Retinoblastoma and phosphate and tensin homolog tumor suppressors

Impact on ductal carcinoma in situ progression

Erik S. Knudsen, Thomas F. Pajak, Maria Qeenan, A. Kathleen Mcclendon, Benjamin D. Armon, Gordon F. Schwartz, Agnieszka K. Witkiewicz

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease. Methods: The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided. Results: Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties. Conclusions: These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of benet.

Original languageEnglish (US)
Pages (from-to)1825-1836
Number of pages12
JournalJournal of the National Cancer Institute
Volume104
Issue number23
DOIs
StatePublished - Dec 2012

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Carcinoma, Intraductal, Noninfiltrating
Retinoblastoma
Phosphoric Monoester Hydrolases
Phosphates
Neoplasms
Confidence Intervals
Breast Neoplasms
Recurrence
Breast
Segmental Mastectomy
Tensins
Tumor Suppressor Genes
Proportional Hazards Models
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Retinoblastoma and phosphate and tensin homolog tumor suppressors : Impact on ductal carcinoma in situ progression. / Knudsen, Erik S.; Pajak, Thomas F.; Qeenan, Maria; Mcclendon, A. Kathleen; Armon, Benjamin D.; Schwartz, Gordon F.; Witkiewicz, Agnieszka K.

In: Journal of the National Cancer Institute, Vol. 104, No. 23, 12.2012, p. 1825-1836.

Research output: Contribution to journalArticle

Knudsen, Erik S. ; Pajak, Thomas F. ; Qeenan, Maria ; Mcclendon, A. Kathleen ; Armon, Benjamin D. ; Schwartz, Gordon F. ; Witkiewicz, Agnieszka K. / Retinoblastoma and phosphate and tensin homolog tumor suppressors : Impact on ductal carcinoma in situ progression. In: Journal of the National Cancer Institute. 2012 ; Vol. 104, No. 23. pp. 1825-1836.
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abstract = "Background: A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease. Methods: The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided. Results: Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR 2.64; 95{\%} confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95{\%} CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95{\%} CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95{\%} CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties. Conclusions: These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of benet.",
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T2 - Impact on ductal carcinoma in situ progression

AU - Knudsen, Erik S.

AU - Pajak, Thomas F.

AU - Qeenan, Maria

AU - Mcclendon, A. Kathleen

AU - Armon, Benjamin D.

AU - Schwartz, Gordon F.

AU - Witkiewicz, Agnieszka K.

PY - 2012/12

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N2 - Background: A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease. Methods: The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided. Results: Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties. Conclusions: These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of benet.

AB - Background: A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease. Methods: The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided. Results: Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties. Conclusions: These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of benet.

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