Abstract Castration-resistant prostate cancer (CRPC) express high levels of the anti-apoptotic proteins Bcl-2 and Bcl-xL, resulting in drug resistance and association with poor prognosis. Docetaxel (Doc), an antimitotic drug that is the first-line treatment strategy for CRPC, is known to provide a small survival benefit but patients eventually become resistant to Doc with little hope for survival. It is apparent that Doc chemotherapy alone is not enough to counteract the high levels of Bcl-2/Bcl-xL present in CRPC. ABT-737 is a small molecule that binds to Bcl-2/Bcl-xL with high affinity and disrupts their interaction with pro-apoptotic Bax/Bak, thus enhancing pro-apoptotic signals when combined with other drugs. We investigated whether ABT-737 can increase Doc-mediated apoptosis in CRPC cells. Our results in androgen-dependent LNCaP and CRPC PC3 cell lines indicate that ABT-737 (1 μM) increases Doc (1 nM)-mediated cell death and caspase-dependent apoptosis, as determined by trypan blue exclusion, annexin-FITC/propidium iodide flow cytometry, and Western blot analysis. Our data suggests that Doc's anti-cancer effect results from prolonged cyclin B1/Cdk1 activation and inactivation of Bcl-2/Bcl-xL by phosphorylation, resulting in increased apoptosis. We show a correlation between high phosphorylation (P) of Bcl-2(Ser70)/Bcl-xL(Ser62) and increased apoptosis by Doc and Doc + ABT-737 treatments. Furthermore, the Cdk1 inhibitor purvalanol A blocks Doc + ABT-737-mediated increases in P-Bcl-2/P-Bcl-xL and subsequent apoptotic cell death. Lentivirus pLKO.1 shRNA stable knockdown of Bax but not Bak lowers cell death LNCaP and PC3 cells after treatment with Doc + ABT-737. In contrast to LNCaP and PC3, the CRPC DU145 cell line is null for Bax, expresses high levels of anti-apoptotic Mcl-1, and is more resistant to ABT-737. Retrovirus pBABE stable expression of Bax in DU145 cells restores sensitivity to Doc + ABT-737 compared to the empty vector control cells. We conclude that ABT-737 can sensitize CRPC cells to Doc treatment and may provide an important combination chemotherapy strategy for improving overall survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2571. doi:10.1158/1538-7445.AM2011-2571
<div>Abstract<p>Purpose: This global phase 1 trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective BCL-2 inhibitor, in patients with relapsed or refractory chronic or small lymphocytic leukemia (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase 2 dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%); fatigue (34.6%); nausea (30.8%); anemia and thrombocytopenia (28.8% each); neutropenia (26.9%); constipation (25.0%); vomiting (23.1%); headache (21.2%); peripheral edema and hypokalemia (17.3% each); and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%); thrombocytopenia (13.5%); and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response of 63.6% and median time to response of 2 (range, 2-8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.</p></div>
Abstract Background: Immune checkpoint inhibitors (ICPIs) have led to dramatic improvement in outcome of several cancers. Program death ligand1 (PD-L1) staining and tumor mutational burden (TMB) have emerged as independent predictive biomarkers of ICPIs in lung cancer. Here we examine the landscape of TMB and PD-L1 expression in breast cancer and present a case of patient with high TMB and PD-L1 negative breast cancer with exceptional response to ICPIs. Methods: Hybrid-capture based comprehensive genomic profiling of 395 cancer related genes using the FoundationOne assay was performed on 14,867 breast carcinomas sequenced in the course of routine clinical care. Ventana (SP-263) PD-L1 status (n=1425) and hormone receptor status was available for a subset of patients. Subgroup analyses were performed based on histological type [invasive lobular carcinoma (ILC, n=740)], molecular subtypes [ER-positive (ER+; n= 1371), HER2-amplified (HER2+; n=1522), and TNBC (n=917)], patient age (≤45, 46-60, ≥61), and local vs. metastatic disease (n=5241 and 6710). Results: Consistent with previous reports, the rates of positive PD-L1 staining are highest in TNBC (14%) and lowest in HER2+, ILC, and ER+ disease (6.0%, 5.1%, 2.3%). Interestingly, the rate of PD-L1 positivity, defined as ≥1% tumor staining, was significantly lower in metastatic disease vs. local disease (6.3% vs. 11.1%; p = 0.005). The frequency of high TMB, defined as >10 mutations/mb, was greatest in ILC and HER2+ disease (13.6% and 9.9%) and lowest in TNBC and ER+ disease (7.0% and 6.9%). Rates of high TMB were associated with increased patient age (3.7%, 9.3%, and 12.8% frequency in patients ≤45, 46-60, and ≥61) and were significantly higher in metastatic vs. local disease (11.1% vs 5.3%; p<2E-23). PD-L1 positive and TMB high populations were not significantly co-occurrent (OR = 1.02, p = 0.87). Similar percentages of PD-L1 positivity were observed in both TMB low (9.3%) and TMB high (9.5%). However, among patients with very high TMB (>20 mut/mb), there was a significant association between TMB and PD-L1 positivity (OR = 2.6, p = 0.023). Nevertheless, even with high cutoff, 79% of the TMB high samples were PD-L1 negative. We also report on a stage IIIb (T4, N2, M0) ER+ HER2- breast cancer patient with high TMB (40muts/mb) and negative PD-L1 IHC who previously progressed on aromatase inhibitor with CDK4/6 inhibitor and chemotherapy but achieved durable complete response of > 1 year with nivolumab in combination with capecitabine. Conclusions: Predictive biomarkers for ICPIs are critical to identify a subset of breast cancer patients who may respond to immunotherapy. TMB high and PD-L1 positivity do not significantly co-occur and the majority of TMB high cases were PD-L1 negative. Nevertheless, this group of patients may still benefit with ICPIs. Further studies are needed to evaluate this subset of patients. Citation Format: Ethan Sokol, Lee Albacker, Aixa Soyano, Ricardo Parrondo, Brenda Ernst, Emmanuel Gabriel, Garrett Frampton, Jeffrey Ross, Siraj Ali, Jon Chung, Saranya Chumsri. Incidence of high tumor mutation burden (TMB) and PD-L1 positivity in breast cancers and potential response to immune checkpoint inhibitors (ICPIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4894.
Autoimmune hepatitis (AIH) is a progressive immune mediated liver disease of unknown origin. Key diagnostic features include hypergammaglobulinemia/elevated serum-IgG, characteristic circulating autoantibodies, periportal hepatitis with interface activity on liver biopsy and the exclusion of hepatotropic viruses. However, the diagnosis is challenging in cholestatic and severe presentations. It can be difficult to differentiate AIH from drug-induced liver injury. Although many patients initially respond to standard immunosuppressive therapy, a significant proportion experiences intolerable side effects or insufficient treatment response. This underlines the need for effective alternative treatment options, which are still very limited and based on rather poor evidence. This review summarises core aspects of the clinical management of AIH with focus on recent achievements and unmet needs.
Autologous hematopoietic stem cell transplantation (auto-HSCT) has improved survival in patients with multiple myeloma (MM) and is increasingly used in elderly patients. The aim of this study was to characterize and compare in-hospital complications and mortality after auto-HSCT in younger (< age 65) versus elderly (> age 65) MM patients utilizing the Nationwide Inpatient Sample. Over a 3-year period (2008 to 2010), 2209 patients with MM were admitted to US hospitals for auto-HSCT. The median age was 59 years, with 1650 patients (74.7%) younger than age 65 and 559 patients (25.3%) 65 or older. Overall, in-hospital mortality in MM patients after auto-HSCT was rare (1.5%) and there was no significant difference in mortality between elderly and younger patients. Elderly patients did have a significantly increased mean length of stay (18.6 days + 10.8 days [SD] versus 16.8 days + 7.2 days [SD], P < .001) and mean total hospital charges ($161,117 + $105,008 [SD] versus $151,192 + $78,342 [SD] , P = .018) compared with younger patients. Elderly patients were significantly more likely than younger patients to develop major in-hospital post-transplantation complications such as severe sepsis (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.40 to 5.21; P = .003), septic shock (OR, 3.10; 95% CI, 1.43 to 6.71; P = .004), pneumonia (OR, 1.62; 95% CI, 1.06 to 2.46; P = .024), acute respiratory failure (OR, 3.44; 95% CI, 1.70 to 6.96; P = .001), endotracheal intubation requiring prolonged mechanical ventilation (OR, 2.19; 95% CI, 1.06 to 4.55; P = .035), acute renal failure (OR, 2.14; 95% CI, 1.38 to 3.33; P = .001), and cardiac arrhythmias (OR, 2.06; 95% CI, 1.52 to 2.79; P <.001). These data may help guide informed consent discussions and provide a focus for future studies to reduce treatment-related morbidity in elderly MM patients undergoing auto-HSCT.
Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and
e21533 Background: We aimed to evaluate post-gastrectomy outcomes in patients (pts) age ≥ 75 using the Nationwide Inpatient Sample (NIS), as population based data in elderly pts are needed given the increased incidence of gastric cancer in the aging population. Methods: We used the NIS database to identify all gastric cancer pts admitted to US hospitals for gastrectomy from 2005-2010. Outcomes in elderly and younger pts were compared. Results: We identified 9455 pts, median age was 68; 3022 pts (32%) were in the elderly group (age ≥ 75) and 6433 (68%) were age 18–74. Elderly pts had more major post-operative (post-op) complications (table), higher in-hospital mortality (7.3% vs. 3.4%, p < 0.001), longer length of stay (LOS) (14.9 ± 11.8 (SD) vs. 13.3 ± 12.1 days, p = 0.010), and higher total hospital charges ($111,281 ± $115,804 vs. $101,559 ± $112,652, p = 0.009) compared to younger pts. In multivariate logistic analysis, age ≥ 75 was a significant predictor of in-hospital mortality (OR 2.00, CI 1.59-2.52, p < 0.001), as were post-op complications such as acute kidney injury (OR 3.02, 95% CI 2.24-4.06, p < 0.001), acute respiratory failure (OR 4.15, 95% CI 3.13-5.49, p < 0.001), severe sepsis/septic shock (OR 11.25, 95% CI 8.30-15.24, p < 0.001), and acute heart failure (OR 2.12, 95% CI 1.55-2.91, p < 0.001). Conclusions: Compared to younger pts with gastric cancer undergoing gastrectomy, elderly pts had significantly increased in-hospital mortality, post-op complications, LOS, and total hospital charges. Early recognition of complications may reduce morbidity/mortality and future studies are essential to determine optimal gastric cancer treatment strategies in the rapidly growing geriatric population. Post-op complication Age 18-74 n (%) Age ≥ 75 n (%) OR (95% CI), P value Deep Vein Thrombosis 113 (1.8) 81 (2.7) 1.54 (1.16-2.06), 0.003 Pneumonia 450 (7.0) 275 (9.1) 1.33 (1.14-1.56), < 0.001 Acute Kidney Injury 252 (3.9) 226 (7.5) 1.99 (1.65-2.39), < 0.001 Acute Respiratory Failure 297 (4.6) 205 (6.8) 1.51 (1.25-1.81), < 0.001 Severe Sepsis/Septic Shock 192 (3.0) 123 (4.1) 1.38 (1.10-1.74), 0.006 Delirium 33 (0.5) 48 (1.6) 3.13 (2.01-4.89), < 0.001 Acute Heart Failure 270 (4.2) 361 (11.9) 3.10 (2.63-3.65), < 0.001
