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Detection of disseminated tumor cells in bone marrow predict late recurrences in operable breast cancer patients.

ABSTRACT: BACKGROUND:Operable breast cancer patients may experience late recurrences because of reactivation of dormant tumor cells within the bone marrow (BM). Identification of patients who would benefit from extended therapy is therefore needed. METHODS:BM samples obtained pre- and post-surgery were previously analysed for presence of disseminated tumor cells (DTC) by a multimarker mRNA quantitative reverse-transcription PCR assay. Updated survival analyses were performed on all patient data (n?=?191) and in a subgroup of patients alive and recurrence-free after 5?years (n?=?156). DTC data were compared to the mitotic activity index (MAI) of the primary tumors. Median follow-up time was 15.3?years. RESULTS:Among the 191 patients, 49 (25.65%) experienced systemic relapse, 24 (49%) within 5-18?years after surgery. MAI and pre- and post-operative DTC status had significant prognostic value based on Kaplan-Meier analyses and multiple Cox regression in the overall patient cohort. With exclusion of patients who relapsed or died within 5?years from surgery, only pre-operative DTC detection was an independent prognostic marker of late recurrences. High MAI (?10) did not predict late recurrences or disease-specific mortality. CONCLUSION:Pre-operative DTC detection, but not MAI status, predicts late recurrences in operable breast cancer.

SUBMITTER: Tjensvoll K

PROVIDER: S-EPMC6873493 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Detection of disseminated tumor cells in bone marrow predict late recurrences in operable breast cancer patients.

Tjensvoll Kjersti K Nordgård Oddmund O Skjæveland Maren M Oltedal Satu S Janssen Emiel A M EAM Gilje Bjørnar B

BMC cancer 20191121 1

<h4>Background</h4>Operable breast cancer patients may experience late recurrences because of reactivation of dormant tumor cells within the bone marrow (BM). Identification of patients who would benefit from extended therapy is therefore needed.<h4>Methods</h4>BM samples obtained pre- and post-surgery were previously analysed for presence of disseminated tumor cells (DTC) by a multimarker mRNA quantitative reverse-transcription PCR assay. Updated survival analyses were performed on all patient ...[more]

PMID: 31752747

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Project description:BackgroundCancer metastasis is the primary cause of cancer-related deaths and remains incurable. Current clinical methods for predicting metastatic recurrence are not sensitive enough to detect individual cancer cells in the body; therefore, current efforts are directed toward liquid biopsy-based assays to capture circulating and disseminated tumor cells (CTCs and DTCs) in the blood and bone marrow, respectively. The most promising strategy is fluorescence-based immunostaining using cancer cell-specific markers. However, despite recent efforts to develop robust processing and staining platforms, results from these platforms have been discordant among groups, particularly for DTC detection. While the choice of cancer cell-specific markers is a large factor in this discordance, we have found that marker-independent factors causing false signal are just as critical to consider. Bone marrow is particularly challenging to analyze by immunostaining because endogenous immune cell properties and bone marrow matrix components typically generate false staining. For immunostaining of whole tumor tissue containing ample cancer cells, this background staining can be overcome. Application of fluorescent-based staining for rare cells, however, is easily jeopardized by immune cells and autofluorescence that lead to false signal.ResultsWe have specifically found two types of background staining in bone marrow samples: autofluorescence of the tissue and non-specific binding of secondary antibodies. We systematically optimized a basic immunofluorescence protocol to eliminate this background using cancer cells spiked into human bone marrow. This enhanced the specificity of automated scanning detection software. Our optimized protocol also outperformed a commercial rare cell detection protocol in detecting candidate DTCs from metastatic patient bone marrow.ConclusionsRobust optimization to increase the signal-to-noise ratio of immunofluorescent staining of bone marrow is required in order to achieve the necessary sensitivity and specificity for rare cell detection. Background immunofluorescent staining in bone marrow causes uncertainty and inconsistency among investigators, which can be overcome by systematically addressing each contributing source. Our optimized assay eliminates sources of background signal, and is adaptable to automated staining platforms for high throughput analysis.

Dataset Information

Detection of disseminated tumor cells in bone marrow predict late recurrences in operable breast cancer patients.

Publications

Detection of disseminated tumor cells in bone marrow predict late recurrences in operable breast cancer patients.

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