Evaluation of Liquid From the Papanicolaou Test and Other Liquid Biopsies for the Detection of Endometrial and Ovarian Cancers

摘要

Although the Papanicolaou (Pap) test has dramatically decreased mortality fromcervical cancer in the screened population, the test generally is unable to detect endometrial or ovarian cancers. These 2 cancers are usually diagnosed at an advanced stage when the prognosis is poor and treatment does not increase relative survival. The most common screening diagnostic test for endometrial cancer is transvaginal ultrasound and for ovarian cancer is transvaginal ultrasound and CA-125. These tests cannot reliably diagnose either cancer, and the high false-positive rates subject women who do not have cancer to unnecessary invasive procedures and associated complications. As a result, much effort has been directed toward developing a screening test to detect these cancers at an early potentially curable stage. A recent study has shown that cells shed fromendometrial and ovarian cancers contain detectable amount of tumor DNA in the fluids obtained during routine Pap tests. Cells collected with a brush (a " Pap brush" inserted into the endocervical canal) are applied to a slide for cytologic examination (the classic Pap smear). The DNA from this fluid is amplified using a polymerase chain reaction (PCR)-based multiplex test to simultaneously assess genetic alterations that commonly occur in endometrial or ovarian cancers. To increase sensitivity, a " Tao brush" has been also used to allow sample collection closer to the anatomical sites of the tumors. The aim of this retrospective study was to determine whether testing for genetic mutations of DNA recovered from the both the plasma and fluids obtained during a routine Pap test would increase sensitivity for ovarian and endometrial cancers. The investigators designed and applied a new multiplex PCR-based test (PapSEEK) to detect mutations in these samples. This assay was applied to Pap brush samples of 382 women with endometrial cancer, 245 women with ovarian cancer, and 714 women without cancer. Among the 382 women with endometrial cancer, 81%(95% confidence interval [ CI], 77%-85%) of the Pap brush samples had detectable mutations (PapSEEK-positive), including 78% with early-stage disease. Among the 245 women with ovarian cancer, 33% (95% CI, 27%-39%) of the Pap brush samples were PapSEEK-positive, including 34% of patients with early-stage disease. In the Pap brush samples from 714 women without cancer, only 1.4% were PapSEEK-positive, yielding a specificity of similar to 99%. The use of intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: genetic alterations were detected in 93% of 123 (95% CI, 87%-97%) patients with endometrial cancer and 45% of 51 (95% CI, 31%-60%) patients with ovarian cancer. In contrast, none of the samples from 125 women without cancer were PapSEEK-positive (specificity, 100%). Finally, 43% (95% CI, 33%-55%) of the plasma samples from the 83 patients with ovarian cancer tested with PapSEEK had detectable circulating tumor DNA. When assays for circulating tumor DNA in plasma were used together with PapSEEK on Pap brush samples, the sensitivity for detecting ovarian cancer increased to 63% (95% CI, 51%-73%). These data demonstrate the potential formutation-based diagnostic screening to detect gynecologic cancers at an early stage when they are more likely to be curable. These findings are promising, but the study was retrospective rather than prospective, and the samples examinedwere derived from patients with known cancers.