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Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers
Bianchini, Giampaolo Pusztai, Lajos Karn, Thomas Iwamoto, Takayuki Rody, Achim Kelly, Catherine M Müller, Volkmar Schmidt, Marcus Qi, Yuan Holtrich, Uwe
Bianchini, Giampaolo
Pusztai, Lajos
Karn, Thomas
Iwamoto, Takayuki
Rody, Achim
Kelly, Catherine M
Müller, Volkmar
Schmidt, Marcus
Qi, Yuan
Holtrich, Uwe
Author
Bianchini, Giampaolo
Pusztai, Lajos
Karn, Thomas
Iwamoto, Takayuki
Rody, Achim
Kelly, Catherine M
Müller, Volkmar
Schmidt, Marcus
Qi, Yuan
Holtrich, Uwe
Becker, Sven
Santarpia, Libero
Fasolo, Angelica
Del Conte, Gianluca
Zambetti, Milvia
Sotiriou, Christos
Haibe-Kains, Benjamin
Symmans, W F
Gianni, Luca
Pusztai, Lajos
Karn, Thomas
Iwamoto, Takayuki
Rody, Achim
Kelly, Catherine M
Müller, Volkmar
Schmidt, Marcus
Qi, Yuan
Holtrich, Uwe
Becker, Sven
Santarpia, Libero
Fasolo, Angelica
Del Conte, Gianluca
Zambetti, Milvia
Sotiriou, Christos
Haibe-Kains, Benjamin
Symmans, W F
Gianni, Luca
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Date
2013-09-23
Date Submitted
Keywords
BREAST CANCER
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Abstract
Abstract Introduction We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. Methods Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0–2.5, 0–5, 5-10 years. Results In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0–2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Conclusions Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.
Language
en