HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. Results: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P <. 001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P =. 01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P <. 001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P =. 02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P =. 01). Conclusions: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer

A framework for the cross-sectoral integration of multi-model impact projections: land use decisions under climate impacts uncertainties

Climate change and its impacts already pose considerable challenges for societies that will further increase with global warming (IPCC, 2014a, b). Uncertainties of the climatic response to greenhouse gas emissions include the potential passing of large-scale tipping points (e.g. Lenton et al., 2008; Levermann et al., 2012; Schellnhuber, 2010) and changes in extreme meteorological events (Field et al., 2012) with complex impacts on societies (Hallegatte et al., 2013). Thus climate change mitigation is considered a necessary societal response for avoiding uncontrollable impacts (Conference of the Parties, 2010). On the other hand, large-scale climate change mitigation itself implies fundamental changes in, for example, the global energy system. The associated challenges come on top of others that derive from equally important ethical imperatives like the fulfilment of increasing food demand that may draw on the same resources. For example, ensuring food security for a growing population may require an expansion of cropland, thereby reducing natural carbon sinks or the area available for bio-energy production. So far, available studies addressing this problem have relied on individual impact models, ignoring uncertainty in crop model and biome model projections. Here, we propose a probabilistic decision framework that allows for an evaluation of agricultural management and mitigation options in a multi-impactmodel setting. Based on simulations generated within the Inter-Sectoral Impact Model Intercomparison Project (ISI-MIP), we outline how cross-sectorally consistent multi-model impact simulations could be used to generate the information required for robust decision making. Using an illustrative future land use pattern, we discuss the trade-off between potential gains in crop production and associated losses in natural carbon sinks in the new multiple crop- and biome-model setting. In addition, crop and water model simulations are combined to explore irrigation increases as one possible measure of agricultural intensification that could limit the expansion of cropland required in response to climate change and growing food demand. This example shows that current impact model uncertainties pose an important challenge to long-term mitigation planning and must not be ignored in long-term strategic decision making

Biological Earth observation with animal sensors

Space-based tracking technology using low-cost miniature tags is now delivering data on fine-scale animal movement at near-global scale. Linked with remotely sensed environmental data, this offers a biological lens on habitat integrity and connectivity for conservation and human health; a global network of animal sentinels of environmen-tal change

Supplementary Material for: Impact of Age on the Management of Primary Melanoma Patients

<b><i>Objectives:</i></b> Age is an understudied factor when considering treatment options for melanoma. Here, we examine the impact of age on primary melanoma treatment in a prospective cohort of patients. <b><i>Methods:</i></b> We used logistic regression models to examine the associations between age and initial treatment, using recurrence and melanoma-specific survival as endpoints. <b><i>Results:</i></b> 444 primary melanoma patients were categorized into three groups by age at diagnosis: 19-45 years (24.3%), 46-70 (50.2%), and 71-95 (25.5%). In multivariate models, older patients experienced a higher risk of recurrence (hazard ratio 3.34, 95% confidence interval, CI, 1.53-7.25; p < 0.01). No significant differences were observed in positive biopsy margin rates or extent of surgical margins across age groups. Patients in the middle age group were more likely to receive adjuvant therapy than those in the older group (odds ratio 2.78, 95% CI 1.19-6.45; p = 0.02) and showed a trend to longer disease-free survival when receiving adjuvant therapy (p = 0.09). <b><i>Conclusion:</i></b> Our data support age as an independent negative prognostic factor in melanoma. Our data suggest that age does not affect primary surgical treatment but may affect decisions of whether or not patients receive postoperative treatment(s). Further work is needed to better understand the biological variables affecting treatment decisions and efficacy in older patients

Supplementary Material for: Outcomes in Melanoma Patients Treated with BRAF/MEK-Directed Therapy or Immune Checkpoint Inhibition Stratified by Clinical Trial versus Standard of Care

<p><b><i>Objectives:</i></b> Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. <b><i>Methods:</i></b> 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. <b><i>Results:</i></b> Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, <i>p</i> = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (<i>p</i> < 0.001), irrespective of stratification by trial status or therapy. <b><i>Conclusion</i></b>: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.</p

Multicenter, International Assessment of the Eighth Edition of the American Joint Committee on Cancer Cancer Staging Manual for Conjunctival Melanoma

MTG4Molecular tumour pathology - and tumour genetic