BRCA1 mutation

P2, N=30, Recruiting, Beijing Cancer Hospital; Beijing Cancer Hospital

Our comprehensive findings underscore the clinical significance of BRCA1/2 mutations in gastric cancer, advocating for further research to elucidate their mechanistic implications and therapeutic opportunities.

We conclude that low dose DNA methyltransferase inhibition can cooperate with low dose PARP inhibition to increase DNA damage predominantly in cells with HRR deficiencies, ultimately producing more cell death than in HRR proficient tumors. We predict that clinical benefit will more likely be apparent in patients with DNA repair defective tumors and are focusing clinical exploration of this drug combination in these patients, with the goals of enhancing tumor cell death at minimal toxicities.

The study highlights the importance of drug repurposing as a strategy for the safe and effective treatment of breast cancer. Synthetic inhibitors often cause severe side effects, emphasizing the need for novel targets and compounds with better therapeutic profiles. Molecular docking identified promising compounds from the ZINC database, suggesting potential new avenues for breast cancer therapy.

The early stage of the cancer is associated with a better prognosis. Complete pathological regression after systemic treatment, particularly in patients with BRCA1 mutation, is a good prognostic factor and can help diminish the range of surgery in the axilla region.

It is crucial for physicians and researchers to equip patients with the best information possible to proactively manage their health, whether it be for IDC prevention or treatment. Overall, our review provided a comprehensive understanding of IDC that enables patients to grasp the nature of the disease with the hope of mitigating IDC risk, decrease the anxiety of a cancer diagnosis, and encourage patients to become more involved in making informed decisions for their healthcare.

Evidence was reviewed from controlled clinical trials in which eribulin, vinorelbine, capecitabine, gemcitabine, gemcitabine plus carboplatin, fam-trastuzumab-deruxtecan, sacituzumab govitecan, olaparib, and talazoparib were used in the second-line treatment for metastatic breast cancer, either as study drugs or as comparators. Exploratory data for fam-trastuzumab-deruxtecan suggest a survival benefit in human epidermal growth factor receptor 2-low, hormone-receptor-negative patients, but further solid evidence is required. Other chemotherapies with lower European Society for Medical Oncology-Magnitude of Clinical Benefit Scale scores may continue to be useful in highly selected patients.

P2, N=23, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

P=N/A, N=200, Recruiting, Abramson Cancer Center at Penn Medicine | Trial completion date: May 2028 --> May 2030 | Trial primary completion date: May 2026 --> May 2028

This review provides a comprehensive overview of BRCA1/2 mutations testing in PC, focusing on the germline and somatic mutations frequencies and the technical approach for their identification. A revision of the main data reported in the literature regarding BRCA1/2 mutations identification will be presented, highlighting the critical issue for the detection both in formalin fixed paraffin embedded (FFPE) and blood samples.

We also highlight the potential of small molecules e.g. p53 activators like XI-011, Tenovin-1, and Nutlin-3a for the treatment of breast and ovarian cancers. The therapeutic efficacy of natural compounds in amelioration of these two types of cancers is also discussed.

While providing survival benefits to previously progressed mCRPC patients presenting deleterious BRCA1/2 gene mutations, PARP inhibitors are not cost-effective and require major price reductions to reach local WTP thresholds.

In patients with mCRPC, we did not find a statistical difference in anti-tumor activity after receiving platinum chemotherapy among patients harboring a pathogenic HRR alterations compared to patients without a HRR alteration. Additionally, we were unable to detect an association between BRCA1/2 mutation status and response to platinum chemotherapy. Platinum chemotherapy, however, had clinically meaningful activity in a subset of patients regardless of HRR alteration status. Additional studies are warranted using genomic data to predict sensitivity to platinum chemotherapy.

In a pre-selected population with HRD according to a genetic test, RAD51 testing identifies patients with different pCR rates under PARPi or platinum-based therapies. Future biomarker-driven studies should consider this information to refine stratification factors and to improve patient selection.

Next-generation sequencing and CRISPR-Cas9 represent significant breakthroughs in genomic tools that open new opportunities to explore MYC's role in TNBC and facilitate the development of personalized treatment plans. This review discusses the future clinical applications of personalized treatment strategies for patients with TNBC.

P2, N=123, Completed, Mario Negri Institute for Pharmacological Research | Unknown status --> Completed

P1, N=19, Active, not recruiting, Arsenal Biosciences, Inc. | N=60 --> 19

P=N/A, N=240, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting

P=N/A, N=3209, Not yet recruiting, Emory University

P=N/A, N=58, Active, not recruiting, Ohio State University Comprehensive Cancer Center | Recruiting --> Active, not recruiting | N=200 --> 58 | Trial completion date: Dec 2023 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2025

P1/2, N=257, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=384 --> 257 | Trial completion date: Dec 2025 --> Dec 2026

P=N/A, N=750, Recruiting, AstraZeneca | Trial completion date: Dec 2031 --> Mar 2033 | Trial primary completion date: Dec 2031 --> Mar 2033

P=N/A, N=26, Recruiting, City of Hope Medical Center | Trial completion date: Dec 2024 --> Jan 2026 | Trial primary completion date: Dec 2024 --> Jan 2026

P3, N=405, Completed, pharmaand GmbH | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Aug 2024

P1, N=10, Completed, Lynkcell Europe | Enrolling by invitation --> Completed | N=30 --> 10

The second patient, with MSI-H and low TMB, experienced significant tumor regression and improved quality of life with a prolonged progression-free survival, although the patient ultimately declined surgery. These cases suggest that combined chemotherapy and immunotherapy may offer a promising treatment option for select pancreatic cancer patients, particularly those with specific genetic profiles, warranting further investigation into personalized approaches to immunotherapy in this malignancy.

BRCA positivity was detected in 23.8% of the patients. A statistically significant association was shown between BRCA mutations and patient and family history.

We found that PARP inhibition increases radiosensitization independent of BRCA1 status for both protons and photons. The combination of protons and PARP inhibition was the most effective in decreasing clonogenic cell survival, increasing DNA damage, and delaying tumor growth.

Although actionable mutations were more frequent in KRASwt tumors, 13.2 % of KRASm PDAC harbored ESCAT alterations, emphasizing the importance of molecular profiling regardless of KRAS status.

P1/2, N=71, Recruiting, Yonsei University | Not yet recruiting --> Recruiting | Trial completion date: May 2023 --> May 2025 | Trial primary completion date: Dec 2022 --> Dec 2024

P=N/A, N=450, Active, not recruiting, Ipsen | Recruiting --> Active, not recruiting | Trial completion date: Mar 2026 --> Jun 2026 | Trial primary completion date: Mar 2026 --> Jun 2026

P1/2, N=490, Recruiting, AstraZeneca | Trial completion date: Jan 2026 --> Aug 2026 | Trial primary completion date: Jan 2026 --> Aug 2026

Despite fact, Cadherin-1(CDH1), Phosphatase and TENsin (PTEN), Partner and Localizer of BRCA2 (PALB2), serine/threonine kinase 11 (STK11), Checkpoint kinase 2 (CHEK2), and tumor protein 53 (TP53) genes have mutations, a BReast CAncer gene 1 (BRCA1) and BReast CAncer gene 2 (BRCA2) genes, documented to inherit significantly increase a chance of developing BRCA. Recognizing the functional importance of genetic mutations has created avenues to prevent breast cancer and is revealing promising therapeutic approaches.

Genomic markers for homologous recombination deficiency (HRD) are other potential drivers of response to PARPi/ARPI combination. Further investigation is needed to refine treatment strategies, including targeting non-HRR mutations, and to expand the role of this combination therapy in earlier stages of prostate cancer.

Combined first-line treatment with PARP inhibitors and NHT is effective and well-tolerated in mCRPC patients with HRR gene mutations, particularly those with BRCA1, BRCA2, or ATM mutations. These findings underscore the potential of this therapeutic combination in managing mCRPC in the Chinese population, suggesting a favorable outcome for those with specific genetic backgrounds.

This combination has recently been approved in the USA, Canada and Europe for patients with mCRPC and a BRCA1/2 gene mutation. This review summarizes the evidence with regards to the pharmacologic activity and clinical efficacy of niraparib with a specific focus on its efficacy in combination with AAP in mCRPC patients with HRR alterations.

Together, these findings demonstrate that regorafenib can attenuate DNA damage response and potentiate the efficacy of PARP inhibitors in PDAC tumors.

These findings highlight the potential for actionable alterations in most early-stage EOC patients and support the exploration of chemotherapy-free regimens for low- to intermediate-risk groups, as well as targeted maintenance therapy for high-risk individuals.

Moreover, the combination of olaparib and NSC-3852 rapidly upregulated γH2AX at 2 h after treatment, and induced S-phase arrest and apoptosis at 24 h after treatment, suggesting that this combination induced apoptosis through accumulation of massive DNA damage. Taken together, these findings demonstrate that NSC-3852 is a sensitizer of olaparib and suggest that the combination of NSC-3852 and olaparib may be a useful therapeutic strategy for homologous recombination-proficient cancers, including cancers with acquired resistance to olaparib and high-grade oral squamous cell carcinoma.

P2, N=67, Active, not recruiting, Tongji Hospital | Completed --> Active, not recruiting | Trial completion date: Jul 2024 --> Dec 2026

The study highlights the long-term risk of BC in HL survivors and suggests that advanced RT techniques and targeted therapies may help reduce the incidence of secondary tumors. Future research should focus on understanding the genetic and biological mechanisms behind treatment-induced cancers.

While LSD-1 itself does not directly cause mutations in BRCA1 or BRCA2 genes, its epigenetic influence sheds light on the potential role of LSD-1 inhibitors as a therapeutic approach in managing breast cancer, particularly in individuals with BRCA1/2 PVs. Targeting LSD-1 may help counteract its detrimental effects and provide a promising avenue for therapy in this specific subgroup of breast cancer.