Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: A systematic review and meta-analysis

Valachis, Antonis; Mauri, Davide; Polyzos, Nikolaos P.; Chlouverakis, Grigoris; Mavroudis, Dimitriοs; Georgoulias, V.

doi:10.1016/j.breast.2011.06.009

Cited by 107 publications

(68 citation statements)

References 25 publications

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“…1 , 2 Several studies have investigated the possibility of identifying biomarkers to distinguish patients sensitive to this therapy from those suited for novel targeted approaches. 3 Recently, analyses of gene expression profiles of tumor blocks from patients enrolled in clinical trials support a relationship between tumor dependence on HER2 signaling (HER2-E by PAM50) and trastuzumab sensitivity.…”

Section: Introductionmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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Through whole-transcriptome profiling of HER2+ breast carcinomas (BCs), we previously showed that those sensitive to trastuzumab are addicted to this oncoprotein and are enriched in immune pathways, raising the hypothesis that HER2 itself regulates immune cell recruitment. In the present study we investigated the relationship between HER2 activity and the pro-trastuzumab tumor immune milieu. Gene expression profiling and immunohistochemistry analysis of 53 HER2+ BCs showed that trastuzumab-sensitive tumors expressed significantly higher levels of chemokines involved in immune cell recruitment, with higher infiltration of T cells and monocytes, and higher levels of PD-1 ligands than tumors that do not benefit from trastuzumab. In vitro analysis in HER2+ BC cells revealed that CCL2 production was induced by HER2 stimulation with EGF/HRG via the PI3K-NF-kB axis, and down-modulated by HER2 inhibition with trastuzumab. CCL2 expression was higher in HER2+/ER− than HER2+/ER+ BC cell lines, and degradation of ER by fulvestrant induced an enhancement in NF-κB transcriptional activity and consequent CCL2 expression. Trastuzumab efficacy relied on CCL2 levels and monocytes present in the tumor microenvironment in FVB mice bearing HER2+ mammary carcinoma cells. HER2 signals were also found to sustain the expression of PD-1 ligands in tumor cells via the MEK pathway.Overall, our results support the concept that the activated HER2 oncogene regulates recruitment and activation of tumor infiltrating immune cells and trastuzumab activity by inducing CCL2 and PD-1 ligands and that ER activity negatively controls the HER2-driven pro-trastuzumab tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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“…HER2 [13], [14] and EGFR [15], [16] and molecular therapies for other growth factor receptors are still investigational. In addition to being therapeutic targets, growth factor receptors might be useful for molecular imaging [17]–[19].…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of Growth Factor Receptors and Membrane-Bound Tumor Markers for Imaging in Male and Female Breast Cancer

et al. 2013

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IntroductionMale breast cancer accounts for 0.5–1% of all breast cancers and is generally diagnosed at higher stage than female breast cancers and therefore might benefit from earlier detection and targeted therapy. Except for HER2 and EGFR, little is known about expression of growth factor receptors in male breast cancer. We therefore investigated expression profiles of growth factor receptors and membrane-bound tumor markers in male breast cancer and gynecomastia, in comparison with female breast cancer.MethodsTissue microarrays containing 133 male breast cancer and 32 gynecomastia cases were stained by immunohistochemistry for a panel of membrane-bound targets and compared with data on 266 female breast cancers.ResultsGrowth factor receptors were variably expressed in 4.5% (MET) up to 38.5% (IGF1-R) of male breast cancers. Compared to female breast cancer, IGF1-R and carbonic anhydrase 12 (CAXII) were more frequently and CD44v6, MET and FGFR2 less frequently expressed in male breast cancer. Expression of EGFR, HER2, CAIX, and GLUT1 was not significantly different between male and female breast cancer. Further, 48.1% of male breast cancers expressed at least one and 18.0% expressed multiple growth factor receptors. Since individual membrane receptors are expressed in only half of male breast cancers, a panel of membrane markers will be required for molecular imaging strategies to reach sensitivity. A potential panel of markers for molecular imaging, consisting of EGFR, IGF1-R, FGFR2, CD44v6, CAXII, GLUT1, and CD44v6 was positive in 77% of male breast cancers, comparable to female breast cancers.ConclusionsExpression patterns of growth factor receptors and hypoxia membrane proteins in male breast cancer are different from female breast cancer. For molecular imaging strategies, a putative panel consisting of markers for EGFR, IGF1-R, FGFR2, GLUT1, CAXII, CD44v6 was positive in 77% of cases and might be considered for development of molecular tracers for male breast cancer.

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“…The study included 235 patients with locally advanced breast cancers and confirmed a beneficial effect of adding trastuzumab to chemotherapy in improving both pathological complete response (pCR) rate and survival outcomes. Subsequent studies confirmed that the addition of trastuzumab as part of neoadjuvant therapy significantly increases pCR with no additional toxicity and is currently the standard of care in this setting 52. As shown in the ACOSOG Z1041 trial, trastuzumab should be administered concurrently to taxane-based chemotherapy, while the administration with anthracyclines should be avoided 53.…”

Section: Targeted Agents For the Treatment Of Her2-positive Early-stamentioning

confidence: 96%

Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib

Kourié¹,

Rassy²,

Clatot³

et al. 2017

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Over the last decades, a better understanding of breast cancer heterogeneity provided tools for a biologically based personalization of anticancer treatments. In particular, the overexpression of the human epidermal growth factor receptor 2 (HER2) by tumor cells provided a specific target in these HER2-positive tumors. The development of the monoclonal antibody trastuzumab, and its approval in 1998 for the treatment of patients with metastatic disease, radically changed the natural history of this aggressive subtype of breast cancer. These findings provided strong support for the continuous research in targeting the HER2 pathway and implementing the development of new anti-HER2 targeted agents. Besides trastuzumab, a series of other anti-HER2 agents have been developed and are currently being explored for the treatment of breast cancer patients, including those diagnosed with early-stage disease. Among these agents, neratinib, an oral tyrosine kinase inhibitor that irreversibly inhibits HER1, HER2, and HER4 at the intracellular level, has shown promising results, including when administered to patients previously exposed to trastuzumab-based treatment. This article aims to review the available data on the role of the HER2 pathway in breast cancer and on the different targeted agents that have been studied or are currently under development for the treatment of patients with early-stage HER2-positive disease with a particular focus on neratinib.

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Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: A systematic review and meta-analysis

Cited by 107 publications

References 25 publications

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

Differential Expression of Growth Factor Receptors and Membrane-Bound Tumor Markers for Imaging in Male and Female Breast Cancer

Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib

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