Next-generation biobanking of metastases to enable multidimensional molecular profiling in personalized medicine.

Great advances in analytical technology coupled with accelerated new drug development and growing understanding of biological challenges, such as tumor heterogeneity, have required a change in the focus for biobanking. Most current banks contain samples of primary tumors, but linking molecular signatures to therapeutic questions requires serial biopsies in the setting of metastatic disease, next-generation of biobanking. Furthermore, an integration of multidimensional analysis of various molecular components, that is, RNA, DNA, methylome, microRNAome and post-translational modifications of the proteome, is necessary for a comprehensive view of a tumor's biology. While data using such biopsies are now regularly presented, the preanalytical variables in tissue procurement and processing in multicenter studies are seldom detailed and therefore are difficult to duplicate or standardize across sites and across studies. In the context of a biopsy-driven clinical trial, we generated a detailed protocol that includes morphological evaluation and isolation of high-quality nucleic acids from small needle core biopsies obtained from liver metastases. The protocol supports stable shipping of samples to a central laboratory, where biopsies are subsequently embedded in support media. Designated pathologists must evaluate all biopsies for tumor content and macrodissection can be performed if necessary to meet our criteria of >60% neoplastic cells and <20% necrosis for genomic isolation. We validated our protocol in 40 patients who participated in a biopsy-driven study of therapeutic resistance in metastatic colorectal cancer. To ensure that our protocol was compatible with multiplex discovery platforms and that no component of the processing interfered with downstream enzymatic reactions, we performed array comparative genomic hybridization, methylation profiling, microRNA profiling, splicing variant analysis and gene expression profiling using genomic material isolated from liver biopsy cores. Our standard operating procedures for next-generation biobanking can be applied widely in multiple settings, including multicentered and international biopsy-driven trials.

Inequalities in survival and care across social determinants of health in a cohort of advanced lung cancer patients in Quebec (Canada): A high-resolution population-level analysis.

BACKGROUND: Advanced lung cancer patients exposed to breakthrough therapies like EGFR tyrosine kinase inhibitors (EGFR-TKI) may experience social inequalities in survival, partly from differences in care. This study examined survival by neighborhood-level socioeconomic and sociodemographic status, and geographical location of advanced lung cancer patients who received gefitinib, an EGFR-TKI, as first-line palliative treatment. Differences in the use and delay of EGFR-TKI treatment were also examined. METHODS: Lung cancer patients receiving gefitinib from 2001 to 2019 were identified from Quebec's health administrative databases. Accounting for age and sex, estimates were obtained for the median survival time from treatment to death, the probability of receiving osimertinib as a second EGFR-TKI, and the median time from biopsy to receiving first-line gefitinib. RESULTS: Among 457 patients who received first-line treatment with gefitinib, those living in the most materially deprived areas had the shortest median survival time (ratio, high vs. low deprivation: 0.69; 95% CI: 0.47-1.04). The probability of receiving osimertinib as a second EGFR-TKI was highest for patients from immigrant-dense areas (ratio, high vs. lowdensity: 1.95; 95% CI: 1.26-3.36) or from Montreal (ratio, other urban areas vs. Montreal: 0.39; 95% CI: 0.16-0.71). The median wait time for gefitinib was 1.27 times longer in regions with health centers peripheral to large centers in Quebec or Montreal in comparison to regions with university-affiliated centers (95% CI: 1.09-1.54; n = 353). CONCLUSION: This study shows that real-world variations in survival and treatment exist among advanced lung cancer patients in the era of breakthrough therapies and that future research on inequalities should also focus on this population.

Advanced Lung Cancer Patients' Use of EGFR Tyrosine Kinase Inhibitors and Overall Survival: Real-World Evidence from Quebec, Canada.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are breakthrough palliative treatments for advanced lung cancer patients with tumors harboring mutations in the EGFR gene. Using healthcare administrative data, three cohorts were created to describe the use of three EGFR-TKIs that are publicly funded in Quebec for specific indications (i.e., 1st-line gefitinib, 1st-line afatinib, and post-EGFR-TKI osimertinib). The main objective was to compare overall survival (OS) among patients receiving these treatments to those in previous experimental and real-world studies. The patients who received EGFR-TKIs for indications of interest between 1 April 2001, and 31 March 2019 (or 31 March 2020, for post-EGFR-TKI osimertinib) were included to estimate the Kaplan-Meier-based median OS for each cohort. An extensive literature search was conducted to include comparable studies. For the gefitinib 1st-line (n = 457), the afatinib 1st-line (n = 80), and the post-EGFR-TKI osimertinib (n = 119) cohorts, we found a median OS (in months) of 18.9 (95%CI: 16.3-21.9), 26.6 (95%CI: 13.7-NE) and 19.9 (95%CI: 17.4-NE), respectively. Out of the 20 studies that we retained from the literature review and where comparisons were feasible, 17 (85%) had similar OS results, which further confirms the value of these breakthrough therapies in real-world clinical practice.

Vitamin D Exposure and Ovarian Cancer Risk and Prognosis.

Given the poor prognosis of ovarian cancer and limited population-level strategies for early detection and long-term treatment success, knowledge of modifiable risk factors for prevention and improved prognosis is important. Vitamin D has received wide scientific interest in cancer research as having the potential to be one such factor. We carried out a systematic narrative review of the literature on vitamin D and ovarian cancer risk and survival. We included 17 case-control and cohort studies on ovarian cancer incidence. Five analyses were of sun exposure, among which three reported an inverse association. Of 11 analyses of dietary vitamin D, two reported an inverse association. Among five studies of 25(OH)D levels, an inverse association was reported in two. Across all studies the findings were inconsistent, but some recent studies have suggested that vitamin D exposure at earlier ages may be important. Only three studies examining vitamin D exposure in relation to survival among ovarian cancer survivors were identified and the findings were inconsistent. The evidence to date supports a null influence of vitamin D on both ovarian cancer risk and survival. Future research should ensure that exposure assessment captures vitamin D exposure from all sources and for the etiologically or prognostically pertinent period.

Methods for sample acquisition and processing of serial blood and tumor biopsies for multicenter diffuse large B-cell lymphoma clinical trials.

Increasingly, targeted therapies are being developed to treat malignancies. To define targets, determine mechanisms of response and resistance, and develop biomarkers for the successful investigation of novel therapeutics, high-quality tumor biospecimens are critical. We have developed standard operating procedures (SOPs) to acquire and process serial blood and tumor biopsies from patients with diffuse large B-cell lymphoma enrolled in multicenter clinical trials. These SOPs allow for collection and processing of materials suitable for multiple downstream applications, including immunohistochemistry, cDNA microarrays, exome sequencing, and metabolomics. By standardizing these methods, we control preanalytic variables that ensure high reproducibility of results and facilitate the integration of datasets from such trials. This will facilitate translational research, better treatment selection, and more rapid and efficient development of new drugs. See all the articles in this CEBP Focus section, "Biomarkers, Biospecimens, and New Technologies in Molecular Epidemiology."

Does percutaneous nephrolithotomy in children cause significant renal scarring?

OBJECTIVE: To determine the frequency of renal parenchymal damage following percutaneous nephrolithotomy (PCNL) in children. PATIENTS AND METHODS: Fifty-six children undergoing PCNL in 60 renal units between January 2000 and December 2004 were included in this prospective study, and were subjected to postoperative technetium-99m dimercaptosuccinic acid ((99m)Tc-DMSA). Using a standard questionnaire, demographics, number, size and location of stones, procedure details, outcome as indicated by clearance with PCNL alone or additional procedures, and follow up were documented. Presence of focal renal damage and its association with the PCNL tract were examined. RESULTS: Out of 60 renal units, cortical defects on (99m)Tc-DMSA scan were seen in 10 renal units (17%). In three of these kidneys, the site of focal defect corresponded to the access site for tract formation during PCNL. Two additional kidneys had scarring at multiple sites, one of which corresponded to the access site during PCNL. In the remaining five kidneys no association between focal renal damage and nephrostomy tract site could be ascertained. No association was seen between renal damage and the size of nephroscope used during PCNL. CONCLUSION: There exists a risk of focal damage to renal parenchyma from the formation of the nephrostomy tract. In our series, focal damage was seen in 5% of patients; this may be an overestimate since preoperative (99m)Tc-DMSA scans were not available for our patients. Meticulous technique is important combined with a smaller nephroscope to minimize renal damage. Long-term follow up of such children is required to assess how many are left with permanent renal scars.