HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Investigation of anaphylactic reaction after patent blue V dye injection

Background Patent blue dye V (PBV) is in widespread use for sentinel node biopsy in breast cancer and melanoma. At present, the best diagnostic approach in investigating possible anaphylaxis due to PBV is not defined. Method We reviewed our experience of patients and the cases reported in the literature that developed an anaphylactic reaction after injection of PBV and suggest a diagnostic protocol. From May 2006 to April 2009 six patients were known to the Cardiff anaesthetics department to have suffered a severe anaphylactic reaction after injection of PBV. We amalgamated the results of the investigations of our patients with those of 42 case reports published in the literature during the last 10 years. Results Of 40 patients with a documented allergy history 31 patients did not have a past medical history of allergy. The median interval between PBV administration and allergic reaction was 15 min (range 1 min–180 min). Of 20 patients with hypotension 18 received inotropes. 4 patients had a fall in blood pressure as their sole symptom. 23 patients had urticaria or other allergic skin manifestations, 8 had blue wheals. 5 patients had bronchospasm. 2 patients had a cardiac arrest. They were successfully resuscitated. The median dose of PBV was 2 ml (range 0.5 ml–5 ml). Tryptase levels were elevated in 14 of 26 tested patients. Skin prick testing was positive in 24 of 30 tested patients. Intradermal testing was positive in all 13 tested patients. Conclusion Most patients experiencing a severe allergic reaction to PBV have no past medical history of allergy. The value of formal allergy skin testing for PBV-related allergy lies in excluding other agents as the causative factor to avoid their exposure in the future

Adverse reactions to patent blue V dye – The NEW START and ALMANAC experience

Background Blue dye with or without isotope has been widely used to identify the sentinel lymph node(s) in breast cancer. Patent blue V is used in the UK while its isomer isosulfan blue is used in the US. The allergic potential of isosulfan blue is well documented (1.4% adverse reactions) but that of patent blue V is less clearly defined. Methods In this paper we review the adverse reactions of patent blue V in 7,917 patients who participated in the NEW START training programme and the ALMANAC trial. All patients underwent sentinel lymph node biopsy for breast carcinoma using patent blue V in combination with 99mTc-albumin colloid. Results In total, 72 of 7,917 (0.9%) patients experienced adverse reactions : non-allergic reactions were observed in 4 (0.05%) patients, 23 (0.3%) patients had minor grade I allergic skin reactions (urticaria, blue hives, pruritis, or generalised rash) and 16 (0.2%) had grade II reactions (transient hypotension/bronchospasm/laryngospasm). Severe Grade III reactions (severe hypotension requiring vasopressor support and/or change/abandoning of planned procedure and/or HDU/ITU admission) were noted in 5 (0.06%) patients. The type of adverse reaction was not specified in 24 (0.3%) patients. No mortality was recorded. Conclusion The allergic potential of patent blue V dye compares favourably with isosulfan blue however both the surgeon and anaesthetist need to be alert to the risk of allergic reactions

Risk assessment in the first fifteen minutes: a prospective cohort study of a simple physiological scoring system in the emergency department

Introduction The survival of patients admitted to an emergency department is determined by the severity of acute illness and the quality of care provided. The high number and the wide spectrum of severity of illness of admitted patients make an immediate assessment of all patients unrealistic. The aim of this study is to evaluate a scoring system based on readily available physiological parameters immediately after admission to an emergency department (ED) for the purpose of identification of at-risk patients. Methods This prospective observational cohort study includes 4,388 consecutive adult patients admitted via the ED of a 960-bed tertiary referral hospital over a period of six months. Occurrence of each of seven potential vital sign abnormalities (threat to airway, abnormal respiratory rate, oxygen saturation, systolic blood pressure, heart rate, low Glasgow Coma Scale and seizures) was collected and added up to generate the vital sign score (VSS). VSSinitial was defined as the VSS in the first 15 minutes after admission, VSSmax as the maximum VSS throughout the stay in ED. Occurrence of single vital sign abnormalities in the first 15 minutes and VSSinitial and VSSmax were evaluated as potential predictors of hospital mortality. Results Logistic regression analysis identified all evaluated single vital sign abnormalities except seizures and abnormal respiratory rate to be independent predictors of hospital mortality. Increasing VSSinitial and VSSmax were significantly correlated to hospital mortality (odds ratio (OR) 2.80, 95% confidence interval (CI) 2.50 to 3.14, P < 0.0001 for VSSinitial; OR 2.36, 95% CI 2.15 to 2.60, P < 0.0001 for VSSmax). The predictive power of VSS was highest if collected in the first 15 minutes after ED admission (log rank Chi-square 468.1, P < 0.0001 for VSSinitial;,log rank Chi square 361.5, P < 0.0001 for VSSmax). Conclusions Vital sign abnormalities and VSS collected in the first minutes after ED admission can identify patients at risk of an unfavourable outcome