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Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.

ABSTRACT: Telomere dysfunction and fusion can drive genomic instability and clonal evolution in human tumours, including breast cancer. Telomere length is a critical determinant of telomere function and has been evaluated as a prognostic marker in several tumour types, but it has yet to be used in the clinical setting. Here we show that high-resolution telomere length analysis, together with a specific telomere fusion threshold, is highly prognostic for overall survival in a cohort of patients diagnosed with invasive ductal carcinoma of the breast (n = 120). The telomere fusion threshold defined a small subset of patients with an extremely poor clinical outcome, with a median survival of less than 12 months (HR = 21.4 (7.9-57.6), P < 0.0001). Furthermore, this telomere length threshold was independent of ER, PGR, HER2 status, NPI, or grade and was the dominant variable in multivariate analysis. We conclude that the fusogenic telomere length threshold provides a powerful, independent prognostic marker with clinical utility in breast cancer. Larger prospective studies are now required to determine the optimal way to incorporate high-resolution telomere length analysis into multivariate prognostic algorithms for patients diagnosed with breast cancer.

SUBMITTER: Simpson K

PROVIDER: S-EPMC4449122 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.

Simpson K K Jones R E RE Grimstead J W JW Hills R R Pepper C C Baird D M DM

Molecular oncology 20150225 6

Telomere dysfunction and fusion can drive genomic instability and clonal evolution in human tumours, including breast cancer. Telomere length is a critical determinant of telomere function and has been evaluated as a prognostic marker in several tumour types, but it has yet to be used in the clinical setting. Here we show that high-resolution telomere length analysis, together with a specific telomere fusion threshold, is highly prognostic for overall survival in a cohort of patients diagnosed w ...[more]

PMID: 25752197

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Project description:BackgroundThe clinical utility and prognostic impact of presumed primary breast or ovarian cancer among patients with an unfavorable subset of cancer of unknown primary site (CUP) remains unclear. We aimed to evaluate the clinical relevance of the presumed primary site of CUP and the clinical outcome of site-specific therapy based on such presumptions.MethodsPatients referred to our center who were diagnosed with unfavorable-subset CUP and treated between April 2007 and March 2015 were enrolled in this study. Data were collected retrospectively from the hospital database and electronic medical records. Presumptive primary breast or ovarian cancer was based on histological and immunohistochemical analyses and metastatic patterns. The outcomes of patients with unfavorable-subset CUP with a putative primary site in the breast or ovary (P-CUP) and of patients with unfavorable-subset CUP, but without P-CUP (U-CUP), were assessed.ResultsA total of 780 patients were referred to our hospital with malignancy of unknown origin. Of these, 409 patients were diagnosed with CUP and 344 patients with unfavorable-subset CUP. Following clinicopathological examination, 40 (11.6%) of the 344 patients had P-CUP and the remaining 303 (88.3%) patients had U-CUP. In total, 136 patients received chemotherapy (22 with P-CUP and 114 with U-CUP). Among the 22 patients with P-CUP, three received hormonal therapy for breast cancer, and 19 received chemotherapy based on the presumed primary organ (breast, 4; ovaries, 15). Conventional platinum-based chemotherapy was administered to 105 patients with U-CUP and non-platinum drug treatment to nine patients. The objective response rates were 61.1% (95% confidence interval [CI]: 38.6-83.6) and 41.1% (95% CI: 31.8-50.4) for patients with P-CUP and U-CUP, respectively. The median overall survival durations were 50.0 months and 16.9 months (log-rank: P = 0.002) for patients with P-CUP and U-CUP, respectively. P-CUP was identified as an independent predictor of good prognosis according to multivariate analysis.ConclusionsPatients with P-CUP had higher response rates and a better prognosis compared with patients with U-CUP. It might thus be reasonable to classify this subset as a new category of CUP with a favorable prognosis.

Project description:BackgroundPatients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and disease-related poor prognostic factors are not well characterized. We aimed to describe patient demographics, disease characteristics, treatment patterns and patient-reported outcomes in a subset of HR+/HER2- ABC patients with these factors [at the time when cyclin-dependent kinase (CDK) 4 and 6 inhibitors were being introduced] and understand how these factors informed treatment decisions at the time of the survey.MethodsReal-world data were derived from a large, multinational, point-in-time survey of oncologists and their consulting patients with HR+/HER2- ABC in the EU5 and USA over March-June 2017, at the start of the changing treatment landscape. Analysis focused on four poor prognostic factors: visceral metastases, liver metastases (subset of visceral metastases), progesterone receptor-negative status and high tumor grade.ResultsIn total, 2259 patients with HR+/HER2- ABC had records eligible for this analysis. At least one poor prognostic factor was present in 63% of patients (most common visceral metastases; least common progesterone receptor-negative status), with varying degrees of overlap between factors. For physician-reported outcomes, pain increased, whereas performance status and activities of daily living declined with presence of poor prognostic factors, especially liver metastases. No clear trends were observed for patient-reported outcomes. Treatment with combined endocrine therapy plus CDK4 and 6 inhibitors was infrequent, as these agents were entering the market.ConclusionsMore than 60% of the HR+/HER2- ABC Adelphi Real World Disease Specific Programme™ sample had ≥1 disease-related poor prognostic factor, and patients appeared to be heterogeneous regarding occurrence and distribution of these factors. These patients typically have increased pain and reduced performance status, highlighting the importance of implementing effective therapy with CDK4 and 6 inhibitors. Future studies could inform how the treatment landscape has evolved over time with respect to patients with poor prognostic factors.

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Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.

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Telomere fusion threshold identifies a poor prognostic subset of breast cancer patients.

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