MRE11A mutation

P2, N=20, Recruiting, Massachusetts General Hospital | Trial completion date: Dec 2026 --> Jun 2027 | Trial primary completion date: Dec 2024 --> Dec 2025

P2, N=37, Completed, Fudan University | Recruiting --> Completed

We clarified the patient's challenging diagnosis and discussed the clinicopathology, immunophenotype, differential diagnosis, and molecular genetic information regarding TFEB/6p21/VEGFA-amplified RCC via exome analysis and a literature review.

P1, N=30, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

P=N/A, N=880, Not yet recruiting, Assistance Publique - Hôpitaux de Paris | Trial completion date: Nov 2027 --> Jul 2029 | Trial primary completion date: Nov 2027 --> Jul 2029

P2, N=25, Completed, Se-Hoon Lee | Recruiting --> Completed | Trial primary completion date: Jun 2023 --> Oct 2023

P1, N=30, Suspended, National Cancer Institute (NCI) | Initiation date: Oct 2023 --> Jul 2023

After January 2022, the addition of standard of care abiraterone/prednisone was allowed after 7 months of study treatment at investigator discretion. Clinical trial information: NCT04126070.PD-L1 Combined Positive Score (CPS) ≥ 1 and/or CD T cell density ≥ 200. Homozygous deletions and/or deleterious mutations in a DDR gene, including and not limited to BRCA2, ATM, CHECK2, BRCA1, PALB2, RAD51D, ATR, NBN, PMS2, GEN1, MLH1, MSH2, MSH6, RAD51C, MRE11A, BRIP1, FAM175A, and CDK12.

60% patients with sBRCA and HRR mutations treated with platinum / PARPi as NACT, achieved partial to pathological complete response (pCR) while 5 cases treated with IO are on follow up. Conclusions CGP identified sBRCA and HRR mutations in wide spectrum of cancers enabling the utility of PARPi as maintenance therapy, hence necessitating sBRCA and HRR testing as standard of care besides germline testing for personalized therapy.

P1, N=30, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=30, Recruiting, National Cancer Institute (NCI) | Initiation date: Jul 2023 --> Oct 2023

P1, N=30, Recruiting, National Cancer Institute (NCI) | Initiation date: Apr 2023 --> Jul 2023

P1, N=30, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

A high rate of HR mutations was detected in ovarian, breast and prostate which is consistent with the PARPi approval in these tumor types. The presence of BRCA1/2 mutations was highly associated with increased LOH value whereas it did not correlate to other HR mutations. Additionally, the pancancer presence of HR gene alterations indicates that the use of such genes as biomarkers of platinum and PARPi treatments should be evaluated in a wider range of tumor types.

P1, N=30, Not yet recruiting, National Cancer Institute (NCI)

Chemotherapy was utilized in 43% of pts with HRRm vs 34% with HRRwt genes (P=0.40); docetaxel was the most common agent, utilized in 26% vs 27% of pts with HRRm vs HRRwt genes... In this rw study, genomic testing was performed frequently in later stages of metastatic disease. Pts with HRRm genes had numerically shorter rwPFS on 1L standard therapies compared with HRRwt pts. While unmet needs exist to optimize mCRPC txs and prolong disease progression irrespective of HRRm mutation status, further studies are warranted to further elucidate the prognostic role of HRRm and BRCA1/2 mutations on clinical outcomes.

In this study histological patterns were not predictive of HRD gene mutations. A marginal increase of neuroendocrine morphology and high-volume cribriform patterns were seen in BRCA1/2 and non- BRCA1/2 HRD mutated prostate carcinomas respectively. This data suggests that histopathologic examination alone is insufficient to distinguish BRCA1/2 and HRD gene mutated prostate cancers, further highlighting the importance of ancillary molecular diagnostics in therapy selection for those who may benefit from PARP inhibitors.

P2, N=28, Recruiting, Se-Hoon Lee | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Jun 2023

MRE11A:p.K464R may be a vital driving factor of Olaparib resistance, which patients who newly acquired MRE11A:p.K464R in post-treatment cfDNA had significantly shorter PFS than those without it. These findings provide potential noninvasive biomarkers for efficacy evaluation and resistance monitoring of Olaparib treatment, and lay the foundation for developing combination treatment after Olaparib resistance.

P2, N=37, Recruiting, Fudan University | Not yet recruiting --> Recruiting | Trial completion date: Apr 2022 --> Dec 2022 | Trial primary completion date: Feb 2022 --> Nov 2022

P=N/A, N=880, Not yet recruiting, Assistance Publique - Hôpitaux de Paris

P2; Active, not recruiting --> Completed

This study analyzed clinical and mutational characteristics of reversion mutations in HRR genes, which could occur as single or multiple variants to restore the function of predisposed pathogenic HRR mutations, resulting in resistance to platinum-based chemotherapies or PARP inhibitors. Monitoring these mutations with tissue or liquid biopsy samples are crucial for treatment guidance.

Mutations in DDR pathways or single DDR genes were associated with preferable ICB efficacy in specific cancers or subpopulations. Findings from our study would provide clues for tailing clinical trials and immunotherapy strategies.

P2, N=20, Recruiting, Massachusetts General Hospital | Not yet recruiting --> Recruiting

Gene enrichment analysis demonstrated that those genes were related to astrocyte differentiation. CONCLUSIONS In our study, CDK4/6 copy number variation was determined as a favorable overall survival biomarker for thalamic glioma, and CDK4/6 copy number variation associated mutant genes were related to astrocyte differentiation, which could be the potential therapeutic targets for thalamic glioma.

In this case-cohort analysis of 442 patients enrolled in the PENELOPE-B trial, the detection of BC predisposition genes was lower than expected with 10%. This is probably due to the low rate of g BRCA 1/2 carriers (3.4%), which could be influenced by the selection criteria of the trial. Patients with g BRCA 1/2 or other BC disposition genes had a comparable outcome to non-carriers in the PENELOPE-B trial.

P2, N=28, Recruiting, Se-Hoon Lee | Not yet recruiting --> Recruiting

P2, N=20, Not yet recruiting, Massachusetts General Hospital

Despite having their two-decade old candidacy as breast cancer genes close to being refuted, it has recently been reported that the MRN genes rise to have potential new roles in clonal hematopoiesis. In this article, we discuss the history and current status of MRN genes' clinical utility in breast cancer and then focus on their recently uncovered and less understood roles in clonal hematopoiesis that likely predispose to health-related disorders such as hematological malignancies and/or cardiovascular morbid events.

P2, N=28, Not yet recruiting, Keunchil Park

Background: The phase II trial WSG-ADAPT TN randomized triple-negative breast cancer (TNBC) patients to receive 12 weeks of neoadjuvant nab-paclitaxel (nab-pac) combined with carboplatin (carbo) vs gemcitabine (gem) and showed a substantial improvement of pathological complete response (pCR: ypT0/is, ypN0) with carbo (45.9% vs 28.7%) . Twelve weeks of neoadjuvant nab-pac/carbo is a highly effective anthracycline-free regimen that leads to an excellent pCR-rate of 64% in tumor BRCA1/2-mutated cases . BRCA1/2 mutation status could support this de-escalation strategy in early TNBC, but further prospective validation of survival impacts in larger cohorts and with longer follow up is needed . More detailed survival analyses will be presented at the meeting.

Moreover, by comparing the NMR data for this cancer-associated mutant with two previously described Mre11 separation-of-nuclease function mutants, a potential allosteric network was detected within Mre11 that connects the active site to regions responsible for recognizing the DNA ends and for dimerization. Together, our data further highlight the dynamics required for Mre11 nuclease function and illuminate the presence of allostery within the enzyme.

P2, N=30, Active, not recruiting, Massachusetts General Hospital | N=223 --> 30

The samples were analyzed by NGS with the OncoDEEP (OncoDNA) panel covering 313 genes.ResultsOnly one of the cases was not evaluable due to the low cellularity of the tumor block. Of the 12 evaluable cases, molecular alterations were identified in 6 of them, as detailed below: in case number 1 (lung cancer) variant of TP53 cDNA c.595G> T-AA p. G199, in case number 2 (lung cancer) mutation in TP53 cDNA c.488a> G-AAp.Y163C and mutation in FANCA cDNA: c.3263C> T-AA: p.S1088F, in case number 3 (lung cancer) variant de TP53 c.DNA: c.455del-Aap.P152Rfs * 18, alteration in MRE11A cDNA: c.1688C> G-AA: p.S563 * and alteration KEAP1 cDNAc.224dup-Aap.L76Afs * 3, in case number 4 (lung cancer) AKT amplification and alteration in BRCA2 cDNA c.2701del-Aap.A902Lfs * 2, in case number 5 (lung cancer) mutation in PI3KCA E545 K, amplification in MDM2 and mutation in TP53 cDNA c.871AA> T-AA p.K291 *, in case number 6 (bladder cancer) amplification of JAK1 and in case number 7 (head and neck cancer) mutation of PI3KCA E545, mutation of TPMT Y240C and mutation in TPMT A154 T.Conclusions This review presents as its objective the analysis of these molecular alterations and their impact on the prognosis, and therapeutic evolution of patients with the aim of integrating clinical and molecular information in a translational oncology study

P2, N=15, Completed, Samsung Medical Center | Recruiting --> Completed | N=28 --> 15 | Trial completion date: Sep 2021 --> Jan 2021 | Trial primary completion date: Sep 2021 --> Jan 2021

P2, N=223, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting

No mutation was identified in RAD51, MRE11A, FAM175A, XRCC2, or MLH3. The involvement of these genes in the hereditary predisposition to cancer cannot be ruled out, although if it exists it is rare or does not seem to involve truncating variants.

Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72-15.7). Stage IV (HR 2.5, 0.74-8.6) and low TMB (HR 2.3, 0.57-9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44-5.2).

Among patients with positive HRD scores, up to 51% were negative by %LOH and up to 63% were negative by the 11-gene panel. Only 3% of patients identified as positive by %LOH and 7% positive by the 11-gene panel were negative by HRD score. Conclusions/Implications: These data show that HR deficiency tests used in clinical trials are not equivalent and should not be considered interchangeable in predicting PARP inhibitor response in clinical practice.

P2, N=50, Not yet recruiting, Fudan University

Our study revealed that HR-DDR mutations occurred in 38.1% of Chinese breast cancer patients, and BRCA2 was the most commonly mutated gene. HR-DDR mutations were associated with a higher TMB value, indicating a potential strategy for immunotherapy in Chinese breast cancer patients. The role of HRD-directed therapies, including poly-ADP ribose polymerase inhibitors and newer agents such as ATR inhibitors, needs to be explored.