Purpose/Objectives: Small cell lung cancer (SCLC) is a highly aggressive disease representing 12-13% of all lung cancers, with 5 year survival rate of only 6%. While most patients respond initially to cytotoxic chemotherapies such as irinotecan, etoposide or carboplatin, resistance rapidly emerges and response to second line agents such as topotecan is limited, and in contrast to non-small cell lung cancer (NSCLC), few targetable oncogenes occur in SCLC. In this study, we tested new compound, STA-12-8666, which binds tumor-concentrated active form of shock protein 90 (HSP90) and has cleavable linker attached to SN-38, the active metabolite of irinotecan. Cleavage of the linker within the tumor provides time-release of SN-38 at high local concentration, while significantly limiting drug exposure and toxicity in non-transformed issue. The goal for this work was to evaluate STA-12-8666 for potential use as a new second line monotherapy, or as adjuvant in the frontline setting. Materials/Methods: Three dose levels of STA-12-8666 were evaluated in comparison to irinotecan, ganetespib, carboplatin, etoposide, and chemotherapy combinations in 4 independent SCLC xenograft models, including parental and cisplatin-resistant derivative cell lines (SCLC1, SR2), and a patient-derived xenograft (PDX). STA-12-8666 was also evaluated in drug combinations. Intratumoral responses were profiled using a mass spectrometry based approach to evaluate kinase pathway activation, and results confirmed by immunohistochemistry and western blot analysis. Pharmacokinetic analysis was performed to benchmark retention of STA-12-8666 to isomolar irinotecan in lung tumors. Results: In all three models, high dose (150 mg/kg) STA-12-8666 was well tolerated. In most cases, three doses administered at weekly intervals caused complete regression of established tumors, with response durable for > 2 months. Those tumors that regrew were responsive to re-dosing with STA-12-8666, and were subsequently eliminated. STA-12-8666 was also effective in limiting or eliminating tumors growth that had progressed following initial treatment on standard first and second line agents for SCLC. Low dose (50 mg/kg) STA-12-8666 controlled but did not eliminate tumors: however, it strongly enhanced the action of 30 mg/kg carboplatin, resulting in tumor elimination. Pharmacokinetic and proteomic analysis confirmed STA-12-8666 concentration in tumors, and identified a signature of DNA damage response biomarkers in STA-12-8666-treated tumors that strongly contrasted with the pattern induced by irinotecan. Conclusions: Together, these results indicate that STA-12-8666 may be a promising therapy in both frontline and second line settings for SCLC and strongly support the evaluation of this compound in Phase I/II clinical trials. Note: This abstract was not presented at the meeting. Citation Format: Anna Gaponova, AS Nikonova,A Deneka,BL Egleston,S Litwin,JS Duncan,K Duncan,H Borghaei,R Mehra,DA Proia,Y Boumber, Erica Golemis. Preclinical testing demonstrates strong activity of STA-12-8666, an HSP90 inhibitor-SN-38 conjugate, in small cell lung cancer (SCLC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1731. doi:10.1158/1538-7445.AM2015-1731
Background: Multidisciplinary care (MDC) in managing localized breast cancer is a resource-intensive treatment strategy that is anecdotally growing in prevalence, but is poorly characterized and thus cannot yet be defined as "standard care." We sought to determine the patterns of MDC care in the United States Medicare patient and assess if survival advantages exist for this paradigm. Methods: Using the Survival, Epidemiology, and End Results (SEER)-Medicare linked dataset, we evaluated patients with non-metastatic breast cancer from 1992 to 2009. MDC was defined as a preoperative visit after breast cancer diagnosis with a surgeon, medical oncologist and radiation oncologist. Two separate analyses were performed: The first evaluated all MDC patients, and the second characterized the subset of patients who saw all three specialties on the same day. We tested for associations between MDC and clinical/demographic variables using logistic regression and evaluated outcomes using propensity score matching. Results: A total of 87,984 invasive nonmetastatic breast cancer patients were included. MDC was utilized in 2.8% of patients, while 13% of these saw all three oncologic specialists on the same date. MDC use did not vary significantly according to AJCC stage. Patients receiving MDC overall were significantly more likely to be younger (continuous variable; OR [95% CI] = 0.99 [0.98-0.99]), black race (1.75 [1.50-2.05]), receive lumpectomy (1.15 [1.03-1.28], have fewer nodes examined (0.98 [0.98-0.99], and receive radiation therapy (1.37 [1.25-1.51]. MDC patients receiving care all on the same date were significantly more likely than non-MDC patients to have lobular histology (OR [95% CI] = 1.48 [1.06-2.06]), black race (3.09 [2.19-4.35], receive mastectomy (1.75 [1.34-2.30]) and receive radiation therapy (1.98 [1.52-2.60]). The use of MDC overall and on the same date increased over time (p < 0.001) and varied widely according to geographic region. There was a 20.8 odds increase in the use of same-date MDC in the Midwest compared to the South (p < 0.001). Patients in rural settings were less likely to receive MDC overall: OR [95% CI] = 0.57 [0.48-0.68] and on the same date (0.27 [0.16-0.48]). Survival data suggest improved outcomes for women undergoing MDC (Table 1). There were 117 breast cancer deaths in the MDC overall group but only 15 such events in the smaller MDC same-day subgroup (limiting its power). Table 1. Propensity score matched outcomes according to MDC. MDC Overall* MDC on Same Date (n = 2,491) (n = 330) HR[95% CI]pHR[95% CI]pAdjusted Overall Survival0.940.80-1.090.4000.360.18-0.720.004Adjusted Breast Cancer Specific Mortality0.750.58-0.960.0240.420.15-1.180.102* Includes MDC patients on same and different dates. Conclusions: The vast majority of Medicare patients having breast cancer did not undergo MDC during the period of study. MDC rates have increased over time, with widely varied MDC utilization across regions. Employing same-day MDC should be considered for patient convenience and may improve outcomes. While not yet widespread, efforts should be made to integrate MDC as standard care across the United States. Citation Format: Churilla TM, Egleston BL, Murphy CT, Sigurdson ER, Hayes SB, Goldstein LJ, Bleicher RJ. Patterns of multidisciplinary care in the management of nonmetastatic invasive breast cancer in the United States Medicare patient. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-25.
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