Pertuzumab Plus Trastuzumab in Patients With Colorectal Cancer With ERBB2 Amplification or ERBB2/3 Mutations: Results From the TAPUR Study.

PURPOSE: The TAPUR Study is a pragmatic phase II basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from two cohorts of patients with colorectal cancer (CRC) with either ERBB2 amplifications or ERBB2 or ERBB3 (ERBB2/3) mutations treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients with measurable CRC were selected for treatment with P + T according to protocol-specified genomic matching rules. Patients had no remaining standard treatment options, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Simon's two-stage design was used with a primary study end point of disease control (DC; objective response [OR] or stable disease of at least 16 weeks duration [SD16+]). Secondary end points include safety, response duration, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-eight patients with CRC with ERBB2 amplification (N = 28) or ERBB2/3 mutations (N = 10) were treated with P + T. For the ERBB2 amplification cohort, DC and OR were observed in 54% and 25% of patients, respectively; the median PFS and median OS (95% CIs) were 17.2 (11.1 to 27.4) weeks and 60.0 (32.1 to 102.3) weeks, respectively. For the ERBB2/3 mutation cohort, DC and OR were observed in 10% and 0% of patients, respectively; the median PFS and median OS were 9.6 (5.1 to 16.0) weeks and 28.8 (7.6 to 146.3) weeks, respectively. Four of 38 patients experienced grade 3 adverse events or serious adverse events including anemia, infusion reaction, diarrhea, left ventricular systolic dysfunction, and decreased lymphocyte count. CONCLUSION: Although P + T treatment does not appear to have antitumor activity in CRC with ERBB2/3 mutations, this combination has antitumor activity in patients with CRC with ERBB2 amplification and warrants further study.

Residential metal contamination and potential health risks of exposure in adobe brick houses in Potosí, Bolivia.

Potosí, Bolivia, is the site of centuries of historic and present-day mining of the Cerro Rico, a mountain known for its rich polymetallic deposits, and was the site of large-scale Colonial era silver refining operations. In this study, the concentrations of several metal and metalloid elements were quantified in adobe brick, dirt floor, and surface dust samples from 49 houses in Potosí. Median concentrations of total mercury (Hg), lead (Pb), and arsenic (As) were significantly greater than concentrations measured in Sucre, Bolivia, a non-mining town, and exceeded US-based soil screening levels. Adobe brick samples were further analyzed for bioaccessible concentrations of trace elements using a simulated gastric fluid (GF) extraction. Median GF extractable concentrations of Hg, As, and Pb were 0.085, 13.9, and 32.2% of the total element concentration, respectively. Total and GF extractable concentrations of Hg, As, and Pb were used to estimate exposure and potential health risks to children following incidental ingestion of adobe brick particles. Risks were assessed using a range of potential ingestion rates (50-1000mg/day). Overall, the results of the risk assessment show that the majority of households sampled contained concentrations of bioaccessible Pb and As, but not Hg, that represent a potential health risk. Even at the lowest ingestion rate considered, the majority of households exceeded the risk threshold for Pb, indicating that the concentrations of this metal are of particular concern. To our knowledge, this is the first study to quantify key trace elements in building materials in adobe brick houses and the results indicate that these houses are a potential source of exposure to metals and metalloids in South American mining communities. Additional studies are needed to fully characterize personal exposure and to understand potential adverse health outcomes within the community.

Mercury hair levels and factors that influence exposure for residents of Huancavelica, Peru.

Between 1564 and 1810, nearly 17,000 metric tons of mercury (Hg) vapor was released to the environment during cinnabar refining in the small town of Huancavelica, Peru. The present study characterizes individual exposure to mercury using total and speciated Hg from residential samples, total Hg in hair, and self-reported questionnaire data regarding factors influencing exposure (e.g., frequency of fish consumption, occupation). Total Hg concentrations in hair from 118 participants ranged from 0.10 to 3.6 µg/g, similar to concentrations found in the USA and lower than concentrations in other Hg-exposed populations around the world. Pearson's correlation coefficients for data in this study suggest that there is a positive correlation between concentrations of total Hg in hair and concentrations of total Hg in adobe bricks, dirt floors, and surface dust; however, these correlations are not statistically significant. Results of a one-way analysis of variance (ANOVA) identified that total Hg concentrations in hair were significantly related to gender (p < 0.001), living in a neighborhood where smelters were previously located (p = 0.021), smoking status (p = 0.003), frequency of house cleaning (p = 0.019), and frequency of fish consumption (p = 0.046). These results highlight the need for further studies to better characterize Hg exposure in Huancavelica, particularly as related to residential contamination. A comprehensive analysis of residential Hg contamination and exposure in Huancavelica will guide the development and implementation of mitigation and remediation strategies in the community to reduce potential health risks from residential Hg exposure.

Residential mercury contamination in adobe brick homes in Huancavelica, Peru.

This is the first study of adobe brick contamination anywhere in the world. Huancavelica, Peru is the site of historic cinnabar refining and one of the most mercury (Hg) contaminated urban areas in the world. Over 80% of homes in Huancavelica are constructed with adobe bricks made from Hg contaminated soil. In this study we measured total Hg concentrations in adobe brick, dirt floor, surface dust, and air samples from the interior of 60 adobe brick houses located in four neighborhoods. Concentrations of total Hg in adobe bricks, dirt floors, and surface dust ranged from 8.00 to 1070 µg/g, 3.06 to 926 µg/g, and 0.02 to 9.69 µg/wipe, respectively, with statistically significant differences between the four neighborhoods. Concentrations of Hg in adobe brick and dirt floor samples in Huancavelica were orders of magnitude higher than in Ayacucho, a non-mining town in Peru. A strong correlation exists between total Hg concentrations in adobe bricks and dirt floors which confirms that adobe bricks were being made on-site and not purchased from an off-site source. A strong correlation between surface dust and adobe bricks and dirt floors indicates that walls and floors serve as indoor sources of Hg contamination. Elemental Hg vapor concentrations were below detection (<0.5 µg/m(3)) in most homes; however in homes with detectable levels, concentrations up to 5.1 µg/m(3) were observed. No statistically significant differences in Hg vapor measurements were observed between neighborhoods. This study demonstrates that building materials used widely in developing communities, such as adobe bricks, may be a substantial source of residential Hg exposure in silver or gold refining communities where Hg is produced or used for amalgamation in artisanal gold production.

Estimations of historical atmospheric mercury concentrations from mercury refining and present-day soil concentrations of total mercury in Huancavelica, Peru.

Detailed Spanish records of cinnabar mining and mercury production during the colonial period in Huancavelica, Peru were examined to estimate historical health risks to the community from exposure to elemental mercury (Hg) vapor resulting from cinnabar refining operations. Between 1564 and 1810, nearly 17,000 metric tons of Hg were released to the atmosphere in Huancavelica from Hg production. AERMOD was used with estimated emissions and source characteristics to approximate historic atmospheric concentrations of mercury vapor. Modeled 1-hour and long-term concentrations were compared with present-day inhalation reference values for elemental Hg. Estimated 1-hour maximum concentrations for the entire community exceeded present-day occupational inhalation reference values, while some areas closest to the smelters exceeded present-day emergency response guideline levels. Estimated long-term maximum concentrations for the entire community exceeded the EPA Reference Concentration (RfC) by a factor of 30 to 100, with areas closest to the smelters exceeding the RfC by a factor of 300 to 1000. Based on the estimated historical concentrations of Hg vapor in the community, the study also measured the extent of present-day contamination throughout the community through soil sampling and analysis. Total Hg in soils sampled from 20 locations ranged from 1.75 to 698 mg/kg and three adobe brick samples ranging from 47.4 to 284 mg/kg, consistent with other sites of mercury mining and use. The results of the soil sampling indicate that the present-day population of Huancavelica is exposed to levels of mercury from legacy contamination which is currently among the highest worldwide, consequently placing them at potential risk of adverse health outcomes.