Impact of RNA Signatures on pCR and Survival after 12-Week Neoadjuvant Pertuzumab plus Trastuzumab with or without Paclitaxel in the WSG-ADAPT HER2+/HR- Trial.

PURPOSE: To identify associations of biological signatures and stromal tumor-infiltrating lymphocytes (sTIL) with pathological complete response (pCR; ypT0 ypN0) and survival in the Phase II WSG-ADAPT HER2+/HR- trial (NCT01817452). EXPERIMENTAL DESIGN: Patients with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer (EBC) were randomized to pertuzumab+trastuzumab (P+T, n = 92) or P+T+paclitaxel (n = 42). Gene expression signatures were analyzed in baseline biopsies using NanoString Breast Cancer 360 panel (n = 117); baseline and on-treatment (week 3) sTIL levels were available in 119 and 76 patients, respectively. Impacts of standardized gene expression signatures on pCR and invasive disease-free survival (iDFS) were estimated by logistic and Cox regression. RESULTS: In all patients, ERBB2 [OR, 1.70; 95% confidence interval (CI), 1.08-2.67] and estrogen receptor (ER) signaling (OR, 1.72; 95% CI, 1.13-2.61) were favorable, whereas PTEN (OR, 0.57; 95% CI, 0.38-0.87) was unfavorable for pCR. After 60 months median follow-up, 13 invasive events occurred (P+T: n = 11, P+T+paclitaxel: n = 2), none following pCR. Gene signatures related to immune response (IR) and ER signaling were favorable for iDFS, all with similar HR about 0.43-0.55. These patterns were even more prominent in the neoadjuvant chemotherapy-free group, where additionally BRCAness signature was unfavorable (HR, 2.00; 95% CI, 1.04-3.84). IR signatures were strongly intercorrelated. sTILs (baseline/week 3/change) were not associated with pCR or iDFS, though baseline sTILs correlated positively with IR signatures. CONCLUSIONS: Distinct gene signatures were associated with pCR versus iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with upregulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.

Patient participation in multidisciplinary tumor conferences: How is it implemented? What is the patients' role? What are patients' experiences?

BACKGROUND: Prior research has shown that around 5%-7% of patients in breast cancer centers in Germany participate in the discussion of their own case within a multidisciplinary tumor conference (MTC). The PINTU study is one of the first to research this practice. The objective is to describe (a) how patient participation in MTCs is implemented, (b) what is the role of patients, and (c) how patients experience MTCs. METHODS: MTCs in six breast and gynecological cancer centers in North Rhine-Westphalia, Germany, with and without patient participation, are studied prospectively by (non)participatory, structured observation. Breast and gynecological cancer patients completed surveys before, directly after, and 4 weeks after MTC participation. Data are analyzed descriptively. RESULTS: Case discussions of a sample of n = 317 patients (n = 95 with MTC participation and n = 222 without) were observed. Survey data were obtained from n = 242 patients (n = 87 and n = 155). Observational data showed heterogeneity in the ways MTC participation was practiced. Among participating patients, 89% had the opportunity to express their opinion and 61% were involved in decision-making. Whereas most patients reported positive experiences and would recommend participation, some had negative experiences and regretted participating. CONCLUSIONS: Due to a lack of recommendations, hospitals implement patient participation in MTCs in many different ways. So far, it is unknown which setting and procedures of MTC participation are beneficial for patients. However, existing evidence on communication in cancer care together with this exploratory study's findings can build the basis for developing recommendations for hospitals that invite their patients to MTCs. CLINICAL TRIAL REGISTRATION NUMBER: German Clinical Trials Register Nr. DRKS00012552.

Roles of cyclooxygenase-2 and phosphorylated Akt (Thr308) in cardiac hypertrophy regression mediated by left-ventricular unloading.

OBJECTIVES: Cyclooxygenase-2 is associated with cardiac hypertrophy during chronic heart failure and is regulated through the PI3K/Akt pathway. Cyclooxygenase-2-induced cell growth through Akt phosphorylation was demonstrated in vitro. In chronic heart failure, left ventricular assist devices lead to hypertrophy regression and molecular changes. Therefore, the expression of cyclooxygenase-2, phosphorylated Akt (p-Akt), and p-Erk 1/2, as well as cardiac hypertrophy before and after left ventricular assist device insertion, was investigated. METHODS: In myocardial tissue before and after left ventricular assist device insertion, the expression of cyclooxygenase-2, p-Akt (Thr308), p-Akt (Ser473), and p-Erk 1/2 was demonstrated by immunohistochemistry and quantified by morphometry. Colocalization of cyclooxygenase-2 and p-Akt (Thr308) was investigated by immuno-doublestaining. RESULTS: A significant decrease of cyclooxygenase-2, p-Akt (Thr308), p-Akt (Ser473), and p-Erk 1/2 protein expression and hypertrophy regression was observed after left ventricular assist device insertion. A significant correlation between cyclooxygenase-2 and p-Akt (Thr308) expression, as well as between cyclooxygenase-2 expression and cardiomyocyte diameter, was observed before, but not after, left ventricular assist device insertion. Only cyclooxygenase-2-positive cardiomyocytes showed significant hypertrophy regression on unloading. Sarcoplasmic colocalization of cyclooxygenase-2 and p-Akt (Thr308) is present before left ventricular assist device insertion and is decreased after unloading, whereas the normal myocardium is completely devoid of it. CONCLUSIONS: Left ventricular assist device treatment is associated with a significant decrease of cyclooxygenase-2, p-Akt (Thr308), p-Akt (Ser473), and p-Erk 1/2, and cardiac hypertrophy regression of cyclooxygenase-2-positive cardiomyocytes. The significant correlation and colocalization in cardiomyocytes of cyclooxygenase-2 and p-Akt (Thr308) before left ventricular assist device insertion suggests a cross-talk between the 2 molecules in the progression of cardiac hypertrophy, which is reversibly regulated by the left ventricular assist device.