Combination of Pertuzumab and Trastuzumab in the Treatment of HER2-Positive Early Breast Cancer: A Review of the Emerging Clinical Data

Jagosky, Megan H.; Tan, Antoinette R.

doi:10.2147/bctt.s176514

Cited by 22 publications

(19 citation statements)

References 70 publications

(95 reference statements)

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“…Other authors have reported similar outcomes in larger patient series and concluded that neoadjuvant chemotherapy with TZ + PZ increases the pCR rate compared with trastuzumab alone to one of around 50-70% [6]. However, it should be mentioned that approximately one-third of patients with HER2-positive early BC treated with TZ experience relapse [16]. This highlights a need to find good biomarkers of the efficacy of anti-HER2 treatment for this aggressive BC phenotype.…”

Section: Discussionmentioning

confidence: 88%

FGFR1 Amplification and Response to Neoadjuvant Anti-HER2 Treatment in Early HER2-Positive Breast Cancer

et al. 2022

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HER2-positive breast cancer (BC) is an aggressive subtype that affects 20–25% of BC patients. For these patients, neoadjuvant therapy is a good option that targets a pathological complete response (pCR) and more breast-conserving surgery. In effect, the outcomes of patients with HER2-positive BC have dramatically improved since the introduction of anti-HER2 antibodies such as trastuzumab (TZ) and/or pertuzumab (PZ) added to chemotherapy. This study sought to examine whether correlation exists between copy number variations (CNVs) in several genes related to the PI3K/AKT pathway (HER2, FGFR1, PIK3CA, AKT3 and MDM2) and the efficacy of anti-HER2 neoadjuvant treatment in patients with early HER2-positive BC. Forty-nine patients received TZ or PZ/TZ and chemotherapy as neoadjuvant treatment. Gene CNVs were determined by quantitative polymerase chain reaction on paraffin-embedded biopsy specimens. The response to 6 months of therapy was assessed by Miller–Payne grading of the tumor on surgical resection; grades 4 and 5, indicating >90% tumor reduction, were defined as a good response. A good response was shown by 64.5% and a pCR by 31.2% of patients. When stratified by anti-HER2 antibody received and gene CNV, it was found that patients with FGFR1 gene amplification or those with FGFR1 amplification treated with TZ alone showed a poor response (p = 0.024 and p = 0.037, respectively). In the subset of patients treated with TZ/PZ combined, the pCR rate was significantly lower among those showing FGFR1 amplification (p = 0.021). Although based on a small sample size, our findings suggest that patients with FGFR1 amplification might benefit less from anti-HER2 antibody therapy.

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Section: Discussionmentioning

confidence: 88%

FGFR1 Amplification and Response to Neoadjuvant Anti-HER2 Treatment in Early HER2-Positive Breast Cancer

et al. 2022

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“…In this sense, the rationale for a combination of trastuzumab with either chemotherapy such as capecitabine or paclitaxel, or with tyrosine kinase inhibitors such as lapatinib, or more recently with a dual inhibitor of both mTOR and PI3K, has proved to be a more potent approach for HER-2-positive breast cancer treatment than trastuzumab alone [ 24 ]. Nowadays, the combined therapy of trastuzumab, pertuzumab, and taxane is the standard for treating metastatic breast cancer [ 25 ]. Our results indicated that PPRHs could be a potential tool in combination therapies with trastuzumab since their gene silencing mechanism contributed to increasing the effect on cell viability with respect to the antibody alone.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Effects of the Combination of Polypurine Reverse Hoogsteen Hairpins against HER-2 and Trastuzumab in Breast Cancer Cells

López-Aguilar

Fernández‐Nogueira

Fuster

et al. 2023

IJMS

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Therapeutic oligonucleotides are powerful tools for the inhibition of potential targets involved in cancer. We describe the effect of two Polypurine Reverse Hoogsteen (PPRH) hairpins directed against the ERBB2 gene, which is overexpressed in positive HER-2 breast tumors. The inhibition of their target was analyzed by cell viability and at the mRNA and protein levels. The combination of these specific PPRHs with trastuzumab was also explored in breast cancer cell lines, both in vitro and in vivo. PPRHs designed against two intronic sequences of the ERBB2 gene decreased the viability of SKBR-3 and MDA-MB-453 breast cancer cells. The decrease in cell viability was associated with a reduction in ERBB2 mRNA and protein levels. In combination with trastuzumab, PPRHs showed a synergic effect in vitro and reduced tumor growth in vivo. These results represent the preclinical proof of concept of PPRHs as a therapeutic tool for breast cancer.

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“…The current treatment of choice for Her2 + breast cancer encompasses the use of the humanized anti-Her2 mAbs trastuzumab and pertuzumab [ 36 ], which have recently been demonstrated to be more effective when co-administered [ 10 ]. Experimentally, the cooperative and synergic effects of mAb combination, in terms of antitumor potential, can be achieved through DNA vaccination [ 19 , 20 , 25 ], which also has the advantage of inducing an active and long-lasting immunological memory able to prolong the therapeutic outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…These mAbs can be used to deliver drugs to the tumor, as in the case of trastuzumab emtansine and trastuzumab deruxtecan [ 5 ], but their main application is to interfere with Her2 signaling and induce tumor cell killing by immune cells or the complement system [ 6 , 7 , 8 , 9 ]. Emerging clinical data support their combined administration to avoid resistance and increase efficacy [ 10 ]. While the ability to induce antibody-dependent cellular cytotoxicity (ADCC) is a proven essential mechanism of their efficacy [ 6 , 7 ], more controversial is the role of complement-mediated cytotoxicity (CDC) and complement-mediated cellular cytotoxicity (CDCC) [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Role of ADCC, CDC, and CDCC in Vaccine-Mediated Protection against Her2 Mammary Carcinogenesis

et al. 2022

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Amplification or mutation of the Her2 oncoantigen in human mammary glands leads to the development of an aggressive breast carcinoma. Several features of this breast carcinoma are reproduced in mammary carcinomas that spontaneously arise in female transgenic mice bearing the activated rat Her2 oncogene under transcriptional control of the mouse mammary tumor virus promoter-BALB-neuT (neuT) mice. We previously demonstrated that carcinoma progression in neuT mice can be prevented by DNA vaccination with RHuT, a plasmid coding for a chimeric rat/human Her2 protein. RHuT vaccination exerts an antitumor effect, mostly mediated by the induction of a strong anti-rat Her2 antibody response. IgG induced by RHuT vaccine mainly acts by blocking Her2 signaling, thus impairing cell cycle progression and inducing apoptosis of cancer cells, but other indirect effector mechanisms could be involved in the antibody-mediated protection. The recruitment of cells with perforin-dependent cytotoxic activity, able to perform antibody-dependent cellular cytotoxicity, has already been investigated. Less is known about the role of the complement system in sustaining antitumor response through complement-dependent cytotoxicity and cellular cytotoxicity in vaccinated mice. This work highlights that the weight of such mechanisms in RHuT-induced cancer protection is different in transplantable versus autochthonous Her2+ tumor models. These results may shed new light on the effector mechanisms involved in antibody-dependent anti-cancer responses, which might be exploited to ameliorate the therapy of Her2+ breast cancer.

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Combination of Pertuzumab and Trastuzumab in the Treatment of HER2-Positive Early Breast Cancer: A Review of the Emerging Clinical Data

Cited by 22 publications

References 70 publications

FGFR1 Amplification and Response to Neoadjuvant Anti-HER2 Treatment in Early HER2-Positive Breast Cancer

FGFR1 Amplification and Response to Neoadjuvant Anti-HER2 Treatment in Early HER2-Positive Breast Cancer

In Vitro and In Vivo Effects of the Combination of Polypurine Reverse Hoogsteen Hairpins against HER-2 and Trastuzumab in Breast Cancer Cells

Role of ADCC, CDC, and CDCC in Vaccine-Mediated Protection against Her2 Mammary Carcinogenesis

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