621 Background: Canadian criteria for identifying patients (pts) and families at risk for hereditary renal cell carcinoma (RCC) were published in 2013. They included characteristics for pts with RCC (age ≤ 45 years, bilateral or multifocal tumours, associated medical conditions and non-clear cell histologies with unusual features) and for any pts who have a family history of specific clinical or genetic diagnoses associated with renal neoplasms. The clinical impact of these criteria on genetic testing had yet to be evaluated. Methods: The Canadian hereditary RCC risk criteria were applied to pts from 16 centres in the Canadian Kidney Cancer Information System prospective database. The primary endpoint was the proportion of pts who met at least one criterion. Secondary endpoints included the number of pts with more than one criterion and the number of pts receiving genetic testing (with or without at risk criteria). Results: From January 2011 to May 2017, 8097 pts were entered in the database. 2827 (35%) met at least one criterion for genetic testing. The majority (83%) met just 1 criterion, while 16% met 2 criteria. The criterion of non-clear cell histology with unusual features contributed the largest proportion of at risk pts (59%), followed by age ≤ 45 years (29%), then first or second degree relative with renal tumour (16%). 69 pts underwent genetic testing, with 59 being classified at risk ( < 3% of at risk). Details about the genetic testing results will be presented. Conclusions: The application of the Canadian hereditary RCC risk criteria to a population database resulted in 35% of pts being identified at risk for hereditary RCC. However, the true incidence of hereditary RCC in this population is unknown as most pts did not undergo genetic testing, and thus the sensitivity or specificity of the criteria cannot be determined. The low proportion of at risk pts that underwent genetic testing was disappointing and highlights that there may be gaps in reporting, knowledge and/or barriers in access to genetic testing. The results have helped determine the proportion of at risk pts in Canada, what criteria are most common, and importantly, have established a foundation and benchmark to improve upon.
Primary hyperparathyroidism is a common endocrinopathy. Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, with one of main manifestations being primary hyperparathyroidism. We retrospectively evaluated a set of 1011 patients who underwent surgery for primary hyperparathyroidism between the years 2018–2022, and found 78 (8 %) patients who underwent reoperations and 27 patients with MEN1 syndrome. In the group of patients with MEN1 syndrome, 7 (35 %) needed reoperations. Patients with multiple endocrine neoplasia syndrome have a higher risk of needing reoperation. Genetic testing can help identify MEN1 syndrome preoperatively and to better evaluate the approach to surgery.
e17005 Background: Docetaxel is currently used to treat both metastatic castrate resistant prostate cancer (mCRPC) and recently metastatic castrate sensitive prostate cancer (mCSPC). The CHAARTED protocol for mCSPC initiated chemotherapy within four months of the start of androgen deprivation therapy (ADT). There is evidence suggesting that docetaxel pharmacokinetics is affected by ADT which is attributed to change in liver metabolism induced by castration. This may explain the difference in docetaxel toxicity between patients (pts) with mCSPC and mCRPC. In this retrospective analysis we will assess whether initiating docetaxel treatment in close proximity to start of ADT therapy for mCSPC is associated with more treatment related toxicity. Methods: We identified all pts with mCSPC treated at The Ottawa Hospital Cancer Center with docetaxel chemotherapy between June 2014 - September 2017. For each patient we calculated the time to chemotherapy (TTC) interval between the start of ADT and the 1st cycle of docetaxel. We checked for an association between TTC and febrile neutropenia (FN) toxicity induced treatment delay or discontinuation, and toxicity induced dose reduction. Results: Eighty three pts were identified. The median TTC was 67 days (range 3-189). Twenty three pts (27.7%) experienced FN. Docetaxel toxicity resulted in 8 patients (9.6%) had their treatment delayed, 30 patients (36.1%) had their dose reduced and 18 (21.6%) had their treatment discontinued before completing the scheduled 6 cycles. No correlation was found between the TTC and FN (P = 0.99), docetaxel dose reduction (P = 0.95), treatment delay (P = 0.06) and treatment discontinuation (P = 0.88). Conclusions: No correlation was found between the timing of docetaxel treatment start and the rate of treatment related toxicity. Therefore, there is no indication for upfront chemotherapy delay from start of ADT unless the patient’s overall condition is not well enough and it is anticipated that ADT treatment may improve their condition. However, the rate of FN (27.7%) is much higher than expected, regardless of TTC and prophylactic granulocyte colony-stimulating factor may be considered in a real world population.
DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer (mPC). Furthermore, because hypermutated MMRd prostate cancers can respond to immune checkpoint inhibitors, there is an urgent need for practical detection tools.We analyzed plasma cell-free DNA-targeted sequencing data from 433 patients with mPC with circulating tumor DNA (ctDNA) purity ≥2%. Samples with somatic hypermutation were subjected to 185 × whole-exome sequencing and capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and IHC.Sixteen patients (3.7%) had somatic hypermutation with MMRd etiology, evidenced by deleterious alterations in MSH2, MSH6, or MLH1, microsatellite instability, and characteristic trinucleotide signatures. ctDNA was concordant with mismatch repair protein IHC and DNA sequencing of tumor tissue. Tumor suppressors such as PTEN, RB1, and TP53 were inactivated by mutation rather than copy-number loss. Hotspot mutations in oncogenes such as AKT1, PIK3CA, and CTNNB1 were common, and the androgen receptor (AR)-ligand binding domain was mutated in 9 of 16 patients. We observed high intrapatient clonal diversity, evidenced by subclonal driver mutations and shifts in mutation allele frequency over time. Patients with hypermutation and MMRd etiology in ctDNA had a poor response to AR inhibition and inferior survival compared with a control cohort.Hypermutated MMRd mPC is associated with oncogene activation and subclonal diversity, which may contribute to a clinically aggressive disposition in selected patients. In patients with detectable ctDNA, cell-free DNA sequencing is a practical tool to prioritize this subtype for immunotherapy.See related commentary by Schweizer and Yu, p. 981.
Glioblastoma multiforme (GBM) is an ultimately fatal disease that affects patients of all ages. Elderly patients (65 years and older) constitute a special subgroup of patients characterized by a worse prognosis and frequent comorbidities.To assess the efficacy of different treatment modalities in terms of survival in elderly patients with GBM.Using retrospective analysis, we extracted, anonymized and analyzed the files of 74 deceased patients (aged 65 or older) treated for GBM in a single institution.Mean survival time was 8.97 months and median survival time 7.68 months. Patients who underwent tumor resection had a mean survival of 11.83 months, as compared to patients who underwent no surgical intervention or only biopsy and had a mean survival of 5.22 months (P < 0.0001). Patients who underwent full radiation treatment had amean survival of 11.31 months, compared to patients who received only partial radiotherapy or none at all and had a mean survival of 4.09 months (P < 0.0001). Patients who underwent chemotherapy had a mean survival of 12.4 months, compared to patients who did not receive any chemotherapy andhad a mean survival of 5.89 months (P < 0.001).Age alone should not be a factor in the decision on which treatment should be given. Treatment should be individualized to match the patient's overall condition and his or her wishes, while taking into consideration the better overall prognosis expected with aggressive treatment.
