Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC). Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21–8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71–36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34–20.87, P < 0.001) and HR 4.75 (95% CI, 1.38–16.29, P = 0.013), respectively. Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 23(9); 2195–202. ©2016 AACR.

Background: Thalidomide is effective as a first-line therapy for the treatment of multiple myeloma (MM), but its use is limited by peripheral neurotoxicity. Objective: To study the occurrence of both myeloma-related neuropathy and thalidomide-induced neuropathy in 31 patients with newly diagnosed MM. Methods: Clinical and electrophysiologic examinations were performed in 31 patients with newly diagnosed MM before and after 4 months of therapy with thalidomide (200 mg/day, total dose: 21 g) aimed at debulking MM, before autologous transplantation. After transplantation, the patients took thalidomide, 200 mg/day for another 3 months (total dose over three months: 18 g) and then underwent a final clinical and electrophysiologic checkup. Results: At baseline, four patients presented a mild sensorimotor peripheral neuropathy related to MM, which tended to worsen slightly during treatment with thalidomide. At the end of treatment, 83% of the patients had clinical and electrophysiologic evidence of a mild sensory rather than motor, axonal, length-dependent polyneuropathy, whereas 100% of the patients showed improvement to the basic pathology (≥partial response). Conclusions: Peripheral neuropathy, sometimes subclinical, and mild in our patients, is a common, early side effect of thalidomide therapy. The high doses (21 g) used in all patients for a relatively short time (4 months) rule out any correlations between neuropathy, total dose, and duration of treatment.

Although modifiable risk factors have been included in previous models that estimate or project breast cancer risk, there remains a need to estimate the effects of changes in modifiable risk factors on the absolute risk of breast cancer. Using data from a case–control study of women in Italy (2569 case patients and 2588 control subjects studied from June 1, 1991, to April 1, 1994) and incidence and mortality data from the Florence Registries, we developed a model to predict the absolute risk of breast cancer that included five non-modifiable risk factors (reproductive characteristics, education, occupational activity, family history, and biopsy history) and three modifiable risk factors (alcohol consumption, leisure physical activity, and body mass index). The model was validated using independent data, and the percent risk reduction was calculated in high-risk subgroups identified by use of the Lorenz curve. The model was reasonably well calibrated (ratio of expected to observed cancers = 1.10, 95% confidence interval [CI] = 0.96 to 1.26), but the discriminatory accuracy was modest. The absolute risk reduction from exposure modifications was nearly proportional to the risk before modifying the risk factors and increased with age and risk projection time span. Mean 20-year reductions in absolute risk among women aged 65 years were 1.6% (95% CI = 0.9% to 2.3%) in the entire population, 3.2% (95% CI = 1.8% to 4.8%) among women with a positive family history of breast cancer, and 4.1% (95% CI = 2.5% to 6.8%) among women who accounted for the highest 10% of the total population risk, as determined from the Lorenz curve. These data give perspective on the potential reductions in absolute breast cancer risk from preventative strategies based on lifestyle changes. Our methods are also useful for calculating sample sizes required for trials to test lifestyle interventions.

Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer Multiple-gene panel analysis in a case series of 255 women with Hereditary Breast and Ovarian Cancer

Background: Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related deaths worldwide. Epidermal Growth Factor Receptor (EGFR)-mutated patients usually benefit from TKIs treatment, but a significant portion show unresponsiveness due to primary resistance mechanisms. We investigated the role of TP53 mutations in predicting survival and response to EGFR-TKIs in EGFR-mutated NSCLC patients, to confirm, on an independent case series, our previous results. Methods: An independent retrospective cohort study was conducted, on a case series of 136 EGFR-mutated NSCLC patients receiving first or second generation TKIs as a first line therapy, and a smaller fraction of patients who acquired the T790M resistance mutation and were treated with third generation TKIs in the second or further line of treatment. TP53 mutations were evaluated in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) of the patients. Results: Forty-two patients (30.9%) showed a TP53 mutation. Considered together, TP53 mutations had no significant impact on time-to-event endpoints. Considering the different TP53 mutations separately, exon 8 mutations confirmed their negative effect on PFS (HR 3.16, 95% 1.59–6.28, p = 0.001). In patients who developed the T790M resistance mutation, treated with third generation TKIs, the TP53 exon 8 mutations predicted worse PFS (even though not statistically significant), and OS (HR 4.86, 95% CI: 1.25–18.90, p = 0.023). Conclusions: TP53 exon 8 mutations confirmed their negative prognostic impact in patients treated with first and second generation TKIs and demonstrated a role in affecting clinical outcome in patients treated with third generation TKIs.