Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Purpose: Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. Methods: We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Results: Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. Conclusions: HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of ‘immune cold’ TNBCs

Training approach-avoidance of smiling faces affects emotional vulnerability in socially anxious individuals

Contains fulltext : 116753.pdf (publisher's version ) (Open Access)Previous research revealed an automatic behavioral bias in high socially anxious individuals (HSAs): although their explicit evaluations of smiling faces are positive, they show automatic avoidance of these faces. This is reflected by faster pushing than pulling of smiling faces in an Approach-Avoidance Task (AAT; Heuer et al., 2007). The current study addressed the causal role of this avoidance bias for social anxiety. To this end, we used the AAT to train HSAs, either to approach smiling faces or to avoid them. We examined whether such an AAT training could change HSAs' automatic avoidance tendencies, and if yes, whether AAT effects would generalize to a new approach task with new facial stimuli, and to mood and anxiety in a social threat situation (a video-recorded self-presentation). We found that HSAs trained to approach smiling faces did indeed approach female faces faster after the training than HSAs trained to avoid smiling faces. Moreover, approach-faces training reduced emotional vulnerability: it led to more positive mood and lower anxiety after the self-presentation than avoid-faces training. These results suggest that automatic approach-avoidance tendencies have a causal role in social anxiety, and that they can be modified by a simple computerized training. This may open new avenues in the therapy of social phobia.6 p

Avelumab Plus Talazoparib in Patients with BRCA1/2 - Or ATM -Altered Advanced Solid Tumors: Results from JAVELIN BRCA/ATM, an Open-Label, Multicenter, Phase 2b, Tumor-Agnostic Trial

Importance: Nonclinical studies suggest that the combination of poly(ADP-ribose) polymerase and programmed cell death 1/programmed cell death-ligand 1 inhibitors has enhanced antitumor activity; however, the patient populations that may benefit from this combination have not been identified. Objective: To evaluate whether the combination of avelumab and talazoparib is effective in patients with pathogenic BRCA1/2 or ATM alterations, regardless of tumor type. Design, Setting, and Participants: In this pan-cancer tumor-agnostic phase 2b nonrandomized controlled trial, patients with advanced BRCA1/2-altered or ATM-altered solid tumors were enrolled into 2 respective parallel cohorts. The study was conducted from July 2, 2018, to April 12, 2020, at 42 institutions in 9 countries. Interventions: Patients received 800 mg of avelumab every 2 weeks and 1 mg of talazoparib once daily. Main Outcomes and Measures: The primary end point was confirmed objective response (OR) per RECIST 1.1 by blinded independent central review. Results: A total of 200 patients (median [range] age, 59.0 [26.0-89.0] years; 132 [66.0%] women; 15 [7.5%] Asian, 11 [5.5%] African American, and 154 [77.0%] White participants) were enrolled: 159 (79.5%) in the BRCA1/2 cohort and 41 (20.5%) in the ATM cohort. The confirmed OR rate was 26.4% (42 patients, including 9 complete responses [5.7%]) in the BRCA1/2 cohort and 4.9% (2 patients) in the ATM cohort. In the BRCA1/2 cohort, responses were more frequent (OR rate, 30.3%; 95% CI, 22.2%-39.3%, including 8 complete responses [6.7%]) and more durable (median duration of response: 10.9 months [95% CI, 6.2 months to not estimable]) in tumor types associated with increased heritable cancer risk (ie, BRCA1/2-associated cancer types, such as ovarian, breast, prostate, and pancreatic cancers) and in uterine leiomyosarcoma (objective response in 3 of 3 patients and with ongoing responses greater than 24 months) compared with non-BRCA-associated cancer types. Responses in the BRCA1/2 cohort were numerically higher for patients with tumor mutational burden of 10 or more mutations per megabase (mut/Mb) vs less than 10 mut/Mb. The combination was well tolerated, with no new safety signals identified. Conclusions and Relevance: In this phase 2b nonrandomized controlled trial, neither the BRCA1/2 nor ATM cohort met the prespecified OR rate of 40%. Antitumor activity for the combination of avelumab and talazoparib in patients with BRCA1/2 alterations was observed in some patients with BRCA1/2-associated tumor types and uterine leiomyosarcoma; benefit was minimal in non-BRCA-associated cancer types. Trial Registration: ClinicalTrials.gov Identifier: NCT03565991.SCOPUS: ar.jinfo:eu-repo/semantics/publishe