Tumor heterogeneity and in vitro chemosensitivity testing in ovarian cancer

Sevin, Bernd‐Uwe; Perras, James P.

doi:10.1016/s0002-9378(97)70599-4

Cited by 26 publications

(26 citation statements)

References 12 publications

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“…Although clonal mutations in somatic cells may initiate the carcinogenesis process, it has become clear that ongoing genetic changes are involved in both disease progression and what has been called clonal divergence. This, in turn, leads to tumor heterogeneity [16]. Because extensive heterogeneity in cellular morphology, cell surface markers, and nuclear chromosomal content exist in human cancers, the end result can lead to differences in tumor growth rate, metabolic characteristics, immunogenicity, and sensitivity to and recovery from exposure to antineoplastic drugs.…”

Section: Discussionmentioning

confidence: 99%

Conservation of in vitro drug resistance patterns in epithelial ovarian carcinoma

Tewari

Mehta

Burger

et al. 2005

Gynecologic Oncology

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Purpose. To compare the in vitro drug resistance profiles of advanced stage primary and recurrent epithelial ovarian cancer specimens using the tritiated thymidine uptake assay.Methods. Extreme drug resistance (EDR) to cisplatin, paclitaxel, 4-hydroxycyclophosphamide, and topotecan was determined for an unselected population of primary and metastatic malignant ovarian tissues, synchronous tumors (primary and metastatic tissues obtained from the same patient at diagnosis), and metachronous lesions (specimens from the same patient before and after chemotherapy).Results. For the large unselected population of malignant tissues (total, N = 6990; primary ovarian, N = 2031; metastatic ovarian, N = 4959), no statistically significant differences were discovered between primary tissues and metastatic lesions when a comparison was made between the percentage of tumors from each group that exhibited extreme drug resistance to the agents assayed. From the library of 6990 specimens, 119 synchronous pairings were identified. These synchronous lesions did not differ significantly in the %EDR between primary and metastatic sites in the same patient; approximately 10% shifted between low drug resistance and EDR. A total of 334 metachronous pairings were identified and the percentage of tissues that exhibited EDR also failed to show a significant difference when primary tumors were compared with matched recurrences in the same patient.Conclusions. For the agents studied, acquired resistance was not a function of disease site. In vitro drug resistance observed at recurrence was not influenced significantly by intervening therapy. It is possible that assay results at diagnosis could be used to guide subsequent therapy at relapse, especially when recurrent tissue is not available for analysis. D

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Section: Discussionmentioning

confidence: 99%

Conservation of in vitro drug resistance patterns in epithelial ovarian carcinoma

Tewari

Mehta

Burger

et al. 2005

Gynecologic Oncology

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“…Biologically and clinically, such heterogeneity translates into differences in tumor growth rate, metabolic characteristics, immunogenicity, and sensitivity to and recovery from exposure to irradiation and cytotoxic drugs [8,12]. If tumor cell populations derive from a cenancestor or single transformed cell, then biological divergence during cell division and proliferation must take place at some point along the spectrum that extends from the clonal origin of neoplasia to the clinical declaration of malignancy.…”

Section: Discussionmentioning

confidence: 99%

Biomarker Conservation in Primary and Metastatic Epithelial Ovarian Cancer

Tewari¹,

Kyshtoobayeva²,

Mehta³

et al. 2000

Gynecologic Oncology

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Purpose. The aim of this study was to compare the overexpression of specific biomarkers in primary advanced and recurrent epithelial ovarian cancers.Methods. Biomarker expression by epithelial ovarian cancer specimens from primary and metastatic sites was examined by immunohistochemistry and flow cytometry. Biomarker expression by subpopulations of tissues consisting of matched pairs of synchronous and metachronous lesions was also studied.Results. A total of 3173 epithelial ovarian cancer specimens were retrieved from women with FIGO Stage III/IV disease. These included lesions from 1036 primary and 2137 metastatic sites. The percentages of biomarker expression for primary and metastatic lesions, respectively, were MDR1, 12 and 10%; p53, 55 and 60%; HER2, 12 and 11%; EGF-R, 26 and 33%; increased microvessel counts (CD31), 21 and 36%. Approximately 73% of both primary and metastatic specimens were aneuploid, and approximately 57% of both sets had an S-phase fraction >7%. Only EGF-R and CD31 expression were found to be significantly different between the primary and metastatic tumors (P < 0.05). Of the paired synchronous cases (n ‫؍‬ 48) evaluated, 88% of aneuploid primary lesions were associated with aneuploid metastases. Similarly, the distributions for MDR1, HER2, and p53 expression did not vary significantly between primary and metastatic sites. Pairings of metachronous cases (n ‫؍‬ 66) revealed that nearly 80% of primary aneuploid tumors (n ‫؍‬ 39) retained their aneuploid status at the time of relapse. Furthermore, there were no significant changes in MDR1, p53, or HER2 expression at relapse.Conclusions. With the exception of EGF-R and CD31, clonal divergence of the biomarkers evaluated in this study probably does not play a significant role in imparting clinical heterogeneity during the advanced and recurrent stages of epithelial ovarian cancer. These particular genes likely undergo alterations early in the tumorigenesis process before metastases have become established.

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“…Typically, however, the choice of a given chemotherapeutic drug is based on clinical trials that determine whether a drug is effective in large numbers of patients. This approach ignores variation to individual patient conditions (Sevin and Perras 1997).…”

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confidence: 99%