Background: Patients with lung cancers may have disproportionately severe coronavirus disease 2019 outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of COVID-19 may inform optimal cancer care during this pandemic. Patients and methods: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n ¼ 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate ([ICU/intubation/DNI] a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n ¼ 46) and compared with controls with lung cancer and no known non-COVID-19 (n ¼ 5166). Results: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease [odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07e9.44 comparing the median (23.5 packyears) to never-smoker and 3.87, 95% confidence interval 1.35e9.68, respectively]. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. Conclusion: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

BackgroundAs large genomics and phenotypic datasets are becoming more common, it is increasingly difficult for most researchers to access, manage, and analyze them. One possible approach is to provide the research community with several petabyte-scale cloud-based computing platforms containing these data, along with tools and resources to analyze it.MethodsBionimbus is an open source cloud-computing platform that is based primarily upon OpenStack, which manages on-demand virtual machines that provide the required computational resources, and GlusterFS, which is a high-performance clustered file system. Bionimbus also includes Tukey, which is a portal, and associated middleware that provides a single entry point and a single sign on for the various Bionimbus resources; and Yates, which automates the installation, configuration, and maintenance of the software infrastructure required.ResultsBionimbus is used by a variety of projects to process genomics and phenotypic data. For example, it is used by an acute myeloid leukemia resequencing project at the University of Chicago. The project requires several computational pipelines, including pipelines for quality control, alignment, variant calling, and annotation. For each sample, the alignment step requires eight CPUs for about 12 h. BAM file sizes ranged from 5 GB to 10 GB for each sample.ConclusionsMost members of the research community have difficulty downloading large genomics datasets and obtaining sufficient storage and computer resources to manage and analyze the data. Cloud computing platforms, such as Bionimbus, with data commons that contain large genomics datasets, are one choice for broadening access to research data in genomics.

Background: Germline genetic alterations are established mediators of breast carcinogenesis, often giving rise to specific forms of genomic instability. BRCA1/2 pathogenic variants (PVs) are emblematic of this phenomenon through their induction of homologous recombination deficiency. While specific patterns of genomic instability may sensitize cancers to therapies such as PARP inhibitors (PARPi) or platinum chemotherapy, their implications for lineage-directed therapies such as endocrine therapy (ET) or CDK4/6 inhibitors (CDK4/6i) are unknown. Herein, we systematically investigated the patterns of association of germline alterations with specific somatic alterations and explored the resulting effect on clinical outcomes. Methods: Patients who underwent germline and matched tumor tissue sequencing utilizing MSK-IMPACT from April 2014 to May 2021 and had available germline analysis results were included. The final analysis presented at SABCS will include 6000 tumors from 5,150 patients, anonymized according to established institutional IRB guidelines to allow for germline analysis on the full cohort. We analyzed genomic data to inform the full spectrum of somatic and germline mutations, ploidy, and allele-specific copy number to determine loss of heterozygosity (LOH). We performed gene- and pathway-level enrichment analyses between somatic variants and germline PVs. Univariable and multivariable Cox proportional hazards models were constructed to assess the association of therapy-specific progression-free survival (PFS) with select germline PVs and germline-somatic interactions. Results: The preliminary analysis includes 2,798 tumors from 2,242 patients with germline and somatic sequencing results. The most frequent germline PVs were: BRCA2 (n = 81), BRCA1 (n = 67), CHEK2 (n = 57), ATM (n = 32), PALB2 (n = 19). The cohort robustly confirmed previously established relationships such as mutual exclusivity of gATM and TP53 variants (OR 0.10, 95% CI 0.032 - 0.33, q = 0.005). Alterations of TP53 were seen in 83% (56/67) of gBRCA1 patients; however, this did not achieve significance when adjusted for receptor subtype (OR 3.90, 95% CI 1.34-11.38, q = 0.15). The size of the cohort allowed discovery of several novel relationships. For instance, gBRCA2 loss was associated with alterations in TGF-B pathway components (OR 3.58, 95% CI 1.70 - 7.56, q = 0.002), potentially relevant to metastatic disease progression. PIK3CA mutations were significantly less prevalent in both gBRCA2 (OR 0.52, 95% CI 0.31 - 0.87, q = 0.063) and gBRCA1 PVs (OR 0.21, 95% CI 0.085 - 0.51, q = 0.014). Our analysis uncovered a strong association between gBRCA2 and somatic RB1 pathogenic alterations (OR 3.58, 95% CI 1.70 - 7.56, q = 0.011), with most variants (80%) encountered in metastatic gBRCA2 tumors. Given the essential role of RB1 in CDK4/6i response, we investigated the effect of BRCA2 status on clinical efficacy of CDK4/6i-ET. Strikingly, gBRCA2 PVs were significantly associated with inferior PFS (HR 2.17, 95% CI 1.46-3.22, p < 0.001) on first line treatment with CDK4/6i-ET. We posited the enrichment of somatic RB1 loss as a potential mechanism of resistance to CDK4/6i. Given the proximity of RB1 to BRCA2 on chromosome 13, we hypothesized that co-LOH of BRCA2 and RB1 predisposes the cancer cells to bi-allelic loss under therapeutic pressure of CDK4/6i. Indeed, 18/26 gBRCA2 (69.2%) tumors evaluable for allele-specific copy number had evidence of RB1 LOH. Discussion: Analysis of germline-somatic interactions yielded novel associations relevant to breast cancer progression and treatment resistance. Among these, we demonstrated BRCA2 carriers to have inferior outcomes to first line CDK4/6i-ET with potential implications for optimal first line therapy and sequencing of CDK4/6i vs PARPi in this patient population. Citation Format: Anton Safonov, Chai Bandlamudi, Paulino Tallón de Lara, Emanuela Ferraro, Fatemeh Derakhshan, Marie Will, Mark Donoghue, Pier Selenica, Joshua Drago, Ezra Rosen, Carlos dos Anjos, Elaine Walsh, Elizabeth A Comen, Mehnaj Ahmed, Barbara Acevedo, Ahmet Zehir, Michael F Berger, David Solit, Larry Norton, Ronglai Shen, Zsofia Stadler, Simon Powell, Jorge S Reis-Filho, Sarat Chandarlapaty, Mark Robson, Pedram Razavi. Comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-08.

No abstract