Chintakuntlawar, Ashish V.

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6–50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: −86.8%; interquartile range [IQR]: −90.7% to −70.9%) compared with the 28 who did not (median: −69.0%; IQR: −78.1% to −27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (−23.5% [CI: −55.3 to 8.3]; Fisher's exact test p -value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.

Abstract Background Median overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed. Methods Fifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches. Results Two of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8—not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7). Conclusions Our single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response.

Abstract Context Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. Objectives, Design, and Setting We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. Patient Context Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. Intervention The intervention was Foundation One tumor interrogation. Main Outcome Measures Main outcome measures included genomic alterations, patient characteristics, and overall survival. Results Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine–refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)—but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. Conclusions Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

AbstractEsthesioneuroblastoma (ENB) is a rare olfactory malignancy that can present with locally advanced disease. At our institution, patients with ENB in whom the treating surgeon believes that a margin-negative resection is initially not achievable are selected to undergo induction with chemotherapy with or without radiotherapy prior to surgery. In a retrospective review of 61 patient records, we identified six patients (10%) treated with this approach. Five of six patients (83%) went on to definitive surgery. Prior to surgery, three of five patients (60%) had a partial response after induction therapy, whereas two of five (40%) had stable disease. Microscopically margin-negative resection was achieved in four of five (80%) of the patients who went on to surgery, while one patient had negative margins on frozen section but microscopically positive margins on permanent section. Three of five patients (60%) recurred after surgery; two of these patients died with recurrent/metastatic ENB. In summary, induction therapy may facilitate margin-negative resection in locally advanced ENB. Given the apparent sensitivity of ENB to chemotherapy and radiotherapy, future prospective studies should investigate the optimal multidisciplinary approach to improve long-term survival in this rare disease.

Abstract Aims/Objective:Congenital antithrombin (AT) deficiency, estrogen-containing oral contraceptive pills (OCPs) and pregnancy are associated with increased risk of venous thromboembolism (VTE). Little is known about reproductive decision-making in women with AT deficiency. We sought to explore the attitudes and choices regarding reproductive health in this population. Study Design/Methods:We conducted a provider-administered survey of women identified from the Mayo Clinic congenital AT deficiency database. Participants were asked to discuss their diagnosis of AT deficiency (age at diagnosis and VTE history including diagnosis and treatment) and questioned about (1) any lifetime methods of contraception, (2) pregnancies and pregnancy outcomes, (3) use of assisted reproductive technology, (4) history of menorrhagia, and (5) how their AT diagnosis had impacted each reproductive health experience and how this impact made them feel (open-ended question). Results:Of 31 women with congenital AT deficiency, 18 (58%) were reached, 8 (26%) were not reachable and 5 (16%) were deceased. Of the 18 women who completed the survey, median age at AT deficiency diagnosis was 40 years (range 7 - 65). Twelve (67%) women had experienced a VTE; 2 and 5 women had VTE in the setting of pregnancy OCP use, respectively. Reported contraceptive methods included OCPs, intrauterine device (IUD), and male condoms. Of the 5 women diagnosed with AT deficiency while taking OCPs, three switched to IUD, one to condoms, and one did not report an alternative method of contraception. Fifteen (83% ) women reported at least one pregnancy (median number of pregnancies = 2; range 1 - 6). Of 42 total pregnancies among the 18 women, 33 (79%) resulted in live term birth, 3 (7%) in live preterm birth, and 6 (14%) in miscarriage/spontaneous abortion at a median of 12 weeks into the pregnancy. Four women (22%) reported the use of anticoagulation during pregnancy (presumed to be low molecular weight heparin, but most women could not specify), and 1 woman reported use of assisted reproductive technology leading to a successful pregnancy. Eleven women (61%) reported menorrhagia, 4 (36%) while on anticoagulation for VTE events. Ten of 18 women (56%) reported that the AT deficiency diagnosis had affected their reproductive health in at least one way. Patient-reported comments are presented in Table 1, and a "word cloud" diagram (an image composed of words from the women's comments regarding contraception), in which the size of each word indicates its frequency) is presented in Figure 1. Conclusion:Women with AT deficiency require careful multidisciplinary management to avoid complications in the settings of hormonal contraception and pregnancy. Many women reported that their reproductive health experiences were impacted by their diagnosis, but also reported successful pregnancy outcomes. Validated questionnaires should be developed to assess women's reproductive health experiences. Strategies for reproductive risk management should be discussed carefully, and patient involvement in reproductive decision-making is key in this population. Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception Word Cloud depicting frequency of women's comments regarding AT deficiency and contraception Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction Hereditary antithrombin (AT) deficiency is an autosomal dominant thrombophilia. It is classified into type 1 (quantitative) or type 2 (qualitative) deficiency based on the AT antigen and activity levels (Haemophilia 2008:14; 1229). The goal of this study was to correlate clinical phenotype with AT molecular defects. Methods After IRB approval, patients with a diagnosis of hereditary AT deficiency established at the Mayo Clinic, Rochester, were identified from the clinical database (1997-2012). AT activity was assayed by a chromogenic Factor Xa assay and AT antigen level was assayed by latex immunoassay. Peripheral blood leukocyte genomic DNA was extracted using standard methods. PCR-amplification and ABI BigDye Terminator cycle sequencing kit was performed for all SERPINC1 exons, intronic splicing regions and the 3’UTR. SERPINC1 sequence was analyzed using Mutation Surveyor software (SoftGenetics). Clinical data were obtained from patient interview and medical record review. An event was defined as an episode of venous thromboembolism (VTE), including deep vein thrombosis and/or pulmonary embolism; arterial thrombosis, including cerebrovascular event and/or myocardial infarction, and an obstetric event, including miscarriages and/or spontaneous abortions. Statistical analysis was performed with SAS 9.1.3 (SAS Institute Inc. Cary, NC). Results Of 30 patients with hereditary AT deficiency; sequence data was available on 22. Twenty-nine (97%) patients were white, and 19 (63%) were females. Six patients (20%) were smokers and 9 (30%) had a body mass index of >30. Based on the AT activity and antigen levels, 18 (81%) had type 1 AT deficiency, while the remainder had type 2. Eleven patients were heterozygous for six novel (all type 1) mutations. One patient was also a homozygous carrier for the Factor V Leiden mutation. The median age at first thrombotic event was 24.4 years (range, 16.2-70.7), and the median age at diagnosis of AT deficiency was 40.7 years (range, 17.8-76). Both, the median ages at first thrombotic event and at diagnosis were comparable in type 1 versus type 2 AT deficiency patients (P=0.52 and 0.97 respectively). Thirteen patients (43%) had unprovoked thrombotic events. Majority had VTE (n=21, 70%), which included one patient each with splanchnic venous thrombosis, and cerebral venous sinus thrombosis. At last follow up, twenty-one patients (70%) were on chronic anticoagulation [17 (81%) were on warfarin, 2 (9.5%) on enoxaparin and 2 (9.5%) were on rivaroxaban]. Median number of events was 1 (range 0-7). Four patients (19%) had bleeding complications from anticoagulation. Only one death was noted in the cohort and cause of death could not be determined. Conclusions Type 1 hereditary AT deficiency is the most clinically prevalent subtype in practice. Of the patients who developed thrombosis; clinical characteristics did not differ between type 1 and type 2 AT deficiency. We report 6 novel mutations in patients with hereditary AT deficiency. Disclosures: No relevant conflicts of interest to declare.

Background: Anaplastic thyroid cancer (ATC) has poor prognosis with median overall survival (OS) of ∼6 months. We previously reported high PD-1/PDL-1 staining in ATC, raising the possibility of the productive application of the immunotherapeutic pembrolizumab. However, having found pembrolizumab to anecdotally have limited single-agent activity in ATC, we sought to alternatively define whether pembrolizumab might synergistically combine with chemoradiotherapy as initial ATC therapy. Methods: An investigator-initiated therapeutic phase 2 trial of pembrolizumab, 200 mg intravenously (IV) every 3 weeks, combined with chemoradiotherapy (docetaxel/doxorubicin, 20 mg/m 2 each IV weekly plus volumetric modulated arc therapy) was initiated as frontline therapy (with or without surgery) in ATC to assess efficacy and toxicities. Six-month OS was selected as the primary endpoint using a Simon's optimal design with interim analysis (targeting accrual of 25 patients; Cohort A: prior resection, Cohort B: no resection). Based on a prior patient cohort-treated similarly, but without pembrolizumab, the design was such that, if 6-month true survival is 75%, the probability of declaring the approach worthy of further pursuit would be 91%. Results: Three patients were enrolled, two with rapidly enlarging unresectable neck masses. Early tumor responses were favorable in all three, and all three satisfactorily completed: intended radiotherapy, preceding and radiotherapy-concurrent pembrolizumab, and concurrent chemoradiotherapy. However, all three patients died <6 months following therapy initiation—one from pulmonary metastases and two from otherwise unexpected fatal pulmonary complications occurring subsequent to chemoradiotherapy completion—prompting study closure. Conclusions: Although initially tolerated and effective in terms of locoregional disease control, disappointing survival outcomes compared with historical controls raise uncertainty that the piloted approach merits further pursuit in ATC.

PURPOSE The purpose of this study was to determine if dose de-escalation from 60 to 66 Gy to 30 to 36 Gy of adjuvant radiotherapy (RT) for selected patients with human papillomavirus–associated oropharyngeal squamous cell carcinoma could maintain historical rates for disease control while reducing toxicity and preserving swallow function and quality of life (QOL). PATIENTS AND METHODS MC1273 was a single-arm phase II trial testing an aggressive course of RT de-escalation after surgery. Eligibility criteria included patients with p16-positive oropharyngeal squamous cell carcinoma, smoking history of 10 pack-years or less, and negative margins. Cohort A (intermediate risk) received 30 Gy delivered in 1.5-Gy fractions twice per day over 2 weeks along with 15 mg/m 2 docetaxel once per week. Cohort B included patients with extranodal extension who received the same treatment plus a simultaneous integrated boost to nodal levels with extranodal extension to 36 Gy in 1.8-Gy fractions twice per day. The primary end point was locoregional tumor control at 2 years. Secondary end points included 2-year progression-free survival, overall survival, toxicity, swallow function, and patient-reported QOL. RESULTS Accrual was from September 2013 to June 2016 (N = 80; cohort A, n = 37; cohort B, n = 43). Median follow-up was 36 months, with a minimum follow-up of 25 months. The 2-year locoregional tumor control rate was 96.2%, with progression-free survival of 91.1% and overall survival of 98.7%. Rates of grade 3 or worse toxicity at pre-RT and 1 and 2 years post-RT were 2.5%, 0%, and 0%. Swallowing function improved slightly between pre-RT and 12 months post-RT, with one patient requiring temporary feeding tube placement. CONCLUSION Aggressive RT de-escalation resulted in locoregional tumor control rates comparable to historical controls, low toxicity, and little decrement in swallowing function or QOL.

6592 Background: Sex, age and ECOG performance status (PS) may affect immune response and the efficacy of cancer immunotherapy with immune checkpoint inhibitors (ICI). We did a meta-analysis to assess the potential sex, age and ECOG PS differences of immunotherapy efficacy in advanced cancer. Methods: PubMed was searched up to January 15, 2019 for randomized controlled trials (RCT) comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs control therapy (without ICI). For sex difference analysis, pooled hazard ratio (HR) of death for men and women was calculated separately, and the heterogeneity between the two estimates was assessed using an interaction test by pooling study-specific interaction HR. Age ( < 65 vs ≥65) and ECOG PS (0 vs ≥1) difference was analyzed similarly. Subgroup analysis by cancer type and line of therapy (frontline vs subsequent) was explored. All analyses were done in Comprehensive Meta Analysis (v2) with random effects models. Results: Thirty phase 2/3 RCTs involving 17,728 patients were included. An OS benefit of immunotherapy was found for both men (HR 0.75, 95% confidence interval [CI] 0.69-0.81, P < 0.01) and women (HR 0.79, 95% CI 0.69-0.90, P < 0.01); for both younger ( < 65; HR 0.75, 95% CI 0.68-0.83, P < 0.01) and older (≥65; HR 0.76, 95% CI 0.69-0.83, P < 0.01) patients; and for both ECOG PS 0 (HR 0.78, 95% CI 0.69-0.89, P < 0.01) and PS ≥1 (HR 0.77, 95% CI 0.71-0.84, P < 0.01) patients. No significant difference of relative benefit from immunotherapy over control therapy was found in patients with different sex ( P = 0.283), age ( P = 0.906) or ECOG PS ( P = 0.783). In melanoma RCTs, compared with women (HR 0.77, 95% CI 0.64-0.94, P < 0.01), men (HR 0.56, 95% CI 0.42-0.76, P < 0.01) had more OS benefit from immunotherapy ( P = 0.037). No significant difference was found in other subgroup analyses by cancer types or line of therapy. Conclusions: Overall we found no evidence of association of sex, age, or ECOG PS with cancer immunotherapy efficacy. However, in melanoma, men might benefit more from immunotherapy than women.