We investigated the agreement between 1) self-reported and technician-measured waist circumference at the level of the umbilicus, 2) circumference measured at the level of the umbilicus and halfway between the lower rib and the iliac crest (the natural waist), and 3) self-reported circumference at the level of the umbilicus and technician-measured circumference at the natural waist. At follow-up in the Danish "Diet, Cancer and Health" study, we recruited 176 men and 240 women for a validation study. Bland-Altman plots were used to evaluate agreement among measurement sites. Multiple regression was used to identify variables explaining the difference between measurements. The participants underestimated their waist circumference; the mean differences were -1.6 cm (95% CI: -2.4 cm, -0.8 cm) in men and -3.0 cm (95% CI: -3.8 cm, -2.3 cm) in women. Limits of agreement were from -11.9 to +8.7 cm among men and -14.9 to +8.9 cm among women. High BMI and large baseline waist circumference were associated with a larger degree of underreporting. Waist circumference measured at the level of the umbilicus was larger than at the natural waist; the mean differences were +0.7 cm (95% CI: +0.4 cm, +1.1 cm) in men and +5.0 cm (95% CI: +4.4 cm, +5.6 cm) in women. The self-reported waist circumference at the level of the umbilicus was correlated with the technician-measured circumference at the natural waist. The circumference at the natural waist was overestimated for women, depending on baseline waist circumference, and slightly underestimated for men, depending on baseline BMI.

HER2 mutations defi ne a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversi ble pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER + patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2 -activating events , as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefi t from neratinib. Collectively, these data defi ne HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations defi ne a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modifi ed by the presence of concurrent activating genomic events in the pathway. These fi ndings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defi ned subset of breast cancer.

Purpose: We evaluated the clinical benefit of tumor molecular profiling to select treatment in the phase I setting. Experimental Design: Patients with advanced solid cancers and exhausted treatment options referred to a phase I unit were included in a prospective, single-center, singlearm open-label study (NCT02290522). Tumor biopsies were obtained for comprehensive genomic analysis including whole-exome sequencing and RNA sequencing. When possible, patients were treated with regimen matched to the genomic profile. Primary endpoint was progression-free survival (PFS). Results: From May 2013 to January 2017, a total of 591 patients were enrolled, with 500 patients undergoing biopsy. Genomic profiles were obtained in 460 patients and a potential actionable target was identified in 352 (70%) of 500 biopsied patients. A total of 101 patients (20%) received matched treatment based on either gene mutations or RNA expression levels of targets available in early clinical trials or off-label treatment. Objective response according to RECIST1.1 was observed in 15 of 101 patients (0% complete response, 15% partial response), with a median PFS of 12 weeks (95% confidence interval, 9.9-14.4). Conclusions: Our study supports the feasibility of genomic profiling to select patients in the phase I setting and suggests that genomic matching can be beneficial for a minor subset of patients with no other treatment options. Randomized studies may validate this assumption. See related commentary by Ratain, p. 1136

Antiangiogenic metargidin peptide (AMEP) is a novel anticancer agent exerting antiproliferative and antiangiogenic effects by binding to αvβ3 and α5β1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I study investigated safety and tolerability of intratumoral plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA). In each patient, two cutaneous lesions were identified (one treated and one control). At day 1 and day 8, plasmid AMEP was injected intratumorally followed by electrotransfer. Patients were monitored weekly until day 29, and at day 64. Local efficacy was assessed at day 29 by direct measurement, and posttreatment biopsies for AMEP mRNA levels were evaluated by reverse transcriptase quantitative polymerase chain reaction. Plasmid copy number in blood and urine was determined by quantitative polymerase chain reaction. Minimal systemic toxicity was observed, including transient fever and transitory increase in C-reactive protein. No related serious adverse events occurred. Plasmid AMEP was detected in plasma but not in urine. AMEP mRNA was found in three of five treated lesions and none of the control lesions. At day 29, all five treated lesions were stable in diameter, whereas four of five control lesions increased more than 20%. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe and that local transfection was obtained.