Kosiorek, Heidi

AbstractBackgroundPhiladelphia chromosome negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia, polycythemia vera, and myelofibrosis, have severe function‐limiting symptom burden that is experienced by the majority of patients. Previous studies have suggested that depression may be present in over a quarter of MPN patients, but to date no studies have evaluated the relationship between depression and other variables such as symptoms.MethodsA 70‐item internet based survey regarding fatigue and mood symptoms was developed by a multidisciplinary team of MPN investigators, patients and patient advocates including Patient Health Questionnaire and the Myeloproliferative Neoplasm Symptom Assessment Form was completed by over 1300 patients with MPN diagnosis.ResultsThere were 309 respondents (23%) with PHQ‐2 scores ≥ 3. In this analysis, we found worse systemic symptom burden in individuals reporting depressive symptoms.ConclusionThis analysis suggests the importance of depression in contributing to as well as confounding symptomatology in MPN patients, and suggests that this critical variable should also be addressed by clinicians and researchers alike when comprehensively assessing symptom burden etiologies.

Abstract Background: Accurate circulating biomarkers for detecting residual disease can help guide therapy decisions, particularly in early-stage cancer patients. However, currently available methods lack the sensitivity required to confidently assess the presence of residual disease in patients with low tumor burden. To address this need, we have developed TARDIS (Targeted Digital Sequencing), a personalized, multiplexed amplicon sequencing method capable of tracking as many as 100 or more mutations simultaneously. Methods: We obtained tumor biopsies and longitudinal plasma samples from patients with early-stage breast cancer, glioblastoma, and pancreatic cancer. Each tumor biopsy was analyzed whole-exome sequencing. Founder mutations were selected, accounting for copy number alterations (analyzed using sequenza) and a consensus allele fraction approach that combined pyclone and custom in-house methods. Patient-specific TARDIS primers were designed to detect these mutations in plasma cfDNA. Error suppression in TARDIS was achieved using a combination of unique molecular identifiers and fragment sizes to group sequencing reads into read families. Results: In 33 patients with early-stage breast cancer treated with neoadjuvant therapy, we targeted between 3 and 116 (mean 30) mutations per patient and analyzed between 1 and 4 longitudinal plasma samples using TARDIS. Prior to treatment, we detected ctDNA in 100% patients with Stage I-III breast cancer (n=32, 95% CI= 89%-100%). We detected tumor-specific mutations in 100% of baseline breast cancer plasma samples. After completion of neoadjuvant therapy and before surgery, ctDNA levels were significantly lower in patients with pathologic complete response (pathCR, no evidence of disease at surgery) compared to patients with residual disease (median tumor fractions 0.003% and 0.017%, respectively, p=0.0058, AUC=0.83). Conclusions: TARDIS enables highly sensitive detection of ctDNA in patients with nonmetastatic cancers. Analysis of longitudinal plasma samples using TARDIS holds promise for personalizing the extent of treatment in patients with curable disease. Multiple clinical validation studies across cancer types are ongoing to define quantitative thresholds for changes in ctDNA levels that could improve clinical decision making. Citation Format: Bradon R. McDonald, Tania Contente-Cuomo, Stephen-John Sammut, Michelle D. Stephens, Ahuva Odenheimer-Bergman, Brenda Ernst, Nieves Perdigones, Suet-Feung Chin, Maria Farooq, Rosa Mejia, Patricia A. Cronin, Karen S. Anderson, Heidi E. Kosiorek, Donald W. Northfelt, Ann E. McCullough, Bhavika K. Patel, Jeffrey N. Weitzel, Thomas P. Slavin, Carlos Caldas, Barbara A. Pockaj, Muhammed Murtaza. Personalized monitoring of treatment response using Targeted Digital Sequencing of circulating tumor DNA [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A51.

AbstractBackground and ObjectivesNeoadjuvant endocrine therapy (NET) for ER+ breast cancer can downstage primary tumors. We evaluated NET efficacy in node‐positive patients.MethodsNode‐positive patients undergoing NET for ER+ breast cancer from 2012 to 2019 were reviewed. Primary endpoints included rates of axillary lymphadenectomy (ALND), pathologic complete response (pCR), and final nodal staging.ResultsThirty‐nine patients were included. Before NET, all were clinically node‐positive (cN1 = 36, 94%; cN2 = 2, 5%; cN3 = 1, 3%; Stage II = 23, 59%, Stage III = 16, 41%). After NET, nine (23%) had clinically persistent axillary disease necessitating ALND. The remaining 30 (77%) underwent sentinel lymph node biopsy (SLNB). Of these, 25 (83%) were SLNB+ on frozen section, undergoing immediate ALND. Five patients were negative on frozen section: one had a confirmed axillary pCR, and four had residual nodal disease on permanent pathology. One underwent delayed ALND, and for the remaining three patients, decision was made to forgo ALND. Final overall axillary staging was: N0 (pCR) = 1, 3%, pN1mic = 1, 3%, pN1 = 20, 51%, pN2 = 12, 30%, pN3 = 5, 13%; Stage II = 16, 41%, Stage III = 23, 59%.ConclusionsWhile NET is reported to downstage primary tumors, downstaging of the axilla was unsuccessful in the majority of patients.

e17587 Background: Radium (Ra)-223 has become the cornerstone treatment in patients with metastatic castrate-resistant prostate cancer (mCRPC) with bone metastases. Ra-223 has been shown to suppress abnormal bone formation by inducing DNA double-strand breaks in tumor cells. This can reduce skeletal-related events, as well as improve survival and quality of life. Studies have indicated mutations that regulate DNA damage response in prostate cancer as susceptible to PARP inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. Methods: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics, genetic mutations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. Results: 239 mCRPC patients treated with Ra-223 were identified. Germline and/or somatic genetic sequencing was available in 50 patients, who had a median age of 61 years at time of diagnosis and 68 years at time of Ra-223 treatment. Median Gleason score at time of diagnosis was 8.0. 100% of patients received prior androgen deprivation therapy. 72% received prior docetaxel, and 18% received prior cabazitaxel. Notable mutations included TP53 (45.2%), TMPRSS2-ERG (28.6%), PTEN (26.2%), BRCA1/2 (14.3%), ATM (9.3%), CDK12 (7.1%), and Rb (4.9%). TMPRSS2-ERG was the second most commonly found mutation, with median OS 12.7 mo versus 15.4 mo in patients without TMPRSS2-ERG mutations (p = 0.099). In patients with CDK12 mutations (2 of 28 tested positive), PFS was 10.4 mo versus 5.6 mo in patients without CDK12 mutations (p = 0.157). The assessment of ALP and PSA response to radium treatment stratified by genetic mutation did not reach statistical significance. Conclusions: Among mCRPC patients treated with Ra-223 at Mayo Clinic, TMPRSS2-ERG was the second most commonly found genetic mutation and had observed worse survival outcomes that approached statistical significance. Prospective studies and increased sample sizes are needed to determine the impact of genetic mutations in response to Ra-223.

Abstract Background: Unlike with solid organ cancers, little data is available on how diabetes mellitus (DM) and hematologic malignancies interact to affect survival and glycemic control. We examined the impact of DM on survival in patients with leukemia and the effect of leukemia on glycemic control. Materials and Methods: Patients with leukemia with and without DM were matched 1:1 (2007–2017), 70 matched pairs (total N=140 pts) were included in the analysis. We compared characteristics between cases and controls and assessed survival with the Kaplan-Meier method and Cox proportional hazards model. Mixed models compared hemoglobin A1c (HbA1c) and glucose levels over time. Results: The median age of patients at diagnosis was 56 (18–94); 60% were male and 89% had acute leukemia. Among those with DM, HbA1c was only recorded in 25 of 70 patients during the year following cancer diagnosis and was 6.8%. There was no change in HbA1c values over time in these DM patients. Mean glucose was significantly different between DM and non-DM patients (p<0.001). Time (days since leukemia diagnosis) was significant (p<0.001) and there was a significant interaction effect (p=0.01). Glucose values increased in the DM patients during the year following diagnosis, while remaining stable in those without DM. Median follow-up time was 23.2 months. Three-year survival was estimated at 46% for DM patients versus 45% in non-DM pts by Kaplan Meier method (p=0.79). Hazard ratio (stratification for matched pairs) was 1.05 (95% CI: 0.57 - 1.94; p=0.88). Three-year relapse-free survival was estimated at 34% for DM patients versus 43% for non-DM patients (p=0.58). Hazard ratio (stratification for matched pairs) = 1.10 (95% CI: 0.61–1.98; p=0.76). Conclusions: DM did not adversely impact survival in patients with leukemia. Leukemia and its treatment did not affect glycemic control. This should be reassuring to hematologists and endocrinologists who treat patients with leukemia and diabetes.

Abstract Background: We have previously examined the link between diabetes mellitus (DM) and malignancy with respect to mortality, but little is known about how the cancer affects glycemic control. Therefore, the aim of this study was to evaluate metabolic parameters in patients with cancer with and without DM. Methods: We selected 1404 patients with newly diagnosed prostate, breast, lung, colorectal, and pancreatic cancer from the institutional cancer registry from 2010–2015. Records were selected and matched 2:1 cancer without DM (n=936) and cancer and concurrent DM patients (n=468). Patients were matched by year of diagnosis, age, gender, and cancer type. Metabolic parameters during the year after cancer diagnosis were examined using linear mixed models with fixed effects for time, cancer type, DM status and individual-specific random effect allowing each patient to have a different intercept. Results: Prostate cancer accounted for the majority of cases (n=199), followed by lung cancer (n=91), breast cancer (n=71), colorectal cancer (n=54), and pancreas cancer (n=53). Mean overall hemoglobin A1c (HbA1c) was 6.9 (1.2)%. Pancreas cancer patients had higher HbA1c overall (p=0.02). There was no change in HbA1c one year post cancer diagnosis (p=0.28). Mean glucose in non-DM was 108(18) mg/dL and 146 (45) mg/dL in DM pts. Lung and pancreas cancer patients had higher glucose values overall (p<0.001). Time (p<0.001), DM (p<0.001) and time * DM (p=0.02) were significant in a mixed model. A decrease in glucose over the year was observed in DM patients across all cancer types. Conclusions: A diagnosis of malignancy does not worsen glycemic control within the first year of cancer diagnosis. This should be reassuring to endocrinologists and oncologists who treat patients with DM and cancer. Longer term studies, and analysis in larger and more diverse patients groups are needed.

AbstractObjectiveTo determine the presence of racial/ethnic differences in patients with anemia and serum folate deficiency.MethodsWe performed a retrospective analysis of data from patient samples collected from January 2010 to October 2018. Reference laboratory ranges were determined by Mayo Clinic Reference Laboratories. Race and ethnicity were classified according to National Institutes of Health categories.ResultsThe analysis comprised 197 974 samples. Hemoglobin, hematocrit, and SF results were available for 173 337, 173 056, and 129 760 samples, respectively. Of the samples, 46 505 (26.8%) showed anemia, with a higher prevalence among American Indian/Alaskan Natives (AI/AN) 42.9% and African Americans (AA) 47.2% (P < .001). SF deficiency was present in 897 (0.7%), with a higher prevalence among AI/AN (9, [1.4%]) and AA (78, [1.2%]) and a lower prevalence in non‐Hispanic whites (NHW) (758, [0.7%]), Hispanics (40, [0.6%]), and Asians (8, [0.3%]). In multivariable analysis, the prevalence of anemia was higher in all non‐NHW racial/ethnic groups: AA (OR, 3.67, [95%CI: 3.47‐3.88, P < .001]), AI/AN (OR, 3.25, [95%CI: 2.71‐3.90, P < .001]), Asians (OR, 1.62, [95%CI: 1.47‐1.77, P < .001]), and Hispanics (OR, 1.41, [95%CI: 1.32‐1.50, P < .001]). SF deficiency was more common in AA (OR, 1.48, [95%CI: 1.17‐1.88, P.001]) and less common in Asians (OR, 0.35, [95%CI: 0.17‐0.70, P = .003]), compared with NHW.ConclusionsWe showed significant racial/ethnic differences in anemia and SF deficiency. Differences were observed especially among NHW, AA, and Asians. We believe that these differences may be explained by social determinants of health. More research is needed regarding the causes of these differences and their clinical implications at a population level.

e20029 Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a pulmonary disorder with neuroendocrine cell proliferation with potential progression to lung neuroendocrine tumor (Lu-NET). Optimal diagnostic and treatment strategies have yet to be well defined. Herein, we aim to describe the Mayo Clinic experience with DIPNECH. Methods: A retrospective analysis was performed of patients diagnosed with DIPNECH within Mayo Clinic between January 2000-Febuary 2019. Cases were identified from clinical databases at Mayo Clinic. Data on demographics, disease characteristics, time of diagnosis, surgery, and last follow up date were extracted. Extent of symptom burden, treatment approaches, disease progression, and disease-free survival (DFS) were evaluated by chart review. Results: A total of 59 patients were identified with a median age of 63(43-81) years. The cohort was predominantly female (93.2%) and non-smoking (76.3%). Most patients (86.4%) had symptomatic disease with chronic cough being the most common (71.2%) followed by exertional dyspnea (44.1%). Imaging typically showed bilateral lung nodules (93.2%) with mosaic attenuation noted 69.5% of the time. Surgical resection was frequently completed to confirm diagnosis (94.9%). Most patients received inhaled glucocorticoids combined with a beta agonist (79.7%). Oral steroid use was seen in 49.2% of patients whereas a somatostatin analog was used in 15.3% following the diagnosis of DIPNECH. These medical interventions led to symptom relief in 23.7% of the patients. The median follow up for all patients was 19.5 months. Progression of tumorlets was seen in 48.7% of patients with only 7(17.9%) patients progressing to a diagnosis of Lu-NET. The 3-year DFS was 90.5%. Conclusions: This is amongst the largest studies completed evaluating DIPNECH patients. DIPNECH remains a rare disease more commonly diagnosed in women in their early 60’s. DIPNECH appears to have an indolent course with obstructive symptoms being the most common finding. A minority of patients experienced symptom relief with therapy. Overall, DIPNECH appears to have a low risk of progressing to Lu-NET based on the observation of this study.

Treatment of polycythemia vera (PV) with the Murine Double Minute 2 (MDM2) antagonist, idasanutlin, in a phase 1 trial was reported by our group to be well tolerated with a high overall response rate (Mascarenhas et al, Blood. 2019 Jun 5). A global, phase 2 trial is currently underway evaluating idasanutlin in hydroxyurea (HU) resistant/intolerant PV patients (NCT03287245). MDM2, a negative regulator of TP53 is upregulated in PV CD34+ cells and inhibition of MDM2 targets PV hematopoietic stem/progenitor cells (HSPC) (Lu et al, Blood. 2014;124(5):771-90). Additional trials of MDM2 antagonists have shown promise, however, there is concern that these agents have the potential to induce TP53 mutations or promote expansion of TP53 mutated clones. Resistance to MDM2 inhibitors has been evaluated in solid tumor cell lines and attributed to either the emergence of de novoTP53 mutations or the selection of TP53 mutated clones. (Michaelis et al, Cell Death Dis. 2011;2:e243; Skalniak et al, Cancers. 2018;10(11)). The effect of MDM2 inhibition on TP53 mutant clones is of particular interest in myeloproliferative neoplasms (MPNs). TP53 mutations have been reported with a low allele burden in ~15% of chronic MPN patients (Kubesova et al, Leukemia. 2018;32(2):450-61), however, TP53 loss of heterozygosity and rapid expansion of TP53 mutant clones is associated with transformation to blast phase (Lundberg et al, Blood 2014,123:2220-8). As reported, in the idasanutlin PV trial, 1/13 patients were identified to have a baseline pathogenic TP53 mutation in hematopoietic cells (VAF 5.5%), using a deep sequencing assay with a limit of detection (LOD) of VAF 0.5%. This patient was a non-responder to idasanutlin and upon treatment had an increasing JAK2V617F and TP53 mutant VAF. End of study hematopoietic cell specimens of all patients were deep sequenced (LOD 0.1%) and revealed that 4 additional patients harbored detectable TP53 mutations after idasanutlin treatment with VAF ranging from 1-12%. In each sample, 1-5 unique TP53 mutations were identified, all within the hotspot domain of the TP53 gene. Deeper sequencing of baseline and follow-up samples revealed these mutations were present at a subclonal level (VAF 0.1-5.5%) and increased over time, indicating that treatment with the MDM2 antagonist promoted expansion of already existing TP53 mutant clones (Table 1, Figure 1). None of the patients who lacked a TP53 mutation at baseline developed a TP53 mutant clone with idasanutlin treatment. There was no clear association of presence of TP53 mutations with prior HU, anagrelide or interferon exposure. There has been careful monitoring of patients to determine whether the expanding TP53 clone has clinical ramifications. Patients were on study for a median of 54 weeks (23-131). The only patient who exemplified resistance to idasanutlin was the single patient with a high burden TP53 mutation (37%). All other patients were taken off study due to patient choice/toxicity. Furthermore, all TP53 mutant and non-mutant patients have had stable disease with no evidence of progression to MF or AML. Sequencing of 2 patients post-discontinuation of idasanutlin revealed that the VAF of the TP53 mutant clones decreased since the agent was discontinued. Updated patient molecular data post-treatment discontinuation will be reported at the meeting. To investigate whether idasanutlin induces de novo TP53 mutations in PV myeloid cells we performed long term HSPC cultures. Mononuclear cells from 6 distinct PV patients were treated continuously with idasanutlin (500 nM) over ~6 weeks and DNA from both treated and untreated colonies were analyzed using next generation sequencing with a LOD of 2% VAF and no TP53 mutations were detected. The combined in vitro and clinical data reveals that treatment with an MDM2 antagonist is not associated with the emergence of de novoTP53 mutations but rather the expansion of prior existing TP53 clones. This does not appear to have clinical repercussions, however, close monitoring of these patients is essential. We recommend that patients be screened for TP53 mutations prior to treatment with an MDM2 antagonist and that if present the TP53 mutant VAF be followed during their treatment course. Resistance to MDM2 inhibition is likely dependent on the TP53 mutant VAF and further studies will need to clarify the ideal dosing schedule of MDM2 antagonists and/or combinatorial therapy to prohibit TP53 mutant clonal expansion. Disclosures Houldsworth: Cancer Genertics: Other: stock in; Sema4: Employment. Rossi:Sema4: Employment. Kiladjian:AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy; Novartis: Honoraria, Research Funding. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hoffman:Merus: Research Funding.

612 Background: The aim of this study was to examine the impact of diabetes mellitus (DM) on survival in neuroendocrine tumor and the impact of neuroendocrine tumor on glycemic control in DM. Methods: Patients with newly diagnosed neuroendocrine tumor with and without DM were matched 1:1 according to age, gender, and year of cancer diagnosis (2005-2017). The file was linked to the electronic medical record to obtain information on DM and neuroendocrine tumor therapies and laboratory results. There were 59 matched pairs (total 118 patients) included in the analysis. We compared characteristics between cases and controls and assessed survival with the Kaplan-Meier method and Cox proportional hazards model. Mixed models compared hemoglobin A1c and glucose levels over time. Results: Median age of patients at diagnosis was 67 (40-86); 41% had stage IV disease. Women constituted 49% of the study population; 22% had pancreatic neuroendocrine tumor and 45% had another GI primary neuroendocrine tumor. No differences in race/ethnicity, marital status, alcohol or tobacco use were detected between cancer patients with and without DM. Mean BMI was significantly different between DM and non-DM patients (31.0 [7.90] versus 26.4 [5.27]); p = 0.011. Among those with DM, mean HbA1c during the year following cancer diagnosis was 7.3%. Mean glucose was significantly different between DM (159.1 [43.5] versus non-DM pts 117 [31.5]); p < 0.001. Median follow-up time was 32.8 (2.4-165.4) months in alive patients. Three year survival was estimated at 72% (95% CI: 60-86%) for DM patients versus 80% (95% CI: 70-92%) in non-DM patients by Kaplan Meier method (p = 0.82 log rank test). Hazard ratio (stratification for matched pairs) = 1.33 (95% CI: 0.56 – 3.16; p = 0.51). Conclusions: DM did not adversely impact survival in patients with neuroendocrine tumor. Neuroendocrine tumor and its treatment did not affect glycemic control. This should be reassuring to oncologists and endocrinologists who treat patients with neuroendocrine tumors and diabetes.