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INTRODUCTION: Immune checkpoint inhibitor (ICI) combinations extend overall survival (OS) while anti-PD-1/L1 monotherapy is non-inferior to sorafenib in treatment-naïve, patients with advanced hepatocellular carcinoma (HCC). Clinicogenomic features are posited to influence patient outcomes. METHODS: The primary objective of this retrospective study was to define the clinical, pathologic, and genomic factors associated with outcomes to ICI therapy in patients with HCC. Patients with histologically confirmed advanced HCC treated with ICI at Memorial Sloan Kettering Cancer Center from 2012 to 2022 were included. Association between clinical, pathological, and genomic characteristics were assessed with univariable and multivariable Cox regression model for progression-free survival (PFS) and OS. RESULTS: Two-hundred and forty-two patients were treated with ICI-based therapy. Patients were predominantly male (82%) with virally mediated HCC (53%) and Child Pugh A score (70%). Median follow-up was 28 months (0.5-78.4). Median PFS for those treated in 1st line, 2nd line andâ ≥â 3rd line was 4.9 (range: 2.9-6.2), 3.1 (2.3-4.0), and 2.5 (2.1-4.0) months, respectively. Median OS for those treated in 1st line, 2nd line, andâ ≥â 3rd line was 16 (11-22), 7.5 (6.4-11), and 6.4 (4.6-26) months, respectively. Poor liver function and performance status associated with worse PFS and OS, while viral hepatitis C was associated with favorable outcome. Genetic alterations were not associated with outcomes. CONCLUSION: Clinicopathologic factors were the major determinates of outcomes for patients with advanced HCC treated with ICI. Molecular profiling did not aid in stratification of ICI outcomes. Future studies should explore alternative biomarkers such as the level of immune activation or the pretreatment composition of the immune tumor microenvironment.
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BACKGROUND: Acute cholangitis (AC) is a common complication of pancreatic ductal adenocarcinoma (PDAC). Herein, we evaluated outcomes after the first AC episode and predictors of mortality and AC recurrence in patients with stage IV PDAC. METHODS: We conducted a single-center, retrospective observational study using institutional databases. Clinical data and outcomes for patients with stage IV PDAC and at least one documented episode of AC, were assessed. Overall survival (OS) was estimated using the Kaplan-Meier method, and Cox regression model was employed to identify predictors of AC recurrence and mortality. RESULTS: One hundred and twenty-four patients with stage IV PDAC and AC identified between January 01, 2014 and October 31, 2020 were included. Median OS after first episode of AC was 4.1 months (95 % CI, 4.0-5.5), and 30-day, 6, and 12-month survival was 86.2 % (95 % CI, 80.3-92.5), 37 % (95 % CI, 29.3-46.6 %) and 18.9 % (95 % CI, 13.1-27.3 %), respectively. Primary tumor in pancreatic body/tail (HR 2.29, 95 % CI: 1.26 to 4.18, p = 0.011), concomitant metastases to liver and other sites (HR 1.96, 95 % CI: 1.16 to 3.31, p = 0.003) and grade 3 AC (HR 2.26, 95 % CI: 1.45 to 3.52, p < 0.001), predicted worse outcomes. Intensive care unit admission, sepsis, systemic therapy, treatment regimen, and time to intervention did not predict survival or risk of recurrence of AC. CONCLUSIONS: AC confers significant morbidity and mortality in advanced PDAC. Worse outcomes are associated with higher grade AC, primary tumor location in pancreatic body/tail, and metastases to liver and other sites.
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Colangitis , Neoplasias Pancreáticas , Humanos , Colangitis/complicaciones , Colangitis/mortalidad , Masculino , Femenino , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Pronóstico , Estadificación de Neoplasias , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/complicaciones , Carcinoma Ductal Pancreático/patología , Anciano de 80 o más Años , Adenocarcinoma/mortalidad , Adenocarcinoma/complicaciones , Adenocarcinoma/patología , Enfermedad Aguda , Factores de RiesgoRESUMEN
Locally advanced gastrointestinal (GI) malignancies have conventionally been treated in a multimodal fashion that combines (neo)adjuvant chemotherapy with or without radiation and definitive surgical resection. Clinical data have demonstrated the reduced responsiveness of GI malignancies with microsatellite instability (MSI) to both adjuvant and neoadjuvant systemic chemotherapy when compared with microsatellite stable (MSS) disease. The elevated tumor mutational burden associated with MSI tumors of all types sensitizes these tumors to the effects of immune checkpoint blockade in the metastatic setting, which led to tumor-agnostic approval of immune checkpoint inhibitors in this context. The recent demonstration of greater sensitivity and high pathologic complete response rates to neoadjuvant immunotherapy in locally advanced GI malignancies may ultimately establish a novel treatment paradigm and herald potential nonoperative management of this distinct subgroup of GI malignancies. This article provides an overview of immune checkpoint inhibitor therapy in locally advanced MSI GI malignancies. It also covers the clinical significance of MSI status across the GI cancer spectrum, the available data demonstrating differential responses of MSI and MSS disease to conventional chemotherapy, and the biological rationale for novel strategies utilizing immunotherapy in the neoadjuvant, adjuvant, and nonoperative settings.
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Neoplasias Gastrointestinales , Inhibidores de Puntos de Control Inmunológico , Inestabilidad de Microsatélites , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/terapia , Terapia Neoadyuvante , Inmunoterapia/métodosRESUMEN
Background: Oncologists are prescribing checkpoint inhibitors with greater frequency, and an awareness of and ability to recognize immune-related adverse events (irAEs) is a key part of the safe administration of these drugs. Case Description: Herein, we report the case of a 26-year-old male diagnosed with de novo metastatic right-sided colon cancer to the liver, with tumor immunohistochemistry demonstrating loss of MSH2 and MSH6, and a pathogenic mutation in MSH2 identified on germline testing, consistent with Lynch Syndrome. The patient received first-line treatment with pembrolizumab. Following 7 months of immune checkpoint blockade (ICB), new pulmonary findings on routine imaging were felt to be concerning for disease progression, despite ongoing excellent clinical status, disease control in the liver, and stable tumor markers. An endobronchial biopsy of one of the mediastinal lymph nodes demonstrated granulomatous inflammation consistent histologically with sarcoidosis, and a diagnosis of sarcoid-like reaction (SLR) secondary to immunotherapy was established. Pembrolizumab was discontinued, and the patient continued active monitoring off of active therapy, with durable cancer control. After 8 months of watchful waiting, new hepatic lesions and increasing abdomino-pelvic lymphadenopathy were identified on imaging, concerning for progression of disease. Inguinal lymph node biopsy demonstrated findings consistent with ongoing SLR. The patient remains with durable cancer control, now 24 months since receipt of ICB. In addition, he remains asymptomatic of the SLR. Conclusions: This case highlights the propensity of SLRs to imitate progression of disease, and the importance of awareness of this adverse effect, to prompt appropriate investigation and management.
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PURPOSE: Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance. EXPERIMENTAL DESIGN: We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT). RESULTS: All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases. CONCLUSIONS: Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas B-raf , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Femenino , Masculino , Proteínas Proto-Oncogénicas B-raf/genética , Persona de Mediana Edad , Anciano , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Mutación , Progresión de la Enfermedad , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Adulto , Inestabilidad Cromosómica , Anciano de 80 o más Años , Amplificación de GenesRESUMEN
BACKGROUND: Mutated KRAS is the most common oncogene alteration in pancreatic cancer (PDAC), and KRAS G12C mutations (KRAS G12Cmut) are observed in 1-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including PDAC. Little is known regarding clinical, genomics and outcome data of this population. METHODS: Patients with PDAC and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center (MSK), and via the AACR Project GENIE database. Clinical, treatment, genomic and outcomes data were analysed. A cohort of patients at MSK with non-G12C KRAS PDAC was included for comparison. RESULTS: Among 3,571 patients with PDAC, 39 with KRAS G12Cmut were identified (1.1%). Median age was 67 years, 56% were female. Median BMI was 29.2 kg/m2, 67% had a smoking history. Median OS 13 months (9.4, not reached (NR)) for stage IV, and 26 months (23, NR) for stage I-III. Complete genomic data (via AACR GENIE) was available for N = 74. Most common co-alterations included: TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (N = 2931) of non-G12C KRAS-mutated PDAC, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). OS did not differ between KRAS G12Cmut and non-G12C KRAS PDAC. Germline pathogenic variants were identified in 17%. N = 2 received KRAS G12C-directed therapy. CONCLUSION: PDAC and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated PDAC, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in PDAC provides a precedent for broader KRAS targeting in PDAC.
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Background: This study, using real-world data, assesses the impact of RS testing on treatment pathways and the associated economic consequences of such testing. This paper pertains to lobular breast cancer. Methods: A retrospective, observational study was undertaken between 2011 and 2019 on a cross-section of hormone receptor-positive (HR+), HER2-negative, lymph node-negative, early-stage breast cancer patients. All patients had ILC and had RS testing in Ireland. The patient population is representative of the national population. Patients were classified as low (RS ≤ 25) or high (RS > 25) risk. Patients aged ≤50 were stratified as low (RS 0-15), intermediate (RS 16-25), or high risk (RS > 25). Results: A total of 168 patients were included, most of whom had grade 2 (G2) tumors (n = 154, 92%). Overall, 155 patients (92.3%) had low RS (≤25), 12 (7.1%) had high RS (>25), and 1 (0.6%) had unknown RS status. In 29 (17.5%) patients aged ≤50 at diagnosis, RS was ≤15 in 16 (55%), 16-20 in 6 (21%), 21-25 in 5 (17%), >25 in 1 (3.5%), and unknown in 1 (3.5%). Post RS testing, 126 patients (78%) had a change in chemotherapy recommendation; all to hormone therapy. In total, only 35 patients (22%) received chemotherapy. RS testing achieved a 75% reduction in chemotherapy use, resulting in savings of 921,543.84 in treatment costs, and net savings of 387,283.84. Conclusions: The use of this test resulted in a 75% reduction in chemotherapy and a significant cost savings in our publicly funded health system.
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Neoplasias de la Mama , Carcinoma Lobular , Humanos , Femenino , Estudios Retrospectivos , Irlanda , Perfilación de la Expresión Génica/métodos , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/patologíaRESUMEN
Esophageal adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, is uncommon in the United States, but is associated with a rising incidence in young adults, and has a traditionally poor prognosis. Despite the incremental benefits that have been made with multimodality approaches to locally advanced disease, most patients will go on to develop metastatic disease, and long-term outcomes remain suboptimal. Over the last decade, PET-CT has emerged as a key tool in the management of this disease, with several prospective and retrospective studies evaluating its role in this disease. Herein, we review the key data pertaining to the use of PET-CT in the management of locally advanced esophageal and GEJ adenocarcinoma, with a focus on staging, prognostication, PET-CT adapted therapy in the neoadjuvant setting, and surveillance.
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Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.
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INTRODUCTION: Despite major advances in surveillance and management, advanced cholangiocarcinoma (CCA) still carries a dismal prognosis. In recent years, several actionable genomic alterations in pancreatobiliary malignancies have been identified. For instance, homologous recombination deficiency (HRD) has been considered a predictive biomarker of clinical response to platinum and poly (ADP-ribose) polymerase (PARP) inhibitors. CASE REPORT: A 53-year-old man with a stage 3 (T4N0M0) BRCA2-mutant CCA developed intolerable toxicity after 44 cycles of gemcitabine/cisplatin. In light of his HRD positivity, treatment was switched to single-agent olaparib. The patient showed a partial radiological response, which was maintained after 8 months of olaparib discontinuation (progression-free survival >36 months). CONCLUSION: Given the durable response observed, olaparib can be a valuable therapeutic tool in BRCA-mutant CCAs. Ongoing and future clinical trials are needed to confirm the role of PARP inhibition in similar patients and to define the clinicopathological and molecular profile of the individuals most likely to benefit.
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Neoplasias de los Conductos Biliares , Tumor de Klatskin , Neoplasias Ováricas , Masculino , Femenino , Humanos , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Tumor de Klatskin/tratamiento farmacológico , Neoplasias Ováricas/patología , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/genética , Conductos Biliares Intrahepáticos/patología , Mutación , Células Germinativas/patología , Proteína BRCA2/genéticaRESUMEN
Poorly differentiated pancreatic neuroendocrine tumors (PDNEC), are a subtype of pancreatic cancer encompassing both small cell and large cell neuroendocrine carcinoma subtypes, and are characterized as distinct in terms of biology and prognosis compared to the more common pancreatic adenocarcinoma. Until recently, there has been a paucity of data on the genomic features of this cancer type. We describe a male patient diagnosed with PDNEC and extensive metastatic disease in the liver at diagnosis. Genomic analysis demonstrated a germline pathogenic variant in BRCA2 with somatic loss-of-heterozygosity of the BRCA2 wild-type allele. Following a favorable response to platinum-based chemotherapy (and the addition of immunotherapy), the patient received maintenance therapy with olaparib, which resulted in a further reduction on follow-up imaging (Fig. 1). After seventeen months of systemic control with olaparib, the patient developed symptomatic central nervous system metastases, which harboured a BRCA2 reversion mutation. No other sites of disease progression were observed. Herein, we report an exceptional outcome through the incorporation of a personalized management approach for a patient with a pancreatic PDNEC, guided by comprehensive genomic sequencing.
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BACKGROUND: Improvements in early detection, screening and treatment of cancer have resulted in a significant improvement in cancer mortality and an increase in the number of cancer survivors globally. Accordingly, a significant rise in the number of cancer survivors in Ireland has been observed. The surveillance of survivors of gastrointestinal malignancies in Ireland is heterogeneous and represents an unmet need for standardisation. AIMS: There are currently no national guidelines in Ireland to guide follow-up practices for these patients. The aim of this study was to establish homogeneity nationally with respect to follow-up of these patients by medical oncologists. METHODS/RESULTS: A consensus group consisting of Irish oncologists with an interest in gastrointestinal malignancies was created to address this issue, and determined that it would be reasonable to adopt the NCCN guidelines for this purpose, but that this recommendation would not be prescriptive, and should be individualised to each patient. CONCLUSION: We hope that this initiative may help to homogenise survivorship practices in this cohort of Irish patients, and may support the implementation of survivorship initiatives by the National Cancer Control Programme (NCCP).
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Supervivientes de Cáncer , Neoplasias Gastrointestinales , Humanos , Sobrevivientes , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/terapia , IrlandaRESUMEN
Metastatic and localized mismatch repair-deficient (dMMR) tumors are exquisitely sensitive to immune checkpoint blockade (ICB). The ability of ICB to prevent dMMR malignant or pre-malignant neoplasia development in patients with Lynch syndrome (LS) is unknown. Of 172 cancer-affected patients with LS who had received ≥1 ICB cycles, 21 (12%) developed subsequent malignancies after ICB exposure, 91% (29/32) of which were dMMR, with median time to development of 21 months (interquartile range, 6-38). Twenty-four of 61 (39%) ICB-treated patients who subsequently underwent surveillance colonoscopy had premalignant polyps. Within matched pre-ICB and post-ICB follow-up periods, the overall rate of tumor development was unchanged; however, on subgroup analysis, a decreased incidence of post-ICB visceral tumors was observed. These data suggest that ICB treatment of LS-associated tumors does not eliminate risk of new neoplasia development, and LS-specific surveillance strategies should continue. These data have implications for immunopreventative strategies and provide insight into the immunobiology of dMMR tumors.
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Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/complicaciones , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Inhibidores de Puntos de Control Inmunológico , Neoplasias Colorrectales/patologíaRESUMEN
PURPOSE: Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. RESULTS: Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3-not reached (NR)], 27.1 months (95% CI: 22.7-NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9-NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2-29) relative to breast (18, 3-55) or ovarian (25, 3-56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC. CONCLUSIONS: ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Genómica , Estudios de Cohortes , Proteínas de la Ataxia Telangiectasia Mutada/genética , Neoplasias PancreáticasRESUMEN
We report a case of a 60-year-old male with metachronous primary malignancies, pancreatic cancer and malignant melanoma which recurred simultaneously. Both cancers were challenging to diagnose and throughout the case at different times, the presence of two active malignancies obscured the clinical picture. A bleeding gastric lesion found in the stomach 6 months after a distal pancreatectomy for pancreatic adenocarcinoma revealed metastatic melanoma, presumed secondary from a melanoma excised from the patient's back 2 years previously. During surgery intended to resect the gastric lesion, peritoneal nodularity was identified, with histology confirming metastatic pancreas cancer. This case highlights two main points of interest. Firstly it emphasises the role for consideration of a genetic predisposition in young patients with more than one primary malignancy. The man in this case was not informed of his family history as he was adopted. If he had knowledge of previous family history, he may have been able to provide information to expedite arrival at the diagnosis of a CDKN2A mutation (melanoma-pancreatic carcinoma syndrome). In addition, this case also raises the issue of the challenges we face when treating synchronous primary malignancies. The two malignancies here behaved equally aggressively and posed obstacles for treatment as there is no mutual method of carcinogenesis that could be targeted with treatment; therefore, treatment modalities had to be chosen to treat each malignancy separately. To date, studies evaluating the role for targeted therapy in the setting of CDKN2A mutations have not conclusively provided meaningful benefits to patients.
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BACKGROUND: Cancer gene panel testing is available in Ireland. The need for a clear strategy to deal with patient information generated from tumour genomic testing is recognised as a challenge in the National Cancer Strategy. However, the public's attitude and opinions regarding these results is not known in Ireland. AIMS: This prospective questionnaire study assessed the knowledge and opinions of patients in a national oncology centre, surrounding cancer gene panel testing. METHODS: An anonymised modified validated questionnaire was completed by volunteering patients in the medical oncology department. It comprised 14 questions which assessed patient's familiarity, intention, benefits and concerns associated with tumour genetic testing using a four-point Likert scale. Patients recorded their primary cancer diagnosis and family cancer history. RESULTS: Eighty-four patients completed the questionnaire with 77 (92%) patients declaring their primary cancer diagnosis. The median age was 56 (range 26 to 83) years. Overall, 42% (n = 35) of oncology patients were familiar/somewhat familiar with testing and 90% (n = 76) stated they would avail of genetic testing if available. Patients with breast cancer were no more likely to avail of genetic testing when compared with the non-breast cancer cohort (n = 21 vs. 56, p = 0.58) though they identified concerns with potential discrimination. CONCLUSION: This is the first prospective Irish study to assess opinions surrounding cancer gene results. Addressing patient's lack of information as regards genetic testing is the first step in establishing a national cancer genetics testing programme in Ireland.
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Pruebas Genéticas/métodos , Neoplasias/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Neoplasias/genética , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
The treatment landscape for metastatic melanoma has been revolutionised by the introduction of immunotherapy and targeted therapies. Despite these advances, some patients exhibit primary or acquired resistance to treatment. We present the case of a resected mucosal melanoma that on relapse underwent transformation to a dedifferentiated state. The relapsed tumour was phenotypically disparate and demonstrated loss of all typical melanoma-associated immunohistochemical markers. Furthermore, it demonstrated aggressive biological behaviour and immunotherapy resistance. We performed genomic profiling of the original and relapsed tumour to further elucidate the mechanisms underlying this rare phenomenon. Mass spectrometry-based single-nucleotide polymorphism genotyping technology was used to screen for mutations in the original and recurrent tumour. Whole-exome sequencing was performed on the original tumour, recurrent tumour and blood. Both the original and recurrent tumour shared a NRAS mutation, a similar aneuploidy profile and proportion of somatic single-nucleotide variants. However, in contrast to the original tumour, the recurrent tumour demonstrated a lower mutational burden and deletions in the CDKN2A/CDKN2B and CHEK2 genes. The genomic similarity between the original and recurrent tumour attests to a common ancestry and the possible existence of nongenomic drivers inciting phenotype plasticity. In contrast, the low mutational load and potential inactivation of tumour suppressor genes in the recurrent tumour may underlie its rapid proliferative rate and immunoresistance. Dynamic treatment models are desired in the future to track the genomic and epigenetic evolution of a tumour to guide optimal therapy choice and sequencing.
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Genómica/métodos , Inmunoterapia/efectos adversos , Melanoma/inducido químicamente , Neoplasias Cutáneas/inducido químicamente , Anciano , Femenino , Humanos , Inmunoterapia/métodos , Melanoma/genética , Melanoma/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
INTRODUCTION: Bevacizumab has demonstrated activity in glioblastoma (GBM), but the true benefits and optimal dose-schedule are debated. A lower dose-schedule than standard-dose bevacizumab (10 mg/kg 2-weekly) might offer similar benefits with lower costs. At our Institution, patients are randomly assigned at time of primary diagnosis to Neuro-Oncologists, who have varying practices in terms of bevacizumab dose-schedule upon progression. METHODS: In a retrospective analysis we examined overall survival (OS), measured from first administered bevacizumab dose until death, according to dose-schedule. Patients with de novo WHO Grade IV GBM who received standard- or reduced-dose (5 mg/kg 2-weekly) bevacizumab were included. MGMT methylation status and time from diagnosis to bevacizumab start were examined as prognostic variables. Clinical benefit and a comparative cost analysis were assessed. RESULTS: In total, 1127 bevacizumab doses were administered to 118 patients [Median: 7, Range: 1-44]. Median OS (mOS) was 5.8 months. 69 (59%) patients received standard-dose bevacizumab (mOS: 5.97 months) and 49 patients received reduced-dose (mOS: 5.7 months). No statistically significant difference in OS between dosing schedule was seen (HR: 1.11, P-value: .584). Patients with MGMT methylated tumors (43%) had improved OS compared to those with unmethylated tumors; 7.03 vs 4.97 months (HR: 0.61, P-value: .027). If all patients were treated with reduced-dose bevacizumab, an estimated 2.4M cost reduction would be observed. CONCLUSIONS: In this retrospective study, reduced-dose bevacizumab schedule resulted in similar OS to standard-dose bevacizumab monotherapy with substantial cost savings. MGMT methylation appears to convey a survival benefit in the setting of bevacizumab treatment for progressive GBM.