Only the combination of all three drugs was sufficient to induce a robust regre

Her erythematous chest wall skin lesion showed a dramatic improvement after receiving two cycles of study treatment and by 6 months the skin lesion had completely resolved. There was one additional ARQ 197 datasheet patient with breast can cer treated for over a year experiencing a total reduction in tumor size of 68% who was confirmed as having PR. Five more patients had SD for more than 4 months. These preliminary efficacy results suggest that the combination of MK 2206 with trastuzumab may offer patients an effective salvage regimen following progression on trastuzumab, or may prevent or delay clinical resistance if used earlier in the disease. The efficacy observed in this phase 1 study supports the hypothesis that a mechanism of resistance to trastu zumab may be mediated by activation of the PI3K AKT pathway in vivo.<br><br> The mechanisms through which the PI3K AKT pathway may be activated in trastuzumab refractory HER2 tumors is currently unknown. Leading candidates include activating mutations of the PIK3CA gene or deletion AZD0530 溶解度 or mutations in PTEN, an inhibitor of the PI3K AKT pathway. We collected circulating nucleic acid to explore this possibility, based on reports that cor related findings in circulating nucleic acid with DNA from tumor specimens. Only three patients were found to have mutations in the PIK3CA gene in circulat ing DNA and none had notably long SD or response to treatment. No PIK3CA mutation was detected in the circulating nucleic acid samples from patients who responded to treatment. Studies have estimated that between 13 and 31% of HER2 breast cancers harbor mutations in PIK3CA.<br><br> Results of PIK3CA mutation status from circulating DNA in this study are at the lower limit of these estimations. One of the limitations of this analysis is that our PIK3CA mutation assessment was restricted to circulating DNA analysis. Tumor biopsies for biomarker analysis prior to treat ment were not mandated and intratumor heterogeneity AMN-107 Nilotinib in PIK3CA mutation status or limitations of detection inherent to circulating DNA mutational analysis may be responsible for the lower than expected PIK3CA muta tional frequency observed. The possibility therefore re mains that tumor samples at primary or metastatic sites might demonstrate mutations that do not appear in circulating nucleic acid.<br><br> Despite these caveats, our analysis of the circulating DNA PIK3CA somatic mutation status does not support the hypothesis that tumors with PIK3CA mutations have improved responsiveness to MK 2206. Conceivably, other molecular aberrations such as p95HER2, PTEN loss of function events or alternative signaling cascades mediated by HER3, and insulin growth factor 1 recep tors or epidermal growth factor receptors that were not assessed in our study, may also be predicted to render tumors resistant to trastuzumab but sensitive to com bined AKT inhibition. Therefore, in an attempt to pre dict preferential benefit from combined AKT inhibitor trastuzumab therapy, exploratory biomarker analyses may need to consider the polygenic nature of trastuzu mab resistance and assess multiple aberrations in the HER2 signaling pathway in each tumor.