TEST:

nCounter® Breast Cancer 360™ Panel

P2; Trial completion date: Nov 2024 --> May 2024 | Trial primary completion date: Dec 2023 --> Apr 2024

P=N/A; GEX of AR adds prognostic information for MBC. Our descriptive analyses illuminate the biological differences between MBCs in relation to outcome and metastatic site.

We are the first study to profile immune microenvironment using both transcriptomic and IHC methods. Our study is also unique in using NPBC and BC>2Y patients as control groups for PABC patients. CD8+ T cells are statistically higher in PABC patients than in NPBC patients using either transcriptomic profiling or multiplex IHC analysis.

Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and showed anti-tumor activity in patients with advanced TNBC. Gene expression analysis of patient tumor samples suggest that TNBCs with greater activation of immune checkpoint pathways and those with proteins dependent on HSP90 activity, including p53 and HER2, may be more susceptible to HSP90 inhibition.ClinicalTrials.gov study identification: NCT02474173

IL20RA and SOX10 represent potential biomarkers for TNBC risk that may serve as a stratification tool for NHB women. The results of this study have the potential to improve assessment and management of TNBC risk among NHB women, thereby contributing significantly to reducing health disparities in breast cancer outcomes.

Our findings reveal significant parallels between ARLI and PPI. Future research will assess how LIFR/pSTAT3 signaling is linked to induction of apoptotic markers in perimenopausal women and will investigate how anomalies in the LIFR/pSTAT3 pathway might contribute to heightened breast cancer risk in women with delayed or incomplete ARLI. This study not only sheds light on the complex biological processes of aging in breast tissue but also opens new avenues for breast cancer risk assessment and prevention strategies.

pILCs are morphologically distinct from cILCs, with higher histologic grade and higher average TILs. Genes more highly expressed in pILCs, including IDO1, GRB7 and CXCL9, have been associated with immune suppression and therapeutic resistance. These alterations are of interest as predictive markers and as potential targets for therapeutic intervention.

pILCs are morphologically distinct from cILCs, with higher histologic grade and higher average TILs. Genes more highly expressed in pILCs, including IDO1, GRB7 and CXCL9, have been associated with immune suppression and therapeutic resistance. These alterations are of interest as predictive markers and as potential targets for therapeutic intervention.

Breast cancers classified as basal-like by PAM50 comprise a histologically heterogeneous group of tumors. Tumors with infiltrating borders are much more likely to be associated with LVI and lymph node metastasis compared with pushing border tumors. Genes more highly expressed in tumors with infiltrative borders include a number of potential therapeutic targets, suggesting unique therapeutic strategies.

Findings from this study show a dynamic range of binding partners for aCT1, many of which regulate gene expression and RNA biology. nCounter analysis shows that a number of pathways are significantly impacted by aCT1, including upregulation of apoptotic factors, leading to the prediction and demonstration that aCT1 can boost the cell death effects of cisplatin and lapatinib in HER2+ breast cancer cells that have become resistant to HER2-targeted agents.

This exploratory analysis of the Neoadjuvant Carboplatin in Triple Negative Breast Cancer (NACATRINE) study aimed to identify the biomarkers of pathological complete response (pCR) in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC) within the context of a clinical trial...We successfully identified gene expression signatures associated with pCR in pretreatment samples of patients with TNBC treated with NAC. Further investigation of these biomarkers is warranted.

Estrogen signaling may therefore serve as a surrogate to AR signaling during progression and in hormone-refractory disease, particularly in prostate cancer patients with stromal-rich tumors. Collectively, the use of agnostic biomarkers developed for breast cancer stratification has facilitated a precise clinical classification of patients undergoing radical prostatectomy and highlighted the therapeutic potential of targeting estrogen signaling in prostate cancer.

In this trastuzumab-treated early HER2-positive breast cancer cohort, we observed four subgroups with different biological pathway enrichment patterns. The subgroup with the combination of low stromal and low immune biological pathway enrichment was associated with a poorer prognosis than those mainly enriched with either stromal or immune pathways. This study shows the diversity of biological signatures within HER2-positive breast cancer, and results could potentially be used in future studies of HER2 target treatments.

These results illuminate the biological differences between mBC in relation to outcome and metastatic site. Better understanding of the mBC GEX subtypes may open new venues for tailored treatment.

Gene expression data determined using the nCounter BC360 panel was available at baseline from two patient cohorts: 1) the CORALLEEN phase II trial which evaluated neoadjuvant ribociclib plus letrozole vs multi-agent chemotherapy in postmenopausal patients with luminal B by PAM50, HR+/HER2- early BC (Prat et al. A mechanistic model was developed, trained on cell line data, and then used to predict treatment outcome of patients with HR+/HER2-/PAM50 Luminal B BC treated with CDK4/6i plus ET. This approach showed significant association with observed outcome and could be used to assign patients to different response groups, indicating the usefulness of the model as a potential marker for response.

The KENDO trial further supports CDK4/6i+ET use in aggressive CT-naïve HR+/HER2- MBC. Biomarkers of immune activation such as IF tumors, higher TILs and presence of TLS pointed towards better survival outcomes. Genomic immunological features also showed prognostic effect, with differences according to treatment arm and/or the immune process or cell line tracked.

Our study shows that PABC is potentially a clinical and molecular different entity with predominance of the basal-like subtype. Moreover, our results suggest the activation of oncogenic pathways related to cell proliferation, DNA damage repair and p53 mutations which may lead to a clinically more aggressive phenotype for PABC patients. Likewise, the enrichment of BRCAness and HRD signatures found in PABC patients in our study may suggest an increased genetic instability due to a breakdown in the DNA damage repair.

Methods 756 pts who received de-escalated NAT were analyzed: trastuzumab + pertuzumab (T + P, n=92) and T + P + paclitaxel (pac, n=42) in ADAPT-HR-/HER2+ (NCT01817452); trastuzumab emtansine (T-DM1, n=118), T-DM1 + endocrine therapy (ET, n=125), and T + ET (n=129) in ADAPT-HR+/HER2+ (NCT01779206), T + P + pac (n=107) and T + P + ET (n=100) in TP-II (NCT03272477); and T + P + pembrolizumab (n=43) in Keyriched-1 (NCT03988036) in HER2-enriched (HER2-E) subtype by PAM50. In one-third of patients (with mainly stage I cancer, higher HER2 expression by immunohistochemistry and gene expression analysis, and low cellularity at 3 weeks), pCR can be achieved without systemic CTx. Identified biomarkers could pave the way for developing new patient selection strategies to spare CTx-associated acute and late toxicities in a clinically meaningful number of patients.

While TP53 mutation was generally a predictor of poor response; in HER2-E it paradoxically was associated with a good early response to aromatase inhibitor which warrants further investigation. Ki67 levels in ER+HER2+ showed higher intratumoral heterogeneity in a subset of patients on treatment suggesting the potential of persistent, proliferating cells leading to later recurrence. Our spatial RNA and protein data further observe the intratumoral heterogeneity that identifies pathways for use as potential spatial biomarkers.

Among patients with HER2-neg BC, gene-expression profiling is similar in ER-neg (i.e., < 1%) vs. ER-low tumors with a high prevalence of PAM50 Basal-like tumors and few differentially expressed genes. In both ER-low and ER-int HER2-neg BCs, PAM50 Basal-like subtype is also associated with higher TIL levels.

Our findings demonstrate that gene expression patterns can predict the response to neoadjuvant TCHP chemotherapy in HER2+ BC. The functional characterization of 39 DEGs suggests that the tumor microenvironment, including adjacent immune cells, plays a significant role in modulating the response to neoadjuvant chemotherapy in HER2+ BC. Table 1.

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 .

Background Early metabolic change on FDG PET/CT was predictive of response to neoadjuvant trastuzumab/pertuzumab (HP) in TBCRC026, with high negative predictive value (NPV) suggesting a lack of decline in SULmax at cycle 1 day 15 (C1D15) best predicts those who will not achieve pathological complete response (pCR) with HP alone. Conclusions The composite HER2/PET biomarker had high prediction power for pCR, however was not superior to the prediction power of PET/CT alone. These data suggest clinical trials informed by early FDG PET/CT biomarkers warrant further evaluation to personalize breast cancer care.

Methods TACT2 was a phase 3, randomised trial testing adjuvant accelerated versus standard Epirubicin in early breast cancer...Table: 307P Comparing the goodness-of-fit of three mCox models using chi-square, brier score and integrated calibration index Conclusions We identified 4 eTNBC B-grp based on distinct biology which provided more accurate 5-year TTR prediction in addition to ClinPath than TNS. The association of the B-grp with survival for other treatments could be further evaluated.

The study has been conceived and will be conducted according to international and local agreements for ethical research. Ethical approval has been granted by two Ethics Committees in Chile.The results will be disseminated to scientific and lay audiences (publications in scientific journals and conferences, seminars and a website for plain language dissemination).

Our study reported unique characteristics between the four TNBC subgroups and showed the potential use of immune checkpoint and PARP inhibitors in subsets of Thai TNBC patients. Our findings warrant further clinical investigation to validate TNBC's sensitivity to these regimens.

ConclusionImmune function plays a key role in CDK4/6i treatment efficacy. Elevated inflammatory profiles within the tumor but also in the peripheric immune system are associated to limited CDK4/6i clinical efficacy, providing new tools for the clinical management of CDK4/6i treatment.

Our study suggests a key role of tumor immunity in resistance to CDK4/6i, with an additional association of macrophages with worse outcome. The correlation of poor response to CDK4/6i with worse survival suggests its utility as a surrogate biomarker. Further investigation of the use of immunotherapeutic agents in this setting is deserved to improve CDK4/6i response.

Gene-expression profiling of matched primary BCs and BMs shows recurrent gene expression modifications in metastatic samples which might have potential therapeutic implications (e.g. acquisition of HER2-E subtyping and increase in ERBB2 mRNA levels). >

Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. Breast cancer diagnosed in very young women has aggressive disease biology. Prognostic and predictive analyses of both intrinsic subtypes and the ROR score are ongoing and will be presented at the meeting. Clinical trial information: NCT00066690.

All patients received trastuzumab + pertuzumab (T+P) q3w as neoadjuvant and adjuvant treatment. This hypothesis-generating translational results suggest that gene expression signatures (particularly ERBB2), baseline sTILs, and low tumor cellularity at week 3 predict pCR after ET + double HER2 blockade. Future neoadjuvant trials are needed to prospectively test the use of baseline gene expression and sTILs analysis, and early on-treatment cellularity measurement to select patients with HR+/HER2+ tumors for de-escalated endocrine-therapy-based approaches. Clinical trial information: NCT03272477.

Multigene expression assays have a prognostic and predictive potential in advanced EBC and further investigation is warranted in order to identify candidates for de-escalated treatment. In addition, intrinsic subtype and immune gene expression have predictive potential.

Conclusions Immune function plays a key role in tumor evolution and CDK4/6i efficacy. Further investigation of immune-tumor crosstalk and the role of immunotherapy in this setting is needed to improve CDK4/6i efficacy.

This exploratory analysis of the NACATRINE trial aimed to identify biomarkers that predict pCR TNBC patients receiving NAC.The NACATRINE trial is a Brazilian, phase II, single-center, randomized, open-label study that compared adding carboplatin to sequential neoadjuvant therapy based on anthracycline and taxane for TNBC...Overall survival (OS) was higher among patients who had downregulated KCNB1, FGF1, and SNAI1 (HR = 4.43, 95% CI 1.00 - 1.58; p=0.04; HR = 4.92, 95% CI 1.10 - 2.83; p= 0.03; HR = 4.86, 95% CI 1.38 - 1.11; p= 0.01) respectively. Similarly, upregulated of ALDH1A1, CXCL9 and FGL2 were associated with a better prognosis (HR = 0.17, 95% CI 0.05 - 0.50; p= 0.003; HR = 0.15, 95% CI 0.04 - 0.50; p = 0.004; HR = 0.21, 95% CI 0.07 - 0.60; p = 0.009), respectively.We identified potentially beneficial gene expression signatures (OS and pCR) for neoadjuvant chemotherapy, suggesting that these markers validated in a prospective study can be used in selecting patients for neoadjuvant chemotherapy in TNBC.

We presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs, which contributes to the understanding of the pathogenesis underlying morphologically distinct metaplasia in MpBCs.

BLIA and BLIS subtypes are distinguished histologically by the level of TILs but otherwise show similar morphologic features. In gene expression analysis, BLIS tumors showed higher expression of four genes (FOXC2, MAPT, BAMBI and HES1). Overexpression of these genes may be useful as clinical markers of the BLIS phenotype, especially in tumors with intermediate TILs, and may also serve as potential targets in this therapeutically challenging subtype of TNBC.

Distinct gene signatures were associated with pCR vs iDFS in HER2+/HR- EBC. The potential role of IR in preventing recurrence suggests that patients with up-regulated IR signatures could be candidates for de-escalation concepts in HER2+ EBC.

P2; Trial completion date: Jul 2023 --> Oct 2022 | Recruiting --> Terminated; Lack of effectiveness

P1; Recruiting --> Completed

Non-luminal intrinsic subtypes are extensively represented in resected BCBMs, even if clinically classified as HR+/HER2-. Our data suggest that basal-like genomic features might be enriched in BCBMs and might be associated with worse survival. Distribution of PAM50 intrisic subtyping on the 65 brain metastases evaluated according to hormone receptor (HR) and HER2 status

The PREDIX Luminal A phase II randomized clinical trial (NCT02592083) included patients with stage 2-3 BC and IHC-defined luminal A biology (ER+ and PR+, HER2-, low proliferation) treated with preoperative ET (tamoxifen or aromatase inhibitor) with or without the addition of CDK4/6i palbociclib, based on the early change of Ki67 levels. The findings of this small hypothesis-generating study indicate an upregulation of immune function during treatment with palbociclib and ET and an altered tumor microenvironment. The prognostic and potential therapeutic implications of sensitizing tumors to subsequent chemotherapy and immunotherapy need to be further investigated in larger studies.

Further characterization according to primary/metastatic and HR status is ongoing. Intrinsic subtype distribution across primary and metastatic breast tumors