Pembrolizumab activity in patients with Fanconi anemia repair pathway competent and deficient tumors.

BACKGROUND: Given the observed antitumor activity of immune-checkpoint-inhibitors in patients with mismatch-repair deficient (MSI-H) tumors, we hypothesized that deficiency in homologous-recombination-repair (HRR) can also influence susceptibility. METHODS: Patients with disease progression on standard of care and for whom pembrolizumab had no FDA approved indication received pembrolizumab. Patients with MSI-H tumors were excluded. Objectives included immune-related objective response rate (iORR), progression-free survival (PFS) and 20-weeks-PFS. Pembrolizumab was given every 3 weeks and scans performed every six. We evaluated a triple-stain (FANCD2foci/DAPI/Ki67) functional assay of the Fanconi Anemia (FA) pathway: FATSI, in treated patients' archived tumors. The two-stage sample size of 20/39 patients evaluated an expected iORR≥20% in the whole population vs. the null hypothesis of an iORR≤5%, based on an assumed iORR≥40% in patients with functional FA deficiency, and < 10% in patients with intact HRR. An expansion cohort of MSI stable endometrial cancer (MS-EC) followed. Exploratory stool microbiome analyses in selected patients were performed. RESULTS: Fifty-two patients (45F,7M;50-evaluable) were enrolled. For the 39 in the two-stage cohort, response evaluation showed 2CR,5PR,11SD,21PD (iORR-18%). FATSI tumor analyses showed 29 competent (+) and 10 deficient (-). 2PR,9SD,17PD,1NE occurred among the FATSI+ (iORR-7%) and 2CR,3PR,2SD,3PD among the FATSI(-) patients (iORR-50%). mPFS and 20w-PFS were 43 days and 21% in FATSI+, versus 202 days and 70% in FATSI(-) patients. One PR occurred in the MS-EC expansion cohort. CONCLUSIONS: Pembrolizumab has meaningful antitumor activity in malignancies with no current FDA approved indications and FA functional deficiency. The results support further evaluation of FATSI as a discriminatory biomarker for population-selected studies.

Body image in and out of the lab: Correspondence between lab-based attentional bias data and body shape dissatisfaction experiences in daily life.

Accumulating lab-based studies have identified attentional biases in processing of negative appearance-related information among individuals with elevated trait body shape and weight dissatisfaction (BD). How these biases translate into experiences of BD in daily life remains unclear and, hence, was the focus of the present study. Thirty-eight women aged between 18-40 years completed a baseline survey and modified dot-probe task with both fat and thin appearance-related stimuli in a laboratory setting. Participants also downloaded a smartphone app that prompted them 10 times per day for 7 days to rate current body dissatisfaction. Results revealed that heightened BD in daily life tended to be transitory, and followed by a substantially lower rating of BD by the next survey (∼1-2 h later). For individuals with elevated trait BD and facilitated attention towards thin body images, this reduction in state BD was more gradual. Surprisingly, delayed disengagement towards thin body images was associated with greater reduction in state BD. Consistent with the hypothesis, moderating effects were not observed when initial state BD level was low. Susceptibility for immediate, short-term attentional biases towards appearance-related information may be a vulnerability factor for the prolonged persistence of negative body image experiences in daily life.