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Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.
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Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Masculino , Estudos Retrospectivos , Proteínas Proto-Oncogênicas c-ret/genética , Carcinoma Neuroendócrino/patologia , Neoplasias da Glândula Tireoide/patologia , Mutação , GenômicaRESUMO
NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC.
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Carcinoma de Células Escamosas , Fatores de Transcrição , Adolescente , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Proteínas de Ciclo Celular , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Glândula Tireoide , Fatores de Transcrição/genéticaRESUMO
NUT carcinoma is a rare, aggressive cancer defined by rearrangements of the NUTM1 gene. No routinely effective treatments of NUT carcinoma exist, despite harboring a targetable oncoprotein, most commonly BRD4-NUT. The vast majority of cases are fatal. Poor awareness of the disease is a major obstacle to progress in the treatment of NUT carcinoma. While the incidence likely exceeds that of Ewing sarcoma, and BRD4-NUT heralded the bromodomain and extra-terminal domain (BET) inhibitor class of selective epigenetic modulators, NUT carcinoma is incorrectly perceived as "impossibly rare," and therefore receives comparatively little private or governmental funding or prioritization by pharma. To raise awareness, propagate scientific knowledge, and initiate a consensus on standard and targeted treatment of NUT carcinoma, we held the First International Symposium on NUT Carcinoma on March 3, 2021. This virtual event had more than eighty attendees from the Americas, Europe, Asia, and Australia. Patients with NUT carcinoma and family members were represented and shared perspectives. Broadly, the four areas discussed by experts in the field included (1) the biology of NUT carcinoma; (2) standard approaches to the treatment of NUT carcinoma; (3) results of clinical trials using BET inhibitors; and (4) future directions, including novel BET bromodomain inhibitors, combinatorial approaches, and immunotherapy. It was concluded that standard chemotherapeutic approaches and first-generation BET bromodomain inhibitors, the latter complicated by a narrow therapeutic window, are only modestly effective in a minority of cases. Nonetheless, emerging second-generation targeted inhibitors, novel rational synergistic combinations, and the incorporation of immuno-oncology approaches hold promise to improve the prognosis of this disease.
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Carcinoma , Sarcoma de Ewing , Carcinoma/genética , Proteínas de Ciclo Celular , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: There is limited information on the management and outcomes of oligometastases (OM) in adenoid cystic carcinoma (ACC). METHODS: Retrospective study of 42 patients with metastatic ACC of the head and neck. Imaging studies were analyzed to identify patients with OM (1-5 lesions) at any point during follow-up. RESULTS: There was radiographic evidence of OM in 33/42 (79%) patients. Eighteen patients had OM when treated for metastases, with median overall survival (OS) of 36.0 versus 9.2 years for patients with polymetastases (6+ lesions, HR 0.38, 95%CI 0.14-0.89). Earlier locally ablative treatment, but not systemic treatment, of patients with OM predicted improved survival 3 years after metastasis (HR 0.15, 95%CI 0.02-0.63) and postponed systemic treatment by 80 more months (HR 0.22, 95%CI 0.07-0.71). CONCLUSIONS: There is a considerable population of ACC patients with detectable oligometastases, and early locally ablative treatment of oligometastases may be associated with improved outcomes.
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Carcinoma Adenoide Cístico , Carcinoma Adenoide Cístico/diagnóstico por imagem , Carcinoma Adenoide Cístico/terapia , Humanos , Estudos Retrospectivos , Tempo para o Tratamento , Carga TumoralRESUMO
AIMS: Tumour grade and RET mutation status, especially the presence of high-risk exon 15 and 16 RET mutations, have been reported to be prognostic in patients with sporadic medullary thyroid carcinoma (MTC). The aims of our study were to evaluate the performance of two recently proposed grading systems and to assess the association between grade and genotype in a cohort of sporadic MTCs. METHODS AND RESULTS: We identified 44 sporadic MTCs. All available tumour slides were examined, and cases were assigned a grade on the basis of either mitotic count and tumour necrosis, or mitotic count, tumour necrosis, and Ki-67 proliferative index, as described in two recent studies. Additional clinicopathological features and outcome information were obtained from the pathology reports and electronic medical records. The presence of RET and RAS mutations was determined either with direct sequencing or with massively parallel sequencing. Both grading systems were prognostic for progression-free survival and disease-specific survival on univariate analysis. There was no correlation between grade and mutation status. Specifically, neither RET nor high-risk RET mutations were enriched in high-grade tumours, as assessed by either grading scheme. CONCLUSION: Our findings suggest that grade is not correlated with RET/RAS mutation status, indicating that grade and genotype may give independent prognostic information.
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Carcinoma Neuroendócrino , Gradação de Tumores , Neoplasias da Glândula Tireoide , Adulto , Idoso , Idoso de 80 Anos ou mais , Arginina-tRNA Ligase/genética , Carcinoma Neuroendócrino/genética , Carcinoma Neuroendócrino/patologia , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Feminino , Genótipo , Humanos , Antígeno Ki-67/análise , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologiaRESUMO
PURPOSE: We evaluated the safety and efficacy of pembrolizumab (pembro) ± radiation therapy (RT) in a phase 2 study among patients with progressive, metastatic adenoid cystic carcinoma (ACC). METHODS AND MATERIALS: Eligible patients had metastatic ACC with progression within the last year and ≥1 measurable lesion. Patients were randomized to pembro alone or with RT to 30 Gy in 5 fractions (pembroRT). The primary endpoint was objective response rate outside the RT field. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and local RT responses. RESULTS: We randomized 20 patients (10 per arm) from 2017 to 2018. We did not observe objective response outside of the radiation treatment field; stable disease (SD) was the best response in 12 (60%) patients and was not different per arm (7 pembro, 5 pembroRT, P = .65). A tumor growth rate decrease (TGR) of >25% was noted among 7 of 12 patients and >75% in 4 patients. There were local responses in the irradiated field among all evaluable pembroRT patients. Median PFS and OS were 4.5/not reached for pembroRT and 6.6 / 27.2 months for pembro patients. One patient developed grade 3 liver enzyme elevation after 27 cycles of therapy. Correlative analyses confirm low levels of programmed death-ligand 1 expression (PD-L1), and CD8 infiltrating T-cells. We identified associations between local response and both MYB/NFIB translocation and PD-L1 expression and between changes in systemic immune populations and RT. CONCLUSIONS: Pembrolizumab and pembroRT were well tolerated. We observed no objective responses, but 60% of patients with PD before the study achieved SD, the majority with decreased TGR and half (n = 10) with clinical benefit (SD >6 months). We observed favorable local responses within the RT field. Additional strategies are needed to further delay progression and effect response.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Adenoide Cístico/tratamento farmacológico , Carcinoma Adenoide Cístico/radioterapia , Idoso , Carcinoma Adenoide Cístico/patologia , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Circulating tumors cells (CTCs) are considered an early step towards metastasis and have been linked to poor prognosis in several types of cancer. CTCs in squamous cell carcinoma of the head and neck (SCCHN) have an unclear role. METHODS: In this prospective study, patients with locally advanced or metastatic SCCHN had CTC counts assessed before starting systemic treatment using the CellSearch System. Select cases also had sequential CTC evaluation. Presence of CTCs was correlated with patient characteristics and outcomes. RESULTS: Forty-eight patients enrolled, and 36 had evaluable clinical data and baseline CTC counts. Twenty-five patients had locally advanced disease (LAD) and 11 had metastatic disease. ≥1 CTCs were detected in six patients with LAD (24%) and four with metastatic disease (36%). On univariate analysis, smoking was associated with CTCs. CONCLUSION: CTCs are not associated with prognosis in patients with LAD and metastatic disease; however, they are present in this patient population, and ≥1 CTCs is associated with a history of smoking. LEVEL OF EVIDENCE: 1b; individual prospective cohort study.
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BACKGROUND: To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC. METHODS: The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response. RESULTS: A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity. CONCLUSIONS: Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.
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Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinolonas/administração & dosagem , Neoplasias das Glândulas Salivares/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Quinolonas/efeitos adversos , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Resultado do TratamentoRESUMO
BACKGROUND: NUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis. METHODS: Clinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS). RESULTS: For 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors. CONCLUSIONS: We identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.
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BACKGROUND: Although high-grade salivary gland cancers (SGCs) often express androgen receptor (AR) and/or HER-2/neu, therapeutically targeting these receptors in SGC remains investigational. We investigated the prevalence of receptor expression and the benefit of adjuvant HER-2 directed therapy in the high-risk postoperative setting and explored the clinical utility of sequentially targeting these receptors in the setting of advanced disease. MATERIALS AND METHODS: We clinically annotated 95 patients with SGC (excluding adenoid cystic carcinoma) treated at our institution from 2002 to 2019 and recorded AR, HER-2/neu status, and tumor genomic profiling results when available. Clinicopathologic information was then integrated with outcomes. RESULTS: Of 95 patients, most had high-risk histologies, with salivary duct carcinoma (SDC) as the most frequent diagnosis (43, 45%). Thirty-five (37%) experienced recurrence (51% SDC). HER-2/neu was positive (1-3+) by immunostaining in 34 of 52 (65%) evaluable cases. There was no difference in survival based on HER-2/neu or AR expression. Nine of 17 (53%) patients with HER-2+ SDC received adjuvant chemoradiation with trastuzumab. Median disease-free survival (DFS) and overall survival (OS) were longer among patients with HER-2/neu 3+ staining tumors who received adjuvant trastuzumab versus those who did not (DFS, 117 vs. 9 months; p = .02; OS, 74 vs. 43 months; p = .02), with no difference among other HER-2/neu subgroups (0-2+). Two of nine (22%) patients treated with adjuvant trastuzumab demonstrated recurrence, both with low HER-2/neu staining intensity (1+). Longer time to recurrence (hazard ratio, 0.94; p = .01) predicted improved outcomes. Both androgen deprivation and HER-2-directed therapies had clinical benefit beyond the first-line metastatic setting, with partial response observed beyond second-line use. CONCLUSION: Although prospective data are lacking, the use of adjuvant trastuzumab in high-risk patients with SGC appears beneficial, particularly among patients with tumors exhibiting HER-2/neu 3+ immunostaining. IMPLICATIONS FOR PRACTICE: Results of this study showed an improved disease-free and overall survival in patients treated with adjuvant trastuzumab for high-risk salivary gland cancers with strong HER-2/neu staining intensity. Following recurrence or metastatic spread, sequential HER-2, and androgen-directed therapies may benefit certain patients with salivary gland cancer.
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Neoplasias da Mama , Neoplasias da Próstata , Neoplasias das Glândulas Salivares , Antagonistas de Androgênios , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos , Receptor ErbB-2/genética , Neoplasias das Glândulas Salivares/tratamento farmacológico , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: Little is known about the long-term impact of local and systemic therapies for recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC), or the clinical significance of molecular alterations. METHODS: We identified 72 R/M cases among 123 ACC patients from our institution. We report long-term outcomes, predictors of recurrence and survival, and the impact of sequential cancer-directed therapy among R/M patients. We integrate genomic data for 36 sequenced ACC patients. RESULTS: Median overall survival (OS) from initial diagnosis was 35.1 ys (95%CI: 25.8-37.3) for R/M ACC patients. 10-y OS among R/M patients was 84.7%, worse for patients with extra-pulmonary metastatic disease (p = 0.02). Only initial disease stage predicted recurrence (OR 1.69, p = 0.03). Longer time to first R/M treatment predicted improved survival (p < 0.01); those treated ≤ 3 years from their R/M diagnosis had poor outcomes (p = 0.01). R/M patients who received systemic therapy vs. active surveillance had similar survival (p = 0.35). Molecular findings predicted outcomes: 10-y OS: 100% MYB, 53.3% PI3K, 32.1% NOTCH1 and others, p = 0.03. PI3K mutations predicted a longer disease-free interval (p = 0.04). CONCLUSIONS: Underlying disease biology remains the strongest predictor of outcomes in R/M ACC. Shorter time to R/M therapy predicts poor outcomes. Molecular alterations are prognostic, and PI3K mutations identify an intermediate-risk ACC subgroup.
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Carcinoma Adenoide Cístico/complicações , Genômica/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Adenoide Cístico/mortalidade , Carcinoma Adenoide Cístico/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Adulto JovemRESUMO
PURPOSE: To determine the maximum tolerated dose and tolerability of (1) afatinib in combination with postoperative radiation therapy (PORT) for patients with intermediate-risk squamous cell carcinoma of the head and neck (SCCHN) and (2) afatinib in combination with PORT and weekly docetaxel for high-risk SCCHN. METHODS AND MATERIALS: An open-label, multicenter, 2-cohort, phase 1 dose-escalation trial was conducted using a 3 + 3 design. Eligible patients had definitive surgery for SCCHN, including the oral cavity, oropharynx, larynx, or hypopharynx and had intermediate- or high-risk pathologic features. Afatinib was given for a 1-week lead in before PORT and daily during 6 to 6.5 weeks of PORT with or without weekly docetaxel. The starting dose was 30 mg and could be escalated to 40 mg or de-escalated to 20 mg. The primary objective was to determine the maximum tolerated dose of afatinib with PORT or PORT + docetaxel. RESULTS: Between April 2013 and November 2017, 27 patients were enrolled and started study treatment, including 16 intermediate-risk patients and 11 high-risk patients, all with Eastern Cooperative Oncology Group performance status of 0 to 1. Most patients (n = 25) had oral cavity cancer and were treated to a median total dose of 60 Gy in the intermediate-risk arm and 65 Gy in the high-risk arm. There was 1 grade 4 event, but no deaths. The maximum tolerated dose was not established owing to dose-limiting toxicities (DLTs) in both arms. In the high-risk arm, DLTs were grade 3 mucositis (n = 3) and grade 3 diarrhea/hypokalemia (n = 1). In the intermediate-risk arm, DLTs were grade 3 mucositis (n = 4) and grade 3 diarrhea (n = 2). CONCLUSIONS: Afatinib in combination with PORT for mucosal SCCHN was difficult to tolerate because of grade 3 toxicity, mostly mucositis, in a cohort of patients requiring high-dose PORT to the oral cavity. This regimen may be better tolerated for a non-oral cavity site or if given in a different schedule.
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Afatinib/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Adulto , Afatinib/efeitos adversos , Idoso , Antineoplásicos/efeitos adversos , Carcinoma de Células Escamosas/patologia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Diarreia/etiologia , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Esquema de Medicação , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hipopotassemia/etiologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias Bucais/terapia , Mucosite/etiologia , Período Pós-Operatório , Estudos Prospectivos , Dosagem RadioterapêuticaRESUMO
AIMS: The activity that the immune checkpoint inhibitor (ICI) cemiplimab has recently demonstrated has led to a paradigm shift in the management of patients with advanced cutaneous squamous cell carcinoma (cSCC). To identify predictive biomarkers of response to ICIs in advanced cSCC, we studied 33 patients who received ICI therapy at the Dana-Farber/Harvard Cancer Center (DF/HCC) and analysed sequencing data for a subset of these patients. METHODS: We collected clinical data using electronic health records and genomic data using the institutional OncoPanel platform of the DF/HCC. We compared tumour genomics with data from previously sequenced cSCC cohorts. RESULTS: We observed high tumour mutational burden regardless of smoking status and response to ICI and longer median overall survival among those patients who achieved an ICI response. We compared the genetic data from our cohort with data from other cohorts that included fewer patients with distant metastatic disease. Although our cohort had a similar genetic landscape to those of comparator cohorts, mutations in PIK3C2B were more common in our study. In our cohort, copy number alterations (CNAs) in the 3q chromosomal arm appeared to predict response to ICI therapy. CONCLUSION: CNAs in the 21-27 bands of chromosome arm 3q, a region that includes PIK3CA, ETV5 and BCL6, may represent predictors of response to ICI and may be candidates for drug targeting in combination or sequence with ICI agents.
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Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 3/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Neoplasias Cutâneas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fatores de Transcrição/genética , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Variações do Número de Cópias de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
BACKGROUND: Radiation therapy for squamous cell cancer of the head and neck with unknown primary (head and neck CUP) has been associated with significant levels of swallowing toxicity. We examined the effect of changes in mucosal dose on development of laryngeal strictures and percutaneous endoscopic gastrostomy (PEG) dependence. METHODS: Retrospective analysis of 58 patients with head and neck CUP treated with intensity-modulated radiation therapy (IMRT) at the Dana Farber Cancer Institute from August 2004 through July 2013. RESULTS: There were no significant differences between any recurrences for groups treated to 56 versus ≥60 Gy to the mucosal surfaces. However, mucosal dose and chemotherapy type were associated with stricture on multivariable analysis; median PEG dependence was decreased for patients treated to 56 Gy. A larynx-sparing approach was associated with improved outcomes for strictures and PEG use. CONCLUSION: In this single institution study, a 56 Gy IMRT-based mucosal dose demonstrated significant improvements in swallowing toxicity. Additional benefit was seen with larynx-sparing IMRT.
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Neoplasias de Cabeça e Pescoço/radioterapia , Neoplasias Primárias Desconhecidas/patologia , Lesões por Radiação/prevenção & controle , Radioterapia de Intensidade Modulada/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Adulto , Idoso , Institutos de Câncer , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/secundário , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mucosa/efeitos da radiação , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Modelos de Riscos Proporcionais , Melhoria de Qualidade , Dosagem Radioterapêutica , Estudos Retrospectivos , Medição de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Análise de Sobrevida , Resultado do TratamentoRESUMO
Pluripotent cells have been used to probe developmental pathways that are involved in genetic diseases and oncogenic events. To find new therapies that would target MYB-driven tumors, we developed a pluripotent zebrafish blastomere culture system. We performed a chemical genetic screen and identified retinoic acid agonists as suppressors of c-myb expression. Retinoic acid treatment also decreased c-myb gene expression in human leukemia cells. Translocations that drive overexpression of the oncogenic transcription factor MYB are molecular hallmarks of adenoid cystic carcinoma (ACC), a malignant salivary gland tumor with no effective therapy. Retinoic acid agonists inhibited tumor growth in vivo in ACC patient-derived xenograft models and decreased MYB binding at translocated enhancers, thereby potentially diminishing the MYB positive feedback loop driving ACC. Our findings establish the zebrafish pluripotent cell culture system as a method to identify modulators of tumor formation, particularly establishing retinoic acid as a potential new effective therapy for ACC.
Assuntos
Blastômeros/imunologia , Carcinoma Adenoide Cístico/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myb/antagonistas & inibidores , Neoplasias das Glândulas Salivares/tratamento farmacológico , Tretinoína/farmacologia , Proteínas de Peixe-Zebra/antagonistas & inibidores , Peixe-Zebra/imunologia , Animais , Blastômeros/patologia , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/imunologia , Carcinoma Adenoide Cístico/patologia , Humanos , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/imunologia , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/imunologia , Neoplasias das Glândulas Salivares/patologia , Células U937 , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/imunologiaRESUMO
Radiologic predictors of response to immune checkpoint blockade (ICPi) in advanced head and neck squamous cell carcinoma (HNSCC) patients could help guide patient selection and management. We analyzed a large institutional cohort of 100 consecutive HNSCC patients treated with ICPi to investigate associations between molecular and radiologic phenotype and assess radiologic predictors of response and survival. Of particular interest was the impact of increased total tumor burden (TB), calculated as the sum of the largest diameter of all measurable lesions according to RECIST 1.1, and early radiologic indicators of response versus progression. Within our cohort, 42% of patients had HPV+ associated disease, 64% had persistent/recurrent head and neck lesions, and 77% had distant metastases. Median TB was 5.4â¯cm. HPV+ disease and increased total mutational burden were associated with distant disease in the absence of locoregional disease (pâ¯<â¯0.01 and pâ¯=â¯0.03, respectively). Forty patients (40%) demonstrated clinical benefit to ICPi, and the median overall survival (OS) on PD-1 therapy was 4.5â¯months. A lower tumor burden at baseline was associated with clinical benefit (pâ¯=â¯0.03) and improved OS (pâ¯<â¯0.01, HR 2.33). There was only one instance of pseudoprogression; indeed any increase in TB on first interval scan was associated with poor OS (pâ¯=â¯0.02, HR 2.39). These data suggest that HNSCC patients who benefit from ICPi are more likely to have lower tumor burden at the onset of treatment and minimal increase in tumor burden while on treatment.
Assuntos
Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Seleção de Pacientes , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carga Tumoral , Adulto JovemRESUMO
While it has been recognized that human papillomavirus-associated (HPV-associated) oropharyngeal cancer (OPC) portends an improved prognosis, distinct patterns of disease recurrence have emerged. Molecular characterization of this subset of HPV patients remains unexplored. We evaluated 52 metastatic HPV+ OPC patients from our institution and paired massively parallel sequencing data with clinical parameters and survival outcomes in 81% of patients. Genomic data were then compared with 2 molecularly defined, curable HPV+ cohorts. Metastatic HPV+ OPC patients with pulmonary-only metastases demonstrated worse outcomes. Nonexclusive somatic alterations in KMT2D and PIK3CA were most frequent, with PRKDC alterations occurring at higher frequency when compared with all sequenced HPV+ OPC patients. PI3K pathway alterations were associated with improved outcomes among metastatic HPV+ OPC patients. We demonstrate subtle differences in the mutational landscape between curable and metastatic HPV+ OPC populations, with a trend towards more frequent DNA repair protein alterations in the latter. We demonstrate improved outcomes when PI3K pathway alterations are present in these patients. We provide molecular insights for this important HPV+ subgroup that have significant therapeutic implications.
Assuntos
Predisposição Genética para Doença/genética , Neoplasias Orofaríngeas/etiologia , Neoplasias Orofaríngeas/genética , Infecções por Papillomavirus/complicações , Fosfatidilinositol 3-Quinases/metabolismo , Adulto , Idoso , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Feminino , Dosagem de Genes , Neoplasias de Cabeça e Pescoço , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Papillomaviridae , Transdução de Sinais , Análise de SobrevidaRESUMO
Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.
Assuntos
Repetições de Microssatélites , Neoplasias/genética , Neoplasias/imunologia , Estudos de Coortes , Exoma , Genômica/métodos , Humanos , Imunidade/genética , MutaçãoRESUMO
PURPOSE: Programmed death-1 (PD-1) inhibitors are approved for the treatment of patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN). Ongoing and planned randomized phase 3 trials are testing the benefit of combining PD-1/programmed death-ligand 1 (PD-L1) inhibitors with chemoradiation for patients with locoregionally confined SCCHN. Few studies have investigated relationships among potential predictive pathologic biomarkers such as PD-L1, PD-L2, and PD-1 in this population and associations between these markers and clinical characteristics. METHODS AND MATERIALS: We retrospectively reviewed records and pathology from 81 patients with locoregional oropharynx SCCHN treated with curative intent. Samples were analyzed for PD-L1, PD-L2, PD-1, CD8, and CD56 expression using immunohistochemistry. Human papilloma virus (HPV) status was determined by p16-immunohistochemistry and confirmed by in situ hybridization or polymerase chain reaction-based HPV typing. Correlations between HPV status, clinical features, and recurrence status with immune markers in both tumor and tumor-associated stroma were determined. Hazard ratios were estimated via Cox proportional hazards model. RESULTS: Tumor PD-L1 expression was inversely associated with age (P = .01) and the highest levels of expression (>30% of tumor cells) were observed in HPV-associated tumors. There was a correlation between tumor and stromal PD-L1 expression (P = < .0001). PD-1 and CD8 expression within tumor deposits was associated with HPV status (P = 0.003 and P = .008, respectively) and decreased local recurrence (P = .001 and P < .001, respectively). In addition to the association between tumor and stromal PD-1 (P < .0001), PD-1 was also correlated with tumor PD-L1 expression (P < .001). CD56+ natural killer cell infiltrates correlated with PD-L1 expression. CONCLUSIONS: In patients with untreated oropharyngeal SCCHN, HPV-associated tumors displayed the highest levels of PD-L1 expression and PD-1+ and CD8+ immune cells. Locally recurrent tumors had lower levels of PD-L1, PD-1, and CD-8 positivity. Whereas almost all SCCHN tumors had CD56+ infiltrating natural killer cells, most tumors didn't have PD-L2 expression. These associations may help predict which patients may benefit most from immunotherapeutic approaches.