Abstract
IntroductionWe 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.MethodsBaseline 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.ResultsIn 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.ConclusionsEarly 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.
Highlights
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
We assessed an independent series of ER-positive patients treated with adjuvant tamoxifen for 5 years and 58 ER-positive patients treated with neoadjuvant letrozole for 3 months for which gene expression profiles are available at baseline, 14 and 90 days after beginning of the neoadjuvant treatment (GSE20181 [16])
Our findings suggest that patients with highly proliferative and high-ER breast cancers have the highest absolute risk for late relapse tumors, despite the fact that their risk of recurrence is modest in the first 5 years on tamoxifen
Summary
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. Given the independent prognostic and predictive values of proliferation and estrogen signaling, we examined in a time-dependent way whether a combination of proliferation, measured by the Mitotic Kinase Gene Expression Score (MKS), and ER-related gene expression, measured by an estrogenrelated gene expression score (ERS), could improve the ability of these variables to predict early versus late relapses in women with ER-positive breast cancer. This information could help in selecting patients for extended adjuvant endocrine therapy based on their persistent risk for late relapses
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