinib (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014) lapatinib , BYL719 (Brady et al, 2014) AZD8931, paclitaxel (Kurata et al, 2014) Hsp90, laptinib ( …”

Section: Other Associated Micromoleculesmentioning

confidence: 99%

“…However, a major limit of immunotherapy with trastuzumab is the development of drug resistance (Nahta, 2012;Brady et al, 2014;Nielsen et al, 2014;Rimawi et al, 2014;Zang et al, 2014;Nam et al, 2015). WenBai et al (2014) referred, trastuzumab resistance was DOI:http://dx.doi.org/10.7314/APJCP.2015.16.7.2591 Recent Progress in HER2 Associated Breast Cancer -a Review characterized by enhanced invasiveness of breast cancer cells with concomitant EMT and elevated TGF-b signaling (Bai et al, 2014).…”

Section: Trastuzumabmentioning

confidence: 99%

“…(Khan et al, 2015), and one possible mechanism may be reversing epithelial-mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling; and Afatinib, an irreversible ErbB family blocker, covalently binds to EGFR, HER2, and ErbB4, and thus irreversibly block signaling from all homo-and heterodimersformed by the ErbB family members, differs from lapatinib and trastuzumab by its broader scope of ErbB receptor inhibition and by its covalent mode of binding resulting in potent and long-lasting activity. (Rimawi et al, 2014) Finally, Taspase1, a highly conserved threonine protease, cleave (mixed-lineage leukemia) MLL which forms complexes with E2F transcription factors to regulate Cyclins E, A, and B expression, required for HER2/neuinduced tumor genesis (Dong et al, 2014).…”

Section: Other Treatmentsmentioning

confidence: 99%

“…Dual HER2-targeting with lapatinib. (a dual reversible tyrosine kinase inhibitor targeting the cytoplasmic domain of EGFR and HER2) and trastuzumab (Rimawi et al, 2014;Scaltriti et al, 2014;Schroeder et al, 2014), with the fomer increasing HER3 expression followed HER2 inhibition, would also be superior to trastuzumab alone. while the lapatinib plus BYL719 combination can overcome acquired lapatinib resistance of breast cancer cells with simultaneous PIK3CA mutation and amplification (Brady et al, 2014).…”

Section: Combined Therapymentioning

confidence: 99%

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Recent Progress in HER2 Associated Breast Cancer

Wang¹,

Lei²,

Mei³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Effects of lapatinib or trastuzumab, alone and in combination, in human epidermal growth factor receptor 2‐positive breast cancer: a meta‐analysis of randomized controlled trials

et al. 2016

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This meta‐analysis compared the efficiency and safety of lapatinib and trastuzumab, alone or in combination, administered with neoadjuvant chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)‐positive breast cancer. For dichotomous variables, the relative risk ratio (RR) and 95% confidence interval (CI) were used to investigate outcome measures: pathological complete response (pCR), neutropenia, diarrhea, dermatologic toxicity, and congestive heart failure (CHF). Eight randomized controlled trials of 2350 participants (837 receiving lapatinib, 913 trastuzumab, and 555 combination therapy) were selected to compare the efficiency and safety of lapatinib to trastuzumab. A significant difference was found between lapatinib and trastuzumab for pCR (RR = 0.82, 95% CI: 0.73–0.93; Z = 3.00; P = 0.003). In six studies, a significant difference was found between trastuzumab and combination therapy for pCR (RR = 1.33, 95% CI: 1.18–1.50; Z = 4.70; P < 0.00001), diarrhea (RR = 14.59, 95% CI: 7.69–27.67; Z = 8.20; P < 0.00001), and dermatologic toxicity (RR = 3.10, 95% CI: 1.61–5.96; Z = 3.39; P = 0.007), but none was found for neutropenia (RR = 1.38, 95% CI: 0.82–2.31; Z = 1.22; P = 0.22) or CHF (RR = 0.14, 95% CI: 0.02–1.17; Z = 1.02; P = 0.07). Combination therapy compared to trastuzumab alone increases the pCR rate of HER2‐positive breast cancer patients with no additional cardiac events. Trastuzumab, which is still the first‐line therapy in breast cancer, increases the pCR rate more than lapatinib.

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A Neoadjuvant, Randomized, Open-Label Phase II Trial of Afatinib Versus Trastuzumab Versus Lapatinib in Patients With Locally Advanced HER2-Positive Breast Cancer

Cited by 37 publications

References 47 publications

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

HER2-family signalling mechanisms, clinical implications and targeting in breast cancer

Recent Progress in HER2 Associated Breast Cancer

Effects of lapatinib or trastuzumab, alone and in combination, in human epidermal growth factor receptor 2‐positive breast cancer: a meta‐analysis of randomized controlled trials

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