EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI ...specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.
Abstract Insertion mutations in exon 20 of the epidermal growth factor receptor gene ( EGFR exon20ins) are rare, heterogeneous alterations observed in non-small cell lung cancer (NSCLC). With a few ...exceptions, they are associated with primary resistance to established EGFR tyrosine kinase inhibitors (TKIs). As patients carrying EGFR exon20ins may be eligible for treatment with novel therapeutics—the bispecific antibody amivantamab, the TKI mobocertinib, or potential future innovations—they need to be identified reliably in clinical practice for which quality-based routine genetic testing is crucial. Spearheaded by the German Quality Assurance Initiative Pathology two international proficiency tests were run, assessing the performance of 104 participating institutes detecting EGFR exon20ins in tissue and/or plasma samples. EGFR exon20ins were most reliably identified using next-generation sequencing (NGS). Interestingly, success rates of institutes using commercially available mutation-/allele-specific quantitative (q)PCR were below 30% for tissue samples and 0% for plasma samples. Most of these mutation-/allele-specific (q)PCR assays are not designed to detect the whole spectrum of EGFR exon20ins mutations leading to false negative results. These data suggest that NGS is a suitable method to detect EGFR exon20ins in various types of patient samples and is superior to the detection spectrum of commercially available assays.
No international consensus regarding the resection of the para-aortic lymph node (PALN) station Ln16b1 during pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) has been reached. The ...present retrospectively investigated 264 patients with PDAC who underwent curative pancreatoduodenectomy or total pancreatectomy between 2005-2015. In 95 cases, the PALN were separately labelled and histopathologically analysed. Metastatic PALN (PALN+) were found in 14.7% (14/95). PALN+ stage was associated with increased regional lymph node metastasis. The median overall survival (OS) of patients with metastatic PALN and with non-metastatic PALN (PALN-) was 14.1 and 20.2 months, respectively. Five of the PALN+ patients (36%) survived >19 months. The OS of PALN+ and those staged pN1 PALN- was not significantly different (P = 0.743). Patients who underwent surgical exploration or palliative surgery (n = 194) had a lower median survival of 8.8 (95% confidence interval: 7.3-10.1) months. PALN status could not be reliably predicted by preoperative computed tomography. We concluded that the survival data of PALN+ cases is comparable with advanced pN+ stages; one-third of the patients may expect longer survival after radical resection. Therefore, routine refusal of curative resection in the case of PALN metastasis is not indicated.
KRAS is the key mutated gene in pancreatic ductal adenocarcinoma (PDAC). Emerging evidence indicates that KRas modulates endocytic uptake. The present study aimed to explore the fate of early ...endosomal trafficking under the control of KRas expression in PDAC.
Surprisingly, PANC-1 cells lacking KRas exhibited significantly enlarged early and late endosomes containing internalized dextran and epidermal growth factor. Endosome enlargement was accompanied by reduced endosomal degradation. Both KRas silencing and lysosomal blockade caused an upregulation of the master regulator of early endosome biogenesis, RAB5A, which is likely responsible for the expansion of the early endosomal compartment, because simultaneous KRAS/RAB5A knockdown abolished endosome enlargement. In contrast, early endosome shrinkage was seen in MIA PaCa-2 cells despite RAB5A upregulation, indicating that distinct KRas-modulated responses operate in different metabolic subtypes of PDAC.
In conclusion, mutant KRAS promotes endosomal degradation in PDAC cell lines, which is impaired by KRAS silencing. Moreover, KRAS silencing activates RAB5A upregulation and drives PDAC subtype-dependent modulation of endosome trafficking.
•Mutant KRAS promotes endosomal degradation in PDAC cell lines.•The endocytic machinery is not identically regulated in different PDACs.•KRAS silencing activates RAB5A early endosome trafficking in subtypes of PDAC.•RAB5A overexpression in turn most likely enlarges the early endosome compartment.
The human epidermal growth factor receptor 2 (HER2) gene amplification status is a crucial marker for evaluating clinical therapies of breast or gastric cancer. We propose a deep learning-based ...pipeline for the detection, localization and classification of interphase nuclei depending on their HER2 gene amplification state in Fluorescence in situ hybridization (FISH) images. Our pipeline combines two RetinaNet-based object localization networks which are trained (1) to detect and classify interphase nuclei into distinct classes normal, low-grade and high-grade and (2) to detect and classify FISH signals into distinct classes HER2 or centromere of chromosome 17 (CEN17). By independently classifying each nucleus twice, the two-step pipeline provides both robustness and interpretability for the automated detection of the HER2 amplification status. The accuracy of our deep learning-based pipeline is on par with that of three pathologists and a set of 57 validation images containing several hundreds of nuclei are accurately classified. The automatic pipeline is a first step towards assisting pathologists in evaluating the HER2 status of tumors using FISH images, for analyzing FISH images in retrospective studies, and for optimizing the documentation of each tumor sample by automatically annotating and reporting of the HER2 gene amplification specificities.
Guidance regarding adjuvant treatment decisions in stage II colorectal cancer (CRC) remains uncertain due to lack of predictive clinical or molecular markers. Recently, postoperative circulating ...tumour (ct)DNA has been demonstrated to be a strong prognostic marker in early colon cancer.
CIRCULATE enrols patients with stage II microsatellite stable CRC in Germany (AIO) and Austria (ABCSG). Within the AIO, screening is supported by ColoPredict Plus 2.0, a molecular registry, and screening platform for interventional trials.
Patient-specific mutations are centrally analysed by next generation sequencing in the resected primary tumour. A postoperative plasma sample is subsequently screened for the specific mutation(s).
ctDNA positive (ctDNApos) patients are randomised (2:1) chemotherapy (capecitabine, oxaliplatin added an investigator's choice) or to follow-up (control group).
ctDNA negative (ctDNAneg) patients are randomised (1:4) to be followed-up within CIRCULATE (control group) or outside the trial. Patients in the control group remain blinded to the ctDNA results.
The primary objective is to compare disease free survival (DFS) of ctDNApos patients with chemotherapy or control. To demonstrate a treatment effect with a hazard ratio of 0.617 (3-year DFS rates 42.5% vs. 25%), 231 ctDNApos and estimated 2079 ctDNAneg patients are randomised.
Secondary aims include to compare overall survival and DFS in the ctDNApos and ctDNAneg patient cohorts and ctDNA kinetics.
The CIRCULATE trial may establish ctDNA for adjuvant treatment decision in stage II colon cancer – and with the secondary objectives – support a ctDNA guided follow up in colon cancer stage II and beyond.
Circulating tumour DNA (ctDNA) is a prognostic biomarker of recurrence in patients with early stage and resected colorectal cancer. The CIRCULATE study evaluates the predictive value of ctDNA with respect to adjuvant treatment in colon cancer stage II. In total, 231 patients with detectable ctDNA (ctDNApos) post resection are randomised 2:1 to chemotherapy or to control (follow-up). Patients without detectable ctDNA (approx. 2079 patients) are randomized 1:4 into control or off-study. The primary endpoint is the disease-free survival.
AIM： To investigate the predictive value of Ki67 and p53 and their correlation with thymidylate synthase （TS） gene expression in a rectal cancer patient cohort treated according to a standardized ...recommended neoadjuvant treatment regimen.METHODS： Formalin fixed, paraffin embedded pre-therapeutical tumor biopsies （n = 22） and post-therapeutical resection specimens （n = 40） from patients with rectal adenocarcinoma （clinical UICC stage Ⅱ/Ⅲ） receiving standardized neoadjuvant 5-fluorouracil （5-FU） based chemoradiotherapy were studied for Ki67 and p53 expression by immunohistochemistry and correlated with TS mRNA expression by quantitative TaqMan real-time PCR after laser microdissection. The results were compared with histopathological tumor regression according to a standardized semiquantitative score grading system.RESULTS： Responders （patients with high tumor regression） showed a significantly lower Ki67 expression than non-responders in the pre-therapeutical tumor biopsies （81.2% vs 16.7%; P 〈 0.05） as well as in the post-therapeutical resection specimens （75.8% vs 14.3%; P 〈 0.01）. High TS mRNA expression was significantly correlated with a high Ki67 index and low TS mRNA expression was significantly correlated with a low Ki67 index in the pre-therapeutical tumor biopsies （corr. coef. = 0.46; P 〈 0.01） as well as in the post-therapeutical resection specimens （corr. coef. = 0.40; P 〈 0.05）. No significant association was found between p53 and TS mRNA expression or tumor regression.CONCLUSION： Ki67 has, like TS, predictive value in rectal cancer patients after neoadjuvant 5-FU based chemoradiotherapy. The close correlation between Ki67 and TS indicates that TS is involved in active cell cycle processes.
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