ERBB3 mutation

We identified MYC amplification and ERBB3 as possible predictors of disease metastases and recurrence. Additional research regarding targetable MYC and ERBB3 therapies are warranted.

This exploratory study comprehensively evaluated clinicopathological, genomic, and immune features and developed a novel prediction model, providing a rational basis for the selection of GC patients with PM for chemoimmunotherapy-involved conversion therapy.

In this report, we present two exceptional responses in hormone receptor-positive, HER2-nonamplified, HER2/HER3 co-mutated metastatic breast cancer patients who were treated with the anti-HER2-directed monoclonal antibodies, trastuzumab and pertuzumab. Both patients acheived exceptional responses to treatment, suggesting that combined trastuzumab, pertuzumab, and endocrine therapy could be a highly effective therapy for these patients and our observations could help prioritize trastuzumab deruxtecan as an early therapeutic choice for patients whose cancers have activating mutations in HER2.

In conclusion, HER2-low ILCs exhibit their own particularities, both on clinical-pathological and molecular levels. Our findings call for larger multicenter validation studies.

In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors.

ERBB3 progenitors could generate both ER and ER cells, potentially serving as cells-of-origin for ER-positive or triple-negative cancers. Short-term treatment with an mTORC1 inhibitor substantially curtailed tumorigenesis in a preclinical model of BRCA2-deficient breast cancer, thus uncovering a potential prevention strategy for BRCA2 mutation carriers.

Although EGFR-mutation testing is increasingly being implemented in the early-stage setting in line with national recommendations, some patients are still not being tested for molecular markers as part of their diagnostic workup-a prerequisite for providing equal access to effective targeted treatments, such as EGFR-TKIs, to eligible patients.

In this article, we review the approach to tissue acquisition and consideration for molecular testing. Common molecular targets of interest in ampullary cancer are also discussed in this review, including HER2/ERBB2, HER3, tumor mutational burden, microsatellite instability, KRAS, and germline BRCA and ATM mutations, along with emerging and rarer alterations.

P2, N=29, Recruiting, National Cancer Institute (NCI) | Initiation date: Jan 2024 --> Apr 2024

Osimertinib, a third-generation tyrosine kinase inhibitor, is approved as first-line therapy for advanced NSCLC and in the adjuvant setting for Stage IB-IIIA resected NSCLC...Trastuzumab deruxtecan has received accelerated FDA approval in HER2-mutated NSCLC. ADCs offer a possible solution to finding a new treatment that could bypass the intracellular resistance mechanism. In this review article, we summarize the mechanism of ADCs and investigational ADCs for EGFR-mutated NSCLC, which include targets to MET amplification, HER3, Trop2, and EGFR, along with other ADC targets being investigated in NSCLC, and discuss future directions that may arise with ADCs in EGFR-mutated NSCLC.

HERTHENA-Lung02 is the first phase III trial to evaluate the safety and efficacy of HER3-DXd versus PBC in patients with progression on a third-generation EGFR TKI. Clinical Trial Registration: NCT05338970 (clinicaltrials.gov); 2021-005879-40 (EudraCT Number).

OncoUrine test after initial TURBT for NMIBC showed promise as to guide patient selection for Re-TURBT and risk stratification in the management of NMIBC. Clinical trial information: NCT05112523.

Arginine Vasopressin Deficiency (AVP-D) was diagnosed, and desmopressin was initiated...While it is effective in adults, its limited tolerance favors the use of cytarabine or cladribine. NCT02670707 is an ongoing trial comparing cytarabine monotherapy versus Vinblastine/Prednisone for frontline treatment. BRAF inhibitors are also being increasingly investigated. Prospective trials to optimize the duration of therapy (LCH-IV) and potential combination therapies are currently underway.

In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.

P1, N=68, Recruiting, Hummingbird Bioscience | Phase classification: P1b --> P1

Here we describe the clinical and genomic characteristics of a large cohort of ERBB2/3-mut breast cancers. We identify a notable enrichment of ERBB2/3-mut in lobular histology and metastatic tumors and tendency for co-alteration with CDH1 and multiple transcription factors reflecting the unique biology of ERBB2/3-mut breast cancers. Further analyses on an expanded cohort (n >6000 pts), including outcomes on HER2-directed antibody-drug conjugates (T-DXd) and targeted therapies such as PI3K inhibitors, will be presented at the 2023 SABCS Annual Meeting.

This analysis showed moderate discrepancy in subtype call of BrM by tissue preparation (frozen vs. FFPE), with LumB classification showing the highest discrepancy, and more commonly called in FFPE tissues. Subtype concordance between ECT and BrM was relatively high.

The immune cell-mediated elimination of clones expressing the acquired resistance mutations is predicted to prolong endocrine control of ER+BC, in an analogous manner to small molecule or monoclonal antibody targeted therapies, but with a more favorable dosing and adverse event profile due to precise immunologic targeting and no DDI. RBI-1000 is anticipated to enter clinical studies in the first half of 2024.

Adjuvant treatment was aromatase inhibitor (AI) +/- ovarian function suppression (OFS) in 288 (46%) pts, while 159 (25%) had tamoxifen only (+/- OFS)... AURORA study sheds light on metastatic tumor alterations acquired under anti-cancer therapy, in ER+/HER2- MBC. We observed a high prevalence of acquired ESR1mut prior to the initiation of first-line therapy, particularly in tumors exposed to adjuvant AI or with primary or secondary ET_resistance. The association of ESR1muts with poorer OS underscores the importance of implementing effective adjuvant ET strategies to prevent the emergence of these mutations.

Thus, the net outcome of the SOS response is a greater probability to evolve new mutations. Deeper understanding of the persister-to-resister transformation, along with the development of next-generation TKIs, EGFR-specific proteolysis targeting chimeras (PROTACs), as well as bispecific antibodies, will permit delaying the onset of relapses and prolonging survival of patients with EGFR lung cancer.

Conclusions The study provided the landscape of ERBB2 alterations in UC that may benefit from anti-HER2 agents. Consideration should be given to developing trials inclusive of patients with UC harboring ERBB2 alterations.

The study evaluates HMBD-001 in combination with standard of care chemotherapy in two cohorts: NRG1 fusions in PDAC (HMBD-001 + nab-paclitaxel + gemcitabine) and in NSCLC (HMBD-001 + docetaxel) and HMBD-001 monotherapy in two other cohorts: NRG1 fusions in other solid tumors and selected HER3 ECD mutations across solid tumors. The primary objectives are to determine the safety and tolerability of all combination regimens and to assess the preliminary anti-tumor activity in terms of objective response rate (ORR) by RECIST v1.1 for all regimens. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression free survival (PFS), overall survival (OS), and pharmacokinetic (PK) and immunogenicity profile analysis.

As expected, gemcitabine and cisplatin was the most commonly applied treatment in this setting (54.2%). In the second-line, either FOLFIRI or FOLFOX were usually applied (20.3% and 13.7%, respectively)... Our analysis shows that patients with BTC who were able to undergo multiple treatment lines had an improved overall survival. Further, in the real-world setting, more alternative treatment regimens complement the recommended therapy lines due to participation in clinical trials or patient fitness and comorbidities.

These results, taken together, demonstrate that Pin1 inhibitor API-1 significantly improves the sensitivity of BRAF-mutant thyroid cancer cells to PLX4032. Thus, this study not only determines the potential antitumor activity of Pin1 inhibitor API-1 in thyroid cancer but also offers an alternative therapeutic strategy for BRAF-mutant thyroid cancers by a combination of Pin1 inhibitor and BRAF kinase inhibitor.

After tumor progression with EGFR TKI therapy and PBC in patients with EGFR-mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR-mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).

A recent REGONIVO trial showed that regorafenib plus nivolumab had an encouraging efficacy in MSS metastatic CRC (mCRC). Regorafenib in combination with PD-1 inhibitor provides a feasible treatment regimen for refractory MSS mCRC with tolerated toxicity. Patients with ERBB2/ERBB3 mutation may be the preferred population for this combination regimen.

Genomic testing might be useful in guiding the decisions regarding adjuvant treatment in BTC.

Mutations of ErbB3's kinase domain did not affect its localization but was responsible for cell viability in CRPC cells. Taken together, we conclude that AR expression regulated ErbB3 expression, its transcriptional activity suppressed ErbB3 nuclear translocation, and HRG binding to ErbB3 promoted it.

However, among the other three discordant cases harboring the mutations reportable by the ODxTT, only one patient had a clinical response with short duration. Among the discordant cases for common EGFR mutations between the ODxTT and the conventional single gene test, there are a certain number of suitable patients responsive to EGFR-TKIs, especially when the cause of the discordant results comes from the difference in the range of detectable variants that are reportable between the tests.

Bile mutations are the same found in tissue samples of CCAs (KRAS, TP53, ERBB3, GNAS, FBXW7, ERB2, IDH2, MAPK2K1 and FGFR3). In clinical suspected malignant strictures, diagnosed as benign or indeterminate, assessment for bile mutations could determine the clinical follow up and is a strong indicator for repeating cytology or biopsy in order to avoid a false negative diagnosis.

HCC CK19+/CK7+ targeted therapy might benefit from a CTNNB1, TP53, ALK, EGFR, MAP2K2, RET, PTEN, and IDH2 panel, standardized for PLC spectrum. This knowledge would allow better understanding the clinical course and PLC heterogeneity, together with improving tumor classification and treatment.

The benefit of N+F+T for HR+ HER2-mutant MBC after progression on CDK4/6 inhibitors is clinically meaningful and, based on this study, N+F+T has been included in National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

In this study we distinguish a shorter TTFT in males vs females, but males also have more advanced disease at diagnosis (stage, B2M) and sex is not a significant predictor of TTFT in MV analysis. Among significant factors identified in MV analysis, small sex differences were found in del11q (p = 0.028) and SF3B1 (p = 0.038), with higher prevalence in males.

P1b, N=54, Recruiting, Hummingbird Bioscience | Not yet recruiting --> Recruiting

HERTHENA-Lung01 is a global, registrational, phase II trial further evaluating HER3-DXd in previously treated advanced EGFR-mutated NSCLC. Clinical Trial Registration: NCT04619004 (ClinicalTrials.gov); 2020-000730-17 (EudraCT).

Conclusions APC mut., MYC, and GATA6 amp. may have negative clinical impacts on the effects of the new combination therapy including T-mab and N-mab.

Recruitment was hampered by a lack of systematic agnostic NGS sequencing and the COVID epidemic. Broader and more systematic agnostic NGS would enable further exploration of HER inhibition in solid tumors

a CR + PR. b 11 pts with CR only had nontarget lesions

Molecular profiling of liquid biopsies at baseline identified alterations that could impact on patient outcomes. Our data suggest that the presence of BRAF pathogenic variants may be a good prognostic factor in stage IV NSCLC patients treated with immunotherapy or chemo-immunotherapy, while pathogenic mutations in ERBB3 could be a biomarker of high risk of disease progression. Additional studies analyzing larger cohorts of patients are needed to clarify these hypotheses.

Fam-trastuzumab-deruxtecan-nxki (T-DXd) is approved for NSCLC with activating ERBB2 mutations...One patient with an ERBB2 transmembrane domain mutation (V659E) achieved a partial response with trastuzumab-emtansine (T-DM1)... Activating ERBB2/ERBB3 alterations can be identified by tissue or plasma next-generation sequencing. Alterations in both genes are more frequently observed in non-squamous NSCLC. Most ERBB2 activating mutations are in the kinase domain and most ERBB3 activating mutations are found in the extracellular domain.

This study found that HER3 membrane was expressed in 98% of NSCLC tumors across all included genomic subtypes. HER3 expression was seen in patients regardless of prior treatment with systemic anticancer therapy. The observation that HER3 membrane is broadly expressed in NSCLC confirms results of previous studies indicating that targeting this cell surface protein might be broadly applicable to patients with diverse subtypes of NSCLC.