Abstract:While results thus far demonstrate the clinical benefit of trastuzumab, some patients do not respond to this therapy. To identify a molecular predictor of trastuzumab benefit, we conducted whole-transcriptome analysis of primary HER2+ breast carcinomas obtained from patients treated with trastuzumab-containing therapies and correlated the molecular portrait with treatment benefit.The estimated association between gene expression and relapse-free survival allowed development of a trastuzumab risk model (TRAR), … Show more
“…CCL2 was found to also be expressed in stromal cells with macrophage morphology, as indicated by arrows in Figure 1D, CCL2 panel. As a possible consequence of high expression of these chemokines, TRAR-low tumors exhibited higher infiltration of CD8+ T cells, as previously described, 9 and monocytes (CD68+ cells) than TRAR-high tumors (p = 0.0063) (Figure 2A). CD68+ cells were mainly localized in tumor stroma and exhibited similar levels of contact with tumor cells in some areas in both TRAR-low and TRAR-high tumors.…”
Section: Resultssupporting
confidence: 76%
“…9 Through gene expression analysis of 53 HER2+ BCs of the Group Herceptin in Adjuvant Therapy (GHEA) cohort we identified responsive tumors (TRAR-low) as those dependent on HER2 signals (HER2-E by PAM50 classification), enriched in immune genes, and highly infiltrated by CD8+ T cells. 9 Confirming the tumor dependence on HER2 signal, TRAR-low tumors exhibited lower levels of the estrogen receptor-related score (ERS), indicative of activity of the ER pathway, 11 than TRAR-high tumors (Figure 1A). 10.1080/2162402X.2018.1512942-F0001Figure 1.Enhanced expression of chemokines in HER2+ BCs classified as sensitive to trastuzumab.…”
Section: Resultsmentioning
confidence: 99%
“…Based on i) the higher infiltration of effector immune cells in TRAR-low than TRAR-high tumors without concomitant increase of immune suppressive cells, ii) the poor prognosis of TRAR-low patients when not treated with trastuzumab 9 , and iii) the emerging data showing that PD-L1 expression by tumor cells could block lymphocyte activity, 13 we analyzed PD-1 ligand expression according to TRAR classification. PD-L1 and PD-L2 were expressed at significantly higher levels in TRAR-low than TRAR-high tumors at the mRNA level (Figure 2C).…”
Section: Resultsmentioning
confidence: 99%
“…4,5 Moreover, based on increasing evidence of the role of both innate and adaptive immunity in trastuzumab mechanism of action, 6,7 immune-related information such as tumor infiltrating lymphocyte count or immune-related signatures were explored and found to be predictive of trastuzumab benefit in several studies. 8 In this context, through transcriptome profiling of archival formalin-fixed paraffin embedded (FFPE) tumor blocks from HER2+ cases treated with adjuvant trastuzumab in our Institute during routine clinical practice, 9 we identified BCs exquisitely sensitive to treatment as those with both tumor dependence on HER2 signaling by PAM50 classification, as well as enriched in immune genes, 9 supporting the predictive power of both addiction to HER2 signaling and immune infiltration because of their ability to identify the same tumors. Thus, as described for some oncogenes that cause pathogenesis of human cancer (e.g., RAS, BRAF, RET/PTC1, and MYC), 10 a direct connection between HER2 activity and tumor immune infiltration may occur.…”
Section: Introductionmentioning
confidence: 85%
“…9 All procedures were in accordance with the Helsinki Declaration (World Medical Association, 2013). Tumor specimens used for research consisted of leftover material of samples collected during standard surgical and medical approaches at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT).…”
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.
“…CCL2 was found to also be expressed in stromal cells with macrophage morphology, as indicated by arrows in Figure 1D, CCL2 panel. As a possible consequence of high expression of these chemokines, TRAR-low tumors exhibited higher infiltration of CD8+ T cells, as previously described, 9 and monocytes (CD68+ cells) than TRAR-high tumors (p = 0.0063) (Figure 2A). CD68+ cells were mainly localized in tumor stroma and exhibited similar levels of contact with tumor cells in some areas in both TRAR-low and TRAR-high tumors.…”
Section: Resultssupporting
confidence: 76%
“…9 Through gene expression analysis of 53 HER2+ BCs of the Group Herceptin in Adjuvant Therapy (GHEA) cohort we identified responsive tumors (TRAR-low) as those dependent on HER2 signals (HER2-E by PAM50 classification), enriched in immune genes, and highly infiltrated by CD8+ T cells. 9 Confirming the tumor dependence on HER2 signal, TRAR-low tumors exhibited lower levels of the estrogen receptor-related score (ERS), indicative of activity of the ER pathway, 11 than TRAR-high tumors (Figure 1A). 10.1080/2162402X.2018.1512942-F0001Figure 1.Enhanced expression of chemokines in HER2+ BCs classified as sensitive to trastuzumab.…”
Section: Resultsmentioning
confidence: 99%
“…Based on i) the higher infiltration of effector immune cells in TRAR-low than TRAR-high tumors without concomitant increase of immune suppressive cells, ii) the poor prognosis of TRAR-low patients when not treated with trastuzumab 9 , and iii) the emerging data showing that PD-L1 expression by tumor cells could block lymphocyte activity, 13 we analyzed PD-1 ligand expression according to TRAR classification. PD-L1 and PD-L2 were expressed at significantly higher levels in TRAR-low than TRAR-high tumors at the mRNA level (Figure 2C).…”
Section: Resultsmentioning
confidence: 99%
“…4,5 Moreover, based on increasing evidence of the role of both innate and adaptive immunity in trastuzumab mechanism of action, 6,7 immune-related information such as tumor infiltrating lymphocyte count or immune-related signatures were explored and found to be predictive of trastuzumab benefit in several studies. 8 In this context, through transcriptome profiling of archival formalin-fixed paraffin embedded (FFPE) tumor blocks from HER2+ cases treated with adjuvant trastuzumab in our Institute during routine clinical practice, 9 we identified BCs exquisitely sensitive to treatment as those with both tumor dependence on HER2 signaling by PAM50 classification, as well as enriched in immune genes, 9 supporting the predictive power of both addiction to HER2 signaling and immune infiltration because of their ability to identify the same tumors. Thus, as described for some oncogenes that cause pathogenesis of human cancer (e.g., RAS, BRAF, RET/PTC1, and MYC), 10 a direct connection between HER2 activity and tumor immune infiltration may occur.…”
Section: Introductionmentioning
confidence: 85%
“…9 All procedures were in accordance with the Helsinki Declaration (World Medical Association, 2013). Tumor specimens used for research consisted of leftover material of samples collected during standard surgical and medical approaches at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT).…”
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.
As most erb‐b2 receptor tyrosine kinase 2 (HER2)‐positive breast cancer (BC) patients currently receive dual HER2‐targeting added to neoadjuvant chemotherapy, improved methods for identifying individual response, and assisting postsurgical salvage therapy, are needed. Herein, we evaluated the 41‐gene classifier trastuzumab advantage risk model (TRAR) as a predictive marker for patients enrolled in the NeoSphere trial. TRAR scores were computed from RNA of 350 pre‐ and 166 post‐treatment tumor specimens. Overall, TRAR score was significantly associated with pathological complete response (pCR) rate independently of other predictive clinico‐pathological variables. Separate analyses according to estrogen receptor (ER) status showed a significant association between TRAR score and pCR in ER‐positive specimens but not in ER‐negative counterparts. Among ER‐positive BC patients not achieving a pCR, those with TRAR‐low scores in surgical specimens showed a trend for lower distant event‐free survival. In conclusion, in HER2‐positive/ER‐positive BC, TRAR is an independent predictor of pCR and represents a promising tool to select patients responsive to anti‐HER2‐based neoadjuvant therapy and to assist treatment escalation and de‐escalation strategies in this setting.
Despite different molecular tumor profiles indicate that human epidermal growth factor receptor 2 (HER2) messenger RNA (mRNA) levels mirror HER2 addiction and trastuzumab benefit in HER2‐positive breast cancer (BC), the identification of noninvasive clinical predictors of trastuzumab sensitivity remains an unmet clinical need. In the current study, we investigated whether intratumor lactate levels reflect HER2 addiction and, in turn, trastuzumab susceptibility. Accordingly, the gene expression profiles of transgenic murine BC cell lines expressing the human d16HER2 variant (HER2‐addicted) or human full‐length HER2 (WTHER2; HER2‐nonaddicted) revealed a significant enrichment of glycolysis‐related gene pathways in HER2‐addicted cells. We studied the metabolic content of 22 human HER2‐positive BC by quantitative nuclear magnetic resonance spectroscopy and found that those cases with higher lactate levels were characterized by higher HER2 transcript levels. Moreover, gene expression analyses of HER2‐positive BC samples from a TCGA data set revealed a significant enrichment in glycolysis‐related pathways in high/HER2‐addicted tumors. These data were confirmed by metabolic analyses of human HER2‐positive BC cell lines with high or low HER2 transcript levels, which revealed significantly more active glycolytic metabolism in high HER2 transcript than in low HER2 transcript cells. Overall, our results provide evidence for noninvasive intratumor lactate detection as a potential metabolic biomarker of HER2 addiction and trastuzumab response suggesting the possibility to use in vivo imaging to assess lactate levels and, in turn, select HER2‐positive BC patients who are more likely to benefit from anti‐HER2 treatments.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
