Biopsy of a tumor site has long been the gold standard for the diagnosis of malignancy. Advanced sequencing technology has enabled us to study the molecular changes driving a particular cancer. As we move towards the molecular era of medicine, repeat tumor biopsies are often obtained to assess for development of resistance, which has both prognostic and therapeutic implications. However, the logistics of obtaining repeat tumor biopsies are complicated—many patients with advanced malignancies are unable or unwilling to undergo another invasive procedure and the skillset and personnel required for these procedures are often time consuming, expensive, and leads to delay in care. Furthermore, it is known that tumors develop heterogeneity over time and disease sites and therefore one biopsy may not provide a complete picture of the tumoral landscape.
e20607 Background: The PD-1 inhibitors nivolumab and pembrolizumab are approved for the treatment of advanced non-small cell lung cancer (NSCLC), but little is known about patterns of disease progression when these agents fail. Understanding patterns of failure is key to developing strategies to improve duration of response to these agents. Methods: We gathered clinical and radiographic data on patients treated at the University of Michigan and the Ann Arbor VA for advanced NSCLC with standard-dose nivolumab (n = 68) or pembrolizumab (n = 23) after progression on platinum-based chemotherapy. Sites of disease progression were described as local (within the same lobe as primary disease), nodal (thoracic), or distant. Results: 91 patients were evaluable, of whom 56 (61.5%) had progression of disease after an average duration of therapy of 3.2 months (95%CI, 2.6-3.8). 10 (17.9%) patients had progression at local sites alone, 3 (5.4%) at nodal sites alone, 12 (21.4%) at distant sites alone, and 31 (55.4%) at a combination of sites. Overall, 41 (73.2%) had progression at distant sites. There was no statistically significant difference in clinical factors ( i.e. age, histology, comorbidity index) between progressors vs. non-progressors or distant-progressors vs. non-distant progressors. Of 37 patients who had prior radiation, 17 (45.9%) had progression at an irradiated site, with patients who had local and/or nodal progression more likely to have received radiation at site of progression (p = 0.01). The most common distant sites of progression were liver (13), bone (10), and brain (9). Conclusions: The most common site of disease progression was distant, with the liver being the most commonly involved site. This may be due to the immunotolerogenic environment of the liver, which is characterized by high IL-10 concentration and propagation of suppressive regulatory T cells, which can dampen activation of cytotoxic T cells. Prior irradiation did not seem to prevent disease progression. Our preliminary analysis suggests that the efficacy of checkpoint inhibitors is hindered in immune-privileged sites. Strategies to overcome immune tolerance should be investigated to improve duration of response to these agents.
Abstract CYP24A1 is the rate limiting catabolic enzyme for 1α,25-dihydroxyvitamin D3 (1,25-D3), the active form of vitamin D. We have previously demonstrated that the mRNA expression of CYP24A1 is an independent prognostic factor for survival in lung adenocarcinoma (AC) and that the antiproliferative effects of 1,25-D3 are inversely proportional to CYP24A1 expression. We then asked if smoking is associated with increased expression of CYP24A1 and a decrease in serum level of 1,25-D3; whether increased CYP24A1 expression was due to epigenetic changes caused by smoking. We measured CYP24A1 mRNA in resected lung AC (n=100) specimens and compared CYP24A1 in smokers (former/current) versus non-smokers. In parallel, we performed metabolism experiments in A549 (high CYP24A1) and SKLU-1 (low CYP24A1) cells to study the functional relevance of increased CYP24A1. We evaluated the promoter methylation status of CYP24A1 in the cancer cell lines and lung AC patients using pyrosequencing PCR analysis. Finally, quantitative chromatin immunoprecipitation PCR (ChIP-qPCR) analysis was performed to validate the CYP24A1 methylation was regulated by histone modifiers. Non-smokers had higher serum levels of 25-D3 compared with smokers (albeit small numbers of non-smokers, n=11). Smoking lung AC patients showed higher mRNA expression of CYP24A1 (P < 0.00374) and poorer 5-year survival compared to nonsmokers in Kaplan-Meir survival analysis (Logrank P < 0.0435). A549 cells catabolized 1,25-D3 to a greater extent compared to SKLU-1 at 48-h treatment of 100 nM 1,25-D3 (5.67 vs 103 pmole 1,25-D3 remained). Smoking increased CYP24A1 expression in lung AC patients through hypomethylation of CYP24A1 promoter. In the pyrosequencing analysis, A549 cells were unmethylated (1.01%) but SKLU-1 cells highly methylated (52.02%). Treatment with the DNA methyltransferase inhibitor 5-aza-2α-deoxycytidine (5-Aza) activates CYP24A1 expression in lung cancer cells. Furthermore, inhibition of histone deacetylases by trichostatin A (TSA) enhances the expression of CYP24A1 in lung cancer cells. ChIP-qPCR reveals that treatment with 5-Aza and/or TSA increases H3K9ac and H3K4me2 and simultaneously decreases H3K9me2 at the CYP24A1 promoter. ChIP-qPCR assay reveals that treatment with 5-Aza and/or TSA increases the recruitment of vitamin D receptor to the CYP24A1 promoter. Taken together, smoking induced the expression of CYP24A1 and showed faster metabolism of 1,25-D and led to poorer survival in lung AC patients, This induction might be related to epigenetic changes in CYP24A1 gene. By increasing the substrate or silencing CYP24A1 gene, the possibility of CYP24A1 gene for chemoprevention will be investigated. Supported by NIH R21CA128193-01-A1 and VA Merit I01CX000333-02. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3124. doi:1538-7445.AM2012-3124
3171 Background: Motexafin gadolinium (MGd) is a redox mediator that selectively targets tumor cells, producing reactive oxygen species. In preclinical models, MGd enhances the activity of several chemotherapy drugs including taxanes. Based on this, a multi-center Phase 1 study with MGd and docetaxel was carried out in patients (pts) with advanced solid tumors, with normal bone marrow, hepatic and renal function. Experimental design: Cohorts of 3–6 pts were treated with MGd, starting at 2.5 mg/kg weekly with docetaxel starting at 30 mg/m2on a weekly X 3 schedule every 28 days. The primary objective was to determine the maximum tolerated dose (MTD) of the combination on this schedule and the dose limiting toxicities (DLT). Results: Eight pts were treated at MGd (2.5- 5mg/kg weekly) along with docetaxel (30mg/m2). The MGd was infused over 0.5h, 30 minutes prior to docetaxel (given IV over 0.5h). There were 8 males with a median age of 61yrs (range 54–76). Diagnoses were NSCLC (3); SCLC (2); Gastric (1); bladder (1); and penile (1). (No of pts in parenthesis) Pts had had a median of 3 prior chemotherapy regimens (range 1–5); 3 pts had had prior radiation. Two pts received 1.5 cycles. At dose level (DL) 1, toxicities >/= 2 were fatigue, diarrhea, leucopenia, neutropenia, hyperglycemia, elevated APTT, seen in 3 pts. At DL 2 (MGd 5.0 mg/kg with docetaxel 30 mg/m2), 1 pt had a DLT (gr 3 rash). Other toxicities >/= gr 2 at DL 2 were nausea, vomiting, diarrhea, fatigue, and dehydration in 2 pts. Data on the last 3 pts is pending. Accrual is ongoing to determine the MTD. Conclusion: MGd in combination with weekly docetaxel is feasible and preliminary results show that there were no gr 4 toxicities. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacyclics
Abstract We assessed the efficacy, tolerability, and cost-effectiveness of a novel neoadjuvant regimen comprising docetaxel-cyclophosphamide alternating with epirubicin-cisplatin (ddDCEP) administered biweekly for 16 weeks in 116 patients with early triple-negative breast cancer. This regimen achieved a high pathological complete response (ypT0/TisN0) rate of 55.2% and favorable survival outcomes (30-month event-free survival, 91.2%; overall survival, 97%). Febrile neutropenia was observed in 4.3% of patients, and 98% completed at least six of eight cycles. ddDCEP was more cost-effective than contemporary carboplatin-based regimens. This novel approach offers an economically viable and effective alternative to current chemoimmunotherapy regimens, and merits further investigation
