De Angelis, Carmine (2017) IDENTIFYING PREDICTIVE MARKERS OF RESPONSE AND RESISTANCE TO POTENT MULTI-AGENT HER2-TARGETED THERAPY. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: IDENTIFYING PREDICTIVE MARKERS OF RESPONSE AND RESISTANCE TO POTENT MULTI-AGENT HER2-TARGETED THERAPY
Creators:
CreatorsEmail
De Angelis, Carminecarmine.deangelis83@gmail.com
Date: 10 April 2017
Number of Pages: 44
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Clinica e Chirurgia
Dottorato: Terapie avanzate medico-chirurgiche
Ciclo di dottorato: 29
Coordinatore del Corso di dottorato:
nomeemail
Di Minno, Giovannidiminno@unina.it
Tutor:
nomeemail
De Placido, SabinoUNSPECIFIED
Date: 10 April 2017
Number of Pages: 44
Uncontrolled Keywords: HER2, PIK3CA, PTEN, TILs
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/06 - Oncologia medica
Date Deposited: 27 Apr 2017 10:11
Last Modified: 14 Mar 2018 11:57
URI: http://www.fedoa.unina.it/id/eprint/11793
DOI: 10.6093/UNINA/FEDOA/11793

Abstract

Background: Dual HER2 blockade with lapatinib plus trastuzumab without chemotherapy resulted in a substantial pathologic complete response (pCR) rate in HER2+ breast cancer patients (TBCRC006). Aberrant activation of the PI3K pathway as well as levels of tumor infiltrating lymphocytes (TILs) at diagnosis has been shown to be associated with response to HER2 targeted therapy. However, the results from these clinical trials are confounded by the co-administration of chemotherapy. In this study, we investigated the predictive value of PI3K-pathway activation and TILs in patients receiving neoadjuvant HER2 targeted therapy without chemotherapy. Methods: Pre-treatment biopsies from patients enrolled in the TBCRC006 trial were used for the aims of this study. PTEN expression status and PIK3CA mutations were assessed by immunohistochemistry and targeted sequencing of tumor DNA, respectively. Hematoxylin and eosin (H&E)-stained slides were evaluated for the % of stromal TILs; a threshold of 60% was used to define high TILs. Single formalin-fixed paraffin-embedded slides from 10 cases were co-stained for CD4, CD8, CD20, CD68, FoxP3, cytokeratin, and DAPI by multiplexed immunofluorescence (m-IF) using PerkinElmer Opal system. Multispectral imaging and digital analysis to visualize and quantify specific immune infiltrates were performed using PerkinElmerVectra system. The results were correlated with pathologic complete response (pCR). Results: Of the 64 evaluable patients, tumor tissue was available from 59 patients for PTEN immunohistochemistry, and DNA was available from 38 cases for mutation analysis. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p=0.04). PIK3CA mutations were identified in 12/38 tumors (32%) and were independent of ER or PTEN expression. No patient whose tumor harbored a PIK3CA mutation achieved pCR (p=0.07). When considered together (35 cases), 0/19 cases (0%) with a PIK3CA mutation and/or PTEN low expression had a pCR compared to 5/16 cases (31%) with PI3KCA wild type and high PTEN (p=0.01). TILs evaluation was available for 59 of the 64 patients who were evaluable for pathologic response. Twelve of 59 pts (20%) exhibited High TILs. The pCR rate was numerically higher in high-TILs compared to low-s-TILs (50% vs. 19%, P = 0.057). Multispectral imaging successfully captured and quantified multiple immune cell types in all the so far m-IF-stained samples. The density of stromal TILs (calculated as the total number of cells positive for the above immune markers/mm2) significantly correlated with % of stromal TILs evaluated on the H&E-stained slides (r = 0.76, P = 0.01). Conclusion: PI3K pathway hyperactivation is associated with resistance to lapatinib and trastuzumab without chemotherapy. If externally confirmed, future studies should investigate targeting PI3K/Akt/mTOR, in addition to HER2, in patients with HER2-positive tumors and evidence of aberrant downstream PI3K pathway activation. High levels of stromal TILs were associated with a numerically higher pCR rate than low stromal TILs in patients with HER2+ breast cancer treated with anti-HER2 agents without chemotherapy. However, the p-value did not reach statistical significance. Characterizing TILs with m-IF is feasible and may help correlate various TIL subpopulations with response to treatment.

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