Are DNA Repair Gene Alterations Associated With the Response to Platinum-Based Regimen and Immune Checkpoint Inhibitors in Patients With Solid Tumors?

We analyzed the antitumor activity of platinum-based chemotherapies and then immune checkpoint inhibitors (ICI) in all-comers patients with solid tumors having a somatic DNA damage repair gene alteration (DDR-GA) identified through a prospective precision medicine study (NCT02534649). Each DDR-GA was classified as pathogenic (Pa), probably pathogenic (PPa), and unknown pathogenicity (UPa) according to OncoKB and ClinVAR databases. Between January 2018 and May 2020, 662 patients were screened. One hundred ninety-nine tumors with DDR-GA were found in 121 (18.3%) patients. Ninety-six patients received platinum-based chemotherapy in the advanced setting. No difference in objective response rate (ORR) under platinum regimen was observed between the 3 DDR-GA groups. The only predictor of worse progression-free survival (PFS) in Cox regression was the existence of a Pa alteration compared to the UPa group: HR = 2.11 (95% CI = 1.2-3.7), P = .009. Forty-eight patients received ICI alone or in combination. We observed a significant trend in better ORR to ICI according to the DDR-GA status: 1/11 (9%) patients in UPa, 5/17 (29.4%) patients in PPa, and 9/20 (45%) patients in Pa (P = .003, Cochran-Armitage trend test), and an increased 6-month PFS probability of 11%, 44%, and 50% in the UPa, PPa, and Pa groups, respectively (P = .37, log-rank test). Overall, somatic pathogenic DDR-GAs were not associated with ORR or PFS to platinum-based chemotherapy in patients with unselected advanced solid tumors. However, DDR-GA seemed to impact ORR and PFS to ICI, paving the way for a therapeutic combination with ICI and molecules targeting the DDR mechanisms, which are currently evaluated in ongoing clinical trials.

Deep learning predicts patients outcome and mutations from digitized histology slides in gastrointestinal stromal tumor.

Risk assessment of gastrointestinal stromal tumor (GIST) according to the AFIP/Miettinen classification and mutational profiling are major tools for patient management. However, the AFIP/Miettinen classification depends heavily on mitotic counts, which is laborious and sometimes inconsistent between pathologists. It has also been shown to be imperfect in stratifying patients. Molecular testing is costly and time-consuming, therefore, not systematically performed in all countries. New methods to improve risk and molecular predictions are hence crucial to improve the tailoring of adjuvant therapy. We have built deep learning (DL) models on digitized HES-stained whole slide images (WSI) to predict patients' outcome and mutations. Models were trained with a cohort of 1233 GIST and validated on an independent cohort of 286 GIST. DL models yielded comparable results to the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in cross-validation and 0.72 for independent testing). DL splitted Miettinen intermediate risk GIST into high/low-risk groups (p value = 0.002 in the training set and p value = 0.29 in the testing set). DL models achieved an area under the receiver operating characteristic curve (AUC) of 0.81, 0.91, and 0.71 for predicting mutations in KIT, PDGFRA and wild type, respectively, in cross-validation and 0.76, 0.90, and 0.55 in independent testing. Notably, PDGFRA exon18 D842V mutation, which is resistant to Imatinib, was predicted with an AUC of 0.87 and 0.90 in cross-validation and independent testing, respectively. Additionally, novel histological criteria predictive of patients' outcome and mutations were identified by reviewing the tiles selected by the models. As a proof of concept, our study showed the possibility of implementing DL with digitized WSI and may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.

Targeting ERBB2 mutations in solid tumors: biological and clinical implications.

Preclinical data have shown that ERBB2 activating mutations are responsive to HER2 tyrosine kinase inhibitors. The aim of this study is to characterize the landscape of ERBB2 mutations in solid tumors and the potential efficacy of ERBB2 targeting.We analyzed the next-generation sequencing results from 17,878 patients with solid tumors and reported the outcome of 4 patients with advanced ERBB2-mutated tumors treated with a combination of trastuzumab and lapatinib.ERBB2 mutations occurred in 510 patients (2.85%). The tumor types with the highest incidence of ERBB2 mutations were the following: bladder (16.6%), small bowel (8.6%), ampullar (6.5%), skin non-melanoma (6.1%), and cervical cancer (5.5%). 49.4% (n = 282) were known as activating mutations. ERBB2 mutation was not mutually exclusive of ERBB2 amplification which occurred in up to 10% of cases. PI3KCA activating mutations were associated with ERBB2 mutations in 12.4% of cases mainly in breast and lung cancer. Four patients (endometrial, colorectal, cholangiocarcinoma, and adenosarcoma of the uterus) were treated with a combination of trastuzumab and lapatinib. All of them experienced tumor shrinkage resulting in stable disease in three cases and partial response in one case. One patient developed secondary resistance. Sequencing of the progressing metastasis allowed the identification of the ERBB2 L869R mutation previously associated with resistance to lapatinib in vitro.These results support further clinical investigation aiming to demonstrate that ERBB2-mutational driven therapy can improve patient care irrespective of histology.

A cross-sectional study of biotechnology awareness and teaching in European high schools.

Undoubtedly, biotechnology has a tremendous impact on our daily lives. As a result of this and in parallel to the advancement of knowledge in this field of applied research, consumer awareness of the potential benefits and risks of this technology has steadily increased, leading to a thorough investigation of the public perception of biotechnology in the past years. Indeed, it has become clear that it is in the general interest of science and especially of applied research to inform the public of its advances. A promising next step is to strengthen biotechnology communication in scholastic institutions. In this paper, we investigate the perception of biotechnology in a specific target group, namely high-school students in the 16-20-year-old age range. We conducted a questionnaire-based survey on a total of 1410 students in six European countries to investigate students' perception, concern, scientific knowledge, and awareness. Our data revealed some unexpected patterns of acceptance and concern about biotechnology. Knowledge analysis indicated that pupils lack specific knowledge about biotechnological applications and their interest in biotechnology appeared to be linked to knowledge. Analysis of specific questions about teaching practices at schools suggests that a better targeted choice in media as vehicles for information together with selected speakers could be instrumental in increasing students' interest in science and more specifically in biotechnology.