Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Hdl Handle:
http://hdl.handle.net/10147/315467
Title:
Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers
Authors:
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
Citation:
Breast Cancer Research. 2013 Sep 23;15(5):R86
Journal:
Breast Cancer Research
Issue Date:
23-Sep-2013
URI:
http://dx.doi.org/10.1186/bcr3481; http://hdl.handle.net/10147/315467
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.
Item Type:
Article
Language:
en
Keywords:
BREAST CANCER

Full metadata record

DC FieldValue Language
dc.contributor.authorBianchini, Giampaoloen_GB
dc.contributor.authorPusztai, Lajosen_GB
dc.contributor.authorKarn, Thomasen_GB
dc.contributor.authorIwamoto, Takayukien_GB
dc.contributor.authorRody, Achimen_GB
dc.contributor.authorKelly, Catherine Men_GB
dc.contributor.authorMüller, Volkmaren_GB
dc.contributor.authorSchmidt, Marcusen_GB
dc.contributor.authorQi, Yuanen_GB
dc.contributor.authorHoltrich, Uween_GB
dc.contributor.authorBecker, Svenen_GB
dc.contributor.authorSantarpia, Liberoen_GB
dc.contributor.authorFasolo, Angelicaen_GB
dc.contributor.authorDel Conte, Gianlucaen_GB
dc.contributor.authorZambetti, Milviaen_GB
dc.contributor.authorSotiriou, Christosen_GB
dc.contributor.authorHaibe-Kains, Benjaminen_GB
dc.contributor.authorSymmans, W Fen_GB
dc.contributor.authorGianni, Lucaen_GB
dc.date.accessioned2014-04-07T10:33:03Z-
dc.date.available2014-04-07T10:33:03Z-
dc.date.issued2013-09-23-
dc.identifier.citationBreast Cancer Research. 2013 Sep 23;15(5):R86en_GB
dc.identifier.urihttp://dx.doi.org/10.1186/bcr3481-
dc.identifier.urihttp://hdl.handle.net/10147/315467-
dc.description.abstractAbstract 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.-
dc.language.isoenen
dc.subjectBREAST CANCERen_GB
dc.titleProliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancersen_GB
dc.typeArticleen
dc.identifier.journalBreast Cancer Researchen_GB
dc.language.rfc3066en-
dc.rights.holderGiampaolo Bianchini et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2014-04-05T11:16:45Z-
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