Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial

Bianchini, Giampaolo; Pusztai, Lajos; Pieńkowski, Tadeusz; Im, Young‐Hyuck; Bianchi, GV; Tseng, Ling Ming; Liu, M.-C.; Lluch, Aña; Galeota, Eugenia; Magazzù, Domenico; Haba, Juan de la; Oh, Do Youn; Poirier, Brigitte; Pedrini, José Luiz; Семиглазов, Владимир; Valagussa, Pinuccia; Gianni, Luca

doi:10.1093/annonc/mdv395

Cited by 116 publications

(86 citation statements)

References 31 publications

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“…9 Chemokine expression in patients of the GHEA dataset was analyzed by calculating the mean of the normalized expression values of all chemokines of the dataset (Supplementary Table S1). Genes significantly up-modulated in human M1 and in M2-polarized macrophages, 42 respectively and genes of the LM22 Cibersort list 43 were analyzed as M1 and M2 gene patterns (Supplementary Table S3) in the GHEA dataset by ssGSEA, as described. 44 ERS score was calculated as described.…”

Section: Methodsmentioning

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: Methodsmentioning

confidence: 99%

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

et al. 2018

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“…In the three arms of the study that neo-adjuvant treatment consisted of doublets of docetaxel, trastuzumab and pertuzumab, the pathologic complete response rate in the breast (pCRB) was lower for the low TILs carcinomas (4.3%) than for the intermediate and high TILs carcinomas (26.9% and 26.4%, respectively). In the triplet arm receiving all three drugs a more balanced pCRB rate was observed (28.6%, 48.9% and 22.2% in the low, intermediate and high TILs groups, respectively) (35). A study of anthracycline and taxane-based neo-adjuvant chemotherapy, which included only Her2-negative patients, showed that 36.5% of ER-negative patients (triple-negative) were lymphocyte-predominant (defined as having more than 60% TILs), while only 12% of ER-positive patients had lymphocyte predominance (36).…”

Section: Tils As a Prognostic Marker And Possible Predictive Marker Omentioning

confidence: 95%

“…Higher TILs numbers were associated with a better rate of pCR overall and in triple-negative and Her2-positive carcinomas but not in ER-positive cancers. Data from the NeoSphere trial that compared different combinations of neo-adjuvant therapies in Her2-positive breast cancers used a three tier TILs grading system (<5%, 5-50% and >50%) and showed that 14%, 69% and 17% of cases belonged to the low, intermediate and high TILs categories, respectively (35). In the three arms of the study that neo-adjuvant treatment consisted of doublets of docetaxel, trastuzumab and pertuzumab, the pathologic complete response rate in the breast (pCRB) was lower for the low TILs carcinomas (4.3%) than for the intermediate and high TILs carcinomas (26.9% and 26.4%, respectively).…”

Section: Tils As a Prognostic Marker And Possible Predictive Marker Omentioning

confidence: 99%

Immune Blockade Inhibition in Breast Cancer

Voutsadakis

2016

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“…20 Tumor tissue was analyzed for PD-L1 expression by immunohistochemistry (IHC), performed on formalin-fixed, paraffin-embedded, 4-mm tissue sections using unconjugated, rabbit anti-human PDL-1 (CD274) clone SP142 (PDL1, Spring Biosciences catalog number M4420). 38 Staining was performed on a Ventana Medical Systems Discovery XT instrument with online deparaffinization and using Ventana's reagents and detection kits. PDL1 was antigen retrieved in Ventana Cell Conditioner 1 (Tris-Borate-EDTA) for 20 min.…”

Section: Feasibility Safety and Efficacymentioning

confidence: 99%

Results of a phase I–II study of adjuvant concurrent carboplatin and accelerated radiotherapy for triple negative breast cancer

et al. 2016

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Purpose: To determine feasibility and explore the clinical efficacy of concurrent radiotherapy and carboplatin as adjuvant treatment of triple negative breast cancer (TNBC).Patients and Methods: Women with Stage I-II TNBC were treated after surgery in a phase I-II prospective trial [NCT01289353]. Weekly carboplatin (AUC D 2.0) was delivered for 6 weeks. Concurrent radiotherapy was delivered in the prone position during weeks 2-4, for a total dose of 40.5 Gy in 15 fractions to the breast, and 46.5 Gy in 17 fractions to the tumor bed. Adverse events (AE) were assessed weekly during treatment, once at 45-60 d, and every 6 mo thereafter, using the Common Terminology Criteria for AE (CTCAE) v3.0.Results: A total of 39 patients accrued and 36 received treatment. Eight patients (22%, exact 95% CI: 10%, 39%) developed grade 2 or greater acute radiation dermatitis. Overall, grade 2 AE were seen in nine and grade 3 in two patients. Twenty-three patients (64%) received additional adjuvant chemotherapy. With a median follow-up of 48 mo, 34/36 (94%) are alive and disease free. One patient died of pulmonary failure with possible but unproven breast cancer recurrence, and one patient died of pelvic malignancy. One patient recurred locally and is alive and disease free after surgical management. Brisk lymphocytic infiltrate was present pre-treatment in 39% of 18 patients with evaluable tumor.Conclusions: Adjuvant concurrent carboplatin and prone accelerated radiotherapy is a well-tolerated and promising treatment of early stage TNBC. The observed 3% compares favorably with the expected 30% recurrence rate within 1-4 y from treatment, warranting further studies.

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Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial

Cited by 116 publications

References 31 publications

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

Immune Blockade Inhibition in Breast Cancer

Results of a phase I–II study of adjuvant concurrent carboplatin and accelerated radiotherapy for triple negative breast cancer

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