The introduction of pertuzumab has greatly improved pathological complete response (pCR) rates in HER2-positive breast cancer, yet effects on long-term survival have been limited and it is uncertain ...which patients derive most benefit. In this study, we determine the prognostic value of BluePrint subtyping in HER2-positive breast cancer. Additionally, we evaluate its use as a biomarker for predicting response to trastuzumab-containing neoadjuvant chemotherapy with or without pertuzumab.
From a cohort of patients with stage II-III HER2-positive breast cancer who were treated with neoadjuvant chemotherapy and trastuzumab with or without pertuzumab, 836 patients were selected for microarray gene expression analysis, followed by readout of BluePrint standard (HER2, Basal and Luminal) and dual subtypes (HER2-single, Basal-single, Luminal-single, HER2-Basal, Luminal-HER2, Luminal-HER2-Basal). The associations between subtypes and pathological complete response (pCR), overall survival (OS) and breast cancer-specific survival (BCSS) were assessed, and pertuzumab benefit was evaluated within the BluePrint subgroups.
BluePrint results were available for 719 patients. In patients with HER2-type tumors, the pCR rate was 71.9% in patients who received pertuzumab versus 43.5% in patients who did not (adjusted Odds Ratio 3.43, 95% CI 2.36-4.96). Additionally, a significantly decreased hazard was observed for both OS (adjusted hazard ratio aHR 0.45, 95% CI 0.25-0.80) and BCSS (aHR 0.46, 95% CI 0.24-0.86) with pertuzumab treatment. Findings were similar in the HER2-single subgroup. No significant benefit of pertuzumab was seen in other subtypes.
In patients with HER2-type or HER2-single-type tumors, pertuzumab significantly improved the pCR rate and decreased the risk of breast cancer mortality, which was not observed in other subtypes. BluePrint subtyping may be valuable in future studies to identify patients that are likely to be highly sensitive to HER2-targeting agents.
Purpose
BluePrint (BP) is an 80-gene molecular subtyping test that classifies early-stage breast cancer (EBC) into Basal, Luminal, and HER2 subtypes. In most cases, breast tumors have one dominant ...subtype, representative of a single activated pathway. However, some tumors show a statistically equal representation of more than one subtype, referred to as dual subtype. This study aims to identify and examine dual subtype tumors by BP to understand their biology and possible implications for treatment guidance.
Methods
The BP scores of over 15,000 tumor samples from EBC patients were analyzed, and the differences between the highest and the lowest scoring subtypes were calculated. Based upon the distribution of the differences between BP scores, a threshold was determined for each subtype to identify dual versus single subtypes.
Results
Approximately 97% of samples had one single activated BluePrint molecular subtype, whereas ~ 3% of samples were classified as BP dual subtype. The most frequently occurring dual subtypes were the Luminal-Basal-type and Luminal-HER2-type. Luminal-Basal-type displays a distinct biology from the Luminal single type and Basal single type. Burstein’s classification of the single and dual Basal samples showed that the Luminal-Basal-type is mostly classified as ‘luminal androgen receptor’ and ‘mesenchymal’ subtypes, supporting molecular evidence of AR activation in the Luminal-Basal-type tumors. Tumors classified as Luminal-HER2-type resemble features of both Luminal-single-type and HER2-single-type. However, patients with dual Luminal-HER2-type have a lower pathological complete response after receiving HER2-targeted therapies in addition to chemotherapy in comparison with patients with a HER2-single-type.
Conclusion
This study demonstrates that BP identifies tumors with two active functional pathways (dual subtype) with specific transcriptional characteristics and highlights the added value of distinguishing BP dual from single subtypes as evidenced by distinct treatment response rates.
Over recent decades it has become clear that the middle atmosphere has a significant impact on surface and tropospheric climate. A better understanding of the middle atmosphere and how it reacts to ...the current increase in the concentration of carbon dioxide (CO.sub.2) is therefore necessary. In this study, we investigate the response of the middle atmosphere to a doubling of the CO.sub.2 concentration, and the associated changes in sea surface temperatures (SSTs), using the Whole Atmosphere Community Climate Model (WACCM). We use the climate feedback response analysis method (CFRAM) to calculate the partial temperature changes due to an external forcing and climate feedbacks in the atmosphere. As this method has the unique feature of additivity, these partial temperature changes are linearly addable. In this study, we discuss the direct forcing of CO.sub.2 and the effects of the ozone, water vapour, cloud, albedo and dynamical feedbacks.
High winter planetary wave activity warms the summer polar mesopause via a
link between the two hemispheres. Complex wave–mean-flow
interactions take place on a global
scale, involving sharpening and ...weakening of the summer zonal flow. Changes
in the wind shear occasionally generate flow instabilities. Additionally, an
altering zonal wind modifies the breaking of vertically propagating gravity
waves. A crucial component for changes in the summer zonal flow is the
equatorial temperature, as it modifies latitudinal gradients. Since several
mechanisms drive variability in the summer zonal flow, it can be hard to
distinguish which one is dominant. In the mechanism coined interhemispheric
coupling, the mesospheric zonal flow is suggested to be a key player for how
the summer polar mesosphere responds to planetary wave activity in the winter
hemisphere. We here use the Whole Atmosphere Community Climate Model (WACCM)
to investigate the role of the summer stratosphere in shaping the conditions
of the summer polar mesosphere. Using composite analyses, we show that in the
absence of an anomalous summer mesospheric temperature gradient between the
equator and the polar region, weak planetary wave forcing in the winter would
lead to a warming of the summer mesosphere region instead of a cooling, and
vice versa. This is opposing the temperature signal of the interhemispheric
coupling that takes place in the mesosphere, in which a cold and calm winter
stratosphere goes together with a cold summer mesopause. We hereby strengthen
the evidence that the variability in the summer mesopause region is mainly
driven by changes in the summer mesosphere rather than in the summer
stratosphere.
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