Molecular analysis distinguishes metastatic disease from second cancers in patients with retinoblastoma.
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ABSTRACT:
SUBMITTER: Racher H
PROVIDER: S-EPMC4970893 | biostudies-literature | 2016 Jul-Aug
REPOSITORIES: biostudies-literature
Publications
Molecular analysis distinguishes metastatic disease from second cancers in patients with retinoblastoma.
Racher Hilary H Soliman Sameh S Argiropoulos Bob B Chan Helen S L HS Gallie Brenda L BL Perrier Renée R Matevski Donco D Rushlow Diane D Piovesan Beata B Shaikh Furqan F MacDonald Heather H Corson Timothy W TW
Cancer genetics 20160603 7-8
The pediatric ocular tumor retinoblastoma readily metastasizes, but these lesions can masquerade as histologically similar pediatric small round blue cell tumors. Since 98% of retinoblastomas have RB1 mutations and a characteristic genomic copy number "signature", genetic analysis is an appealing adjunct to histopathology to distinguish retinoblastoma metastasis from second primary cancer in retinoblastoma patients. Here, we describe such an approach in two retinoblastoma cases. In patient one, ...[more]
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Project description:ImportanceIn heritable retinoblastoma, there is a significantly increased risk of second primary cancers (SPCs). Improved knowledge about the incidence and influence of heritability and treatment is important during therapy for patients with retinoblastoma.ObjectiveTo assess the incidence of SPC in patients diagnosed with retinoblastoma in Denmark from 1943 to 2013 with a focus on heritability and the association of external radiotherapy with mortality.Design, setting, and participantsIn this retrospective cohort study, data were extracted from the Danish Ocular Oncology Group Database containing complete data on all patients diagnosed with retinoblastoma , and obtained from the Danish Cancer Registry, which includes information on all patients with cancer from 1943 to December 31, 2013. Data analysis was conducted from December 1, 2017, to October 1, 2019. Data on 323 patients were included.ExposuresHeritability and retinoblastoma treatment.Main outcomes and measuresStandardized incidence rate, excess absolute risk, cumulative incidence of SPC, and mortality from SPC. Association of heritability and treatment with outcomes was estimated.ResultsOf the 323 patients included in the analysis, 181 were men (56%), 133 had heritable retinoblastoma (41%), and 190 had nonheritable retinoblastoma (59%). The median age at diagnosis of SPC was 32.4 (interquartile range, 15.4-43.9) years in patients with heritable retinoblastoma and 38.6 (interquartile range, 20.5-49.4) years in those with nonheritable retinoblastoma. Twenty-five SPCs were identified in patients with heritable retinoblastoma vs 14 in patients with nonheritable retinoblastoma. Standardized incidence rate (SIR) of SPC in patients with heritable retinoblastoma was 11.39 (95% CI, 7.37-16.81) with an excess absolute risk of 70 cases per 10 000 person-years; the highest SIRs were for sarcoma (181.13; 95% CI, 98.94-303.92) and malignant melanoma (26.78; 95% CI, 9.78-58.30). The SIR for SPC in patients with nonheritable retinoblastoma was 1.52 (95% CI, 0.81-2.60). The cumulative incidence of SPCs at age 60 years was significantly higher in patients with heritable retinoblastoma (51%) compared with those with nonheritable retinoblastoma (13%) (P < .001) (hazard ratio, 5.0; 95% CI, 2.5-10.3). No significant differences were identified in overall risk of SPC in patients with heritable retinoblastoma treated with 3 different modalities: external radiotherapy, plaque (but no external) radiotherapy, and enucleation only, but an increased proportion of sarcomas was noted in the irradiated field. Mortality due to SPC was also higher in survivors of heritable retinoblastoma compared with those with nonheritable retinoblastoma (cumulative mortality, 34% vs 12% at age 60 years; P = .03).Conclusions and relevanceThe findings of this study suggest that the incidence and mortality associated with SPC were significantly higher in patients with heritable retinoblastoma vs patients with nonheritable retinoblastoma. The largest increases in risk were noted for sarcoma and malignant melanoma. External radiotherapy did not appear to increase the risk. These findings are relevant when treating patients with retinoblastoma to manage the risk for SPC.
| S-EPMC7582127 | biostudies-literature
Project description:ImportanceTo date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs).ObjectiveTo assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs.Design, setting, and participantsPopulation-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020.ExposuresReceipt of immunotherapy or other anticancer agents.Main outcomes and measuresThe primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs.ResultsAmong 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 (95% CI, 0.08-18.04) for small intestine cancer, 1.93 (95% CI, 1.14-3.05) for lung and bronchus cancer, 2.77 (95% CI, 1.02-6.03) for kidney cancer, and 7.29 (95% CI, 2.93-15.02) for myeloma. From 2011 to 2016, SIRs were 9.23 (95% CI, 1.12-33.35) for small intestine cancer, 1.54 (95% CI, 0.71-2.93) for lung and bronchus cancer, 2.66 (95% CI, 0.73-6.82) for kidney cancer, and 5.90 (95% CI, 1.61-15.10) for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher (SIR, 1.65; 95% CI, 1.35-2.00) in the pre-ICIs period and 98% higher (SIR, 1.98; 95% CI, 1.57-2.45) in the post-ICIs period than the overall cancer incidence rate in the general population.Conclusions and relevanceIn this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma.
| S-EPMC7726633 | biostudies-literature
Project description:BackgroundMetastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer-specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios.Materials and methodsWe identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next-generation sequencing-based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities.ResultsA high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination.ConclusionsOur cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. The Oncologist 2017;22:152-157Implications for Practice: Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic problem but has important prognostic and therapeutic implications. Approaches to aid histologic analysis may improve clinician and pathologist confidence in this increasingly common clinical scenario. Our series provides early support for incorporating paired comprehensive genomic profiling in clinical situations in which determination of metastatic recurrence versus a distinct second primary cancer would influence patient management.
| S-EPMC5330711 | biostudies-literature
Project description:BackgroundSecond primary cancers (SPCs) are increasing due to improving survival in first primary cancers. Previous studies on SPCs in renal cell carcinoma (RCC) have focused on treatment and other risk factors, but data of RCC as an SPC are scarce.ObjectiveIn this study, we want to elucidate the risk for any SPC after RCC, and in reverse order, for RCC as an SPC after any cancer. We additionally consider how family histories influence the risks.Design setting and participantsPatient data were obtained from the Swedish Cancer Registry from years 1990 through 2015, and family data were obtained from the Multigeneration Register.Outcome measurements and statistical analysisWe employed standardized incidence ratios to estimate bidirectional relative risks of subsequent cancer associated with RCC.Results and limitationsWe identified 17 587 RCCs (60% in male patients). The highest increases for SPCs were observed for nervous system hemangioblastoma (HB; 26.8), adrenal (12.09) tumors, and renal pelvic cancer (6.32). In the reverse order, RCC as an SPC, nervous system HB (17.01), and adrenal tumors (15.34) were associated with the highest risks. Risks for many other sites (12 sites and subsites) were increased bidirectionally. For women, a total of seven sites and subsites were increased bidirectionally, and many were shared with men. The only significant sex difference in SPCs was the higher lung cancer risk in women (2.41) than in men (1.28). Patients with a family history of HBs or of prostate, colorectal and lung cancers showed high risks of these cancers as SPCs after RCC. Family history accounted for 30% of prostate cancers after RCC.ConclusionsThe bidirectional study design was able to suggest risk factors for SPCs and offered a clinical take-home message urging to consider strategies for early detection and prevention of SPCs. Readily available information on lifestyle (eg, smoking) and family history (eg, prostate cancer) may reveal targets for risk reduction with prognostic benefits.Patient summaryClose to 10% of kidney cancer patients develop another cancer. The cause for these other cancers may not depend on kidney cancer.
| S-EPMC8317822 | biostudies-literature
Project description:Background and aimsBiliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers.Approach and resultsThis multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI: 6.4%-16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI: 3.1%-11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7-1.8 mo); median overall survival was 7.6 months (95% CI: 5.8-9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%).ConclusionsAlthough this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile.
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Project description:PURPOSE:We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis. PATIENTS AND METHODS:Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated. RESULTS:Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were TP53 (33%), CDKN2A (11%), APC (10%), KTM2D (8%), PTEN (8%), and BRCA2 (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently CHEK2 (1.9%), BRCA1 (1.5%), BRCA2 (1.5%), and MSH6 (1.4%). Novel gene fusions were identified, including a RBM47-CDK12 fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant. CONCLUSION:Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.
| S-EPMC6778956 | biostudies-other
Project description:Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary tumours (SPTs).This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated.We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9-2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)).The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families.
| S-EPMC3694232 | biostudies-other
Project description:ContextClinical applications of genomic assessment of thyroid cancers are rapidly evolving.Objectives, design, and settingWe studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable.Patient contextProgressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites.InterventionThe intervention was Foundation One tumor interrogation.Main outcome measuresMain outcome measures included genomic alterations, patient characteristics, and overall survival.ResultsSamples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine-refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)-but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC.ConclusionsWhereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.
| S-EPMC7263749 | biostudies-literature
Project description:Survivors of hereditary retinoblastoma have a high risk of second primary malignancies, but it has not been investigated whether specific RB1 germline mutations are associated with greater risk of second primary malignancies in a large cohort. We conducted a retrospective cohort study of 199 survivors of hereditary retinoblastoma with a documented RB1 germline mutation diagnosed between 1905 and 2005. In total, 44 hereditary retinoblastoma survivors developed a second primary malignancy after a median follow-up of 30.2 years (range 1.33-76.0). A significantly increased risk of second primary malignancy was observed among carriers of one of the 11 recurrent CGA>TGA nonsense RB1 mutations (hazard ratio (HR) = 3.53; [95% confidence interval (CI) = 1.82-6.84]; P = .000), and there was a significantly lower risk for subjects with a low penetrance mutation (HR = .19; [95% CI = .05-.81]; P = .025). Our findings suggest a genotype-phenotype correlation for second primary cancers of retinoblastoma survivors and may impact on long-term surveillance protocols of patients with hereditary retinoblastoma, if confirmed by future studies.
| S-EPMC3365233 | biostudies-literature
Project description:There is growing interest in the application of molecular profiling, including sequencing, genotyping, and/or mRNA expression profiling, to the analysis of patient tumors with the objective of applying these data to inform therapeutic choices for patients with advanced cancers. Multiple clinical trials that are attempting to validate this personalized or precision medicine approach are in various stages of development and execution. Although preliminary data from some of these efforts have fueled excitement about the value and utility of these studies, their execution has also provoked many questions about the best way to approach complicating factors such as tumor heterogeneity and the choice of which genetic mutations to target. This commentary highlights some of the challenges confronting the clinical application of molecular tumor profiling and the various trial designs being utilized to address these challenges. Randomized trials that rigorously test patient response to molecularly targeted agents assigned based on the presence of a defined set of mutations in putative cancer-driving pathways are required to address some of the current challenges and to identify patients likely to benefit from this approach.
| S-EPMC4334817 | biostudies-literature