Citations

e20092 Background: More than 5,000 premenopausal women are diagnosed (dx’d) with lung cancer annually in the United States. Improvements in treatment are contributing to a growing population of young survivors. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Since 1997, we mailed annual surveys to patients seen at Mayo Clinic for lung cancer who consented to join a research cohort. Surveys queried menopausal status and age of menopause. Those who were dx’d under age 50, who were treated with curative intent, and who reported that they were premenopausal at the time of the cancer dx were included in this analysis. “Immediate” treatment-related menopause was defined as reporting age of menopause as the same as the age at diagnosis or 1 year (yr) older. Results: Of 182 survey respondents to date (mean time from dx to 1st survey: 26 mos, SD 24 mos, range 12-202 mos), 85 (mean age 44 yrs, SD 5, range 34-48) received chemo during the yr after diagnosis, 26 of whom also received targeted therapy during that yr. Lung cancer dx occurred 1958-2016. Platinum drugs, taxanes, and etoposide were the most common chemotherapies. 46% of chemo recipients (mean age 47, SD 2, range 41-49) experienced immediate menopause, 9% (mean age 43 yrs, SD 5, range 35-48) experienced menopause at least 2 yrs after the age of dx, and 45% (mean age 40 yrs, SD 5, range 25-48) remained pre- or peri-menopausal at their final survey (on average 3 years after dx, SD 2, range 1-10). Only 3 patients received targeted therapy alone, and the remaining 94 (mean age 42 yrs, SD 6 years) received no systemic therapy within a year of diagnosis. 15% of these 94 (mean age 45 yrs, SD 3, range 41-49) experienced immediate menopause, 16% (mean age 43 yrs, SD 4, range 36-49) experienced menopause 2+ yrs after the age of diagnosis, and 69% (mean age 41 yrs, SD 7, range 20-49) remained pre- or perimenopausal at their final survey (on average 4 yrs after dx, SD 3, range 1-10). Conclusions: Chemotherapy for lung cancer causes amenorrhea in a substantial proportion of women dx’d with lung cancer while premenopausal. Further research on fertility and menopausal symptoms after lung cancer treatment, and on differences between regimens, is warranted.

Abstract Objective: More than 5,000 premenopausal women are diagnosed with lung cancer annually in the United States. Limited data exist regarding the risk of treatment-related amenorrhea, a surrogate for infertility and early menopause, after systemic therapies for lung cancer. Methods: Premenopausal women diagnosed with lung cancer under age 50 were surveyed at diagnosis and annually thereafter about their menstrual status as a part of the Mayo Clinic Epidemiology and Genetics of Lung Cancer Research Program. Types of lung cancer-directed treatments were recorded, and frequencies of self-reported menopause at each survey were calculated. Results: A cohort of 182 premenopausal women were included in this study, with average age at lung cancer diagnosis 43 years (SD 6). Among the 85 patients who received chemotherapy, 64% self-reported that they had become menopausal within a year of diagnosis. Platinum salts were universally included in these chemotherapy regimens, and the majority of these women also received taxanes within 1 year of diagnosis. Only 15% of the 94 patients who did not receive systemic therapy within 1 year of diagnosis experienced self-reported menopause. Three patients received targeted therapy alone, two of whom remained premenopausal at the final qualifying survey, completed a median of 3 years after diagnosis. Conclusions: Chemotherapy for lung cancer patients appears to increase risk of early loss of menses in survivors.

Abstract Background: This is an update of the safety and efficacy of durvalumab monotherapy in pts with locally advanced/metastatic urothelial carcinoma (UC) from an ongoing, phase 1/2 open-label study (NCT01693562). Methods: Pts received 10 mg/kg every 2 weeks up to 12 months or until unacceptable toxicity, progression, or starting another anticancer therapy. Pts were stratified by tumor PD-L1 expression (Ventana PD-L1 [SP263] Assay [PD-L1 cutoff: ≥25% of tumor cells and/or immune cells with membrane staining]) and treatment line. Results: As of the data cutoff (16Oct2017), 201 UC pts with Stage IV disease received treatment, with a median follow-up of 16.9 months (range, 0.4-37.7). Across treatment lines, objective response rate (ORR) by blinded independent central review was 17.4% (95% CI, 12.4, 23.4) in all pts; 27.5% in the PD-L1 ≥25% group vs 5.8% in the PD-L1 <25% group. The responses have been durable regardless of PD-L1 status, with the median duration of response not yet reached in the PD-L1 ≥25% group and 12.2 months in the PD-L1 <25% group. Responses lasted ≥12 mo in 62.9% of responders (max 25.7+ mo). Overall, median OS was 10.5 months (95% CI, 6.9, 15.7); 19.8 months in the PD-L1 ≥25% group vs 4.8 months in the PD-L1 <25% group (Table). Pts previously treated with platinum based chemotherapy also reported similar durable responses. At least one treatment-related AE was reported in 120 pts (59.7%), including fatigue (39 [19.4%]), decreased appetite and rash (18 [9.0%] each), and diarrhea (16 [8.0%]). Grade 3/4 treatment-related AEs occurred in 19 (9.5%) pts; 6 (3.0%) treatment discontinuations and 2 (1.0%) deaths were attributed to treatment-related AEs. Conclusions: With extended follow-up, durvalumab continues to show durable clinical activity in UC pts, especially in the PD-L1 ≥25% group with an acceptable toxicity profile. PD-L1 ≥25%PD-L1 <25%PD-L1 unknownTotalAll UCn=102n=86n=13N=201Confirmed ORR, %27.55.815.417.4(95% CI)(19.1, 37.2)(1.9, 13.0)(1.9, 45.4)(12.4, 23.4)CR, %7.83.57.76.0PR, %19.62.37.711.4Median DoR, monthsNR12.2NRNR(min, max)(2.7, 25.7+)(8.6, 21.7+)(14.5+, 14.6+)(2.7, 25.7+)Median PFS, months (95% CI)1.9 (1.4, 2.7)1.4 (1.3, 1.5)2.8 (1.4, NE)1.5 (1.4, 1.8)6-month PFS rate, %28.68.625.220.412-month PFS rate, %22.37.125.216.2Median OS, months (95% CI)19.8 (9.3, NE)19.8 (9.3, NE)4.8 (3.3, 8.1)NR (4.9, NE)10.5 (6.9, 15.7)6-month OS rate, %67.645.869.258.912-month OS rate, %57.629.561.546.6 Citation Format: Peter O'Donnell, Christophe Massard, Bhumsuk Keam, Sang-We Kim, Terry Friedlander, Myung-Ju Ahn, Michael Ong, Michael Gordon, Marcus Butler, Scott Antonia, Gerardo Colon-Otero, Martin Gutierrez, Sumati Gupta, Alexander Spira, Alexandra Drakaki, Michele Maio, Feng Xiao, Natasha Angra, Shaad Abdullah, Thomas Powles. Updated efficacy and safety profile of durvalumab monotherapy in urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT031.

Abstract Background: Bioluminescence imaging (BLI) of firefly luciferase expressing cells is widely used for analysis of growth, metastasis and drug response in tumor xenografts. D-luciferin, a commonly used luciferase substrate, has limited brain distribution that may undermine BLI for intracranial xenografts. The synthetic luciferin cyclic alkylamino-luciferin (CycLuc1) is a purported brain penetrant luciferase substrate not yet tested in intracranial xenografts. We compared BLI with CycLuc1 and D-luciferin in a glioblastoma (GBM) xenograft model. Methods: GBM6 cells were lentivirally transduced to express LUC2=tdTomato fusion protein. In vivo BLI were performed in orthotopic and heterotopic xenografts established in athymic nude mice. Concentrations of D-luciferin and CycLuc1 were measured by LC-MS/MS. Results: In a dose-response analysis, CycLuc1 at 5 mg/kg provided robust and reproducible imaging; however, an increased photon flux was observed with 10 mg/kg, while escalation to 15 or 20 mg/kg provided marginal additional gains in photon flux. In comparison of CycLuc1 (5 or 25 mg/kg) and D-luciferin (30 or 150 mg/kg, respectively) with serial, crossover BLI at both dose levels, CycLuc1 resulted in less variability and significantly higher photon flux as compared to D-luciferin in GBM6 intracranial xenografts (15 days after implantation). On average BLI with 25 mg/kg CycLuc1 resulted in ~8 fold greater photon flux from these early-stage xenografts as compared to 150 mg/kg D-luciferin (2.9±0.6x106 vs. 3.3±2.8x105 p/sec/cm2, p<0.001). Interestingly, bioluminescence emission with CycLuc1 and D-luciferin was comparable in xenografts imaged 28 days after implantation. In samples harvested after last imaging session, there was no significant difference in substrate distribution in intracranial tumors (tumor to plasma ratios for CycLuc1 and D-luciferin were 0.012 ± 0.020 and 0.012 ± 0.015, respectively; p=0.89). These results suggest that intracranial tumors at early stage may comprise relatively intact blood-brain barrier, which is disrupted at later stage. Consistent with notion that suboptimal delivery may interfere with D-luciferin mediated BLI in intracranial xenografts, photon flux in heterotopic tumors with D-luciferin or CycLuc1 was comparable (4.9±4.6x108 vs. 1.3±0.8x108 p/sec/cm2, p=0.10). Conclusions: These findings demonstrate that CycLuc1 may be a superior BLI substrate as compared to D-luciferin for monitoring tumor growth of intracranial GBM xenografts. Citation Format: Shiv K. Gupta, Minjee Kim, Bianca-Maria Marin, Lihong He, Katelyn Swanson, Tuma Tuma, Brett L. Carlson, Mark A. Schroeder, William F. Elmquist, Jann N. Sarkaria. Synthetic luciferin, CycLuc1, improves bioluminescence imaging for intracranial glioblastoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4112.

OBJECTIVE Although it is still early in its application, laser interstitial thermal therapy (LiTT) has increasingly been employed as a surgical option for patients with mesial temporal lobe epilepsy. This study aimed to describe mesial temporal lobe ablation volumes and seizure outcomes following LiTT across the Mayo Clinic’s 3 epilepsy surgery centers. METHODS This was a multi-site, single-institution, retrospective review of seizure outcomes and ablation volumes following LiTT for medically intractable mesial temporal lobe epilepsy between October 2011 and October 2015. Pre-ablation and post-ablation follow-up volumes of the hippocampus were measured using FreeSurfer, and the volume of ablated tissue was also measured on intraoperative MRI using a supervised spline-based edge detection algorithm. To determine seizure outcomes, results were compared between those patients who were seizure free and those who continued to experience seizures. RESULTS There were 23 patients who underwent mesial temporal LiTT within the study period. Fifteen patients (65%) had left-sided procedures. The median follow-up was 34 months (range 12–70 months). The mean ablation volume was 6888 mm 3 . Median hippocampal ablation was 65%, with a median amygdala ablation of 43%. At last follow-up, 11 (48%) of these patients were seizure free. There was no correlation between ablation volume and seizure freedom (p = 0.69). There was also no correlation between percent ablation of the amygdala (p = 0.28) or hippocampus (p = 0.82) and seizure outcomes. Twelve patients underwent formal testing with computational visual fields. Visual field changes were seen in 67% of patients who underwent testing. Comparing the 5 patients with clinically noticeable visual field deficits to the rest of the cohort showed no significant difference in ablation volume between those patients with visual field deficits and those without (p = 0.94). There were 11 patients with follow-up neuropsychological testing. Within this group, verbal learning retention was 76% in the patients with left-sided procedures and 89% in those with right-sided procedures. CONCLUSIONS In this study, there was no significant correlation between the ablation volume after LiTT and seizure outcomes. Visual field deficits were common in formally tested patients, much as in patients treated with open temporal lobectomy. Further studies are required to determine the role of amygdalohippocampal ablation.