The molecular characteristics of recurrent ovarian cancers following chemotherapy treatment have been poorly characterized. Such knowledge could impact salvage therapy selection. Since 2008, we have profiled 168 patients' ovarian cancers to determine the expression of proteins that may predict chemotherapy response or are targets for drugs that are in clinical trials for ovarian cancer treatment. Expression of EGFR, HER2, VEGF, ER, c-Met, IGF1R, Ki67, COX2, PGP/MDR1, BCRP, MRP1, ERCC1, MGMT,

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... RRM1, TOPO1, TOP2A, and SPARC was measured by immunohistochemical analyses at Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. Our univariate analysis of 56 primary and 50 recurrent tumors from patients with advanced stage ovarian serous carcinoma revealed that PGP and ERCC1 were significantly up-regulated in recurrent lesions (p<0.05). To determine whether these or any of the other markers were differentially expressed in specimens obtained from the same individual at diagnosis and at recurrence, we analyzed forty-three matched tumor specimens from 19 advanced stage ovarian carcinoma patients. We confirmed the expression differences in PGP and ERCC1 that were observed in the cohort analysis, but discovered that the expression levels of BCRP, RRM1, and COX2 were also discordant in >40% of the matched tumor specimens. These results may have implications both for the use of biomarkers in therapy selection as well as for their discovery and validation. Expression of these and other candidate response biomarkers must be evaluated in much larger studies and, if confirmed, support the need for profiling of recurrent tumor specimens in future clinical trials. on June 9, Introduction Ovarian cancer is the most lethal gynecologic malignancy. Worldwide, 224,747 women were diagnosed with ovarian cancer in 2008 and 140,163 died from this disease(1). Most patients diagnosed with advanced stage ovarian cancer respond to first-line platinum-taxane therapy (2), but >75% of these patients will ultimately recur. Thus, despite the improvement in survival time with the addition of taxanes to platinum-based chemotherapy regimens, most patients with advanced stage disease (i.e., mostly high grade serous carcinomas) have recurrences and undergo multiple subsequent regimens of chemotherapy that are mostly palliative. Only 28% of patients with stage III/IV cancer survive five years after diagnosis (3). Genomic profiling analyses have revealed that ovarian carcinomas are molecularly complex and heterogeneous. In addition to differences between tumors with different histologies (e.g., serous, endometrioid, mucinous, clear cell) (4), genotypic and phenotypic heterogeneity is also observed in tumors of the same histologic type and grade. Indeed, gene expression analyses of high grade serous carcinomas obtained from patients prior to treatment classify them into at least three sub-groups which may correlate with different prognostic outcomes (5, 6). It is likely that molecular characteristics of a patient's tumor will be correlated with response to therapy, analogous to what has already been observed in cancers of the breast (e.g., tamoxifen/aromatase inhibitors with expression of the estrogen receptor (ER); trastuzumab with HER2 expression/gene amplification), colon (e.g., EGFR inhibitors with KRAS WT genotype) and, most recently, lung (e.g crizotinib with Alk rearrangements or mutations). These biomarkers are currently employed as companion diagnostics to identify patients who are most likely to respond to these drugs. Interestingly, despite the clinical use of these drugs in breast cancer treatment for more than a decade (trastuzumab) or for more than thirty years (tamoxifen), it has only been recently recognized that expression of these key therapy-selection markers may vary significantly in metastases compared to the corresponding primary tumors. In a recent large breast cancer study, 15%, 30% and 5% of the tumors showed discordant expression of ER, PR, and HER2 in metastatic vs. primary specimens (7), thereby supporting previous observations that HER2 amplification could be gained during breast cancer progression (8). Such studies have raised questions concerning the need to evaluate temporally proximal tumor samples for diagnostic markers prior to selecting therapy. In ovarian cancer, surgical de-bulking procedures are medically indicated for approximately 30% of patients who relapse, but the other patients do not routinely undergo surgical biopsies that would on June 9,