Summary Somatic mutations of ERBB2 (HER2) and ERBB3 (HER3) are found in a wide range of cancers. Preclinical modelling suggests that a subset lead to constitutive HER2 activation, but most remain biologically uncharacterized. We sought to prospectively define the biologic and therapeutic significance of known oncogenic HER2 and HER3 mutations and variants of unknown biological significance by conducting a multi-histology, genomically selected, ‘basket’ study utilizing the pan-HER kinase inhibitor neratinib (SUMMIT; Clinicaltrials.gov NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours harbouring kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to further refine our biological understanding of both characterized and novel genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

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Objective: To determine if the change in iron status from an iron biofortified efficacy trial results in a change in energy efficiency for Indian girls. Methods: 56 Indian girls (12‐15 years) were randomly assigned to receive iron biofortified pearl millet or traditional pearl millet for 6 months. Blood and energy efficiency measurements were taken before and after the intervention. Energy efficiency was calculated by recording O2 and CO2 consumption during sub‐maximal exercise tests on a Monark 874E ergometer. General linear models were used to evaluate the effect of the iron biofortification intervention on energy efficiency of the girls. Results: Consuming iron biofortified pearl millet resulted in an increase in hemoglobin after 3 months (p=0.05). Energy efficiency decreased in both treatment and control groups, but was significantly higher in the treatment group (p=0.02). Conclusion: Consuming biofortified pearl millet improved hemoglobin status in Indian girls and prevented a decline in energy efficiency over 6 months. Grant Funding Source: Supported by HarvestPlus

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