ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer.

The European Society for Medical Oncology (ESMO) held a virtual consensus-building process on epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer in 2021. The consensus included a multidisciplinary panel of 34 leading experts in the management of lung cancer. The aim of the consensus was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where the available evidence is either limited or conflicting. The main topics identified for discussion were: (i) tissue and biomarkers analyses; (ii) early and locally advanced disease; (iii) metastatic disease and (iv) clinical trial design, patient's perspective and miscellaneous. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the recommendations developed, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation.

EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer.

BACKGROUND: Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. PATIENTS AND METHODS: We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. RESULTS: Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. CONCLUSIONS: EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC).

BACKGROUND: Mammary analogue secretory carcinoma (MASC) is a recently described pathologic entity. We report the case of a patient with an initial diagnosis of salivary acinic cell carcinoma later reclassified as MASC after next-generation sequencing revealed an ETV6-NTRK3 fusion. PATIENTS AND METHODS: This alteration was targeted with the pan-Trk inhibitor entrectinib (Ignyta), which possesses potent in vitro activity against cell lines containing various NTRK1/2/3 fusions. RESULTS: A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Structural modeling predicts that this alteration sterically interferes with drug binding, correlating to decreased sensitivity to drug inhibition observed in cell-based assays. CONCLUSIONS: This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810).

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

Epidermal growth factor receptor exon 20 insertions in advanced lung adenocarcinomas: Clinical outcomes and response to erlotinib.

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertions (exon20ins) represent approximately 10% of EGFR-mutant lung adenocarcinomas, and are associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Clinical outcomes in comparison with patients with sensitizing EGFR mutations are not well established. METHODS: Patients with stage IV lung adenocarcinomas with EGFR exon20ins were identified through routine molecular testing. Clinicopathologic data were collected. Overall survival (OS) was measured from the diagnosis of stage IV disease, and in patients treated with EGFR TKIs, the time to progression (TTP) on erlotinib was measured. RESULTS: One thousand eight hundred and eighty-two patients with stage IV lung adenocarcinomas were identified: 46 patients had EGFR exon20ins (2%), and 258 patients had an EGFR exon 19 deletion (exon19del)/L858R point mutation (14%). Among 11 patients with lung adenocarcinomas with EGFR exon20ins who received erlotinib, 3 patients (27%) had a partial response (FQEA, 1; ASV, 1; and unknown variant, 1). TTP for patients with EGFR exon20ins and patients with EGFR exon19del/L858R on erlotinib were 3 and 12 months, respectively (P < .01). Responses to chemotherapy were similar for patients with lung adenocarcinomas with EGFR exon20ins and patients with lung adenocarcinomas with EGFR exon19del/L858R. Median OS from the diagnosis of stage IV disease for patients with EGFR exon20ins and patients with EGFR exon19del/L858R was 26 months (95% confidence interval, 19 months-not reached n = 46) and 31 months (95% confidence interval, 28-33 months; n = 258), respectively (P = .53). CONCLUSIONS: The majority of patients with advanced lung adenocarcinomas harboring EGFR exon20ins do not respond to EGFR TKI therapy. Standard chemotherapy should be used as first-line therapy. These patients have an OS similar to that of patients with sensitizing EGFR mutations. Individuals with certain variants such as FQEA and ASV may respond to erlotinib.

Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.

BACKGROUND: HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied dacomitinib in patients with HER2-mutant or amplified lung cancers. PATIENTS AND METHODS: As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral dacomitinib at 30-45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity. RESULTS: We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of dacomitinib (95% CI 7-21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of dacomitinib with mirtazapine. CONCLUSIONS: Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2-targeted agents in specific HER2-driven lung cancers. CLINICALTRIALSGOV: NCT00818441.

Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing.

BACKGROUND: EGFR T790M is the most common mutation associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Baseline EGFR T790M mutations in EGFR TKI-naïve patients have been reported, but the frequency and their association with response to EGFR TKIs remain unclear. PATIENTS AND METHODS: The frequency of baseline EGFR T790M as detected by routine molecular genotyping was determined by reviewing clinical results obtained at our institution from 2009 to 2013. We also collected outcome data for treatment with EGFR TKIs. RESULTS: To define the incidence of EGFR T790M, we reviewed 2774 sequentially tested patients with lung cancer who underwent molecular testing using a mass spectrometry-based assay, and 11 (0.5%) had baseline EGFR T790M. Compiling results from several molecular techniques, we observed EGFR T790M in tumors from 20 patients who had not previously been treated with an EGFR TKI. In all cases, EGFR T790M occurred concurrently with another EGFR mutation, L858R (80%, 16/20), or exon 19 deletion (20%, 4/20). Two percent of all pre-treatment EGFR-mutant lung cancers harbored an EGFR T790M mutation. Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. The response rate was 8% (1/13, 95% confidence interval 0%-35%). For the patients who received erlotinib, the median progression-free survival was 2 months and the median overall survival was 16 months. CONCLUSIONS: De novo EGFR T790M mutations are rare (<1%) when identified by standard sensitivity methods. TKI therapy for patients with baseline EGFR T790M detected by standard molecular analysis has limited benefit.

Lactose drives Enterococcus expansion to promote graft-versus-host disease.

Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

Commentary on "DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma."

PURPOSE: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. EXPERIMENTAL DESIGN: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. RESULTS: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable effect on clinical outcomes. CONCLUSIONS: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.

Genomic Alterations and Outcomes with VEGF-Targeted Therapy in Patients with Clear Cell Renal Cell Carcinoma.

Background: Mutations in VHL, PBRM1, SETD2, BAP1, and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease. Limited information is available regarding the correlation between genomic alterations and outcomes in patients with metastatic disease, including response to VEGF-targeted therapy. Objective: To explore correlations between mutational profiles and cancer-specific outcomes, including response to standard VEGF-targeted agents, in patients with metastatic cc RCC. Methods: A retrospective review of 105 patients with metastatic ccRCC who had received systemic therapy and had targeted next-generation sequencing of tumors was conducted. Genomic alterations were correlated to outcomes, including overall survival and time to treatment failure to VEGF-targeted therapy. Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%). Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status (p = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status (p = 0.01, median 6.4 months for MT versus 11.0 months for WT). Shorter overall survival was associated with TERT mutations (p = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations (p = 0.02, median 28.7 months for MT versus not reached for WT). Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease. BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis.

Clonal B cells in Waldenström's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling.

Waldenström's macroglobulinemia (WM) is a B-cell non-Hodgkin's lymphoma (B-NHL) characterized by immunoglobulin M (IgM) monoclonal gammopathy and the medullary expansion of clonal lymphoplasmacytic cells. Neoplastic transformation has been partially attributed to hyperactive MYD88 signaling, secondary to the MYD88 L265P mutation, occurring in the majority of WM patients. Nevertheless, the presence of chronic active B-cell receptor (BCR) signaling, a feature of multiple IgM+ B-NHL, remains a subject of speculation in WM. Here, we interrogated the BCR signaling capacity of primary WM cells by utilizing multiparametric phosphoflow cytometry and found heightened basal phosphorylation of BCR-related signaling proteins, and augmented phosphoresponses on surface IgM (sIgM) crosslinking, compared with normal B cells. In support of those findings we observed high sIgM expression and loss of phosphatase activity in WM cells, which could both lead to signaling potentiation in clonal cells. Finally, led by the high-signaling heterogeneity among WM samples, we generated patient-specific phosphosignatures, which subclassified patients into a 'high' and a 'healthy-like' signaling group, with the second corresponding to patients with a more indolent clinical phenotype. These findings support the presence of chronic active BCR signaling in WM while providing a link between differential BCR signaling utilization and distinct clinical WM subgroups.

Cancer-testis antigen expression and immunogenicity in AL amyloidosis.

Light-chain amyloidosis (AL) is a plasma cell dyscrasia closely related to multiple myeloma. In multiple myeloma, the cancer-testis antigens (CTAs) CT7 (MAGE-C1), CT10 (MAGE-C2) and MAGE-A CTAs are expressed in up to 80% of cases. In this study, we investigated the expression and immunogenicity of several CTAs in patients with AL amyloidosis in a total of 38 bone marrow specimens by employing standard immunohistochemistry techniques on paraffin-embedded archival tissues. Plasma samples from 35 patients (27 with matched bone marrow samples) were also analyzed by ELISA for sero reactivity to a group of full-length CTA proteins. CT7 was present in 25/38 (66%) while CT10 was demonstrated in 3/38 and GAGE in 1/38 AL amyloid cases. The expression pattern was mostly focal. There were no significant differences with regard to organ involvement, response to treatment, or prognosis in CTA positive compared to negative cases. None of the specimens showed spontaneous humoral immunity to CT7, but sero reactivity was observed in individual patients to other CTAs. This study identifies CT7 as the prevalent CTA in plasma cells of patients with AL amyloidosis. Further analyses determining the biology of CTAs in AL amyloidosis and their value as potential targets for immunotherapy are warranted.

cis-diamminedichloroplatinum (II) (cisplatin) alters microtubule assembly dynamics.

Cisplatin is an highly effective chemotherapeutic agent which produces a cumulative dose-limiting peripheral neuropathy. In this study, a possible role for microtubule abnormalities in cisplatin-induced toxicity was explored. CD rats (300 g) were injected daily ip with five doses of cisplatin (2 mg/kg) or every other day ip with two doses of cisplatin (10 mg/kg). The day after the last dose, the rats were killed and tubulin was purified from their testes. The maximal rate of cold-induced microtubule disassembly was consistently slower for testis tubulin purified from cisplatin-treated rats compared with control rats. Overnight in vitro coincubation of polymerized bovine brain tubulin with cisplatin followed by a purifying cycle of assembly and disassembly yielded tubulin capable of forming morphologically normal but short microtubules (average length: cisplatin-treated, 2.5 microns; control, 3.7 microns). Cisplatin coincubation markedly reduced the rate of cold-induced microtubule disassembly, producing a half-maximal effect at approximately 0.3 mM. The cold stability of cisplatin-treated microtubules could be partially reversed by diethyldithiocarbamate. Carboplatin, a cisplatin analog which does not cause clinical peripheral neuropathy, was less capable of producing microtubule disassembly abnormalities. These findings demonstrate the ability of cisplatin to alter microtubule disassembly by direct tubulin modification, an abnormality which may contribute to cisplatin-induced peripheral neuropathy.

Waldenstrom's macroglobulinemia and sensorineural hearing loss.

Waldenstrom's macroglobulinemia, (WM) first described in 1944, is an uncommon disease caused by the abnormal production of immunoglobulin M monoclonal macroglobulin. Presenting signs and symptoms most frequently include fatigue or generalized weakness; tendency to bleed from mucosal surfaces; characteristic retinal lesions, including dilated and tortuous retinal veins, retinal hemorrhages, and exudates; lymphadenopathy; hepatosplenomegaly; sensory motor peripheral neuropathy; worsening normochromic anemia; increased sedimentation rate; and extremely high serum viscosity. Hearing loss is an unusual presenting symptom of WM; only 6 cases are reported in literature. The etiology of hearing loss is unclear; however, hyperviscosity and thrombus formations are the most likely causes. We present a patient diagnosed with WM whose initial presenting symptoms were hearing loss and progressive sensory peripheral neuropathy with subsequent development of lymphadenopathy and hyperviscosity syndrome. Treatment with Fludarabine lead to improvement of her hearing and neurological deficits, as well as resolution of her other hyperviscosity-related symptoms.

[Arterial phenomenon of autonomization of vascularized island flaps reviewed by expansion of the vascular pedicle. An experimental study in the rat]. / Les phénomènes artériels de l'autonomisation des lambeaux cutanés en îlot vasculaire revus par l'expansion d'un pédicule vasculaire. Une étude expérimentale chez le rat.

This experimental study performed in rats examined the possible vascular extensions of a periprosthetic membrane neoflap with an axial vascular pedicle towards an adjacent cutaneous angiotome. 22 Wistar rats were operated. After tattooing the superficial iliac circumflex angiotome, the adjacent epigastric pedicle was expanded. After expansion and a two-month rest period, clinical and microangiographic studies were performed. In 50% of cases, the iliac island skin flap raised on the periprosthetic membrane created by the epigastric pedicle was considered to be viable. The microangiographic results were identical. The pathophysiological mechanism is analysed in the light of the literature.

[Posterolateral sural fasciocutaneous island flap with proximal aponeurotic pedicle. Anatomical study and use for cutaneous cover of the knee. Apropos of 9 clinical cases]. / Le lambeau sural postéro-latéral en îlot fascio-cutané à pédicule aponévrotique proximal. Etude anatomique et application à la couverture cutanée du genou. A propos de neuf cas cliniques.

The authors propose an elaborate variant of the classical saphenous or lateral leg fascio-cutaneous flap with a proximal pedicle for the cover of post-traumatic skin defects of the knee. The original feature of this flap resides in the purely aponeurotic or adipo-fascial pedicle which increases the arc of rotation, while minimizing cutaneous sequelae of the donor site. Twenty four injected cadaveric dissections were used to define the neurovascular content of the lateral sural fascia: the lateral and medial superficial sural arteries and their territory of perfusion, accompanying veins and the short saphenous vein, as well as the lateral and medial sural cutaneous nerves. The technique of harvesting of the island flap is described. Nine patients were operated between 1991 and 1994, with an uncomplicated postoperative course in terms of flap vitality and donor site. The skin cover of the knee was considered to be of excellent quality, stable and sensitive, with a follow-up ranging from 6 months to 3 years four months.

Mass and functional capacity of regenerating muscle is enhanced by myoblast transfer.

Morphology and functional capacity of homotopically transplanted extensor digitorum longus muscles (EDL) of adult SCID mice that received 1 x 10(6) myoblasts [stably transfected to express nuclear localizing beta-galactosidase under the control of the myosin light-chain 3F promoter/enhancer] 2 days posttransplantation were evaluated 9 weeks after transplantation, to determine whether the injection of exogenous myoblasts had an effect on muscle regeneration. Regenerated muscles that received exogenous myoblasts were compared to similarly transplanted muscles that received (a) no further treatment, or (b) sham injection of the vehicle (without myoblasts) and to unoperated EDL. Nine weeks after myoblast transfer, myofibers containing donor-derived nuclei could be identified after staining with X-gal solution. Judging from its size and poor functional performance compared to muscles subjected to transplantation only, sham injection provided a secondary trauma to the regenerating muscle from which it failed to fully recover. In comparison to the sham-injected muscle, the myoblast-injected muscles weighed 61% more and had 50% more myofibers and 82% more cross-sectional area occupied by myofibers at the muscles' widest girths. Their absolute twitch and tetanic tensions were threefold and twofold greater, respectively, and their specific twitch and tetanic tensions were 71% and 50% greater, respectively, than those of sham-injected muscles. In many parameters, the regenerating muscle subjected to myoblast transfer equaled or exceeded those of muscles that were transplanted only (received only one trauma). Absolute twitch and tetanic tensions were 73% and 65% greater, respectively, and specific twitch tensions of the muscles receiving myoblasts were 50% greater than forces generated by muscles subjected to whole-muscle transplantation only.

Effects of administration of mannitol and furosemide in the renal hemodynamics of the dog.

The action site of mannitol and furosemide in the nephron level was studied in two groups of dogs which, alternatively, were given both diuretics. The furosemide preferential action site was confirmed in the ascending limb of Henle's loop. It is suggested that mannitol acts on the descending limb of this loop, and that the dilution effects of this diuretic on the ascending limb are due to contamination. Changes in urinary excretion of potassium were not observed during mannitol administration. This fact coincides with the action site suggested for this substance.