GATA3 mutation

Our findings collectively provide unprecedented insights into the significance of age and ethnicity on the molecular and clinical characteristics of BC patients.

Adding the CDK4/6 inhibitor palbociclib enhanced the antitumor activity of EP0062 or fulvestrant in ESR1-mutant models but not in HER2-enriched or PTEN-mutant PDX models...EP0062 triggers an E2F1 downmodulation which mediates a potent antiproliferative activity. For EP0062-resistant tumors that remain ER-driven, the addition of palbociclib displays a potent antitumor effect.

Our study provides valuable insights into the understanding of age- and ethnic-driven molecular and clinical disparities in breast cancer patients. By unraveling the intricate relationship between genetic alterations and clinical outcomes, we underscore the potential for personalized treatment strategies in BC patients guided by molecular profiles. Nevertheless, further investigations are warranted to elucidate the underlying mechanisms that govern these dynamic processes.

Clinicopathologic features are prognostic beyond 10 years. Conversely, molecular features, such as copy number alterations, TP53 mutations and intrinsic subtype which have early prognostic significance, have little prognostic value after 10 years.

A monolayer of tumor cells with an inverted nuclear pattern, positive staining for GATA3, and KRAS mutation are essential for pathological diagnosis. Owing to its satisfactory prognosis, the surveillance and follow-up of patients with PRNRP should be additionally formulated.

We further show an increase in frameshifting rate at the premature termination sequence found in the HEXA gene of Tay-Sachs disease patients, or a breast cancer cell line that harbors a tumor-driving frameshift mutation in GATA3. Although the overall increase in frameshifting would need further improvement for clinical applications, our results underscore the potential of exogenous factors, such as Eu eRF1, to increase frameshifting in human cells.

In contrast, in HR-negative breast cancer, the HER2-low group displayed a higher frequency of PIK3CA mutations and PI3K pathway alterations. These findings offered valuable insights for the precise targeted treatment of HER2-low breast cancer in different HR statuses.

These clinicopathologic and genetic findings support SCAND as a tumor entity distinguishable from EMPSGC. In addition, the characteristic frameshift extension mutations in GATA3 contribute to the establishment of the tumor-type concept of SCAND.

T418Hfs*89) and amplification of FOXA1, genes not uncommonly altered in breast mucinous carcinomas. In this primary skin mucinous carcinoma, GATA3 and FOXA1 driver genetic events were identified, consistent with a possible developmental relationship between skin and breast mucinous neoplasms.

P2, N=1, Terminated, Institut Curie | N=48 --> 1 | Trial completion date: Dec 2026 --> Nov 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2025 --> Nov 2023; Financial partner providing study drug could no longer support the trial

P2, N=48, Active, not recruiting, Institut Curie | Recruiting --> Active, not recruiting

It also has clinical relevance in squamous cell carcinomas and soft tissue sarcomas. This paper reviews the structure and function of GATA3, its role in cancer and its use and pitfalls as an immunohistochemical marker.

As compared to CDH1-wildtype IDC-NSTs, NL-BCs less frequently harbored GATA3 mutations (0% vs 47%, p=0.03) but no significant differences were detected when compared to matched ILCs. NL-BCs with CDH1 bi-allelic genetic alterations are vanishingly rare, predominantly comprise IDCs with special histologic features, and have genomic features akin to luminal B ER-positive BCs.

In conclusion, mutations in CDH1 predicted resistance to paclitaxel and epirubicin. Our data suggest that CDH1 mutations should be explored further as a predictive biomarker for potential application.

Furthermore, TP53 mutations had significant prognostic importance in HER2-positive BC patients with HR-negative (HR=3.712, P=0.0266), pCR (HR=6.253, P=0.0268) and who received trastuzumab-only targeted therapy (HR=4.145, P=0.0105). Regard to diverse hormone receptor status or neoadjuvant efficacy, the genetic mutation maps of Chinese HER2+ patients receiving NAT are disparate. Our study found that TP53 mutations have significant prognostic value in patients with NAT for HER2-positive BC and patients benefit differently depending on HR status, neoadjuvant regimens and response.

Survival Curve Utilizing a curated Gene Set Developed by a Gradient-Boosting Multivariable Model (A) OS of platinum-based therapy treated KM with curated Gene set. (B) OS of platinum-based therapy treated MSK with curated Gene set.

P2, N=48, Recruiting, Institut Curie | Not yet recruiting --> Recruiting

This extensive study has revealed tumor burden, driver genes, co-occurrence, mutual exclusivity, and survival effects of mutations on a US Midwestern breast cancer cohort, paving the way for developing personalized therapeutic strategies.

P2, N=48, Not yet recruiting, Institut Curie

Using a deep-learning-based workflow, we developed models to predict the clinicopathological features, multi-omics features and prognosis of patients with HR/HER2 breast cancer using pathological WSIs. This work may contribute to efficient patient stratification to promote the personalized management of HR/HER2 breast cancer.

A subtype of GATA3 mutations are mutually exclusive with TP53 mutations and are associated with increased MDM2 amplification, making them an ideal target for clinical trials involving MDM2 inhibitors.

These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.

For monitoring tumor burden using ctDNA, our results suggest that truncal mutations are the best candidates, as they are highest in circulating levels. For confident tracking of subclonal mutations in ctDNA, liquid biopsies are not yet to substitute metastatic tissue biopsies and instead demonstrate support to the current gold standard.

TCF7L2, C11orf30 (EMSY), IRF2BP2, NFE2L2, EPC1 and FRK were highly expressed in preM cases with p values of 0.004, 0.008, 0.007, 0.019, 0.01 and 0.03, respectively. Together this data suggests that breast cancer in patients with no germline predisposition to cancer differ biologically in preM patients as compared to postM tumors and these differences should be considered in treatment and management plans of these patients.

Her most recent was creatinine 1.52 mg/dL and GFR 38 mL/min, uric acid 5.6 mg/dL adequately controlled with allopurinol 200 mg daily...This variant is absent on gnomAD database, which shows rarity of the mutation.Results GATA3 mutation is associated with hypoparathyroidism, sensorineural deafness and renal dysplasia (OMIM 146255). The exact prevalence of this disorder is not known but is very rare, with only about a dozen cases reported in the literature and one case reported on the American continent, which shows importance of genetic testing in kidney disorders.

ESR1 amplification and activating MAP3K mutations are potential drivers of acquired resistance to adjuvant ETs employing estrogen deprivation in HR+ HER2- BC. MAP3K mutations are associated with worse prognosis in patients with metastatic disease.

The SOFT clinical trial randomised 3066 premenopausal women with HR+ EBC to adjuvant endocrine therapy with tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS for 5 years...Younger women aged < 40 years (N=359) compared with women aged ≥ 40 years (N=917) had significantly higher frequencies of mutations in GATA3 (19% vs 16%) and CN amplifications (47% vs 26%), but significantly lower frequencies of mutations in PIK3CA (32% vs 47%), CDH1 (3% vs 9%), and MAP3K1 (7% vs 12%). Additionally, there were significantly higher frequencies of genomic features suggestive of HRD (27% vs 21%), and a higher proportion of younger patients with PIK3CA mutations with concurrent CN amplifications (23% vs 11%).

ESR1 mRNA and ER-associated gene expression is lower in ER positive cancers of younger compared to older patients, while immune infiltration is higher. The cytotoxic and endocrine effects of adjuvant chemotherapy could both contribute to the survival benefit seen in younger patients, but the relative contributions of these effects may vary by ER and immune phenotype. We hypothesize that in immune-high/ER-low cancers, the cytotoxic effect of chemotherapy may drive the benefit, whereas in immune-low/ER-intermediate cancers chemotherapy induced ovarian suppression may play a more important role.

Co- mutations in TP53 occurred at overall low MAF. Further research is needed to characterize the functional impact of these low level TP53 co-mutations and develop therapeutic strategies to target GATA3 mutant MBC.