Peethambaram, Prema P.

e14018 Background: Cancer survival rates are improving. Therefore, management of cardiovascular complications has now become a crucial clinical concern. Cardio-oncology is the sub-specialty that assists in the overall management of cancer patients in a multi-disciplinary manner. Mayo Clinic cardio-oncology practice was initiated to work closely with our oncology colleagues for early detection of cardiovascular complications in response to cancer-therapy. Majority of the patients visit our cardio-oncology clinic once, we thought it is important to study the group of patients that visited frequently due to cardiovascular complications. Aim: To evaluate the most common cardiovascular complication in patients with 2 or more visits to our cardio-oncology clinic. Methods: From 2012-2017, there were > 2500 patients visits to our clinic, with 24 patients having 2 or more visits. Data including patients’ demographics, ethnicity, chemotherapeutic medications, primary cancer type, cardiovascular risk factors, echocardiography and clinical outcomes were collected. Cardiotoxicity was defined as the decrease in left ventricular ejection fraction (LVEF) of > 10% to a value of < 53%. Heart failure was diagnosed based on Framingham’s criteria or by a cardiologist. Results: There were 19 women (80%) and 5 men (20%). Median age at the time of diagnosis was 56 years [19-76]. The most common malignancy was breast cancer (70%), followed by B-cell lymphoma (12%) and acute myeloid leukemia (8%). Thirty percent had > 2 risk factors for cardiovascular disease. 75% of the patients had an LVEF of < 53, of these 67% developed heart failure with 58% preserved and 42% reduced ejection fraction. Those with heart failure had received a mean anthracycline dose of 305 ± 91.8mg/m2. With initiation of ACEI, B-Blockers, and diuretics (GDMT) 79% showed recovery of LVEF to ≥53 during the follow up. Conclusions: In our experience, most patients who were seen at least twice in the cardio-oncology clinic for heart failure had received a dose of > 300mg/m2 anthracycline. With GDMT over 75% of the patients recovered. Care in the cardio-oncology clinic plays a key role in optimizing these clinical outcomes.

Abstract Background: The combination of cyclin dependent 4/6 kinase inhibitors (CDK4/6i) with endocrine therapy (ET) has resulted in clinically significant improvements in progression-free survival (PFS) and overall survival (OS) in hormone-receptor (HR)-positive metastatic breast cancer (MBC). However, most patients’ disease ultimately progresses on CDK4/6i and ET. Therefore, further research is necessary to understand the mechanisms driving primary and secondary resistance. PROMISE is a multicenter prospective cohort study enrolling women with HR-positive MBC commencing treatment with palbociclib + letrozole (1st line) or palbociclib + fulvestrant (2nd Line). The study provides a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify molecular or cellular features associated with primary endocrine resistance (e.g. disease progression ≤ 12 months on treatment) and acquired resistance to CDK 4/6i. Additionally, patient derived xenografts and organoids are created to test new drug strategies designed to overcome resistance to CDK 4/6i and ET. Here, we present initial sequencing results from pretreatment biospecimens collected from PROMISE study participants. Methods: On-study tumor biopsies and blood samples were collected for DNA/RNA sequencing (TempusTM). The analyzed biospecimens were all obtained prior to initiation of palbociclib and ET. We correlated patient clinical characteristics (phenotypes) with molecular data and responses to protocol treatment. The data were analyzed using a series of cutting-edge bioinformatics pipelines for somatic and germline mutations in addition to copy number alterations (CNAs). The study database was locked for analysis on 06/20/2019. Results: We analyzed the somatic single nucleotide variants/INDELs (sSNV/INDEL) profiles across the tumor samples to determine the genes that were least likely to occur as a result of background mutation processes. Twenty-six patients had somatic copy number alterations (sCNA) and/or sSNV/INDEL in at least one of 18 genes with the most significant sSNV/INDEL profiles (p &lt; 0.03) which included clinically and biologically relevant genes. The genes with the most statistically significant sSNV/INDEL mutation profiles were GATA3, PIK3CA, CDH1, and ESR1 (p &lt; 0.0009). We observed a high percentage of tumors with somatic alterations in GATA3 (23% sSNV/INDEL, 15% sCNA), PIK3CA (38%, 12%), CDH1 (19%, 50%) and ESR1 (19%, 58%). ESR1 mutations were more frequent in patients receiving 2nd line treatment. Other frequently altered genes included TP53 (15%, 46%), MAP2K4 (8%, 50%), DNAAF1 (8%, 50%), and CDKN1B (8%, 35%). Further, ZNF317 and F3 were altered in 9 and 7 patients, respectively. Twenty-four samples had alterations in at least one of the CDK4/6 pathway genes (RB1, CCNE2, CCND1, CDK6, ESR1, CDKN2A, CCND3, CDK4, CDK2 and CCNE1). Four patients progressed on therapy; three of the four patients had mutations in PIK3CA, and one had a mutation in ESR1. Results of the RNA sequencing data (N=26) will be presented at the SABCS meeting. Conclusions: This is the first report of a prospective study designed to characterize the genomic landscape of ER+/HER2- MBC prior to palbociclib treatment. We observed high frequencies of known targetable alterations in PIK3CA and ESR1, including in patients that progress, which is consistent with previous reports. RNA sequencing data will be presented at the meeting. Citation Format: Ciara C O Sullivan, Krishna R Kalari, Vera J Suman, Peter T Vedell, Ann Moyer, Erin Carlson, Jason Sinnwell, Tejaswi Alaparthi, Xiaojia Tang, Kevin Thompson, Jaeyun Sung, Alvaro Moreno-Aspitia, Donald Northfelt, Minetta C Liu, Tufia C Haddad, Prema Peethambaram, Saranya Chumsri, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Paula Gill, Mohammad Ranginwala, Asad Javed, Sameer Batoo, Brendan P. McMenomy, Richard Weinshilboum, Liewei Wang, Matthew P Goetz. Comprehensive tumor sequencing to identify biomarkers of palbociclib response: First report of the PROMISE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-07.

Abstract Introduction: CDK 4/6 inhibitors (CDK4/6i) are FDA approved for treatment of hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Recent work demonstrated that a rise in MCV was correlated with longer median progression free survival (Anampa et al, Haemoatologica 2018). We performed a single-institution retrospective analysis to evaluate whether palbociclib induced early changes in MCV serve as a pharmacodynamic biomarker to predict response to CDK4/6i. Methods: We identified a retrospective cohort of 81 patients with HR+, HER2- MBC treated with CDK4/6i as first line metastatic treatment at Mayo Clinic, Rochester. Hematologic indices were abstracted pretreatment and at the start of each cycle through the start of cycle 4 (C4). Wilcoxon signed test was used to examine the changes in MCV (ΔMCV) comparing pretreatment up to C4 and ΔMCV between cycles. Optimal cut points for ΔMCV were determined using Cutoff finder (Budczies et al., PLOS One 2012). Cox proportional hazard regression analysis was performed to evaluate associations of MCV and time to treatment failure (TTF), which was defined as the time from the start of the analyzed cycle to treatment discontinuation for any reason(in months). As eight comparisons were made, a Bonferroni correction established p-value &lt;0.00625 as the adequate cutoff for statistical significance. Statistical analyses were performed using JMP (SAS Institute Inc, Cary, NC). Results: 60/81 patients had pretreatment and at least one subsequent lab data point that included MCV. The pretreatment mean hemoglobin (Hgb) was 12.8 [standard deviation (SD) 1.37 g/dL] and 6/60 (10.2%) patients with Hgb &lt;11.0 g/dL. Mean pretreatment MCV was 89.0 femtoliters/cell [fl (SD 4.63)] and no macrocytosis (defined as MCV &gt;100 fl) was observed. At C4, the mean Hgb was 12.1 g/dL (SD 1.11) with 4/49 (8.2%) with Hgb &lt;11.0 g/dL. The C4 mean MCV was 96.6 fl (SD 5.23) and 8/29 (16.3%) developed macrocytosis. Wilcoxon signed analysis showed a significant increase in ΔMCV pretreatment to C2 [n=51, median 1.5 with interquartile range (IQR) -0.1-3.2, p&lt;0.0001], C2 to C3 (n=44, median 2.9, IQR 1.4-5.2, p&lt;0.0001), and C3 to C4 (n=41, median 3.4, IQR 1.9-4.9, p&lt;0.0001). A rise in MCV≥8.15 from pretreatment to C4 was associated with a non-statistically significant improvement in TTF [n=49, hazard ratio (HR) 0.38, p = 0.06]. Between C2 and C3, a rise in MCV ≥2.9 was associated favorably with TTF (n=44, HR 0.36, p = 0.029). The estimated probability of remaining on treatment at 30 months was higher in those with C2-C3 ΔMCV ≥2.9 [44.1%; 95% Confidence Interval (CI) 17.3-68.2%] compared to those with a C2-C3 ΔMCV &lt;2.9 (10.1%; 95%CI 1.5-28.7%). Discussion: We observed an increase in MCV in all patients receiving CDK4/6i by start of C4. The rise in MCV during CDK4/6i treatment may reflect drug induced cell-cycle arrest in hematopoietic cells. Evaluation in larger studies is needed to validate dynamic changes in MCV as a predictive biomarker of response to CDK4/6i therapy. Citation Format: Grace Mei Yee Choong, Roberto A Leon-Ferre, Ciara C O'Sullivan, Kathyrn J Ruddy, Tufia C Haddad, Timothy J Hobday, Prema P Peethambaram, Charles L Loprinizi, Minetta C Liu, Vera J Suman, Matthew P Goetz, Karthik V Giridhar. Evaluation of mean corpuscular volume (MCV) as a pharmacodynamic predictive biomarker in patients receiving CDK4/6 inhibitors for metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-42.

5028 Background: Edmonston vaccine strains of MV have significant antitumor activity against ovarian cancer xenografts (Peng et al, Cancer Res, 2002). Oncolytic selectivity is due to overexpression of the MV CD46 receptor in ovarian cancer cells. Furthermore, engineering the virus to express the marker peptide CEA (MV-CEA) allows real time monitoring of viral gene expression/propagation in vivo. Methods: We are conducting a Phase I trial of MV-CEA in patients (pts) with recurrent, taxol and platinum refractory, ovarian or primary peritoneal carcinoma. Eligible pts should have protective anti-MV antibody (ab) titers and normal CEA levels. A standard phase I cohorts of three statistical design is employed. MV-CEA is administered IP via a port-a-cath, q 4 wks for up to 6 cycles. Results: To date, 12 pts have received viral doses from 103 to 106 TCID50. No dose-limiting toxicity has been observed. Most common toxicities included grade 1–2 nausea (4 pts); grade 1–2 fatigue (4 pts); grade 1 fever (3 pts); grade 1 abdominal pain (2 pts). One pt had grade 2–3 arthralgias in cycles 4–6. There was no treatment induced immunosuppression as assessed by DTH, CD4, CD8, immunoglobulin and complement levels, no significant increase in the titers of anti-MV abs in serum or ascites in response to treatment, and no development of anti-CEA abs. Viral genomes were detected in the peripheral blood mononuclear cells of 2 asymptomatic pts by QRT-PCR. No CEA elevation in the serum was observed in the dose range tested, and there was no viral shedding in urine or mouth gargle specimens. Testing of pt tumor samples for CD46 by IHC demonstrated overexpression of the target receptor in 7/8 pts. Best objective response was stable disease (2 - 9 mo duration) in 5 pts, while 3 pts had significant decrease in CA125 levels, of 44%, 72%, and 78%, respectively. Conclusions: In this first human application of an engineered oncolytic MV strain, we have observed excellent tolerance after repeat IP administration of the virus. Despite the low doses employed so far, there is early evidence of biologic activity. Dose escalation continues to the target dose of 109 TCID50. No significant financial relationships to disclose.

PURPOSE To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes ( ATM , BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

Background: Adherence to surveillance guidelines in resected colon cancer has significant implications for patient morbidity, cost of care, and healthcare utilization. This study measured the underuse and overuse of imaging for staging and surveillance in stage I–II colon cancer. Methods: The OptumLabs database was queried for administrative claims data on adult patients with stage I–II colon cancer who underwent surgery alone in 2008 through 2016. Use of PET and CT imaging was evaluated during both initial staging (n=6,921) and surveillance for patients with at least 1 year of follow-up (n=5,466). “High use” was defined as >2 CT abdominal/pelvic (CT A/P) or PET scans per year during surveillance. Results: Overall, 27% of patients with stage I–II colon cancer did not have a staging CT A/P or PET scan and 95% did not have a CT chest scan. However, rates of staging CT A/P and CT chest scans increased from 62.0% (2008) to 74.8% (2016) and from 2.3% (2008) to 7.1% (2016), respectively. Staging PET use was overall very low (5.2%). During surveillance, approximately 30% of patients received a CT A/P or PET and 5% received a CT chest scan within the first year after surgery. Of patients who had surveillance CT A/P or PET scans, the proportion receiving >2 scans within the first year (high use) declined from 32.4% (2008) to 9.6% (2016) (P = .01). Conclusions: Although PET use remains appropriately low, many patients with stage I–II colon cancer do not receive appropriate staging and surveillance CT chest scans. Among those who do receive these scans during surveillance, high use has declined significantly over time.

Abstract Introduction: The role of surveillance imaging in diffuse large B-cell lymphoma (DLBCL) after treatment with curative intent is debated. In 2013, the American Society of Hematology (ASH) Choosing Wisely® campaign (Hicks LK, et al. Blood 2013) released a recommendation to "limit surveillance CT scans in asymptomatic patients following curative-intent treatment for aggressive lymphoma." This was based on previous studies demonstrating a lack of survival benefit as well as a significant impact on the patient in terms of cost, anxiety, incidental findings and radiation exposure. Similar findings have been described regarding the use of PET imaging, especially in low risk patients. We aimed to study the changes in practice patterns of surveillance imaging for DLBCL survivors treated with curative intent before and after the publication of the ASH Choosing Wisely® campaign. Methods: Administrative claims data from a large U.S commercial insurance database (OptumLabs Data Warehouse) were used to retrospectively identify adult patients with an incident diagnosis of DLBCL between 2008 and 2016 and at least one year of follow-up. We excluded those who did not receive treatment with curative intent: RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) x 6 cycles or RCHOP x 3-5 cycles plus radiation. Patients were also excluded if they had a co-existing or second cancer, or if they received any chemotherapy/radiation during their surveillance period, as to exclude anyone with a recurrence of their lymphoma. The surveillance period started 90 days after the last chemotherapy or radiation and continued for the duration of follow-up. Surveillance imaging was defined as any PET, PET-CT, CT chest, CT abdomen, and/or CT pelvis. To examine trends over time, three time periods were defined: 2008-2010, 2011-2013 and 2014-2016. The Cochran Armitage test was used to test the trend hypothesis. Results: A total of 1,472 patients were included. Cohort characteristics by time period are described in Table 1. Surveillance imaging frequency decreased from 84% in Year 1 of surveillance to 43% in Year 5 (Figure 1). Overall, surveillance imaging during the first 3 surveillance years significantly decreased over the three time periods (Figure 2) (P<0.01 for Years 1 and 2, P=0.04 for Year 3). Imaging surveillance for the first two years of surveillance did not significantly decrease from 2008-2010 to 2011-2013 (P>0.05), but significantly decreased from 2011-2013 to 2014-2016 (P<0.01). Of the groups that received imaging surveillance during year 1, the median number of scans during the first year was 2 (inter-quartile range, 1-2) and did not significantly change over time. In addition, PET/PET-CT surveillance decreased from 49% in Year 1 to <10% in Year 5. PET/PET-CT also decreased over the three time periods, from 62% (2008-2010) to 48% (2011-2013) to 43% (2014-2016) during the first year of surveillance and 40% to 31% to 25% during the second year. Younger age (<65 years versus ≥65 years) was associated with higher imaging utilization (86% versus 81%, respectively), and specifically PET/PET-CT utilization (55% versus 43%, respectively), during the first year of surveillance. However, race (white versus non-white) did not significantly affect imaging (85% versus 83%) or PET utilization (50% versus 47%) during the first year of surveillance. Conclusions: Our study demonstrates that the rate of surveillance CT and PET imaging in DLBCL patients treated with curative intent decreased significantly in the years after the publication of the ASH Choosing Wisely® campaign. However, over half of the DLBCL patients diagnosed in 2014-2016 continued to undergo surveillance imaging, indicating either incomplete guideline dissemination or ongoing debate regarding optimal surveillance practice. Future studies are necessary to determine whether such a decline in surveillance imaging is sustained and to examine factors (patient, provider, and payer) associated with surveillance imaging in DLBCL. Disclosures No relevant conflicts of interest to declare.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or beta–human chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.