Ki67: a time-varying biomarker of risk of breast cancer in atypical hyperplasia

Santisteban, Marta; Reynolds, Carol; Fritcher, Emily G. Barr; Frost, Marlene H.; Vierkant, Robert A.; Anderson, Stephanie S.; Degnim, Amy C.; Visscher, Daniel W.; Pankratz, V. Shane; Hartmann, Lynn C.

doi:10.1007/s10549-009-0534-7

Cited by 65 publications

(63 citation statements)

References 39 publications

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“…Recent studies have shown that Ki-67 LI in atypical hyperplasia predicts future breast cancer risk (11) and is associated with the progression of carcinogenesis from ductal hyperplasia to DIN (10,26). Moreover, Ki-67 LI after short-term presurgical treatment predicts recurrencefree and overall survival in women with early breast cancer, supporting the use of this biomarker to tailor adjuvant treatment and to screen drugs in a cost-effective manner (2-4, 27).…”

Section: Discussionmentioning

confidence: 99%

“…In other words, the window-of-opportunity trial model can exploit the existence of the field cancerization, which is well documented in breast cancer (9), to get important clues on the preventive effect of the investigational agent. Moreover, recent studies have shown that Ki-67 LI is positively associated with carcinogenesis progression (10) and its level of staining in atypical lesions in core biopsies of nonmalignant lesions may predict subsequent breast cancer risk, going from a 10-year cumulative incidence of breast cancer of 3% for lesions with Ki-67 LI less than 2% to 14% in those with Ki-67 LI 2% or more (11).…”

Section: Introductionmentioning

confidence: 99%

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Lapatinib Activity in Premalignant Lesions and HER-2–Positive Cancer of the Breast in a Randomized, Placebo-Controlled Presurgical Trial

DeCensi

Puntoni

Pruneri

et al. 2011

Cancer Prevention Research

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Dual epidermal growth factor receptor (EGFR) and HER2 targeting with the tyrosine kinase inhibitor lapatinib is approved for treating advanced HER2-positive breast cancer and can prevent estrogen receptor (ER)-negative mammary tumors in HER2 transgenic mouse models. Ki-67 labeling index (LI) has prognostic and predictive value and can be used to screen drugs' therapeutic and preventive potential in a clinical model of short-term presurgical therapy of breast cancer. We conducted a randomized, placebo-controlled trial of lapatinib (1500 mg/d) administered orally for three weeks between biopsy and surgery in 60 women with HER-2-positive breast cancer to assess lapatinib biomarker (including the primary endpoint, Ki-67 LI) and clinical activity in invasive breast cancer, adjacent ductal intraepithelial neoplasia (DIN, which comprises ductal carcinoma in situ and atypical ductal hyperplasia), and distant ductal hyperplasia without atypia (DH). Ki-67 LI increased progressively in association with disease stage, increasing in the placebo arm, for example, by medians of 3% in DH to 20% in DIN to 30% in invasive cancer. Ki-67 LI in cancer tissue decreased by a mean (AESD) of 9.3% (AE34.2) in the lapatinib arm and increased by 15.1% (AE30.9) in the placebo arm (P ¼ 0.008). Compared with placebo, lapatinib reduced Ki-67 significantly more in ER-negative tumors (by 34.8%; P ¼ 0.01) but not significantly more in ER-positive tumors (by 12.3%; P ¼ 0.2) and reduced Ki-67 more (nonsignificantly) in cytosol PTEN-overexpressing tumors (P ¼ 0.057). The prevalence of DIN in post-treatment surgical specimens of both arms was similar (70%-76%), with a median Ki-67 of 15% (range, 5%-35%) on lapatinib versus 20% (5%-60%) on placebo (P ¼ 0.067). The prevalence of DH also was similar in both arms (>90%), with a median Ki-67 of 1% (1%-7%) on lapatinib versus 3% (1%-5%) on placebo (P ¼ 0.006). Other results of lapatinib versus placebo, respectively, were as follows: Median tumor diameter at surgery of 18 mm (11 mm-57 mm) versus 24 mm (10 mm-37 mm; P ¼ 0.009); partial response of 13.6% versus 3.7%, stable disease of 59.1% versus 40.7%, and progression of 27.3% versus 55.6% (P-trend ¼ 0.035). In conclusion, short-term lapatinib decreased cell proliferation in DIN, DH, and invasive HER-2-positive (especially ER-negative) breast cancer, thus providing the rationale for further clinical development of lapatinib for breast cancer prevention in high-risk patients, including those with HER-2-positive DIN.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lapatinib Activity in Premalignant Lesions and HER-2–Positive Cancer of the Breast in a Randomized, Placebo-Controlled Presurgical Trial

DeCensi

Puntoni

Pruneri

et al. 2011

Cancer Prevention Research

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“…The expression of this marker was not significant in our study (p00.181), while Ki67 biomarker expression was highly significant (p00.001). Ki67 has been appeared as a time-varying biomarker of breast cancer [32].…”

Section: Discussionmentioning

confidence: 99%

Molecular Markers in Peripheral Blood of Iranian Women with Breast Cancer

Oloomi

Bouzari

Mohagheghi

et al. 2012

Cancer Microenvironment

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A biomarker is a quantifiable laboratory measure of a disease specific biologically relevant molecule that can act as an indicator of a current or future disease state. The purpose of this study is to detect the expression of RNA biomarkers using Cytokeratin 19 (CK-19), Mammaglobin (MAM), Carcinoembryonic antigen (CEA), Mucin (MUC), C-Myc, erb-B2, a proliferation marker (Ki-67), Epidermal growth factor receptor (Her2/neu) and Estrogen receptor (ER) in Iranian women who were diagnosed with breast cancer. In this study, 90 samples; 60 cancer patients and 30 healthy controls were considered. 73.4 % patients were in stage I/II and 26.6 % were in stage III/IV. Patients were selected prior to the administration of any adjuvant systemic therapy. Total RNA extraction was obtained from peripheral blood of each patient and healthy control. Reverse transcription polymerase chain reaction (RT-PCR) method was used for detection of mRNA of the selected biomarkers of circulating breast cancer cells in blood. Molecular characterization is assessed as a method for early detection of breast cancer. For this purpose, eleven specific primers were selected and RT-PCR was used. The data of RT-PCR revealed that expression of MUC1, CK19, CEA, MAM, erbB-2, Ki67 and C-Myc biomarkers were significantly different between breast cancer patients and healthy controls. On the other hand, ERα, ERβ and Her2 markers were not significantly different between the two mentioned groups.

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“…These investigators carefully evaluated p16 ink4a expression by immunohistochemistry on excisional biopsies containing atypical hyperplasia from 233 women with long-term follow-up (median ¼ 14.5 years). They previously found significantly increased risk associated with elevated COX-2 and Ki67 in atypical hyperplasia in the same cohort (5,6). In the current study, however, they found no association between p16 ink4a and risk, whether considered alone, or in combination with COX-2 and Ki67.…”

mentioning

confidence: 84%