Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.

BACKGROUND: HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied dacomitinib in patients with HER2-mutant or amplified lung cancers. PATIENTS AND METHODS: As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral dacomitinib at 30-45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity. RESULTS: We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of dacomitinib (95% CI 7-21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of dacomitinib with mirtazapine. CONCLUSIONS: Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2-targeted agents in specific HER2-driven lung cancers. CLINICALTRIALSGOV: NCT00818441.

A phase I trial of stereotactic external beam radiation for subfoveal choroidal neovascular membranes in age-related macular degeneration.

Effective treatment for neovascular age-related macular degeneration (AMD) is currently limited. Radiation therapy, a therapeutic approach with known antiangiogenic properties, has been investigated as a modality to prevent severe visual loss in AMD. Most of the studies using external beam radiation employed <25 Gy to the whole eye, which is below the dose of radiation that is toxic to the retina and optic nerve ( approximately 50 Gy and approximately 59 Gy, respectively). Stereotactic fractionated external beam radiation (St-EBR) is a method that allows radiation to be delivered to a small, defined area. We investigated the effects of St-EBR in incremental doses up to 40 Gy on neovascular AMD. Patients with clinical signs and fluorescein angiography demonstrating neovascular AMD, visual acuity (VA) better than 20/400 and ineligible for laser treatment (MPS criteria) or who refused to have laser photocoagulation were enrolled in the study. Each patient was treated with radiation at incremental dosages from 20 Gy to 40 Gy. After completion of the radiation course, all patients were followed-up at 3 and 7 weeks and 3, 6, and 12 months. Best-corrected VA (ETDRS), slit-lamp and fluorescein angiographic evaluations were performed at each visit. 94 eyes of 89 patients were treated from October 1997 to April 2000. The VA was 0.82+/-0.35 before treatment, 0.83+/-0.36 at 6 months, and 0.89+/-0.33 at 12 months. No patients suffered any significant acute side effects. No significant benefits in either VA or in membrane size were derived from increasing the doses of radiation. Our results are consistent with trends of a palliative benefit of radiotherapy in neovascular AMD and support further investigation of radiotherapy. Since there is no evidence that therapeutic effectiveness is dose dependent, our data provide no justification for potentially dangerous escalations in radiation dosage for treating neovascular AMD.

c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination.

The p53 protein is subject to Mdm2-mediated degradation by the ubiquitin-proteasome pathway. This degradation requires interaction between p53 and Mdm2 and the subsequent ubiquitination and nuclear export of p53. Exposure of cells to DNA damage results in the stabilization of the p53 protein in the nucleus. However, the underlying mechanism of this effect is poorly defined. Here we demonstrate a key role for c-Abl in the nuclear accumulation of endogenous p53 in cells exposed to DNA damage. This effect of c-Abl is achieved by preventing the ubiquitination and nuclear export of p53 by Mdm2, or by human papillomavirus E6. c-Abl null cells fail to accumulate p53 efficiently following DNA damage. Reconstitution of these cells with physiological levels of c-Abl is sufficient to promote the normal response of p53 to DNA damage via nuclear retention. Our results help to explain how p53 is accumulated in the nucleus in response to DNA damage.

Integration of new chemotherapeutic agents into chemoradiotherapy for stage III non--small cell lung cancer: focus on docetaxel.

Randomized clinical trials have shown that combinations of chemotherapy plus thoracic radiation improve survival compared with radiotherapy alone in stage III non--small cell lung cancer (NSCLC). Furthermore, two recent studies have concluded that concurrent chemoradiotherapy produces superior results to sequential administration. Dependent on the dose and schedule used, chemotherapy may contribute by eradicating distant micrometastases by improving local control as a radiosensitizer, or through both mechanisms. In general, sequential approaches in which full-dose platinum-based chemotherapy precedes thoracic radiation or surgery have improved outcome by impacting distant metastases. In contrast, concurrent chemoradiotherapy using low-dose cisplatin is reported to improve survival by reducing local recurrence without an impact on distant failure rates. In view of these observations, chemoradiotherapy strategies integrating both radiosensitizing agents and dose levels of chemotherapy effective against micrometastases may prove to be most efficacious. Because distant metastases remain the major site of failure, it also is likely that more effective chemotherapy will be required to further improve the current level of response and survival. Fortunately, several newly available chemotherapeutic agents are both highly active against NSCLC and are potent radiosensitizers. In this report we review recent data regarding integration of new chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC, focusing on trials investigating docetaxel. Encouraging results, including those of the Southwest Oncology Group trial 9504, suggest that docetaxel will play a major role in the future of combined-modality therapy for locally advanced NSCLC. Semin Oncol 28 (suppl 9):26-32.

Neoadjuvant therapy for non-small cell lung cancer.

Clinical trials evaluating neoadjuvant or preoperative therapy for locally advanced non-small cell lung cancer (NSCLC) have demonstrated the feasibility, tolerability and activity of this approach. Three randomized trials have reported improved survival in patients with stage III NSCLC treated with preoperative chemotherapy followed by surgical resection compared to surgery alone. Combinations of neoadjuvant chemotherapy plus thoracic radiotherapy have also been investigated, generally resulting in higher rates of pathologic response, but higher toxicity rates as well. The best approach to neoadjuvant therapy remains to be determined and may well be substage dependent. In bulky stage III NSCLC, the role of surgery itself remains unclear and is the subject of an ongoing intergroup trial in the US. Regardless, neoadjuvant therapy has emerged as an important paradigm for clinical research since it serves as an in vivo test of chemosensitivity in patients, and represents a 'window of opportunity' for testing new chemotherapeutic agents and novel strategies. Among the new chemotherapeutic agents being investigated in this setting is docetaxel, one of the most active agents in first- and second-line chemotherapy of NSCLC, and a potent radiosensitizer. Preliminary studies have confirmed the feasibility of integrating docetaxel into neoadjuvant treatment strategies and encouraging results have been reported.

An investigation of the molecular basis for the synergistic interaction of tirapazamine and cisplatin.

PURPOSE: To determine if the observed tirapazamine (TPZ)-cisplatin synergistic cell kill was mediated at the cellular level by impairment of upregulation of key proteins involved in repair of DNA interstrand crosslinks. Cisplatin sensitivity has been shown to be dependent on the expression of the two DNA repair proteins ERCC1 and XPA. ERCC1 expression has also been shown to be upregulated by cisplatin exposure. Therefore, these studies were undertaken to determine if hypoxia-activated TPZ pretreatment inhibited the cells' normal protective response to cisplatin via inhibiting the upregulation of ERCC1 and/or XPA expression. METHODS AND MATERIALS: Two different cell lines, one cisplatin sensitive and one cisplatin resistant, were treated with TPZ, cisplatin, both drugs together (which results in additive cytotoxicity), or TPZ followed by cisplatin (which results in synergistic cytotoxicity). All cells were exposed to 1 h of hypoxia to bioactivate the TPZ. Expression of ERCC1 and XPA were evaluated at the mRNA and protein level at 24 or 48 h after drug exposure. RESULTS: In the cisplatin-sensitive non-small-cell lung cancer cell line, ERCC1 expression at the mRNA or protein level was not significantly altered in any of the treatment groups. In the cisplatin-resistant ovarian cancer cell line, ERCC1 expression was upregulated by TPZ, but not by cisplatin alone. The change in protein expression was less pronounced than the change in mRNA level. XPA expression was not significantly changed from baseline in either cell line at the mRNA or protein level. CONCLUSION: In contrast to reports in the literature, this study did not demonstrate cisplatin inducing its own repair by upregulating the DNA crosslink repair proteins ERCC1 or XPA. Therefore, the TPZ-cisplatin synergism cannot be mediated through hypoxia-activated TPZ inhibiting this cellular protective response. TPZ alone, however, was able to alter repair protein expression, which may play a role in mediating its cytotoxicity.

Role of a DT-diaphorase mutation in the response of anal canal carcinoma to radiation, 5-fluorouracil, and mitomycin C.

PURPOSE: To determine, retrospectively, the status of the bp 609 mutation in the DT-diaphorase gene in anal canal carcinoma patients who have undergone radical radiotherapy with concurrent 5-fluorouracil (5-FU) and mitomycin C (MMC), to determine the relationship of the mutant form of the gene to treatment outcomes. METHODS AND MATERIALS: Paraffin blocks of pretreatment tumor biopsies were obtained on 49 patients who underwent treatment with curative intent using radiation, infusional 5-FU and bolus MMC from January 1991 to December 1993. DNA was extracted and subjected to polymerase chain reaction (PCR) analysis using primers that encompassed the bp 609 C to T mutation. Restriction endonuclease cleavage with Hinf 1 and gel electrophoresis were used to determine the polymorphism status of each patient. RESULTS: DNA of 46 patients was successfully amplified. The 46 patients were distributed as follows: 26 (56.5%) C/C-homozygous wildtype, 18 (39%) T/C-heterozygous, and 2 (4.5%) T/T-homozygous mutant. Eleven of 46 patients had suffered treatment failure. The status of the bp 609 polymorphism in this group was 5 (45.5%) C/C, 5 (45.5%) C/T, and 1 (9%) T/T. CONCLUSION: In this series, there was not an overrepresentation of the mutant allele in patients with treatment failure, suggesting that the bp 609 alteration is not a strong determinant of treatment outcome.

DT-diaphorase: possible roles in cancer chemotherapy and carcinogenesis.

DT-diaphorase [also called NAD(P)H:menadione oxidoreductase; NAD(P)H:(quinone acceptor) oxidoreductase; quinone reductase, azo-dye reductase] (EC.1.6.99.2) has been shown to have a role in activation of quinone-containing cancer chemotherapeutic prodrugs to their active form, as well as inactivation of a variety of xenobiotics involved in carcinogenesis. To illustrate the basis of this dichotomy, a brief review of the historical and recent background of studies on DT-diaphorase is given. Recent data from the laboratory of the authors on the nature of the protein coded for by a recently identified human polymorphism, a C to T transition at nucleotide 609 of DT-diaphorase cDNA, and the frequency of this mutation in anal canal carcinoma patients is presented. Finally, a series of questions about the role of DT-diaphorase in both normal and malignant cells is raised based on the results of others that have been published in the last 2-3 years.

Cognition in Parkinson disease: an event-related potential perspective.

Auditory event-related potentials (ERP) elicited in a target detection stimulus paradigm and pattern-shift visual ERPs were studied in 20 male patients with idiopathic Parkinson disease (PD) and 20 age-matched normal controls. Patients showed significantly increased latencies for both the P200 and P300 components of the auditory ERP. Patients and controls showed no significant differences in latency of the visual ERP but patients showed significantly decreased amplitude. Only one of five neuropsychological measures, the Symbol Digit Modalities test (SDMT), showed a significant negative correlation with P300 latency. The significant association between the two measures that showed impairments in the PD patients (P300 latency and SDMT scores) suggested that these measures reflect a common, disrupted aspect of cognitive function in PD.