Human Epidermal Growth Factor Research Articles

Population Pharmacokinetic Analysis of Tucatinib in Healthy Participants and Patients with Breast Cancer or Colorectal Cancer.

Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers. A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks. A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics. The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model. NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192.

Immune modulation and epigenetic therapies for enhanced outcome of treatment in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor expression. While traditional TNBC treatment primarily relies on systemic chemotherapy, epigenetic modification has an important role in immune evasion and tumor progression. Recent classifications of TNBC into “hot” and “cold” tumors, based on immune activity and mutation burden, have revealed that poor response to immune checkpoint inhibitors (ICIs) in these tumors is due to low tumor-infiltrating lymphocytes and the presence of immunosuppressive cells. Emerging treatments such as ICIs and poly(ADP-ribose) polymerase inhibitors offer promising alternatives. The tumor microenvironment (TME) shapes immune responses in TNBC, and a limited subset of patients has shown encouraging responses to ICIs in treating TNBC at both early and advanced stages. However, combination therapies face challenges, including medication interactions and side effects. Epigenetic modulators, such as histone deacetylase and DNA methyltransferase inhibitors, also show promise in reversing epigenetic changes by enhancing anti-tumor immunity in TNBC. The frequent expression of indoleamine 2,3-dioxygenase 1 (IDO1) in TNBC, which catalyzes the conversion of tryptophan to kynurenine, contributes to immune suppression in TNBC patients. High IDO1 levels impair the tumoricidal activity of natural killer cells and correlate with poor responses to anti-PD-L1 therapy, which can be improved using IDO1 inhibitors. Targeting myeloid-derived suppressor cells, regulatory T-cells, and tumor-associated macrophage, along with utilizing epigenetic mechanisms, show promise in modulating the immunosuppressive TME in TNBC. Combining these approaches with standard therapies, along with biomarker-guided patient selection, can enhance treatment efficacy. Clinical trials and preclinical models are essential for optimizing these strategies. This study emphasizes the importance of understanding the mechanisms of modulation, tumor-immune interactions, and the potential of epigenetic therapies in improving treatment outcomes in TNBC.

The epidemiology, treatments and outcomes of patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive early breast cancer in Taiwan.

Aim: Estimate patient counts, treatment patterns and outcomes of a subset of patients with early breast cancer (EBC) presenting with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive features, who are at high-risk of recurrence, in Taiwan.Materials & methods: Data from Taiwan's National Health Insurance Research Database and Taiwan Cancer Registry from 1 January 2011 to31 December 2020 were analyzed.Results: There were 4500 patients with high-risk EBC (10.4% of all patients with EBC) from 2012 to 2018, with an annual average incidence of 643 that increased over time. Five-year progression was 24.8% in patients with high-risk EBC and 8-year survival was low (69.6%).Conclusion: Patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive high-risk EBC clinical features are an increasing high-risk subset of all patients with EBC.

Deep-learning based discrimination of pathologic complete response using MRI in HER2-positive and triple-negative breast cancer

Distinguishing between pathologic complete response and residual cancer after neoadjuvant chemotherapy (NAC) is crucial for treatment decisions, but the current imaging methods face challenges. To address this, we developed deep-learning models using post-NAC dynamic contrast-enhanced MRI and clinical data. A total of 852 women with human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer were randomly divided into a training set (n = 724) and a validation set (n = 128). A 3D convolutional neural network model was trained on the training set and validated independently. The main models were developed using cropped MRI images, but models using uncropped whole images were also explored. The delayed-phase model demonstrated superior performance compared to the early-phase model (area under the receiver operating characteristic curve [AUC] = 0.74 vs. 0.69, P = 0.013) and the combined model integrating multiple dynamic phases and clinical data (AUC = 0.74 vs. 0.70, P = 0.022). Deep-learning models using uncropped whole images exhibited inferior performance, with AUCs ranging from 0.45 to 0.54. Further refinement and external validation are necessary for enhanced accuracy.

Apolipoproteins have a major role in cellular tumor dormancy in triple negative breast cancer: In-silico study

Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptors and has a poor prognosis as it is resistant to chemotherapy. A new treatment option for this type of cancer may be by putting these malignant cells into dormancy. The oocyte’s embryonic milieu presents a unique tumor reversion microenvironment by inducing growth arrest and changing cells’ phenotypes. We conducted an in-silico study to determine the most likely oocyte extract (OE) proteins involved in inducing dormancy using HDock, CluPro, and molecular dynamic (MD) simulation. Results showed low energy scores for complexes between OE proteins and four surface markers: K1C14, CLD3, CLD4, and ITA6. Apolipoprotein A1 (APOA1) and Apolipoprotein C3 (APOC3) showed the highest stability and affinity with these four surface markers: K1C14, CLD3, CLD4, and ITA6. These proteins are involved in key tumor-related pathways such as angiogenesis, proliferation, apoptosis, and migration. This will pave the way for exploring novel therapeutic options to induce dormancy in TNBC cells.

Preliminary investigation of MMP8 (rs11225395) and MMP9 (rs3787268) polymorphisms association with breast cancer risk in pashtun women of Pakistan.

Single Nucleotide polymorphisms (SNPs) in MMP8 and MMP9 have been widely associated with breast cancer risk in different ethnicities with inconsistent results. There is no such study conducted so far in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. Therefore, this study was conducted to check MMP8 (rs11225395) and MMP9 (rs3787268) polymorphism with breast cancer risk in the selected population. This study, consisting of 300 breast cancer patients and 168 gender and age-matched healthy controls was subjected to confirm MMP8 and MMP9 polymorphisms. Clinicopathological data and blood samples were taken from all the participants. DNA was extracted and SNPs were confirmed using the T-ARMS-PCR protocol. Based on our study results, significant associations were observed between the MMP8 rs11225395 risk allele (G) and increased breast cancer risk, with the G allele frequency higher in patients (65%) compared to controls (51%) (OR = 1.752, 95% CI = 1.423-3.662, p = 0.002). Genotypes GG (OR = 4.218, p = 0.005) and AG (OR = 7.286, p = 0.0001) of MMP8 rs11225395 were also significantly associated with elevated breast cancer risk. Similarly, MMP9 rs3787268 exhibited a higher frequency of the risk allele (A) in breast cancer cases (81%) compared to controls (41%), correlating strongly with increased risk (OR = 6.320, p = 0.0001). Genotypes AA (OR = 14.500, p = 0.0001) and AG (OR = 2.429, p = 0.077) of MMP9 rs3787268 containing the risk allele showed significant associations with heightened breast cancer risk. Subgroup analyses based on age, disease progression, tumor size, and grade revealed noteworthy associations for both MMP8 rs11225395 and MMP9 rs3787268. MMP8 rs11225395 genotypes displayed significant correlations with age (p = 0.066), disease progression (p = 0.0001), larger tumor size (p = 0.005), and higher tumor grade (p = 0.006). Similarly, MMP9 rs3787268 genotypes were significantly associated with age (p = 0.001), disease progression (p = 0.010), larger tumor size (p = 0.018), and higher tumor grade (p = 0.037). Logistic regression analyses further underscored these genetic variants' potential role as biomarkers in breast cancer, particularly in relation to specific hormone receptor statuses such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) positivity. The results revealed significant associations between the mutant alleles and genotypes of MMP8 (rs11225395) and MMP9 (rs3787268) with increased breast cancer risk in the Pashtun population of Khyber Pakhtunkhwa, Pakistan. However, more investigation will be required on large data sets to confirm the selected SNPs and other SNPs in the selected and other related genes with the risk of breast cancer.

Updates in Systemic Treatment of Hormone Receptor-Positive Early-Stage Breast Cancer.

Hormone-receptor positive (HR +) and human epidermal growth factor receptor 2 (HER2) negative early breast cancer (eBC) is a heterogeneous disease with several contributing factors for increased risk of recurrence, including tumor features, individual biomarkers, and genomic risk. The current standard approach in the management of HR + /HER2neg eBC includes chemotherapy and endocrine therapy (ET), and additional therapies based on risk profile, menopausal status, and genetics are sometimes appropriate. The risk of recurrence is more pronounced in patients with high-risk eBC including large tumor size, nodal involvement, high proliferative index, and genetic predisposition. In premenopausal patients with high-risk eBC, ovarian function suppression in combination with adjuvant ET improves survival. In postmenopausal patients, extended aromatase inhibitor (AI) therapy can be considered. Recent trials have identified novel treatment approaches to reduce the risk of recurrence in high-risk HR + /HER2neg eBC including the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to adjuvant ET. For patients with germline BRCA1/BRCA2 mutations, adjuvant poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have been shown to improve overall survival (OS). However, despite these recent advances, the risk of recurrence remains substantial, highlighting an area of unmet need. There are several ongoing clinical trials further investigating the role of CDK 4/6 inhibitors and immunotherapy in high-risk HR + /HER2neg eBC.

Evaluation of Treatment and Recurrence-Free Survival in Patients with Early HER2-Positive Breast Cancer: Real-Life Data Comparing Public and Private Healthcare

Abstract Introduction The present study was designed to compare the treatment provided in private and public health care facilities for women positive for early breast cancer of the human epidermal growth factor receptor 2 (HER2) subtype, who received anti-HER2 therapy in neoadjuvant or adjuvant settings, with an evaluation of the recurrence-free survival (RFS) and pathological complete response (pCR) rates. Materials and Methods The current is a retrospective study carried out at the Instituto Brasileiro de Controle do Cancer (IBCC Oncologia), in the city of São Paulo, Brazil. We included patients treated between 2015 and 2020. Results The study included 472 medical records of early HER2-positive breast cancer patients treated in the public and private health care systems who received neoadjuvant or adjuvant treatments. The pathological complete response (pCR) was related to a lower recurrence rate and a longer recurrence-free survival (RFS). The results showed no statistically significant difference between the public and private health care systems in terms of RFS. Discussion Although the public health care patients were diagnosed with more advanced diseases than the private health care patients, both presented similar survival rates. In spite of the small number of patients evaluated, the dual HER2 blockade did not improve the clinical outcomes. These findings should be confirmed through studies with a larger number of patients and a longer follow-up period.

Secondary Transcriptomic Analysis of Triple-Negative Breast Cancer Reveals Reliable Universal and Subtype-Specific Mechanistic Markers.

Background/Objectives: Breast cancer is diagnosed in 2.3 million women each year and kills 685,000 (~30% of patients) worldwide. The prognosis for many breast cancer subtypes has improved due to treatments targeting the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In contrast, patients with triple-negative breast cancer (TNBC) tumors, which lack all three commonly targeted membrane markers, more frequently relapse and have lower survival rates due to a lack of tumor-selective TNBC treatments. We aim to investigate TNBC mechanistic markers that could be targeted for treatment. Methods: We performed a secondary TNBC analysis of 196 samples across 10 publicly available bulk RNA-sequencing studies to better understand the molecular mechanism(s) of disease and predict robust mechanistic markers that could be used to improve the mechanistic understanding of and diagnostic capabilities for TNBC. Results: Our analysis identified ~12,500 significant differentially expressed genes (FDR-adjusted p-value < 0.05), including KIF14 and ELMOD3, and two significantly modulated pathways. Additionally, our novel findings include highly accurate mechanistic markers identified using machine learning methods, including CIDEC (97.1% accuracy alone), CD300LG, ASPM, and RGS1 (98.9% combined accuracy), as well as TNBC subtype-differentiating mechanistic markers, including the targets PDE3B, CFD, IFNG, and ADM, which have associated therapeutics that can potentially be repurposed to improve treatment options. We then experimentally and computationally validated a subset of these findings. Conclusions: The results of our analyses can be used to better understand the mechanism(s) of disease and contribute to the development of improved diagnostics and/or treatments for TNBC.

A quality initiative in BRCA testing and timing of BRCA test prior to surgery in HER2- early stage breast cancer.

287 Background: The University of Pittsburgh Medical Center (UPMC) collaborated with Integra Connect PrecisionQ (IC) on a quality initiative to improve BRCA 1/2 (BRCA) testing in patients (pts) with early-stage (I-III) human epidermal growth factor receptor negative (HER2-) breast cancer (BC). The project involved developing a baseline of BRCA testing, reviewing the results with leadership, conducting a focus group with physicians to identify improvements, and then monitoring the results of BRCA testing thereafter during a post-baseline period. The project sought to improve the identification of pts who may be eligible for olaparib given the updated approval on March 11, 2022, for early-stage high-risk germline BRCA mutated pts. We aim to show the improvement in BRCA testing and timing of test in relation to surgery among HER2- BC pts at UPMC. Methods: Using the de-identified IC PrecisionQ database, 202 UPMC pts with early-stage HER2- BC were selected for medical chart curation as baseline group. Pts in the baseline group received surgery between 7/1/2021 to 6/30/2022. The baseline data was reviewed with UPMC clinical leadership and findings were discussed among a focus group of 8 physicians on 7/17/2023. Following the meeting, UPMC practices performed genetic testing at the office as opposed to sending pts to directly to genetic counseling. Post-baseline, we evaluated 70 pts who underwent surgery between 8/1/2023 to 1/31/2024 to assess BRCA rates and timing of BRCA testing in relation to surgery. Descriptive analyses were performed and proportions were compared using a chi-squared test. Results: Among the baseline cohort of 202 pts, 72% were hormone receptor positive (HR+) and 28% were hormone receptor negative (HR-). Among the post-baseline cohort of 70 pts, 77% were HR+ and 23% were HR-. The rate of BRCA testing at baseline was 44% compared to 56% post-baseline (p 0.05). Among HR+ pts, BRCA testing increased from 38% to 50% and among HR- pts, BRCA testing increased from 67% to 81%. The rate of BRCA testing prior to surgery at baseline was 58% (N= 88) compared to 80% (N=40) post-baseline (p &lt;0.01). Among HR+ pts age &lt;65, BRCA testing at baseline was 46% (N=54) compared to 51% (N=35) post-baseline. Among HR- pts age &lt;65 BRCA testing at baseline was 84% (N=25) compared to 100% (N=9) post-baseline. Conclusions: The quality initiative at UPMC that focused on BRCA testing among HER2- BC pts led to an improvement from 44% to 56% of pts being tested. Among those who were tested, there was an increase from 58% to 80% tested prior to surgery. Given the recent updates on January 4 th , 2024 by ASCO and SSO recommending BRCA1/2 testing to all women younger than age 65 with breast cancer, such QIs can be a useful tool to align a practice’s approach to new standards of care.

Real-World Clinical Outcomes With Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG) is approved for the treatment of metastatic triple-negative breast cancer (mTNBC). We report the real-world clinical effectiveness and toxicity data of SG in patients with mTNBC. A multi-institution retrospective study of patients with mTNBC treated with SG from January 2021 to May 2023 was conducted. Demographic and clinicopathologic variables were collected. Univariate and multivariate Cox regression models were used for survival analysis. A total of 115 patients were included. The median age at SG initiation was 60 years (range, 31-85). All patients were female; 73 (63.5%) were White and 31 (27.0%) were Black. The median number of previous therapies in the metastatic setting was two (range, 0-8). Sixty-one (56.0%) patients had primary refractory disease. Median relative dose intensity was 92% (range, 33%-100%). Grade 3 or higher adverse events (AEs) were seen in 50.9% of patients, which included neutropenia (35.7%), anemia (27.0%), vomiting (16.5%), fatigue (8.7%), and diarrhea (7.0%). Dose reductions and treatment discontinuation due to AEs were required in 51.3% and 13.2%, respectively. The objective response rate (ORR) was 27.8%. Median overall survival was 9.6 months (95% CI, 7.8 to 12.9) and median progression-free survival (PFS) was 4.8 months (95% CI, 3.6 to 5.9). In patients with human epidermal growth factor receptor 2 (HER2)-low mTNBC who received trastuzumab deruxtecan (T-DXd) after SG, the ORR to T-DXd was 34.8% and median PFS was 7 months (95% CI, 4.6 to 10.1). In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

The Systemic Immune-Inflammation Index is a Predictor of Chemotherapy Sensitivity and Disease-Free Survival in Patients With Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer

BackgroundThe relationship between the systemic immune-inflammation index (SII), chemotherapy sensitivity, and prognosis in HR+HER2– breast cancer (BC) has not been extensively studied. Patients and methodsClinical data from 980 patients diagnosed with HR+HER2– BC between June 2012 and June 2016 were collected. Patients were divided into low- and high-SII groups according to median SII value. Differences among variables were assessed using the chi-squared test. The inverse probability of treatment weighting (IPTW) method was used to control bias. The associations between clinicopathological factors, baseline SII, and disease-free survival (DFS) were analyzed using Kaplan–Meier curves and Cox analyses. ResultsThe median follow-up period was 37 months (5-77). 480 patients underwent neoadjuvant chemotherapy, and low baseline SII values were associated with higher pathological complete response (pCR) rates than those in the high SII group (16.4% vs. 9.2%; P = .019). Multivariate analyses revealed that larger tumor size, more lymph node involvement, high Ki-67 score, and high baseline SII were independent prognostic factors for worse outcomes in patients with HR+HER2– BC. The risk for metastasis/recurrence was higher in the high SII group compared with that in the low SII group (hazard ratio 2.07 [95% CI, 1.35-3.19]; P = .001). After IPTW, a similar result was obtained, in that a high SII value was significantly associated with worse DFS among patients with HR+HER2– BC. ConclusionA low baseline SII was associated with higher pCR rates after neoadjuvant chemotherapy and was an independent prognostic factor for better DFS outcomes in patients with HR+HER2– BC.

Unveiling the Clinical Path of Microinvasive Breast Cancer: A Comparative Study With Tis-T1 Breast Cancer.

The prognosis of microinvasive breast cancer (MIBC) is controversial, with a high reported rate of local recurrence (LR). This study aimed to evaluate the characteristics, treatments, and prognosis of patients with MIBC compared to those with carcinoma insitu (CIS) or early invasive cancer. Patients who diagnosed with CIS or stage I breast cancer were retrospectively enrolled. Using the Kaplan-Meier method, local recurrence-free survival (LRFS), systemic recurrence-free survival (SRFS), and cancer-specific survival (CSS) were compared according to T stage. The prognostic factors associated with LRFS were identified using the Cox proportional hazards model. According to T stage, 517 (21.6%), 200 (8.4%), 207 (8.7%), 363 (15.2%), and 1101 (46.1%) patients had Tis, T1mi, T1a, T1b, and T1c tumors, respectively. The proportion of human epidermal growth factor receptor 2-positive tumors was significantly higher in patients with MIBC (p < 0.0001). The administered adjuvant treatments also showed differences according to T stage (p < 0.0001). During the 73-month median follow-up period, patients with MIBC showed significantly worse LRFS than those with T1a or T1c tumors (p = 0.002). There was no significant difference in SRFS and CSS. In the Cox regression analysis, tumor multiplicity (p = 0.017), Ki-67 (p = 0.025), cancer subtype (p = 0.034), adjuvant endocrine therapy (p = 0.003), and adjuvant radiation therapy (p < 0.0001) were significant prognostic factors associated with LRFS. The risk of LR was higher in patients with MIBC than in those with small invasive breast cancer. Therefore, if indicated, adjuvant endocrine and radiation therapies should be administered to prevent undertreatment in patients with MIBC.

Ferroptosis - a potential feature underlying neratinib-induced colonic epithelial injury.

Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) that irreversibly binds to human epidermal growth factor receptors 1, 2 and 4 (HER1/2/4), is an approved extended adjuvant therapy for patients with HER2-amplified or -overexpressed (HER2-positive) breast cancers. Patients receiving neratinib may experience mild-to-severe symptoms of gut toxicity including abdominal pain and diarrhoea. Despite being a highly prevalent complication in gut health, the biological processes underlying neratinib-induced gut injury, especially in the colon, remains unclear. Real-time quantitative polymerase chain reaction (RT-qPCR) and histology were integrated to study the effect of, and type of cell death induced by neratinib on colonic tissues collected from female Albino Wistar rats dosed with neratinib (50mg/kg) daily for 28 days. Additionally, previously published bulk RNA-sequencing and CRISPR-screening datasets on human glioblastoma SF268 cell line and glioblastoma T895 xenograft, and mouse TBCP1 breast cancer cell line were leveraged to elucidate potential mechanisms of neratinib-induced cell death. The severity of colonic epithelial injury, especially degeneration of surface lining colonocytes and infiltration of immune cells, was more pronounced in the distal colon than the proximal colon. Sequencing showed that apoptotic gene signature was enriched in neratinib-treated SF268 cells while ferroptotic gene signature was enriched in neratinib-treated TBCP1 cells and T895 xenograft. However, we found that ferroptosis, but less likely apoptosis, was a potential histopathological feature underlying colonic injury in rats treated with neratinib. Ferroptosis is a potential feature of neratinib-induced colonic injury and that targeting molecular machinery governing neratinib-induced ferroptosis may represent an attractive therapeutic approach to ameliorate symptoms of gut toxicity.

Retracted: MicroRNA-495 Confers Increased Sensitivity to Chemotherapeutic Agents in Gastric Cancer via the Mammalian Target of Rapamycin (mTOR) Signaling Pathway by Interacting with Human Epidermal Growth Factor Receptor 2 (ERBB2).

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Na Li, Mei Han, Ning Zhou, Yong Tang, Xu-Shan Tang. MicroRNA-495 Confers Increased Sensitivity to Chemotherapeutic Agents in Gastric Cancer via the Mammalian Target of Rapamycin (mTOR) Signaling Pathway by Interacting with Human Epidermal Growth Factor Receptor 2 (ERBB2). Med Sci Monit, 2018; 24: CLR5990-5972. DOI: 10.12659/MSM.909458.

Comprehensive Genomic Assessment of Advanced-Stage GI Stromal Tumors Using the Japanese National Center for Cancer Genomics and Advanced Therapeutics Database.

Clinical utility of comprehensive genomic profiling (CGP) for precision medicine has become evident. Although there are several reports on the genomic landscape of GI stromal tumors (GISTs), large-scale data specific to GIST are limited, especially in Asia. Additionally, the applicability of molecular-targeted agents identified using CGP has not been extensively examined. We investigated the status of genomic alterations in Japanese patients with advanced GISTs using the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database to identify novel treatment strategies and drug development. We retrospectively reviewed the clinical and CGP data of patients with advanced-stage GIST registered in the C-CAT database to assess the genomic landscape and potential actionable alterations. Data from 144 patients were reviewed. Oncogenic alterations were detected frequently in KIT (78%), CDKN2A (37%), CDKN2B (29%), RB1 (11%), STK11 (10%), TP53 (9%), PDGFRA (6%), and SDHB (6%). Loss of CDKN2A/CDKN2B was only observed in KIT/PDGFRA-mutated GISTs, while alterations in SDHA/SDHB were only detected in KIT/PDGFRA wild-type GISTs. Among 119 KIT/PDGFRA-mutated GISTs, 95 (80%) had oncogenic genomic alterations and 29 (24%) had actionable alterations, excluding KIT and PDGFRA. However, among 25 KIT/PDGFRA wild-type GISTs, 22 (88%) had oncogenic alterations and 11 (44%) had actionable alterations. Representative candidate drugs for genome-matched therapies in KIT/PDGFRA-mutated and wild-type GISTs were as follows: pembrolizumab for tumor mutation burden-high in one and two patients, respectively; poly-adenosine diphosphate ribose polymerase inhibitors for alterations related to homologous recombination deficiency in 12 and one patient, respectively; NTRK inhibitor for ETV6-NTRK3 fusion in one with KIT/PDGFRA wild-type GIST; and human epidermal growth factor receptor 2-antibody-drug conjugate in one with KIT/PDGFRA-mutated GIST. This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.

Treatment patterns and clinical outcomes in HER2-low metastatic breast cancer, 2018–2023: A retrospective observational study.

398 Background: Current treatment options for patients (pts) with hormone receptor–positive (HR+) human epidermal growth factor receptor 2–low (HER2-low) (immunohistochemistry [IHC] 1+, IHC 2+/in situ hybridization–negative) metastatic breast cancer (mBC) who progress after endocrine therapy (ET) with or without targeted therapy, including CDK4/6 inhibitors (CDK4/6i) or inhibitors of the PIK3CA/AKT/mTOR pathway, have been limited to chemotherapy (CT).In this study, we assessed recent treatment patterns and clinical outcomes in US pts with HR+/HER2-low mBC. Methods: This was a retrospective observational study using the nationwide Flatiron Health electronic health record-derived de-identified database. Pts aged ≥18 years with no prior cancer (excluding non-melanoma skin cancer), de-novo or recurrent HR+/HER2-low mBC diagnosed between January 2018 and December 2022, and who received any line of treatment (LOT) for mBC (excluding clinical trials) were included. Demographic and clinical characteristics were captured prior to and at the index date (date of mBC diagnosis). Pts were followed up from index date to death, last activity date, or end of the study (September 30, 2023). Real-world overall survival (rwOS) from mBC diagnosis and real-world progression-free survival (rwPFS) from the start of each LOT was calculated using the Kaplan-Meier method. Results: A total of 2692 pts were eligible. Median follow up from mBC diagnosis was 38.3 months (interquartile range [IQR] 24.4, 53.4) and median age at mBC diagnosis was 65.0 years (IQR 56.0, 73.0); 45.3% of pts had de-novo mBC. Median LOT was 2.0 (IQR 1.0, 3.0) up to the end of the study (55.1% of pts received second-line [2L], 28.9% third-line [3L], 15.2% fourth-line [4L], and 7.2% fifth-line [5L] therapy). Serial ET cycles accounted for 65.7% of 2L, 45.2% of 3L, 27.9% of 4L, and 18.5% of 5L therapy. The most common drug categories by LOT are shown in the Table. Median rwOS was 43.0 months (95% confidence interval [CI] 40.0, 46.0). rwPFS was 20.5 months (95% CI 19.0, 22.3) in first-line [1L] therapy, 15.6 months (95% CI 14.0, 18.9) in 2L, 17.1 months (95% CI 13.5, 22.8) in 3L, and 13.4 months (95% CI 9.9, not estimable) in 4L. Conclusions: Treatment of HR+/HER2-low mBC has been heterogenous by LOT and mainly characterized by initial use of ET-based therapy followed by higher CT use in later lines. This is associated with diminishing effectiveness, highlighting a need for new treatments. Top five drug categories by LOT, n (%). 1L (n=2692) 2L (n=1484) 3L (n=778) 4L (n=408) 5L (n=195) ET + CDK4/6i 1537 (57.1) 694 (46.8) 217 (27.9) 76 (18.6) 25 (12.8) Endocrine monotherapy 684 (25.4) 202 (13.6) 126 (16.2) 52 (12.8) 21 (10.8) ET + mTORi 9* 61 (4.1) 55 (7.1) 25 (6.1) 17 (8.7) ET + CT 50 (1.9) 74 (5.0) 45 (5.8) 29 (7.1) 22 (11.3) CT alone 269 (10.0) 270 (18.2) 210 (27.0) 161 (39.5) 82 (42.1) CDK4/6i alone 69 (2.6) 29* 8* 3* 3* *Not a top five drug category in the specified LOT.

Utilization and patient characteristics for the trastuzumab reference and biosimilars, and other human epidermal growth factor receptor 2 inhibitors in the United States.

Trastuzumab is an antihuman epidermal growth factor receptor 2 monoclonal antibody used to treat breast and other cancers. Trastuzumab biosimilars were approved in the United States beginning in 2017. Utilization information on these biosimilars is limited. To examine utilization patterns and characteristics of patients treated with trastuzumab (biosimilars and reference) and other human epidermal growth factor receptor 2 products. We evaluated health care claims data from the Biologics and Biosimilars Collective Intelligence Consortium distributed research network, representing a large, geographically diverse US population of commercially insured individuals. We queried 4 distributed research network health plan partners to capture product usage data and patient information from October 1, 2016, to October 31, 2022. Patients were required to be continuously enrolled in their health plan for at least 365 days before their first observed trastuzumab utilization date in this study period. Data were aggregated across data partners. More than 16 million eligible health plan members representing more than 31 million person-years of data were evaluated. We identified 5,984 incident treatment episodes; 3,878 (64.8%) episodes were with the reference trastuzumab. The mean ages were consistent across trastuzumab products (60.2 to 65.1 years) and at least 80% of the episodes were among female patients. The mean comorbidity index score was 1.2 (SD = 1.9) among users of the reference vs the biosimilars (range 1.2-2.5). Other clinical characteristics (eg, diabetes, hypertension) were comparable across products. The proportion of total incident episodes of the reference trastuzumab decreased substantially over time (96% in 2016 vs 28% in 2021) as utilization of the biosimilars increased (eg, use of trastuzumab-anns increased from 2% [2019] to 36% [2021]). Similar utilization trends were seen among patients with and without metastatic breast cancer. Trastuzumab biosimilars utilization has grown since their introduction to the US market. Exploration of these biosimilars' comparative effectiveness and safety to their reference product is warranted.

Clinical and Genomic Characterization of ERBB2-Altered Gallbladder Cancer: Exploring Differences Between an American and a Chilean Cohort.

Gallbladder cancer (GBC) is a biliary tract malignancy characterized by its high lethality. Although the incidence of GBC is low in most countries, specific areas such as Chile display a high incidence. Our collaborative study sought to compare clinical and molecular features of GBC cohorts from Chile and the United States with a focus on ERBB2 alterations. Patients were accrued at Memorial Sloan Kettering Cancer Center (MSK) or the Pontificia Universidad Católica de Chile (PUC). Clinical information was retrieved from medical records. Genomic analysis was performed by the next-generation sequencing platform MSK-Integrated Mutation Profiling of Actionable Cancer Targets. A total of 260 patients with GBC were included, 237 from MSK and 23 from PUC. There were no significant differences in the clinical characteristics between the patients identified at MSK and at PUC except in terms of lithiasis prevalence which was significantly higher in the PUC cohort (85% v 44%; P = .0003). The prevalence of ERBB2 alterations was comparable between the two cohorts (15% v 9%; P = .42). Overall, ERBB2 alterations were present in 14% of patients (8% with ERBB2 amplification, 4% ERBB2 mutation, 1.5% concurrent amplification and mutation, and 0.4% ERBB2 fusion). Notably, patients with GBC that harbored ERBB2 alterations had better overall survival (OS) versus their ERBB2-wild type counterparts (22.3 months v 11.8 months; P = .024). The prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2-targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.

Implementation of Choosing Wisely guidelines: Omission of lymph node surgery

ObjectivesIn 2016, the Choosing Wisely campaign published guidelines recommending omission of sentinel lymph node biopsy in clinically node-negative women ≥70 years with early-stage (cT1-2), hormone receptor-positive, and human epidermal growth factor receptor 2–negative breast cancers. This study aimed to evaluate the implementation of this guideline. MethodsThe National Cancer Database was queried from 2017 to 2020. All patients who met criteria for lymph node surgery omission were included and compared with those who underwent lymph node surgery. ResultsOf 138,648 patients who met criteria for lymph node surgery omission, 26,070 (21.0%) had lymph node surgery omission and 109,482 (79.0%) underwent lymph node surgery. Those who had lymph node surgery omission were older (median 79 [75–84] vs 75 [72–79] years, P < .01) and had increased comorbidities (28.3% with Charlson/Deyo score ≥3 had lymph node surgery omission vs 20.2% with score 0, P < .01). Academic/research institutions most frequently practiced lymph node surgery omission (25.8% vs 16.5% community cancer programs, 19.3% comprehensive community cancer programs, and 20.6% integrated network cancer programs, P < .01). A greater percentage of lymph node surgery omission was noted with ductal carcinoma (21.4% vs 17.6% lobular and 19.4% mixed, P < .01) and lower-grade tumors (21.7% of grade 1 vs 19.4% of grade 2 and 17.8% of grade 3, P < .01). Throughout the period studied, the overall rate of lymph node surgery omission increased from 17.7% in 2017 to 23.1% in 2020 (P < .01). ConclusionDespite the evidence-based Choosing Wisely guideline recommending lymph node surgery omission in selected patients with breast cancer, more than 75% of patients meeting criteria were still being subjected to lymph node surgery as of 2020. Future work is warranted to determine factors affecting implementation of the Choosing Wisely guideline.