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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.
The polarization of Λ and Λ¯ hyperons along the beam direction has been measured relative to the second and third harmonic event planes in isobar Ru+Ru and Zr+Zr collisions at √sNN = 200 GeV. This is the first experimental evidence of the hyperon polarization by the triangular flow originating from the initial density fluctuations. The amplitudes of the sine modulation for the second and third harmonic results are comparable in magnitude, increase from central to peripheral collisions, and show a mild pT dependence. The azimuthal angle dependence of the polarization follows the vorticity pattern expected due to elliptic and triangular anisotropic flow, and qualitatively disagree with most hydrodynamic model calculations based on thermal vorticity and shear induced contributions. The model results based on one of existing implementations of the shear contribution lead to a correct azimuthal angle dependence, but predict centrality and pT dependence that still disagree with experimental measurements. Thus, our results provide stringent constraints on the thermal vorticity and shear-induced contributions to hyperon polarization. Comparison to previous measurements at RHIC and the LHC for the second-order harmonic results shows little dependence on the collision system size and collision energy.