ER-L

In conclusion, HR+/MP-H2 cancers closely resemble TN breast cancers in transcriptional and clinical features and benefit from similar treatment strategies.

HER2-low breast cancer, defined by low HER2 protein expression (IHC score of 1+ or 2+ without HER2 gene amplification), has achieved clinical significance, particularly following the DESTINY-Breast trials, which demonstrated the efficacy of trastuzumab deruxtecan (T-DXd) in the population of patients with advanced HER2-low disease...This review aims to consolidate current knowledge on HER2-low and ER-low breast cancers, focusing on the challenges associated with their identification, the implications for treatment, and future directions in clinical management. By examining recent studies and interlaboratory assessments, this review emphasizes the critical need for accurate and reproducible testing and reporting, and for the development of tailored therapeutic strategies for these "low" expression cancers.

Managing Li-Fraumeni syndrome (LFS) and its associated cancers, particularly in young patients, necessitates a comprehensive and multidisciplinary approach. Early genetic testing for TP53 mutations is crucial in identifying LFS, enabling personalized treatment plans and proactive surveillance strategies.

This would provide patients with ER-low tumors the same treatment opportunities as patients with TNBC, within studies and within clinical routine. This work was financially supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in accordance with terms and conditions of a Master Collaboration Agreement between the company and Karolinska Institutet.

ODX does not appear to add significant additional information to inform treatment decisions for most patients with ER-low BC. Incorporating weak ER staining intensity in addition to low percentage of nuclear positivity identifies about twice as many ER-low patients, although with reduced specificity for high RS. Our study supports the contention that most ER-low early BC should be regarded similarly to ER-negative BC.

This study provides a stratification based on the sexual differences in GBM, which associates the poor prognosis with the presence of immunosuppressive myeloid cells in the necrotic areas. This new stratification could change the current prognosis of GBM and identifies those who respond to BVZ treatment.

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Histological and nuclear grades, as well as the presence of a DCIS component, were associated with low ER-positive breast cancer. In contrast, the presence of tumor necrosis, as well as Grade 3 features and a high Ki-67 proliferation index indicated TNBC.

Most ER-low+/HER2- breast cancers are basal-like, with RS ≥26 suggesting these tumors are similar to triple-negative disease.

Including patients with ER-low-positive BC in clinical trials for triple-negative breast cancer (TNBC) might improve the understanding of this entity and allow novel therapeutic approaches. The design and conduction of randomized clinical trials regarding this subgroup of patients are greatly anticipated.

In summary, although the quantity of variants increased throughout HER2-positive breast cancer progression, the genomic composition remained largely consistent, thus yielding no new major processes beside those already operational in primary disease. Our results suggest that integrated genomic and transcriptomic analyses may be key in establishing therapeutic options.

Identification of optimal therapies for all subsets of breast cancer is necessary in the pursuit of personalized medicine. These results confirm that ERneg and ERlow tumors are pathologically and transcriptionally distinct from ERhigh tumors. Although subtle differences exists in the underlying biology of ERlow compared to ERneg tumors, similar therapeutic management excluding ET for patients with ERlow and ERneg disease is recommended in the Swedish context.

In this large cohort of women with ER low-positive breast cancers, adjuvant endocrine therapy was administered in the majority of cases, including those with PR >10% expression. Receiving adjuvant endocrine therapy was associated with better DFS, especially when HER2 expression was negative.

P=N/A, N=68, Active, not recruiting, Mayo Clinic | Trial completion date: Dec 2023 --> Dec 2024

Expression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2- premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR, ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors. Trial registration This trial was retrospectively registered in the ISRCTN database the 6th of December 2019, trial ID: https://clinicaltrials.gov/ct2/show/ISRCTN12474687 .

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This study suggests that the tumor features and clinical management of ER-low tumors vary significantly by PR expression. Within ER-low tumors, PR- tumors more closely resemble ER- BC, while PR+ tumors exhibit less aggressive characteristics. In ER-low disease selected for treatment with NAC, response is similar to ER- regardless of PR status.

Women with ER Low Positive tumours diagnosed in a time period when adjuvant therapy was available had tumours of smaller size, lower grade, and lower proliferative status, and similar prognosis to those with ER ≥ 10% compared to women diagnosed earlier.

Conclusions The HER2E subtype within ER+/HER2- disease is a small but clinically relevant patient subgroup that is not constituted by misclassified cases and is less ER dependent than other luminal subtypes. It does not represent a distinct biological entity, but it is nevertheless associated with potentially targetable molecular features, for instance in form of a high immune response and high FGFR4 expression.

Conclusions ER-low breast cancer has characteristics and prognosis similar to ER-negative breast cancer when treated as TNBC. The use of ≥10% as threshold for ER positivity is supported by this study.

Routinely diagnosed ER-low positive BC includes a proportion of ER-negative cases. We recommend repeat testing of BC showing 1-9% ER expression and using a cut-off ≥10% expression to define ER positivity to help better inform treatment decisions.

In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations.

ER-low positive/HER2-negative cases demonstrate a high rate of FOXC1 or SOX10 expression, and these cases might be better categorized as a basal-like phenotype/subtype. FOXC1 and SOX10 testing may be used for the intrinsic phenotype prediction for ER-low positive/HER2-negative patients.

We conclude that ER and PR expression may help predict response to NAT in HER2 and TN BC and should be taken into account in residual tumours. Also, changes observed in the phenotype after NAT suggest the need to reevaluate biomarkers in surviving residual tumour cells.

P=N/A, N=68, Active, not recruiting, Mayo Clinic | Trial completion date: Jun 2023 --> Dec 2023

These findings suggest that RNA analysis using NGS is an alternative to IHC and FISH. RNA provides continuous data that can determine cut-off points predicting response to therapy and should be explored in predicting ADC response.ERBB2 mRNA levels (FPKM) in various HER2 IHC groupsIHC ScoreValid NMeanMedianMinimumMaximumQuartile RangeStd.Dev.Zero1923124363537170110Zero vs one315115545253208104Zero to one vs one18397302172845365222One Vs two134954231591094273284Two vs three4752376499371385971835310

P=N/A, N=68, Active, not recruiting, Mayo Clinic | Trial completion date: Dec 2022 --> Jun 2023

Our study suggests that the tumor features and clinical management of ER-low tumors vary significantly by PR expression. Overall ER-low/PR- more closely resembles ER- BC, and ER-low/PR+ acts as an intermediate between ER- and ER+ disease. In ER-low disease selected for treatment with NAC, response is similar to ER- regardless of PR status.

Background : Recently, the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu, Daiichi Sankyo, Inc.) for patients with unresectable or metastatic HER2-low breast carcinoma (i.e., immunohistochemical (IHC) HER2 score of 1+ or 2+ with no high-level HER2 amplification by in situ hybridization using the 2018 American Society of Clinical Oncology and the College of American Pathologists testing guidelines) who have received prior chemotherapy in the metastatic setting or developed disease recurrence... IHC evaluation in HER2-low/ER+ versus HER2 0/ER+ breast carcinomas correlates with the HER2 RNA expression score by Oncotype DX. Given its association with lower Nottingham grade and lower Oncotype DX recurrence score, HER2-low/ER+ early-stage breast carcinoma could represent a less-aggressive variant.

Nevertheless, a proportion may retain some degree of ER signaling dependency, and the possibility of responding to some degree to endocrine therapy cannot be completely ruled out. This review article discusses the most important considerations regarding the definition of ER positivity, pathology assessment, prognosis, and therapeutic implication of ER breast cancer from the medical oncology perspective.

Background: NeoALTTO showed increased pathological complete response (pCR) with paclitaxel combined with dual over single anti-HER2 blockade. The trial included six initial weeks of treatment with lapatinib (L), trastuzumab (T) or their combination (L+T) followed by chemotherapy (CHT)... Biomarkers of early T-cell and monocyte-macrophage activation, as well as HER2 downregulation hold the potential to reliably identify patients likely to achieve a pCR and a favorable prognosis. New effective treatments need to be explored for cases lacking an early GEP response.

Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity.

For ER-low patients, findings suggest that ET with AI/T + AI may be a reasonable treatment alternative. This effect should be assessed in randomized studies.

Different immune features indicated a broad involvement of several immune cell types in PRs to AIs, suggesting that the immune system might be associated with resistance of ER+ breast tumors to AI treatment. Spatial gene expression profiling is ongoing to characterize these tumors further and investigate potential mechanisms of AI resistance.

The L391F mutation resulted in an increased binding affinity for Lasofoxifene (LAS) (dAff -0.34), Giredestrant (GIR) (dAff -0.18), Elacestrant (ELA) (dAff -0.08) and Amcenestrant (AMC) (dAff -0.41), while a decreased binding affinity was observed for 4OH-Tamoxifen (TAM) (dAff 0.01), Imlunestrant (IML) (dAff 0.15), Fulvestrant (FUL) (dAff 0.43), and Camizestrant (CAM) (dAff 0.02). The study suggests that genomic variability in drug targets detectable through ctDNA may modulate therapeutic response. Preclinical models are under development to investigate the combined endocrine resistance mechanism suggested by the significant co- occurrence between ESR1 mutations in SERDs/SERMs docking sites and ESR1 hotspot mutations and provide valuable additional insights for drug development and future treatment algorithms.

Despite lacking the transcriptional activity, ERα-LBD is found to promote breast cancer growth and resistance to the ERα antagonist fulvestrant...Intriguingly, ERα-LBD expression and function does not appear to be restricted to cancers that express full length ERα but also promotes growth of triple-negative breast cancers and ERα-LBD transcript (ESR1-LBD) is also present in BC samples from both ERα(+) and ERα(-) human tumors. These findings point to ERα-LBD as a potential mediator of breast cancer progression and therapy resistance.

Tumors with <20% ER expression were associated with worse outcomes. In our cohort, patients with BCs with ER expression levels <20% had poor clinical outcomes similar to those of patients with TNBC.

Patients with ER breast cancer have clinicopathological characteristics that differ from those with ER tumors. Although this study was limited by the small sample size of the ER group, no benefit from hormone therapy was observed in the ER group compared with the ER group.