Beschreibung:
<jats:p>Ovarian cancer is the most lethal gynecologic malignancy. About 75% of ovarian cancer patients relapse and/or develop chemo‐resistant disease after initial response to standard‐of‐care treatment with platinum‐based therapies. <jats:styled-content style="fixed-case">HER</jats:styled-content>2 amplifications and overexpression in ovarian cancer are reported to vary, and responses to <jats:styled-content style="fixed-case">HER</jats:styled-content>2 inhibitors have been poor. Next generation sequencing technologies in conjunction with testing using patient‐derived xenografts (<jats:styled-content style="fixed-case">PDX</jats:styled-content>) allow validation of personalized treatments. Using a whole‐genome mate‐pair next generation sequencing (<jats:styled-content style="fixed-case">MP</jats:styled-content>seq) protocol, we identified several high grade serous ovarian cancers (<jats:styled-content style="fixed-case">HGS</jats:styled-content>‐<jats:styled-content style="fixed-case">OC</jats:styled-content>) with <jats:styled-content style="fixed-case">DNA</jats:styled-content> alterations in genes encoding members of the <jats:styled-content style="fixed-case">ERBB</jats:styled-content>2 pathway. The efficiency of anti‐<jats:styled-content style="fixed-case">HER</jats:styled-content>2 therapy was tested in three different <jats:styled-content style="fixed-case">PDX</jats:styled-content> lines with the identified alterations and high levels of <jats:styled-content style="fixed-case">HER</jats:styled-content>2 protein expression. Treatment responses to pertuzumab or pertuzumab/trastuzumab were compared in each <jats:styled-content style="fixed-case">PDX</jats:styled-content> line WITH standard carboplatin and paclitaxel combination treatment. In all three <jats:styled-content style="fixed-case">PDX</jats:styled-content> models, <jats:styled-content style="fixed-case">HER</jats:styled-content>2‐targeted therapy resulted in significant inhibition of tumor growth compared with untreated controls. However, the responses in each case were inferior to those to chemotherapy, even for chemo‐resistant lines. When chemotherapy and <jats:styled-content style="fixed-case">HER</jats:styled-content>2‐targeted therapy were administered together, a significant regression of tumor was observed after 6 weeks of treatment compared with chemotherapy alone. Post‐treatment analysis of these tissues revealed that inhibition of the <jats:styled-content style="fixed-case">ERBB</jats:styled-content>2 pathway occurred at the level of phosphorylation and expression of downstream targets. In conclusion, while targeting of presumably activated <jats:styled-content style="fixed-case">ERBB</jats:styled-content>2 pathway alone in <jats:styled-content style="fixed-case">HGS</jats:styled-content>‐<jats:styled-content style="fixed-case">OC</jats:styled-content> results in a modest treatment benefit, a combination therapy including both chemotherapy drugs and <jats:styled-content style="fixed-case">HER</jats:styled-content>2 inhibitors provides a far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to <jats:styled-content style="fixed-case">HER</jats:styled-content>2‐targeted therapy.</jats:p>