Objectives Universal screening of upper tract urothelial carcinoma (UTUC) for Lynch syndrome by mismatch repair (MMR) protein immunohistochemistry (IHC) has been recommended by some investigators. Herein, we assess this recommendation retrospectively by simulating its performance on a retrospective, unselected cohort of UTUCs, with comparison to the established setting of colorectal and endometrial adenocarcinoma. Methods We assessed for complete loss of MMR protein (MLH1, MSH2, MSH6, and PMS2) IHC in 74 consecutive cases of UTUC and then tabulated clinical and pathologic factors. MMR findings from same-institution colorectal and endometrial adenocarcinomas were tabulated for comparison. Results We observed loss of at least one MMR protein in 12% in our UTUC cohort (three MSH2/MSH6, three MSH6 only, one MLH1/PMS2, and two PMS2 only). Of these nine cases (seven males, two females, median age 67 years, five associated with colorectal adenocarcinoma), at least three (4% of the overall cohort) proved to be Lynch syndrome. Overall, MMR loss in UTUC was comparable to colorectal (11%; 50 of 471 cases) and endometrial (12%; 12 of 101 cases) adenocarcinomas. Conclusions The rate of MMR loss observed in UTUC was comparable to that in the established setting of colorectal and endometrial adenocarcinomas, supporting universal UTUC screening at our institution and others.
Background Acute myeloid leukemia (AML) accounts for 1% of all newly diagnosed cancers with a mean age at diagnosis of 68. Although the majority present de novo, AML can be secondary to conditions such as myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). The subset of patients with AML transformed from MPN continues to remain a therapeutic challenge with little data to support clinical efficacy. A large retrospective review of 273 patients revealed no significant improvement in overall survival in this patient population for those diagnosed between 1989 and 2016. Prognosis remains dismal with an overall survival of 5-7 months. Treatment options are limited and often with little proven clinical utility. Even the addition of hypomethylating agents to treatment options has failed to show any improvement in survival necessitating the investigation of new treatment options (Chihara et al, ASH 2016). In this case series, we present two AML cases that have transformed from myelofibrosis and were successfully treated with the combination of cytarabine and venetoclax. Objective Our primary objective was to determine the clinical efficacy of the combination of cytarabine and venetoclax in patients with myelofibrosis with leukemic transformation. Methods This is an observational, retrospective case series of two patients that were treated with cytarabine and venetoclax at Virginia Commonwealth University from 2018 to 2019. Both patients had previously been confirmed as meeting WHO criteria for myelofibrosis on bone marrow examination. Upon transformation to acute myeloid leukemia, again confirmed on bone marrow biopsy, both patients were transitioned to the following regimen: cytarabine 20 mg/m2 on days 1-10 of 28-day cycle in combination with venetoclax with rapid dose escalation to goal of 600mg daily with dose adjustments for medication interactions. The patient's response to therapy and side effect monitoring were performed at regular intervals in the outpatient clinic. Results Our study consisted of two females, age 65 (patient 1) and 71 (patient 2) with a median age of 68 and bone marrow biopsy confirmed diagnosis of myelofibrosis. Both females had grade 3+ fibrosis on marrow examination and both harbored JAK2 mutations on initial diagnosis of myelofibrosis. Patient 2 also demonstrated a 20q deletion. Neither female was deemed a suitable candidate for transplantation due to their age and considerable comorbidities. On transformation to leukemia, blast count burden was 27% and 23%, respectively. Patient 1 had received decitabine prior to the cytarabine/venetoclax regiment while the other had no previous therapy for her myelofibrosis or leukemia. Patient 1 was maintained on the regiment with for 10 months and nearly completed 9 cycles before patient decompensated and was transitioned to comfort care and eventually died. Complications during her treatment course included an elevated uric acid requiring a dose of rasburicase, neutropenic fever and subdural hematoma that resolved without any intervention. Patient 2 has completed 6 cycles of therapy and is now 8 months post initiation of therapy. Her most recent bone marrow biopsy showed a hypocellular bone marrow (20-30% cellularity) and severe myelofibrosis (reticulin 3/3+) with less than 1% blasts. She remains independent of transfusions. Conclusions Our case series demonstrates that the combination of cytarabine and venetoclax can be effectively used in patients with AML transformed from myelofibrosis. In a disease historically with an overall survival of 6 months, one patient survived 10 months and the other is 8 months out and currently in remission from her AML on her most recent bone marrow biopsy, and independent of transfusions. Overall, therapy has been well tolerated with manageable adverse events. Although future prospective studies are needed, the combination of cytarabine and venetoclax offers a reasonable treatment option for secondary AML transformed from myelofibrosis. Disclosures Yazbeck: Gilead Sciences: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
e15105 Background: ALK-rearrangements are a powerful and highly prevalent driver in cancer biology. The advent of potent tyrosine kinase inhibitors has led to the development of numerous laboratory tests and FDA approved therapies for the detection and treatment of ALK-positive cancers. The vast majority of reported ALK rearrangements involve exon 20 with fusions involving exons 17-19 occasionally reported. While less common, ALK-rearrangements occurring earlier in the ALK gene have not been well characterized. This is largely because most clinically available biomarker testing is only optimized for detection of rearrangements involving the common regions. To this end, we aimed to investigate the prevalence of early exon ALK rearrangements (eALKr). Methods: Two pathology databases, including the Tempus deidentified database, were retrospectively queried to characterize eALKr, which were defined as any rearrangement that involved ALK exons 1-16. Demographic information and tumor type were recorded. Identification of eALKr was performed via targeted amplicon-based RNA sequencing, targeted hybrid capture DNA sequencing and whole transcriptome sequencing. Select specimens with early ALK fusions were also evaluated for ALK detection using available FDA-approved methods (immunohistochemistry [IHC] and fluorescent in-situ hybridization [FISH]). Results: Out of the specimens that underwent NGS testing in the two databases, the prevalence of eALKr was 0.05% (73/143,959) across the databases and 10.3% (73/709) for all tumors with ALK rearrangements. Across the 73 rearrangements, there were 58 unique 5’ partner genes of which 46 were only identified once. eALK rearrangements were identified in all exons from exons 1 to 16 except for exon 13, with exon 4 being the most common. Prostatic, breast and ovarian serous carcinoma were the most common tumor types (Table 1). In three cases IHC and FISH were unreliable due to the early rearrangement location (0/3 IHC positive, 1/3 FISH positive). FISH was negative for samples with rearrangements in exon 2 and 4 and showed an atypical (deletion) pattern with a rearrangement involving exon 12. Conclusions: A non-trivial number of eALKr were detected within two database using next generation sequencing (0.05% of total cancer cases; 10.3% of ALK fusion cases). These novel eALK rearrangements were predominantly in tumor types not normally associated with ALK fusions. FDA approved testing modalities are only optimized to detect common ALK rearrangements, which in part may be a reason why eALK-rearrangements are poorly characterized, with limited prevalence and treatment data available. [Table: see text]
Uterine leiomyosarcoma (LMS) is a highly aggressive but rare malignancy with a dismal prognosis. In nearly all cases, LMS is unsuspected prior to resection for a presumed leiomyoma. The risk of occult uterine LMS is reported to be 0.2% (1 in 500) in the largest cohort study of women undergoing surgery for presumed fibroid disease. The major problem is that there is no reliable preoperative method to distinguish LMS from a leiomyoma (LM) or STUMP (smooth muscle tumor of uncertain malignant potential), and the patient's prognosis for LMS is even poorer if the tumor is transected, which occurs in procedures performed for LM. Effective therapy for LMS is lacking and most patients eventually succumb to the disease. Thus, there is a considerable need for a reliable preoperative test to triage patients into the proper surgical procedure for LMS. TP53 alterations are reportedly associated with uterine LMS in about 40% of cases. We screened plasma for TP53 variants in patients with pathologically confirmed LMS. We evaluated TP53 circulating tumor DNA (ctDNA) by deep next-generation sequencing in a cohort of 7 patients with LMS, 1 patient with STUMP, and 3 patients with LM. Clinical data were reviewed to assess disease burden. LMS patients' tumor burden ranged from no evidence to extensive metastatic disease. DNA extraction was performed using the QIAamp DNA Micro Kit, QIAamp DNA FFPE Tissue Kit, or QIAamp MinElute ccfDNA Mini Kit. DNA quality was assessed using the TapeStation Genomic DNA kit. NGS libraries targeting the entire exonic region of the p53 gene were prepared using the QIASeq Targeted DNA Custom Panel. Sequencing was performed on the MiSeq system using 150bp paired end sequencing with a minimum read depth of 2x0.5M reads for plasma and 2x1M reads for formalin-fixed paraffin embedded and fresh-frozen tissue samples. Raw sequencing data were demultiplexed by bcl2fastq to generate the FASTQ files. Then raw sequencing reads were aligned to the human reference genome GRCh38 by BWA-MEM 0.7.9a-r786. SmCounter2 was used for p53 variants calling and variants quality control. We discovered TP53 ctDNA variants in 5 of 7 (71.4%) LMS cases including p.E258V, p.R248Q, P.R337C, p.E221*, p.R174_R175delinsWC, but not in the control cases of LM or STUMP. In the 5 plasma samples with TP53 mutated LMS, the patients had extensive metastatic disease and in the 2 TP53 wild-type LMS and STUMP cases, the patients had no evidence of disease. To our knowledge, this is the first pilot study to demonstrate the comparative use of TP53 ctDNA in patients with LMS, LM, and STUMP. Further study of these rare LMS is needed to determine the preoperative utility of NGS TP53 ctDNA mutational status as a useful molecular biomarker to help guide surgery and avoid unwarranted manipulation and pelvic contamination of undetected LMS. Supported by the Gottlieb, Buss and Snyder Endowments in Surgical Oncology Citation Format: Jean R. Lopategui, Bonnie Balzer, Yizhou Wang, Chintda Santiskulvong, Carissa A. Hyunh, Chun Yat Ong, Manuel Arana, Matthew Gayhart, Farin Amersi, Allan W. Silberman. Circulating TP53 tumor DNA as a potential biomarker for pre-operative identification of uterine leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 447.
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