Oxidative stress plays an important role in cancer development and treatment. Recent data implicate the tumor suppressor BRCA1 in regulating oxidative stress, but the molecular mechanism and the ...impact in BRCA1-associated tumorigenesis remain unclear. Here, we show that BRCA1 regulates Nrf2-dependent antioxidant signaling by physically interacting with Nrf2 and promoting its stability and activation. BRCA1-deficient mouse primary mammary epithelial cells show low expression of Nrf2-regulated antioxidant enzymes and accumulate reactive oxygen species (ROS) that impair survival in vivo. Increased Nrf2 activation rescues survival and ROS levels in BRCA1-null cells. Interestingly, 53BP1 inactivation, which has been shown to alleviate several defects associated with BRCA1 loss, rescues survival of BRCA1-null cells without restoring ROS levels. We demonstrate that estrogen treatment partially restores Nrf2 levels in the absence of BRCA1. Our data suggest that Nrf2-regulated antioxidant response plays a crucial role in controlling survival downstream of BRCA1 loss. The ability of estrogen to induce Nrf2 posits an involvement of an estrogen-Nrf2 connection in BRCA1 tumor suppression. Lastly, BRCA1-mutated tumors retain a defective antioxidant response that increases the sensitivity to oxidative stress. In conclusion, the role of BRCA1 in regulating Nrf2 activity suggests important implications for both the etiology and treatment of BRCA1-related cancers.
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Background: EGFR mutation and ALK rearrangement testing is standard in the management of advanced non-sq NSCLC patients (pts). Previously at our centre, EGFR/ALK biomarker testing ...was requested by medical oncologists (MO). In June 2013 we implemented biomarker RT, defined as pathologists requesting EGFR/ALK at time of diagnosis of non sq-NSCLC irrespective of stage. The objective of this study was to test the hypothesis that if pathologists requested biomarker testing, appropriate tissue would be preserved and selected for testing, which would improve success rates of biomarker testing. Methods: Retrospective review of advanced non-sq NSCLC pts seen by MO at Sunnybrook Odette Cancer Centre from March 2010 to April 2014. Pt and EGFR/ALK test characteristics were compared before and after RT using Chi-square tests of association. Time outcomes were compared using Mann-Whitney U tests. Results: Of the 310 pts included, median age was 68, 44% female, 47% Caucasian, 93% adenocarcinoma, 22% EGFR+, 1% ALK+ and 84% either presented with or developed stage IV. Samples tested for EGFR and ALK were respectively: 53%, 51% core biopsies; 25%, 32% surgical resections; 20%, 16% cytology. The number of biomarker tests across all stages increased with RT (EGFR 70% vs 95%, p < 0.001 / ALK 44% vs 83%, p < 0.001). RT improved the rate of successfully completed tests (EGFR 86% vs 96%, p = 0.04 / ALK 83% vs 97%, p = 0.04). The remainder of tests were unsuccessful due to inconclusive results (EGFR 9% vs 4%, p = 0.25 / ALK 7% vs 2%, p = 0.25), insufficient tissue (EGFR 3% vs 0%, p = 0.33 / ALK 10% vs 0%, p = 0.03) or cancellation due to appropriate tissue not being sent from holding lab to testing lab (EGFR 2% vs 0, p = NS / ALK 0% vs 2%, p = NS). From core biopsies, there was trend to improved success of EGFR testing with RT (82% vs 97%, p = 0.06) and significant improvement of ALK testing (82% vs 100%, p = 0.04), with no impact on success from cytology samples. Rebiopsy rate for biomarker testing was low in both cohorts. Turnaround time for EGFR testing decreased 19 days (IQR 15-25) vs 17 days (IQR 12-21), p = 0.02; ALK was unchanged. Conclusions: Implementation of RT improved successful completion of EGFR/ALK testing.
Optimal first-line systemic therapy for patients with advanced nonsquamous (nonsq) non-small-cell lung cancer (NSCLC) requires confirmation of EGFR/ ALK status, which can delay treatment. We ...evaluated the impact of reflex testing, defined as pathologists initiating EGFR/ ALK testing at the time of diagnosis of nonsq NSCLC, on time to treatment (TTT).
We conducted a retrospective review of patients with nonsq NSCLC with medical oncology consultation at Sunnybrook Odette Cancer Centre between March 18, 2010 and April 30, 2014. Data were compared during routine and reflex testing. TTT was defined as the interval between the first medical oncology visit with advanced NSCLC and the initiation of systemic therapy.
A total of 306 patients were included (n = 232 for routine testing, n = 74 for reflex testing). There was a trend to improvement in median TTT with reflex testing (36 days interquartile range {IQR}, 16 to 71 days v 26 days IQR, 8 to 41 days, P = .071). Omitting patients with intentional delays in systemic therapy for low-volume disease, poor performance status, comorbidity management, and/or radiation therapy, median TTT improved (34 days IQR, 15 to 67 days v 22 days IQR, 8 to 42 days, P = .049). Time to optimal first-line systemic therapy according to published guidelines improved (median, 36 days IQR, 16 to 91 days v 24 days IQR, 8 to 43 days, P = .036). There was no impact on receipt of any first-line systemic therapy (55% v 59%, P = .66). The quality of biomarker testing improved, with fewer unsuccessful tests ( EGFR, 14% v 4%, P = .039; and ALK, 17% v 3%, P = .037).
Reflex testing of EGFR/ ALK improved the time to optimal systemic therapy and the quality of biomarker testing for patients with advanced nonsq NSCLC.
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