Association of high TUBB3 with resistance to adjuvant docetaxel-based chemotherapy in gastric cancer: translational study of ITACA-S.

BACKGROUND: No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III ß-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported. METHODS: We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival. RESULTS: Patients with TUBB3 protein levels >750 and <750 amol/µg were 21.9% and 78.1%, respectively, and were well-balanced between treatment arms. TUBB3 protein levels were not prognostic. Whereas no survival differences according to the 2 arms were observed in the subgroup with low TUBB3 expression (5-year OS 47% vs 40%; p = 0.44), patients with high TUBB3 had a clinically meaningful poorer OS when receiving docetaxel-based versus 5-FU/LV chemotherapy (5-year OS 31% vs 54%; p = 0.09), with a statistically significant interaction between TUBB3 and treatment (p = 0.049). CONCLUSIONS: The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.

Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD-L1 in Gastric Cancer Patients Treated with Either Adjuvant 5-FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the ITACA-S Trial.

BACKGROUND: Patients with high microsatellite instability (MSI) gastric cancer (GC) show improved survival and no benefit or harm from adjuvant and/or perioperative chemotherapy. The role of immune microenvironment in GC is largely unknown. MATERIALS AND METHODS: In the present study, 256 tumor tissue blocks were centrally collected from patients enrolled in ITACA-S, a randomized adjuvant trial of 5-FU/LV versus sequential FOLFIRI and cisplatin-docetaxel. MSI status was assessed by multiplex PCR, inflammatory reaction by H&E morphological assessment, and programmed death-ligand 1 (PD-L1) expression by immunohistochemistry. RESULTS: Overall, 9% patients had MSI-high tumors, 23% had high inflammatory reaction, 11% had tumor PD-L1 ≥ 1%, and 11% had stromal PD-L1 ≥ 1%. A significant association with disease-free survival (DFS) and overall survival (OS) was found for MSI-high (hazard ratio [HR], 0.43; p = .02; HR, 0.40; p = .02) and high inflammatory reaction (HR, 0.55; p = .010; HR, 0.53; p = .008) but not for PD-L1. At multivariable analysis, only MSI showed an independent association with both DFS (p = .02) and OS (p = .01), whereas inflammatory reaction showed an independent association only with OS (p = .04). Patients with tumor PD-L1 ≥ 1% had a significantly longer DFS in sequential chemotherapy than in than 5-FU/LV arm (interaction p = .04) and a trend for OS (interaction p = .12). CONCLUSION: Our data suggest that MSI status could be a useful prognostic biomarker in patients with radically resected stage II-III GC and should be used as stratification factor in future trials. Tumor PD-L1 ≥ 1% should be further investigated as a potential predictor of benefit from intensive chemotherapy. IMPLICATIONS FOR PRACTICE: In this post hoc analysis of patients with radically resected gastric cancer randomized to an intensive sequential chemotherapy regimen versus 5-FU/LV monotherapy as adjuvant treatment in the ITACA-S trial, MSI-high status was independently associated with better disease-free survival and overall survival (OS) and inflammatory reaction was independently associated with better OS. Moreover, tumor PD-L1 expression ≥1% was associated with greater benefit from intensive sequential chemotherapy compared with 5-fluorouracil plus leucovorin (5-FU/LV), whereas PD-L1 expression <1% was not, conditioning a statistically significant interaction between such biomarker and treatment arms. The meta-analysis of individual patients' data from available studies could yield data on the role of MSI status that could inform clinical decisions.

Sorafenib Versus Observation Following Radical Metastasectomy for Clear-cell Renal Cell Carcinoma: Results from the Phase 2 Randomized Open-label RESORT Study.

BACKGROUND: In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy. OBJECTIVE: To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radical metastasectomy in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves. RESULTS AND LIMITATIONS: At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test p = 0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3 AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm. CONCLUSIONS: This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy. PATIENT SUMMARY: This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.

Maintenance Therapy With Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients With RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined. OBJECTIVE: To determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen. DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018. INTERVENTIONS: Patients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A. RESULTS: Overall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07; P = .01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B. CONCLUSIONS AND RELEVANCE: In patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02476045.

Tp53 status as guide for the management of ethmoid sinus intestinal-type adenocarcinoma.

OBJECTIVE: Intestinal-type adenocarcinoma (ITAC) of the ethmoid sinus is a rare, occupational-related tumor. Optimal treatment consists of surgery and radiotherapy, while chemotherapy is still investigational. The molecular profile of ITAC is characterized by the occurrence of TP53 mutations associated with genotoxic agents such as wood dust. We investigated the role of p53 functionality in relation to the primary treatment. MATERIALS AND METHODS: We retrospectively reviewed 100 medical charts of consecutive patients with a first diagnosis of ITAC treated at our Institute; 74 patients were evaluable for TP53 analysis. Thirty (41%) were treated from 1991 to 2006 with craniofacial resection followed by radiotherapy (Group A), compared with 44 patients (59%) treated from 1996 to 2006 with cisplatin-based induction chemotherapy (PFL) followed by standard treatment (Group B). RESULTS: Five-year OS in Group A was 42%, while in Group B it was 70% (p = 0.041); 5-year DFS in Group A was 40%, while in Group B it was 66%, (p = 0.009) (p = 0.061 and 0.003 at Cox multivariable OS and DFS analyses). Analyzing each group according to p53 functional status, only for Group B patients (who received preoperative chemotherapy) both OS and DFS were in favor of functional p53 (p = 0.023 and p = 0.010, respectively). No impact of p53 functional status as a biomarker was observed in Group A. CONCLUSIONS: Functional p53 may predict PFL-chemotherapy efficacy, offering a possible increase in survival when induction chemotherapy is given to a selected population. On the other hand, upcoming innovative approaches should be explored in the presence of non-functional p53.

Natural history of imatinib-naive GISTs: a retrospective analysis of 929 cases with long-term follow-up and development of a survival nomogram based on mitotic index and size as continuous variables.

Gastrointestinal stromal tumor (GIST) natural history per se has not been extensively investigated yet, with most data being drawn from large studies with a relevant referral bias. Hence, the estimation of prognosis still remains a critical issue. We retrospectively evaluated 929 GISTs resected between 1980 and 2000 in 35 Italian institutions. A total of 526 patients were found to be suitable for refining risk assessment through the development of a survival nomogram. Median follow-up was 126 months. On testing for potential prognostic parameters, age, tumor site, size, and mitotic index proved to be predictors of OS on both univariable and multivariable Cox model analyses, whereas necrosis and cytonuclear atypia were significant on univariable analysis only. The discriminative ability of the model, including the parameters selected after a backward procedure (C=0.72), improved compared with the National Institutes of Health 2002 (C=0.64) and the National Comprehensive Cancer Network 2007 (C=0.63). On the basis of these data we developed a prognostic nomogram for survival that considers site, size, and mitotic index as continuous variables, providing estimates stratified for patients aged ≤65 and >65 years. This nomogram is a tool based on survival. It overcomes problems that result from artificial categorization of continuous variables. We believe that in the future this should also be attempted by nomograms based on the risk of relapse.

Influence of antibiotic treatment on breast carcinoma development in proto-neu transgenic mice.

The effect of prolonged antibiotic treatments on tumor development was evaluated in proto-neu transgenic mice, which spontaneously develop mammary carcinomas. Virgin transgenic mice were treated with metronidazole/ciprofloxacin or gentamicin through the drinking water. The hazard ratio [HR; 95% confidence interval (95% CI)] of breast cancer occurrence in metronidazole/ciprofloxacin-treated mice was more than triple that for controls [3.11 (1.13-8.53); P = 0.028], whereas only a slight increase in HR (95% CI) was observed in gentamicin-treated mice [1.39 (0.56-3.47); P = 0.481]. Tumor growth rate in gentamicin-treated mice was significantly faster than in untreated control mice (P = 0.043). Moreover, mammary glands from mice treated with either antibiotic regimen showed increased lobulization, with more numerous and more developed terminal ductal lobular units than in controls. These results indicate that prolonged exposure to relevant doses of antibiotics affects the mammary glands in this particular model of HER-2/neu transgenic mice; further studies to understand the precise mechanism by which antibiotic treatments influence mammary gland differentiation are critical.

Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double-blind, randomized study.

OBJECTIVE: To evaluate the effect of soy isoflavones and melatonin in relieving menopausal symptoms. METHODS: Double-blind, multicenter, randomized trial performed according to a 2 x 2 factorial design. Treatment groups: (1) soy isoflavones+melatonin; (2) soy isoflavones alone; (3) melatonin alone; (4) placebo. 80 mg of soy isoflavones, 3 mg of pure melatonin or placebo were supplemented to participants for 3 months. Severity of menopausal symptoms was recorded at baseline and after 3 months using the Greene Climacteric Scale. RESULTS: 388 consecutive women were screened: not eligible 98, refused informed consent 28. Randomized 262 and analyzed 232; twelve women withdrew because of adverse events. Median percent differences between basal and final scores were 39% in the isoflavones + melatonin group, 38% in the isoflavones alone group, 26% in the melatonin alone group and 38% in the placebo group. Placebo response was much higher than planned, making it meaningless to perform any statistical test. With regard to somatic and vasomotor symptoms, outcome was similar among the four groups, whereas improvement of psychological symptoms was higher in the isoflavones+melatonin group than in the other three. CONCLUSIONS: Present data do not show any advantage of isoflavones or melatonin over placebo for the relief of menopausal symptoms. However, the effect in psychological symptoms in the isoflavones + melatonin group should be further investigated.