BRCA2 mutation

4 pts received TT at recurrence, within clinical trials: one with grade 3 meningioma and ALK rearrangement treated with alectinib, one with PTCH1 mutant medulloblastoma treated with vismodegib, and two with high TMB treated with nivolumab/ipilumumab. The incidence of targettable molecular alterations in adult CNS tumor patients was lower than in GBM. Nevertheless, in a few selected cases TT have the potential to increase treatment options at recurrence and improve outcomes.

Our study provides an example of implementation of molecular profiling in an academic pre-screening program. Further analysis will investigate treatment matching rates, drug access schemes, and their impact on treatment efficacy and survival.

HRD genomic instability tests and multigene panel assessments serve as synergistic tools in EOC clinical settings, proving essential for identifying patients likely to benefit from PARPi therapy. These tools also enhance the detection of HRR and MMR gene variants, aiding in preventive care. Further investigations into the genetic profiles of HRD-negative tumors are crucial for advancing cancer risk management and developing novel therapeutic avenues.

Cisplatin-based chemotherapy is the recommended therapy for muscle-invasive bladder cancer (MIBC)...Patients with high levels of NETs predicted poor response to neoadjuvant chemotherapy. This study was the first to reveal the correlation between the level of NETs in MIBC and the efficacy of chemotherapy, which may provide a theoretical basis regarding NETs inhibitors.

Virtually all PSROC participants in the SOLO2/ENGOT-Ov21 experienced one or more AE whilst on placebo. Furthermore, study investigators attributed one quarter of AEs to be related to placebo therapy and dose alterations and treatment changes were made based on these AE. Further work is needed to improve measurement and categorization of AEs in trials of maintenance therapy in PSROC.

Additionally, we discuss current preventive measures for BRCA1/2 mutation carriers and targeted treatment options based on the concept of synthetic lethality. Finally, we explore the challenges of acquired therapy resistance and discuss potential alternative avenues for targeting BRCA1/2 mutant tumors.

The prevalence and spectrum of BRCAm in OC patients from Yunnan Province are different from those in other groups. BRCA status testing is advised for all OC patients, particularly those with a family history of HBOC.

Our study shows that GBC is potentially a clinically and molecularly different entity, with specific epidemiological, clinical, and histological features, as well as a distinctive altered immune state and genetic signature. Nevertheless, further studies are needed to better understand the biology of GBC and to identify new targets against which develop new, more effective, targeted therapies.

Despite the rarity of NTRK fusions in pancreatic cancer, larotrectinib and entrectinib have exhibited effectiveness in NTRK fusion-positive pancreatic cancers. Additionally, repotrectinib, a next-generation NTRK inhibitor, has shown promising activity in NTRK positive pancreatic cancer patients who have developed acquired resistance to previous NTRK inhibitors. Immune checkpoint inhibitors, such as pembrolizumab and dostarlimab, have proven to be effective in dMMR/MSI-H pancreatic cancers...It is crucial to continue implementing comprehensive screening strategies that encompass the ability to detect all these tumor-agnostic biomarkers. This will be essential in identifying pancreatic cancer patients who may benefit from these therapies.

This study provides insights into the effect of NACT on the tumor molecular landscape. While BRCA1/2 and HRD status remained stable, an increase in TIL proportion and changes in the mutational profiles were observed post-treatment.

These findings indicate that addressing both anxiety and depression in genetic counseling is crucial for enhancing mental and overall well-being. Interventions should focus on stress management to improve the quality of life, emphasizing depression treatment to enhance physical health outcomes.

Genomic profiling yields clinically actionable information for approved therapies and evidence of resistance, and it may uncover rational therapeutic opportunities regardless of tumor type.

Introduction: TALAPRO-2 (NCT03395197) demonstrated that first-line talazoparib + enzalutamide significantly improved radiographic progression-free survival versus placebo + enzalutamide for patients with metastatic castration-resistant prostate cancer (mCRPC). These results are supportive of the ability of F1LCDx to sensitively detect alterations in HRR genes, and the likely overall modest impact of CHiP in calling HRR gene alteration status in this study. These results support the complementary benefits of ctDNA testing to tumor tissue testing in assessing current disease alteration status, particularly AR.

We developed a novel method to determine genomic instability for characterizing the consequences of HRD using OCA Plus, which was developed using CGP of cancer FFPE samples to aid research into precision oncology. By combining genomic instability assessment with DNA repair pathway analysis such as mutations in BRCA1/2 and other genes in HRR pathway, OCA Plus will support research into the mechanisms underlying HRD.

The FDA (US Food and Drug Administration) has approved olaparib as a front-line maintenance therapy in combination with bevacizumab for patients with newly diagnosed advanced ovarian, fallopian tube, or primary peritoneal cancer with HRD+ status. We have demonstrated that the TSO500-HRD assay can accurately determine HRD status in ovarian tumors.

Using a 3D spheroid model from primary cells, we confirmed the 2D monoculture results and demonstrated not only increased caspase activity under the combined treatment but also a substantial gain in cytotoxicity compared to the mono-treatment. Our study proposes ADAM17 inhibition sensitizing ovarian cancer to olaparib treatment and improving treatment response.

P1, N=18, Recruiting, University of Washington | Trial primary completion date: Sep 2024 --> Dec 2025

P1/2, N=116, Recruiting, Cantargia AB | Trial primary completion date: Aug 2026 --> Jun 2025

Considering high incidence of breast cancer and lack of correlation of basal morphology with BRCA1/2 mutation, the molecular methods should be used for screening for BRCA1/2 mutations. This will not only help in familial screening but also in deciding targeted therapy with PARP (poly-ADP ribose polymerase) inhibitors.

P=N/A, N=1395, Recruiting, Beth Israel Deaconess Medical Center | N=500 --> 1395 | Trial completion date: Mar 2028 --> Dec 2032 | Trial primary completion date: Mar 2027 --> Dec 2032

Our results offer insights into the real-world application of CGP testing for patients with mCRPC at a cooperative hospital for cancer genomic medicine in Japan. Thus, urologists require a comprehensive understanding of the current status of CGP testing to enhance mCRPC management.

In this large hospital-based cohort of patients with very early-onset breast cancer, we found no clear evidence that gBRCA1/2m significantly affects OS after adjusting for known prognostic factors.

Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.

KRAS-mut represents a genotypically distinct group of ECs. Overlap exists with genomic predictors (TMB-high, MSI-high) of immunotherapy response, suggesting a possible biomarker-driven combination option with immunotherapy. Clinical trials to evaluate these strategies should be developed.

P=N/A, N=50, Active, not recruiting, Abramson Cancer Center at Penn Medicine | Recruiting --> Active, not recruiting

P1, N=18, Not yet recruiting, Emory University | Initiation date: Sep 2024 --> Dec 2024

The use of ICG was associated with an increase in the resection of samples with residual malignant foci. Overall, hypointense areas had a higher positive PPV for malignant foci in comparison with hyperintense ICG areas (46% vs 30%), which could be interpreted in the context of dynamic changes in the tumor microenvironment or enhanced permeability and retention effect following neoadjuvant chemotherapy.

We found that in cell lines, HRD was associated with sensitivity to PARP inhibition in breast cancer, but not at a pan-cancer level. By generating large-scale, pan-cancer datasets on HRD predictions in cell lines, we aim to facilitate efforts to improve our understanding of HRD and its utility as a biomarker.

Single-cell analyses confirmed deletion rate differences in gBRCA1/2 vs. non-carrier tumors as well as cells engineered to harbor gBRCA1/2 . The centrality of deletion-associated chromosomal instability to tumorigenesis shapes interpretation of the somatic evolution of non-malignant tissue and guides strategies for precision prevention and early detection.

Our study highlights generally low neovascular expression of PSMA in specific histopathological subtypes of breast cancer, which will likely hamper the development of an adequate theranostic strategy.

P2, N=50, Active, not recruiting, AstraZeneca | Trial primary completion date: May 2024 --> Nov 2024

In the case of the strong implication of BRCA PV/LPV with a negative result with one genetic test, different platforms could be considered in limited cases. Careful interpretation and further studies for the cross-validation of gene analysis platforms are needed.

P1, N=54, Active, not recruiting, Abramson Cancer Center at Penn Medicine | Phase classification: P1/2 --> P1 | Trial completion date: Apr 2024 --> Dec 2024 | Trial primary completion date: Apr 2024 --> Dec 2024

These results are crucial for characterizing candidates for AKT pathway-targeted molecular therapies and conceptualizing optimal treatment strategies. Clinical trial registration: This study is an observational study and is therefore not registered with the clinical trials registration.

There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool.

High fecal composition of Phascolarctobacterium was associated with prolonged PFS in patients with BRCA1/2mut-negative ovarian cancer receiving PARPi therapy. Our results would provide new insights for future research.

The risk of TNBC was 5.560 times higher in BRCA1/2 carriers than in non-carriers. There is a significant relationship between BRCA1/2 carrier and BC hormone receptor negativity, tumour grade, and BC diagnosis age.

P1, N=13, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

Among patients with advanced BTC, ctDNA-based genotyping showed acceptable concordance with tissue genomic profiling. Liquid biopsy using ctDNA could be a valuable complement to tissue-based genomic analysis in BTC.

P2, N=32, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Sep 2024 --> Sep 2025

Estrogen receptor one (ESR1) gene mutations, driving resistance to aromatase inhibitors (AIs), may guide the use of fulvestrant or emerging oral selective estrogen receptor degraders (SERDs) like elacestrant. Targeting mutations like breast cancer gene 1 and 2 (BRCA 1/2) with Poly (ADP-ribose) polymerase (PARP) inhibitors or the PI3K/AKT/mTOR pathway provides therapeutic options. The advent of antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) and novel agents targeting Trophoblast cell surface antigen-2 (Trop-2) introduces further complexity, underscoring the need for early intervention targeting specific genomic alterations in metastatic BC.

P2, N=136, Active, not recruiting, AGO Research GmbH | Recruiting --> Active, not recruiting