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Introduction: Double-negative prostate cancer, an androgen receptor-independent prostate cancer without features of neuroendocrine tumors, is refractory to treatment but could be an ideal candidate for individualized treatment. Case presentation: An 85-year-old patient with metastatic castration-resistant prostate cancer without prostate-specific antigen progression presented with local recurrence and liver and lung metastases 6 months after orchiectomy and apalutamide. A liver tumor biopsy led to a diagnosis of double-negative prostate cancer. FoundationOne® CDx showed BRCA2 mutation and high tumor mutation burden. Olaparib and pembrolizumab were administered sequentially, and the patient responded to each treatment for 5 months until radiographic progression. Conclusion: Sequential use of olaparib and pembrolizumab may be effective for double-negative prostate cancer with BRCA2 mutations and high tumor mutation burden.
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BACKGROUND: The simplified Pulmonary Embolism Severity Index (sPESI) has limitations when evaluating acute pulmonary embolism (PE) in patients with concurrent malignancy. Despite its utility in predicting outcomes among cancer patients, the role of the Eastern Cooperative Oncology Group Performance Status (ECOG PS) in acute PE remains underexplored. This study aims to assess the prognostic significance of ECOG PS ≥ 3 on short- and long-term mortality in acute PE with malignancy, correlating it with the sPESI. METHODS AND RESULTS: We retrospectively analyzed 44 hemodynamically stable acute PE patients with unresectable or metastatic malignancies ineligible for curative treatment at Kameda Medical Center, a tertiary medical facility in Japan, from April 1, 2019, to March 2, 2023. Of these patients, 16 (36.4%) had ECOG PS ≥ 3. No 30-day mortality occurred in patients with ECOG PS ≤ 2, compared to 18.8% in those with ECOG PS ≥ 3 (p = 0.04). Groups were similar in the sPESI scores, hospital-onset PE proportion, and initial treatments. Post PE diagnosis, 92.9% of ECOG PS ≤ 2 patients and 50% of ECOG PS ≥ 3 patients received chemotherapy (p = 0.002). Cox regression analysis revealed ECOG PS ≥ 3 was independently associated with increased overall survival hazard (adjusted HR = 4.0; P = 0.002). CONCLUSIONS: ECOG PS ≥ 3 suggests a poorer short-term prognosis and independently predicts a worse long-term prognosis in hemodynamically stable acute PE patients with advanced malignancies.
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INTRODUCTION: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy has a potential efficacy in a specific subset of non-squamous non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations following tyrosine kinase inhibitor (TKI) treatment. However, there is a dearth of investigations on the effectiveness of ABCP therapy as the primary outcome of EGFR-TKI use. METHODS: A single-center retrospective analysis was performed on 24 cases of stage IV EGFR-positive non-squamous NSCLC patients who received one or more lines of EGFR-TKI therapy and subsequently initiated ABCP therapy within the timeframe of April 1, 2019, to April 30, 2023. This study assessed overall survival and progression-free survival associated with ABCP therapy, further analyzing the overall survival data based on EGFR subgroups. RESULTS: The mean age of the cohort was 65 ± 9 years with 14 females (58%). The performance status (PS) was recorded as 0 in 13 out of 24 patients (54%) and 1 in 11 out of 24 patients (46%). Thirteen (54%) patients had a history of smoking. Adenocarcinoma histology was prevalent in all cases. The EGFR mutations included Ex19del in 14 patients (58%) and L858R in 10 (42%) patients. At ABCP therapy initiation, liver metastases were evident in three cases (13%) and brain metastases in eight (33%). Programmed death ligand 1 (22C3) expression levels varied, with <1%, 1-49%, and ≥50% observed in five, 11, and five cases, respectively, while data were missing for three cases. The median follow-up duration was 14.1 months, with median overall survival estimated at 23.6 months (95% CI: 14.5 months - not reached) and median progression-free survival at 5.6 months (95% CI: 4.9-11.5 months). The EGFR L858R mutation showed a favorable trend in overall survival compared with the EGFR Ex19del mutation (not evaluated vs. 23.6 months). CONCLUSIONS: ABCP therapy for EGFR-positive non-squamous NSCLC is a promising option, similar to immune checkpoint inhibitor-free platinum-based combination therapy. Therefore, prospective trials are necessary to confirm the efficacy of these treatments.
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The serine-threonine protein kinase B-RAF (BRAF) fusions are rarely observed in non-small cell lung cancer (NSCLC) accounting for less than 1%, and therapeutic evidence for molecular-targeted drugs is lacking, unlike for BRAF V600E mutation by RAF and MEK inhibitors. A 75-year-old female patient with no smoking history and mild renal dysfunction developed recurrent lung adenocarcinoma and was initially treated with pembrolizumab immunotherapy followed by chemotherapy using docetaxel showing a certain efficacy but the disease finally progressed. Comprehensive genome profiling showed a novel SLC44A1-BRAF fusion and the tumor progression was controlled with the MEK inhibitor trametinib. Because of the rarity of NSCLC with BRAF fusion, the description of this case would be helpful for the treatment strategy for such tumors.
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The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the ability to distinguish between focal amplification and polysomy, a task for which simple MET copy number measurement proves insufficient. To effectively differentiate between the two, it is crucial to utilize comparative measures, including in situ hybridization (ISH) with the centromere or next generation sequencing (NGS) with adjacent genes. Despite the promising potential of MET amplification treatment, the judicious selection of patients is paramount to maximize therapeutic efficacy. The effectiveness of MET inhibitors can fluctuate depending on the extent of MET amplification. Future research must seek to establish the ideal threshold value for MET amplification, identify the most efficacious combination therapies, and innovate new targeted treatments for patients exhibiting MET amplification.
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IMPORTANCE: Precision oncology using comprehensive genomic profiling (CGP) by next-generation sequencing is aimed at companion diagnosis and genomic profiling. The clinical utility of CGP before the standard of care (SOC) is still not resolved, and more evidence is needed. OBJECTIVE: To investigate the clinical utility of next-generation CGP (FoundationOne CDx [F1CDx]) in patients with previously untreated metastatic or recurrent solid tumors. DESIGN, Setting, and Participants: This multicenter, prospective, observational cohort study enrolled patients with previously untreated advanced solid tumors between May 18, 2021, and February 16, 2022, with follow-up through August 16, 2022. The study was conducted at 6 hospitals in Japan. Eligible patients were aged 20 years or older and had Eastern Cooperative Oncology Group performance status of 0 to 1 with previously untreated metastatic or recurrent cancers in the gastrointestinal or biliary tract; pancreas, lung, breast, uterus, or ovary; and malignant melanoma. EXPOSURE: Comprehensive genomic profiling testing before SOC for advanced solid tumors. MAIN OUTCOMES AND MEASURES: Proportion of patients with actionable or druggable genomic alterations and molecular-based recommended therapy (MBRT). RESULTS: A total of 183 patients met the inclusion criteria and 180 patients (92 men [51.1%]) with a median age of 64 years (range, 23-88 years) subsequently underwent CGP (lung [n = 28], colon/small intestine [n = 27], pancreas [n = 27], breast [n = 25], biliary tract [n = 20], gastric [n = 19], uterus [n = 12], esophagus [n = 10], ovary [n = 6], and skin melanoma [n = 6]). Data from 172 patients were available for end point analyses. Actionable alterations were found in 172 patients (100.0%; 95% CI, 97.9%-100.0%) and druggable alternations were identified in 109 patients (63.4%; 95% CI, 55.7%-70.6%). The molecular tumor board identified MBRT for 105 patients (61.0%; 95% CI, 53.3%-68.4%). Genomic alterations included in the companion diagnostics list of the CGP test were found in 49 patients (28.5%; 95% CI, 21.9%-35.9%) in a tumor-agnostic setting. After a median follow-up of 7.9 months (range, 0.5-13.2 months), 34 patients (19.8%; 95% CI, 14.1%-26.5%) received MBRT. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that CGP testing before SOC for patients with advanced solid tumors may be clinically beneficial to guide the subsequent anticancer therapies, including molecularly matched treatments.
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Melanoma , Medicina de Precisión , Masculino , Femenino , Humanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Prospectivos , Mutación , Genómica , Recurrencia , Melanoma Cutáneo MalignoRESUMEN
Giant cell tumor of soft tissue (GCTST) is a defined disease entity that has a morphology similar to giant cell tumor of bone (GCTB). The malignant transformation of GCTST has not been reported, and a kidney primary is extremely rare. We report the case of a 77-year-old Japanese male, who was diagnosed with primary GCTST of the kidney and showed peritoneal dissemination, considered to be a malignant transformation of GCTST, in 4 years and 5 months. Histologically, the primary lesion showed characteristics of round cells with not prominent atypia, multi-nucleated giant cells, and osteoid formation, and carcinoma components were not found. The peritoneal lesion was characterized by osteoid formation and round to spindle-shaped cells, but differed in nuclear atypia, and multi-nucleated giant cells were not detected. Immunohistochemical and cancer genome sequence analysis suggested these tumors were sequential. This is a first report of a case that we could diagnose as primary GCTST of the kidney and could be determined as malignant transformation of GCTST in the clinical course. Analysis of this case will be examined in the future when genetic mutations and the disease concepts of GCTST are established.
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Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).
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Genómica , Neoplasias , Humanos , Japón , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Medicina de PrecisiónRESUMEN
BACKGROUND: Precision medicine with gene panel testing based on next-generation sequencing for patients with cancer is being used increasingly in clinical practice. HER2, which encodes the human epidermal growth factor receptor 2 (HER2), is a potentially important driver gene. However, therapeutic strategies aimed at mutations in the HER2 extracellular domain have not been clarified. We therefore investigated the effect of EGFR co-targeted therapy with HER2 on patient-derived cancer models with the HER2 extracellular domain mutation E401G, based on our previous findings that this mutation has an epidermal growth factor receptor (EGFR)-mediated activation mechanism. METHODS: We generated a xenograft (PDX) and a cancer tissue-originated spheroid (CTOS) from a patient's cancer containing an amplified HER2 E401G mutation. With these platforms, we compared the efficacy of afatinib, a tyrosine kinase inhibitor having anti-HER2 and anti-EGFR activity, with two other therapeutic options: lapatinib, which has similar properties but weaker EGFR inhibition, and trastuzumab plus pertuzumab, for which evidence exists of treatment efficacy against cancers with wild-type HER2 amplification. Similar experiments were also performed with H2170, a cell line with wild-type HER2 amplification, to contrast the characteristics of these drug's efficacies against HER2 E401G. RESULTS: We confirmed that PDX and CTOS retained morphological and immunohistochemical characteristics and HER2 gene profiles of the original tumor. In both PDX and CTOS, afatinib reduced tumor size more than lapatinib or trastuzumab plus pertuzumab. In addition, afatinib treatment resulted in a statistically significant reduction in HER2 copy number at the end of treatment. On the other hand, in H2170 xenografts with wild-type HER2 amplification, trastuzumab plus pertuzumab was most effective. CONCLUSIONS: Afatinib, a dual inhibitor of HER2 and EGFR, showed a promising effect on cancers with amplified HER2 E401G, which have an EGFR-mediated activation mechanism. Analysis of the activation mechanisms of mutations and development of therapeutic strategies based on those mechanisms are critical in precision medicine for cancer patients.
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Antineoplásicos , Neoplasias , Humanos , Afatinib , Lapatinib , Antineoplásicos/uso terapéutico , Receptor ErbB-2/metabolismo , Trastuzumab , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Mutación , Línea Celular Tumoral , Receptores ErbB/genéticaRESUMEN
Tackling cancer is a major challenge right on the global level. Europe is only the tip of an iceberg of cancer around the world. Prosperous developed countries share the same problems besetting Europe-and the countries and regions with fewer resources and less propitious conditions are in many cases struggling often heroically against a growing tide of disease. This paper offers a view on these geographically wider, but essentially similar, challenges, and on the prospects for and barriers to better results in this ceaseless battle. A series of panels have been organized by the European Alliance for Personalised Medicine (EAPM) to identify different aspects of cancer care around the globe. There is significant diversity in key issues such as NGS, RWE, molecular diagnostics, and reimbursement in different regions. In all, it leads to disparities in access and diagnostics, patients' engagement, and efforts for a better understanding of cancer.
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We here present a 33-year-old woman who was referred to our hospital with a complaint of back pain and was found to have elevated IgG and hypercalcemia, as well as osteolytic lesions of pelvis and spines. 18F-FDG-PET/CT scan revealed numerous uptakes in the bones. An examination of the bone marrow revealed increased plasma cells (10.2%). Despite clinical similarities to multiple myeloma, any evidence of plasma cell clonal proliferation, including serum M-protein and light chain restriction, was not found. A reexamination of the bone marrow with a biopsy revealed the proliferation of abnormal cells with chromogranin A and synaptophysin expression but no expression of hematopoietic and epithelial cell markers. Based on these results together with extra-adrenal lesions, a diagnosis of malignant paraganglioma was made. Malignant paraganglioma is known to frequently cause bone metastasis and skeletal related events, whose clinical manifestations are similar to those of multiple myeloma. Since patients with osteolytic lesions, hypercalcemia, and hypergammaglobulinemia are likely to be referred to hematologists, malignant paraganglioma should be considered as a differential diagnosis.
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Hipercalcemia , Mieloma Múltiple , Paraganglioma , Femenino , Humanos , Adulto , Mieloma Múltiple/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Fluorodesoxiglucosa F18/metabolismo , Paraganglioma/diagnósticoRESUMEN
Background: SARS-CoV-2 (COVID-19) elicits a T-cell antigen-mediated immune response of variable efficacy. To understand this variability, we explored transcriptomic expression of angiotensin-converting enzyme 2 (ACE2, the SARS-CoV-2 receptor) and of immunoregulatory genes in normal lung tissues from patients with non-small cell lung cancer (NSCLC). Methods: This study used the transcriptomic and the clinical data for NSCLC patients generated during the CHEMORES study [n = 123 primary resected (early-stage) NSCLC] and the WINTHER clinical trial (n = 32 metastatic NSCLC). Results: We identified patient subgroups with high and low ACE2 expression (p = 1.55 × 10-19) in normal lung tissue, presumed to be at higher and lower risk, respectively, of developing severe COVID-19 should they become infected. ACE2 transcript expression in normal lung tissues (but not in tumor tissue) of patients with NSCLC was higher in individuals with more advanced disease. High-ACE2 expressors had significantly higher levels of CD8+ cytotoxic T lymphocytes and natural killer cells but with presumably impaired function by high Thymocyte Selection-Associated High Mobility Group Box Protein TOX (TOX) expression. In addition, immune checkpoint-related molecules - PD-L1, CTLA-4, PD-1, and TIGIT - are more highly expressed in normal (but not tumor) lung tissues; these molecules might dampen immune response to either viruses or cancer. Importantly, however, high inducible T-cell co-stimulator (ICOS), which can amplify immune and cytokine reactivity, significantly correlated with high ACE2 expression in univariable analysis of normal lung (but not lung tumor tissue). Conclusions: We report a normal lung immune-tolerant state that may explain a potential comorbidity risk between two diseases - NSCLC and susceptibility to COVID-19 pneumonia. Further, a NSCLC patient subgroup has normal lung tissue expressing high ACE2 and high ICOS transcripts, the latter potentially promoting a hyperimmune response, and possibly leading to severe COVID-19 pulmonary compromise.
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PURPOSE: The prognosis of patients with non-small-cell lung cancer (NSCLC), traditionally determined by anatomic histology and TNM staging, neglects the biological features of the tumor that may be important in determining patient outcome and guiding therapeutic interventions. Identifying patients with NSCLC at increased risk of recurrence after curative-intent surgery remains an important unmet need so that known effective adjuvant treatments can be offered to those at highest risk of recurrence. METHODS: Relative gene expression level in the primary tumor and normal bronchial tissues was used to retrospectively assess their association with disease-free survival (DFS) in a cohort of 120 patients with NSCLC who underwent curative-intent surgery. RESULTS: Low versus high Digital Display Precision Predictor (DDPP) score (a measure of relative gene expression) was significantly associated with shorter DFS (highest recurrence risk; P = .006) in all patients and in patients with TNM stages 1-2 (P = .00051; n = 83). For patients with stages 1-2 and low DDPP score (n = 29), adjuvant chemotherapy was associated with improved DFS (P = .0041). High co-overexpression of CTLA-4, PD-L1, and ICOS in normal lung (28 of 120 patients) was also significantly associated with decreased DFS (P = .0013), suggesting an immune tolerance to tumor neoantigens in some patients. Patients with DDPP low and immunotolerant normal tissue had the shortest DFS (P = 2.12E-11). CONCLUSION: TNM stage, DDPP score, and immune competence status of normal lung are independent prognostic factors in multivariate analysis. Our findings open new avenues for prospective prognostic assessment and treatment assignment on the basis of transcriptomic profiling of tumor and normal lung tissue in patients with NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Antígeno B7-H1/análisis , Antígeno CTLA-4/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Pulmón/química , Neoplasias Pulmonares/tratamiento farmacológico , Estudios Prospectivos , Estudios Retrospectivos , TranscriptomaRESUMEN
Comprehensive genomic profiling (CGP) provides information regarding cancer-related genetic aberrations. However, its clinical utility in recurrent/metastatic head and neck cancer (R/M HNC) remains unknown. Additionally, predictive biomarkers for immune checkpoint inhibitors (ICIs) should be fully elucidated because of their low response rate. Here, we analyzed the clinical utility of CGP and identified predictive biomarkers that respond to ICIs in R/M HNC. We evaluated over 1100 cases of HNC using the nationwide genetic clinical database established by the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) and 54 cases in an institution-based study. The C-CAT database revealed that 23% of the cases were candidates for clinical trials, and 5% received biomarker-matched therapy, including NTRK fusion. Our institution-based study showed that 9% of SCC cases and 25% of salivary gland cancer cases received targeted agents. In SCC cases, the tumor mutational burden (TMB) high (≥10 Mut/Mb) group showed long-term survival (>2 years) in response to ICI therapy, whereas the PD-L1 combined positive score showed no significant difference in progression-free survival. In multivariate analysis, CCND1 amplification was associated with a lower response to ICIs. Our results indicate that CGP may be useful in identifying prognostic biomarkers for immunotherapy in patients with HNC.
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Cowden syndrome is a rare autosomal dominant disorder characterized by multiple hamartomas in various tissues, including the skin, mucous membranes, and gastrointestinal tract. Germline mutations of the PTEN tumor suppressor gene are responsible for Cowden syndrome. Cowden syndrome is associated with an increased risk of breast, thyroid, renal and uterine cancers; however, ovarian cancer rarely develops in women with Cowden syndrome, although somatic PTEN mutation often occurs in some types of ovarian carcinomas. Herein we report the first case of ovarian carcinosarcoma that developed in a woman with Cowden syndrome. A 55-year-old woman with a history of breast cancer, thyroid goiter, and palatal papillomatosis presented with pelvic distention. CT scan revealed a pelvic tumor suggesting ovarian cancer. She underwent a total abdominal hysterectomy, a bilateral salpingo-oophorectomy, and an omentectomy, but the surgical cytoreduction was suboptima( l >2 cm residual disease). Pathological examination showed a mixed tumor composed of high-grade carcinoma and heterologous sarcoma. Immunohistochemically, tumor cells were positive for p53. She was diagnosed with stage â ¢C ovarian carcinosarcoma. Genetic testing detected a PTEN variant, confirming the diagnosis of Cowden syndrome. She received paclitaxel/ carboplatin chemotherapy. However, no response was observed and she died of disease 2 months postoperatively.
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Carcinosarcoma , Síndrome de Hamartoma Múltiple , Neoplasias Ováricas , Carcinosarcoma/complicaciones , Carcinosarcoma/cirugía , Femenino , Mutación de Línea Germinal , Síndrome de Hamartoma Múltiple/complicaciones , Síndrome de Hamartoma Múltiple/genética , Síndrome de Hamartoma Múltiple/cirugía , Humanos , Histerectomía , Persona de Mediana Edad , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugíaRESUMEN
BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.
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Antineoplásicos , Neuroblastoma , Adulto , Antineoplásicos/efectos adversos , Niño , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/genética , Ftalazinas/efectos adversos , Piperazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Poli(ADP-Ribosa) PolimerasasRESUMEN
INTRODUCTION: Clinical sequencing has provided molecular and therapeutic insights into the field of clinical oncology. However, despite its significance, its clinical utility in Japanese patients remains unknown. Here, we examined the clinical utility of tissue-based clinical sequencing with FoundationOne® CDx and FoundationOne® Heme. Between August 2018 and August 2019, 130 Japanese pretreated patients with advanced solid tumors were tested with FoundationOne® CDx or FoundationOne® Heme. RESULTS: The median age of 130 patients was 60.5 years (range: 3 to 84 years), and among them, 64 were males and 66 were females. Major cancer types were gastrointestinal cancer (23 cases) and hepatic, biliary, and pancreatic cancer (21 cases). A molecular tumor board had been completed on all 130 cases by October 31, 2019. The median number of gene alterations detected by Foundation testing, excluding variants of unknown significance (VUS) was 4 (ranged 0 to 21) per case. Of the 130 cases, one or more alterations were found in 123 cases (94.6%), and in 114 cases (87.7%), actionable alterations with candidates for therapeutic agents were found. In 29 (22.3%) of them, treatment corresponding to the gene alteration was performed. Regarding secondary findings, 13 cases (10%) had an alteration suspected of a hereditary tumor. Of the 13 cases, only one case received a definite diagnosis of hereditary tumor. CONCLUSIONS: Our study showed that clinical sequencing might be useful for detecting gene alterations in various cancer types and exploring treatment options. However, many issues still need to be improved.
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Predisposición Genética a la Enfermedad , Neoplasias Pancreáticas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Niño , Preescolar , Femenino , Hemo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Japón , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Pancreáticas/genética , Adulto JovenRESUMEN
Patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) have a poor prognosis. Recently, the use of immune checkpoint inhibitors (ICIs) for drug treatment has been expanding . However, the response rate to immunotherapy is low. Therefore, the identification of predictive biomarkers of response and resistance to ICIs is required for various types of malignant tumors. We report the case of a patient with recurrent and metastatic HNSCC who simultaneously showed different responses to nivolumab in metastatic lesions. After administering nivolumab, metastasis to the multiple cervical lymph node metastases showed a significant reduction, whereas a new metastasis to the right axillary lymph node occurred . Each surgical specimen was analyzed using the cancer gene panel test (FoundationOne CDx) to elucidate why treatment response is distinct among the same patient. Next-generation sequencing revealed MYC amplification and programmed cell death-1 loss in the right axillary lymph nodes but not cervical lymph nodes. Furthermore, t he histopathological findings suggested that MYC amplification regulated programmed death-ligand 1 expression and was involved in a decreased response to ICIs. This result is expected to help predict the efficacy of ICI treatment and select therapeutic agents.
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Neoplasias de Cabeza y Cuello , Nivolumab , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Humanos , Nivolumab/farmacología , Nivolumab/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológicoAsunto(s)
Coriocarcinoma/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Adulto , Coriocarcinoma/patología , Coriocarcinoma/cirugía , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos XRESUMEN
Amplification (amp) of MET can be observed in cases of focal gene copy number gain, such as MET-driven amp, or with a gain of chromosome 7, such as aneuploidy. Several studies have shown that only high-level focal MET amp (MET/CEP7 ratio ≥5) is oncogenic, with such tumors responding to targeted therapy. However, there are few reports on how to distinguish between focal amplification and aneuploidy using next-generation sequencing (NGS). A total of 1025 patients with advanced solid tumors (typically pre-treated) were tested with a non-invasive comprehensive cfDNA NGS panel (Guardant360) from July 2014 to June 2019. Since bioinformatics upgrades of Guardant360 were undergoing in September 2018, focal MET amp was determined by our independent algorithm using the cohorts tested before September 2018 (291 patients), and validation was performed in the remaining cohort (734 patients). MET alterations (alts) associated with aberrant signaling were found in 110 patients (10.7%) among nine different cancer types, most commonly in non-small cell (12.2%, 62/510) and small cell (33.3%, 3/9) lung cancers, gastroesophageal cancer (19.4%, 7/36), and prostate adenocarcinoma (15.6%; 5/32). Among 291 patients tested before September 2018, 37 (12.7%) had MET alts. Among these, 24 (64.9%) had amps, 5 (13.5%) had exon 14 skipping, and 13 (35.1%) had single nucleotide variants (SNVs). Co-alterations, such as amp + SNVs, were found in four samples (10.8%). Among 24 MET amps, 29.2% (7/24) were focal according to our algorithm. MET copy number was significantly higher with focal amp compared to non-focal amp (mean copy number 3.26 vs. 2.44, respectively, p = 0.00304). In 734 patients tested after September 2018, our definition of focal MET amp was detected in 4.2% (31/734). Overall, focal amplification based on our algorithm was 3.7% (=38/1025). This study describes an approach to distinguish focal and non-focal MET amplification using comprehensive genomic profiling of cfDNA in advanced cancer patients. Focal MET amp accounted for ~30% of all MET amp, which was found in 3.7% of patients with diverse cancers and was associated with a higher plasma copy number. Clinical studies are warranted to assess the clinical utility of targeted therapies for tumors with focal MET amplification detected by NGS of cfDNA.