RESUMEN
Adenoid cystic carcinoma (ACC) is a rare, usually slow-growing yet aggressive head and neck malignancy. Despite its clinical significance, our understanding of the cellular evolution and microenvironment in ACC remains limited. We investigated the intratumoral microbiomes of 50 ACC tumor tissues and 33 adjacent normal tissues using 16S rRNA gene sequencing. This allowed us to characterize the bacterial communities within the ACC and explore potential associations between the bacterial community structure, patient clinical characteristics, and tumor molecular features obtained through RNA sequencing. The bacterial composition in the ACC was significantly different from that in adjacent normal salivary tissue, and the ACC exhibited diverse levels of species richness. We identified two main microbial subtypes within the ACC: oral-like and gut-like. Oral-like microbiomes, characterized by increased diversity and abundance of Neisseria, Leptotrichia, Actinomyces, Streptococcus, Rothia, and Veillonella (commonly found in healthy oral cavities), were associated with a less aggressive ACC-II molecular subtype and improved patient outcomes. Notably, we identified the same oral genera in oral cancer and head and neck squamous cell carcinomas. In both cancers, they were part of shared oral communities associated with a more diverse microbiome, less aggressive tumor phenotype, and better survival that reveal the genera as potential pancancer biomarkers for favorable microbiomes in ACC and other head and neck cancers. Conversely, gut-like intratumoral microbiomes, which feature low diversity and colonization by gut mucus layer-degrading species, such as Bacteroides, Akkermansia, Blautia, Bifidobacterium, and Enterococcus, were associated with poorer outcomes. Elevated levels of Bacteroides thetaiotaomicron were independently associated with significantly worse survival and positively correlated with tumor cell biosynthesis of glycan-based cell membrane components.
Asunto(s)
Carcinoma Adenoide Quístico , Neoplasias de Cabeza y Cuello , Microbiota , ARN Ribosómico 16S , Humanos , Carcinoma Adenoide Quístico/microbiología , Carcinoma Adenoide Quístico/patología , Neoplasias de Cabeza y Cuello/microbiología , Neoplasias de Cabeza y Cuello/patología , Femenino , Masculino , Persona de Mediana Edad , ARN Ribosómico 16S/genética , Anciano , Adulto , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificaciónRESUMEN
Aggressive breast cancers harbor TP53 missense mutations. Tumor cells with TP53 missense mutations exhibit enhanced growth and survival through transcriptional rewiring. To delineate how TP53 mutations in breast cancer contribute to tumorigenesis and progression in vivo, we created a somatic mouse model driven by mammary epithelial cell-specific expression of Trp53 mutations. Mice developed primary mammary tumors reflecting the human molecular subtypes of luminal A, luminal B, HER2-enriched, and triple-negative breast cancer with metastases. Transcriptomic analyses comparing MaPR172H/- or MaPR245W/- mammary tumors to MaP-/- tumors revealed (1) differences in cancer-associated pathways activated in both p53 mutants and (2) Nr5a2 as a novel transcriptional mediator of distinct pathways in p53 mutants. Meta-analyses of human breast tumors corroborated these results. In vitro assays demonstrate mutant p53 upregulates specific target genes that are enriched for Nr5a2 response elements in their promoters. Co-immunoprecipitation studies revealed p53R172H and p53R245W interact with Nr5a2. These findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer. SIGNIFICANCE: Our findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer. NR5A2 may be an important therapeutic target in hard-to-treat breast cancers such as endocrine-resistant tumors and metastatic triple-negative breast cancers harboring TP53 missense mutations.
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Neoplasias Mamarias Experimentales , Transcriptoma , Proteína p53 Supresora de Tumor , Animales , Femenino , Humanos , Ratones , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/metabolismo , Mutación , Mutación Missense , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
First use of AXL-targeting in adenoid cystic carcinoma (ACC); with positive results, ACC now included in AXL studies.
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Tirosina Quinasa del Receptor Axl , Carcinoma Adenoide Quístico , Humanos , Carcinoma Adenoide Quístico/tratamiento farmacológico , Tirosina Quinasa del Receptor Axl/antagonistas & inhibidores , Tirosina Quinasa del Receptor Axl/efectos de los fármacosRESUMEN
INTRODUCTION: Poorly differentiated primary sarcomatoid parotid malignancies are extremely rare. These tumors have not been consistently studied by morphology, immunohistochemistry, or molecular techniques. CASE PRESENTATION: We report three unusual cases of parotid gland poorly-differentiated sarcomatoid malignancy investigated by fine-needle aspiration and studied histologically, by immunohistochemistry and molecular investigations. Aspirates showed poorly specific polymorphous sarcomatoid malignancy in all cases. Histologically, all cases were polymorphous high-grade malignancies, and additionally, one case showed epithelial structures and was finally classified as salivary carcinosarcoma. Immunohistochemistry showed classical melanocytic markers negativity but positivity for PRAME, CD10, and WT1 in all three tumors and for CD56 in two tumors, which can potentially be supportive of melanocytic origin. Although not entirely specific, molecular characterization also suggested the melanocytic lineage of these tumors. CONCLUSION: Although rare, primary malignant melanoma of salivary gland was already described, but undifferentiated/dedifferentiated amelanotic forms are unknown in this localization up today. Further case reports of similar presentations are required to confirm the unequivocal primary origin of these obscure neoplasms in the parotid gland.
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Biomarcadores de Tumor , Inmunohistoquímica , Melanoma , Neoplasias de la Parótida , Adulto , Anciano , Femenino , Humanos , Masculino , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biopsia con Aguja Fina , Carcinosarcoma/patología , Carcinosarcoma/diagnóstico , Diferenciación Celular , Melanoma/patología , Melanoma/diagnóstico , Glándula Parótida/patología , Neoplasias de la Parótida/patología , Neoplasias de la Parótida/diagnósticoRESUMEN
OBJECTIVES: Lung metastases in adenoid cystic carcinoma (ACC) usually have indolent growth and the optimal timing to start systemic therapy is not established. We assessed ACC lung metastasis tumor growth dynamics and compared the prognostic value of time to progression (TTP) and tumor volume doubling time (TVDT). METHODS: The study included ACC patients with ≥1 pulmonary metastasis (≥5 mm) and at least 2 chest computed tomography scans. Radiology assessment was performed from the first scan showing metastasis until treatment initiation or death. Up to 5 lung nodules per patient were segmented for TVDT calculation. To assess tumor growth rate (TGR), the correlation coefficient (r) and coefficient of determination (R2) were calculated for measured lung nodules. TTP was assessed per RECIST 1.1; TVDT was calculated using the Schwartz formula. Overall survival was analyzed using the Kaplan-Meier method. RESULTS: The study included 75 patients. Sixty-seven patients (89%) had lung-only metastasis on first CT scan. The TGR was overall constant (median R2 = 0.974). Median TTP and TVDT were 11.2 months and 7.5 months. Shorter TVDT (<6 months) was associated with poor overall survival (HR = 0.48; p = 0.037), but TTP was not associated with survival (HR = 1.02; p = 0.96). Cox regression showed that TVDT but not TTP significantly correlated with OS. TVDT calculated using estimated tumor volume correlated with TVDT obtained by segmentation. CONCLUSION: Most ACC lung metastases have a constant TGR. TVDT may be a better prognostic indicator than TTP in lung-metastatic ACC. TVDT can be estimated by single longitudinal measurement in clinical practice.
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Carcinoma Adenoide Quístico , Neoplasias Pulmonares , Humanos , Pronóstico , Carcinoma Adenoide Quístico/patología , Carga Tumoral , Factores de Tiempo , Neoplasias Pulmonares/diagnóstico por imagen , Pulmón/patología , Estudios RetrospectivosRESUMEN
The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells from ferroptosis inducers, and ferroptosis inhibitors reverse the effects of mutant p53 loss in vivo. Single-cell transcriptomic data revealed that mutant p53 protects cells from undergoing ferroptosis through NRF2-dependent regulation of Mgst3 and Prdx6, which encode two glutathione-dependent peroxidases that detoxify lipid peroxides. Thus, mutant p53 protects TNBCs from ferroptotic death.
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Adenocarcinoma , Ferroptosis , Neoplasias de la Mama Triple Negativas , Animales , Humanos , Ratones , Línea Celular Tumoral , Ferroptosis/genética , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
AIM: To investigate safety and effectiveness of iGlarLixi in adults with type 2 diabetes mellitus (T2DM) observing fast during Ramadan from Gulf countries. METHODS: This planned subgroup analysis of the SoliRam - a multinational, prospective, non-interventional, real-world, observational study - focused on participants from Gulf countries. Primary endpoint was proportion of participants experiencing ≥1 episode of severe and/or symptomatic documented (<70 mg/dL [<3.9 mmol/L]) hypoglycemia. RESULTS: A total of 241 individuals with T2DM (mean age: 58.1 years; male: 54.4%; mean duration of diabetes: 13.3 years) were included. All 234 eligible participants followed during Ramadan were able to fast for ≥25 days and no participants broke fast due to hypoglycemia. Primary endpoint was reported in one participant (0.5%) during fasting hours during Ramadan. Improvements (mean ± SD change) in HbA1c (-1.0 ± 1.0% [-11 ± 10 mmol/mol]), FPG (-22.5 ± 29.7 mg/dL), and body weight (-1.5 ± 2.0 kg) were observed from pre-Ramadan to post-Ramadan. Three participants (1.2 %) reported an adverse event (AE) of any cause and one (0.4%) reported a gastrointestinal AE. CONCLUSIONS: iGlarLixi is an effective and well-tolerated treatment in people with T2DM from Gulf countries, including during Ramadan fasting, and is associated with low risk of hypoglycemia.
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Diabetes Mellitus Tipo 2 , Hipoglucemia , Adulto , Humanos , Masculino , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inducido químicamente , Hipoglucemiantes/efectos adversos , Estudios Prospectivos , Ayuno/efectos adversos , Hipoglucemia/epidemiología , Hipoglucemia/inducido químicamente , Islamismo , GlucemiaRESUMEN
B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (<5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high (>70% moderate or strong diffuse intensity). The associations between B7-H4 expression and clinicopathologic characteristics, as well as overall survival, were assessed. Among all tumors, B7-H4 expression was more prevalent in ACC (94%) compared with those of SC (67%), MEC (44%), SDC (32%), and acinic cell carcinomas (0%). Normal salivary gland tissue did not express B7-H4. High expression of B7-H4 was found exclusively in ACC (27%), SDC (11%), and MEC (8%). In SDC, B7-H4 expression was associated with female gender (P = .002) and lack of androgen receptor expression (P = .012). In ACC, B7-H4 expression was significantly associated with solid histology (P < .0001) and minor salivary gland primary (P = .02). High B7-H4 expression was associated with a poorer prognosis in ACC, regardless of clinical stage and histologic subtype. B7-H4 expression was not prognostic in the non-ACC SGC evaluated. Our comparative study revealed distinct patterns of B7-H4 expression according to SGC histology, which has potential therapeutic implications. B7-H4 expression was particularly high in solid ACC and was an independent prognostic marker in this disease but not in the other SGC assessed.
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Neoplasias de la Mama , Carcinoma de Células Acinares , Carcinoma Adenoide Quístico , Carcinoma Mucoepidermoide , Carcinoma , Neoplasias de las Glándulas Salivales , Humanos , Femenino , Carcinoma Adenoide Quístico/patología , Pronóstico , Carcinoma de Células Acinares/patología , Neoplasias de las Glándulas Salivales/patología , Carcinoma Mucoepidermoide/patología , Carcinoma/patología , Glándulas Salivales/química , Glándulas Salivales/metabolismo , Glándulas Salivales/patología , Biomarcadores de Tumor/análisisRESUMEN
Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.
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Carcinoma , Neoplasias de Cabeza y Cuello , Humanos , Masculino , Femenino , Cisplatino/efectos adversos , Lapatinib , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Supervivencia sin Progresión , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
The TP53 tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream analyses revealed that deletion of mutant Trp53 activated the cyclic GMP-AMP Synthase-Stimulator of Interferon Genes pathway but did not cause apoptosis implicating other mechanisms of tumor regression. Furthermore, we determined that only tumors with stable mutant p53 are dependent on mutant p53 for growth.
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Neoplasias de la Mama Triple Negativas , Proteína p53 Supresora de Tumor , Animales , Humanos , Ratones , Genes p53 , Mutación , Mutación Missense , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente Tumoral , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Carcinoma Adenoide Quístico , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Pronóstico , Genes Supresores de Tumor , Neoplasias de Cabeza y Cuello/genética , Transcriptoma , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
PURPOSE: Adenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets. EXPERIMENTAL DESIGN: Tumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm software. The B7-H4 antibody-drug conjugate AZD8205 was tested in ACC patient-derived xenografts (PDX). RESULTS: RNA deconvolution revealed that most ACCs are immunologically "cold," with approximately 30% being "hot." ACC-I tumors with a poor prognosis harbored a higher density of immune cells; however, spatial analysis by IMC revealed that ACC-I immune cells were significantly restricted to the stroma, characterizing an immune-excluded TME. ACC-I tumors overexpressed the immune checkpoint B7-H4, and the degree of immune exclusion was directly correlated with B7-H4 expression levels, an independent predictor of poor survival. Two ACC-I/B7-H4-high PDXs obtained 90% complete responses to a single dose of AZD8205, but none were observed with isotype-conjugated payload or in an ACC-II/B7-H4 low PDX. CONCLUSIONS: Spatial analysis revealed that ACC subtypes have distinct TMEs, with enrichment of ACC-I immune cells that are restricted to the stroma. B7-H4 is highly expressed in poor-prognosis ACC-I subtype and is a potential therapeutic target.
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Carcinoma Adenoide Quístico , Humanos , Carcinoma Adenoide Quístico/tratamiento farmacológico , Carcinoma Adenoide Quístico/genética , Inhibidor 1 de la Activación de Células T con Dominio V-Set , Pronóstico , Biomarcadores de Tumor , Microambiente TumoralRESUMEN
INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) protein overexpression, gene amplification, and activating mutations have been identified in a subset of salivary gland carcinoma (SGC) histologies (HER2-positive), especially in salivary duct carcinoma, and represent an important therapeutic target. AREAS COVERED: The evidence for targeting HER2 in the adjuvant setting is limited to small retrospective series. Conversely, there are prospective trials supporting the use of anti-HER2 therapy in patients with unresectable, recurrent, or metastatic HER2-positive SGC, including trastuzumab plus docetaxel, trastuzumab plus pertuzumab, trastuzumab-pkrb plus nanoxel, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-Dxd). EXPERT OPINION: HER2-targeting should be considered for patients with advanced HER2-positive SGC. There are no data to guide the selection of one anti-HER2 agent over another in the palliative setting. Trastuzumab plus docetaxel can be considered for patients with a high disease burden, while trastuzumab plus pertuzumab is a good option for patients with low disease burden or borderline performance status. T-DM1 or T-Dxd can be considered upon disease progression on trastuzumab-combination therapies, although these antibody-drug conjugates can also be used upfront. Future research should investigate predictive biomarkers, the combination of HER2 and androgen blockade, and the application of novel therapies from breast cancer.
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Neoplasias de la Mama , Carcinoma , Femenino , Humanos , Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Docetaxel , Receptores ErbB , Estudios Prospectivos , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Glándulas Salivales/patología , TrastuzumabRESUMEN
PURPOSE: We conducted a phase II trial evaluating the efficacy of VEGFR inhibitor axitinib and PD-L1 inhibitor avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (R/M ACC). PATIENTS AND METHODS: Eligible patients had R/M ACC with progression within 6 months before enrollment. Treatment consisted of axitinib and avelumab. The primary end point was objective response rate (ORR) per RECIST 1.1; secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Simon's optimal two-stage design tested the null hypothesis of ORR ≤5% versus ORR ≥20% at 6 months; ≥4 responses in 29 patients would reject the null hypothesis. RESULTS: Forty patients enrolled from July 2019 to June 2021; 28 were evaluable for efficacy (six screen failures; six evaluable for safety only). The confirmed ORR was 18% (95% CI, 6.1 to 36.9); there was one unconfirmed partial response (PR). Two patients achieved PR after 6 months; thus, the ORR at 6 months was 14%. The median follow-up time for surviving patients was 22 months (95% CI, 16.6 to 39.1 months). The median PFS was 7.3 months (95% CI, 3.7 to 11.2 months), 6-month PFS rate was 57% (95% CI, 41 to 78), and median OS was 16.6 months (95% CI, 12.4 to not reached months). Most common treatment-related adverse events (TRAEs) included fatigue (62%), hypertension (32%), and diarrhea (32%). Ten (29%) patients had serious TRAEs, all grade 3; four patients (12%) discontinued avelumab, and nine patients (26%) underwent axitinib dose reduction. CONCLUSION: The study reached its primary end point with ≥4 PRs in 28 evaluable patients (confirmed ORR of 18%). The potential added benefit of avelumab to axitinib in ACC requires further investigation.
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Carcinoma Adenoide Quístico , Humanos , Axitinib/efectos adversos , Carcinoma Adenoide Quístico/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversosRESUMEN
Adenoid cystic carcinoma (ACC) is an aggressive malignancy that most often arises in salivary or lacrimal glands but can also occur in other tissues. We used optimized RNA-sequencing to analyze the transcriptomes of 113 ACC tumor samples from salivary gland, lacrimal gland, breast or skin. ACC tumors from different organs displayed remarkedly similar transcription profiles, and most harbored translocations in the MYB or MYBL1 genes, which encode oncogenic transcription factors that may induce dramatic genetic and epigenetic changes leading to a dominant 'ACC phenotype'. Further analysis of the 56 salivary gland ACC tumors led to the identification of three distinct groups of patients, based on gene expression profiles, including one group with worse survival. We tested whether this new cohort could be used to validate a biomarker developed previously with a different set of 68 ACC tumor samples. Indeed, a 49-gene classifier developed with the earlier cohort correctly identified 98% of the poor survival patients from the new set, and a 14-gene classifier was almost as accurate. These validated biomarkers form a platform to identify and stratify high-risk ACC patients into clinical trials of targeted therapies for sustained clinical response.
RESUMEN
BACKGROUND: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number alterations (SCNAs), and clinical implications of PD-L1 and immune-cell patterns in oral precancer (OPC). METHODS: The authors evaluated spatial CD3, CD3/8, and CD68 density (cells/mm2 ) and PD-L1 (membranous expression in cytokeratin-positive intraepithelial neoplastic cells and CD68) patterns by multiplex immunofluorescence in a 188-patient prospective OPC cohort, characterized by clinical, histologic, and SCNA risk factors and protocol-specified primary end point of invasive cancer. The authors used Wilcoxon rank-sum and Fisher exact tests, linear mixed effect models, mediation, and Cox regression and recursive-partitioning analyses. RESULTS: Epithelial, but not CD68 immune-cell, PD-L1 expression was detected in 28% of OPCs, correlated with immune-cell infiltration, 9p21.3 loss of heterozygosity (LOH), and inferior oral cancer-free survival (OCFS), notably in OPCs with low CD3/8 cell density, dysplasia, and/or 9p21.3 LOH. High CD3/8 cell density in dysplastic lesions predicted better OCFS and eliminated the excess risk associated with prior oral cancer and dysplasia. PD-L1 and CD3/8 patterns revealed inferior OCFS in PD-L1 high intrinsic induction and dysplastic immune-cold subgroups. CONCLUSION: This report provides spatial insight into the immune landscape and drivers of OPCs, and a publicly available immunogenomic data set for future precancer interrogation. The data suggest that 9p21.3 LOH triggers an immune-hot inflammatory phenotype; whereas increased 9p deletion size encompassing CD274 at 9p24.1 may contribute to CD3/8 and PD-L1 depletion during invasive transition. The inferior OCFS in PD-L1-high, immune-cold OPCs support the development of T-cell recruitment strategies.
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Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Antígeno B7-H1 , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Genómica , Neoplasias de Cabeza y Cuello/metabolismo , Linfocitos Infiltrantes de Tumor , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Recurrencia Local de Neoplasia/metabolismo , Estudios Prospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Microambiente Tumoral/genéticaRESUMEN
PURPOSE: The combination of cisplatin and radiation or cetuximab and radiation improves overall survival of patients with locoregionally advanced head and neck carcinoma. NRG Oncology conducted a phase 3 trial to test the hypothesis that adding cetuximab to radiation and cisplatin would improve progression-free survival (PFS). METHODS AND MATERIALS: Eligible patients with American Joint Committee on Cancer sixth edition stage T2 N2a-3 M0 or T3-4 N0-3 M0 were accrued from November 2005 to March 2009 and randomized to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Outcomes were correlated with patient and tumor features. Late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). RESULTS: Of 891 analyzed patients, 452 with a median follow-up of 10.1 years were alive at analysis. The addition of cetuximab did not improve PFS (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.89-1.26; P = .74), with 10-year estimates of 43.6% (95% CI, 38.8- 48.4) for arm A and 40.2% (95% CI, 35.4-45.0) for arm B. Cetuximab did not reduce locoregional failure (HR, 1.21; 95% CI, 0.95-1.53; P = .94) or distant metastasis (HR, 0.79; 95% CI, 0.54-1.14; P = .10) or improve overall survival (HR, 0.97; 95% CI, 0.80-1.16; P = .36). Cetuximab did not appear to improve PFS in either p16-positive oropharynx (HR, 1.30; 95% CI, 0.87-1.93) or p16-negative oropharynx or nonoropharyngeal primary (HR, 0.94; 95% CI, 0.73-1.21). Grade 3 to 4 late toxicity rates were 57.4% in arm A and 61.3% in arm B (P = .26). CONCLUSIONS: With a median follow-up of more than 10 years, this updated report confirms the addition of cetuximab to radiation therapy and cisplatin did not improve any measured outcome in the entire cohort or when stratifying by p16 status.
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Cisplatino , Neoplasias de Cabeza y Cuello , Humanos , Cetuximab/efectos adversos , Cisplatino/efectos adversos , Resultado del Tratamiento , Quimioradioterapia/métodos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapiaRESUMEN
BACKGROUND: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC. METHODS: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry. RESULTS: Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, median progression-free and overall survival was 5 and 7 months, respectively. Bimiralisib was well tolerated, with expected hyperglycemia. Pharmacokinetic values were consistent with published studies. NOTCH1 mutations were detected in 83.3% of ctDNA. Staining for tumor cl-NOTCH1 was negative. The trial closed early due to sponsor insolvency. CONCLUSION: Although the trial was small, outcomes with bimiralisib were better than the historical standard of care; Results will need to be confirmed in a larger trial. The lack of cl-NOTCH1 was consistent with loss-of-function mutations and validated our mutation function algorithm. The ability to detect NOTCH1 mutations in blood will help future studies. (ClinicalTrials.gov Identifier: NCT03740100).