ER amplification

P3, N=96, Recruiting, UNICANCER | Not yet recruiting --> Recruiting

CGP detects a wide spectrum of mutations in ESR1, including missense and indel mutations and fusions. When LBx TF is < 1%, sensitivity for ESR1mut is reduced and repeat testing should be considered. ESR1mut can coexist with complementary or competing resistance mechanisms, particularly when ESR1 is a minor allele, which could impact benefit from novel ET approved for patients with ESR1 mutations.

P3, N=96, Not yet recruiting, UNICANCER | Initiation date: May 2023 --> Oct 2023

The efficacy of combination therapy with the PARP inhibitor olaparib and 17b-estradiol was analyzed in vitro and in vivo.Results and DiscussionsHigh ER levels converted the estrogen 17b-estradiol from a growth promoter to a growth suppressor, increasing R-loop formation, DNA damage, and apoptosis...ConclusionR-loop-induced DNA damage has the potential to be therapeutically leveraged in breast tumors expressing high ER levels through combination therapy with 17b-estradiol and inhibitors of the DNA damage response. Clinical testing of the combination of 17b-estradiol and a PARP inhibitor is warranted.

This study shows that pILCs show some degree of sTILs and PD-L1 expression; however, this was not associated with a survival improvement. Additional large trials are needed to understand immune infiltration in lobular cancer, especially in the pleomorphic subtype.

HER2-low breast cancers have significant genetic differences from HER2-positive cases. Genetic heterogeneity exists in HER2-low breast cancers and impacts on NAC response in this subgroup.

In this investigation, we first demonstrate clear matriptase activation following Fulvestrant (ICI) and Tykerb (Lapatinib) treatment in HER2-amplified, estrogen receptor (ER)-positive BT474, MDA-MB-361 and ZR-75-30 or single ER-positive MCF7 cells, respectively...We also demonstrate that matriptase activation is not a universal hallmark of stress, with Etoposide treated cells showing a larger degree of matriptase activation than Lapatinib and ICI-treated cells...Novelly, we demonstrate that endogenous and exogenous matriptase activation are ROS-mediated in vitro and inhibited by N-acetylcysteine (NAC). Lastly, we demonstrate matriptase-directed NAC treatment results in apoptosis of several breast cancer cell lines either alone or in combination with clinically used therapeutics. These data demonstrate the contribution of ROS-mediated survival, its independence of kinase-mediated survival, and the plausibility of using matriptase activation to indicate the potential success of antioxidant therapy.

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.

Larger tumors and nodal involvement were more likely to be found in patients with ER+/HER2- ILC with higher BMI which might be explained by a delayed diagnosis in these patients. Higher grade also seemed to be associated with higher BMI. In multivariable analyses, BMI was not found to be an independent prognostic factor.

We investigated the value of ESR1 amplification in predicting long-term outcome in tamoxifen-treated postmenopausal women with early breast cancer with and without nodal involvement... We suggest focal ESR1 amplification as predictor of improved long-term outcome in postmenopausal women with node-positive ER+ early breast cancer.

IHC ERα protein expression, evaluated by Allred score, correlated significantly with focal ESR1 amplification (P < 0.0001; χ2 test), but was not prognostic by itself. Focal ESR1 amplification is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received tamoxifen for 5 years.