The role of serum thymidine kinase 1 activity in neoadjuvant-treated HER2-positive breast cancer: biomarker analysis from the Swedish phase II randomized PREDIX HER2 trial.

BACKGROUND: Thymidine kinase 1 (TK1) plays a pivotal role in DNA synthesis and cellular proliferation. TK1 has been studied as a prognostic marker and as an early indicator of treatment response in human epidermal growth factor 2 (HER2)-negative early and metastatic breast cancer (BC). However, the prognostic and predictive value of serial TK1 activity in HER2-positive BC remains unknown. METHODS: In the PREDIX HER2 trial, 197 HER2-positive BC patients were randomized to neoadjuvant trastuzumab, pertuzumab, and docetaxel (DPH) or trastuzumab emtansine (T-DM1), followed by surgery and adjuvant epirubicin and cyclophosphamide. Serum samples were prospectively collected from all participants at multiple timepoints: at baseline, after cycle 1, 2, 4, and 6, at end of adjuvant therapy, annually for a total period of 5 years and/or at the time of recurrence. The associations of sTK1 activity with baseline characteristics, pathologic complete response (pCR), event-free survival (EFS), and disease-free survival (DFS) were evaluated. RESULTS: No association was detected between baseline sTK1 levels and all the baseline clinicopathologic characteristics. An increase of TK1 activity from baseline to cycle 2 was seen in all cases. sTK1 level at baseline, after 2 and 4 cycles was not associated with pCR status. After a median follow-up of 58 months, 23 patients had EFS events. There was no significant effect between baseline or cycle 2 sTK1 activity and time to event. A non-significant trend was noted among patents with residual disease (non-pCR) and high sTK1 activity at the end of treatment visit, indicating a potentially worse long-term prognosis. CONCLUSION: sTK1 activity increased following neoadjuvant therapy for HER2-positive BC but was not associated with patient outcomes or treatment benefit. However, the post-surgery prognostic value in patients that have not attained pCR warrants further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02568839. Registered on 6 October 2015.

Variation among populations of Clarkia Unguiculata (Onagraceae) along altitudinal and latitudinal gradients.

We investigated phenotypic variation in 15 traits in greenhouse-grown plants from 16 populations of Clarkia unguiculata from three elevational habitats and six latitudinal transects. Populations from the lowest and highest elevations were geographically and ecologically marginal within the species' range. We (1) describe patterns of trait variation with elevation and latitude; (2) compare latitutidinal variation between marginal and central areas of the species' range; and (3) compare patterns of variation within C. unguiculata to interspecific patterns within the genus. Although there was some evidence that traits varied clinally (i.e., increased/decreased monotonically) along environmental gradients, interaction effects between altitude and latitude dominated patterns of variation. For most traits, latitudinal trends at the low-elevation margin of the species' range differed from trends at mid- and high-elevation areas. Based on interspecific comparisons, populations at the hotter, more arid ends of both environmental gradients were expected to have rapid development, small flowers and vegetative size, low levels of herkogamy and protandry, and high rates of gas exchange. Instead, we found that while some traits were correlated with one gradient in the expected way (e.g., development time with elevation, gas-exchange physiology with latitude), all traits were not consistently associated with each other along both gradients, and intraspecific patterns of variation differed from interspecific patterns.