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

Enteral lactoferrin supplementation for very preterm infants : a randomised placebo-controlled trial

Background: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. Methods: In this randomised, placebo-controlled trial, very preterm infants (born before 32 weeks' gestation) in 37 UK hospitals were allocated randomly (1:1) within 72 hours after birth to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose (same dose) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers and outcomes assessors were unaware of group assignment. The primary outcome was microbiologically-confirmed or clinically-suspected lateonset infection (occurring >72 hours after birth). The trial was registered with the International Standard Randomised Controlled Trial Number 88261002. Findings: We recruited 2203 participants between May 2014 and September 2017. Four infants had consent withdrawn or unconfirmed leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants were available for inclusion in the intention-to-treat analyses. In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: risk ratio (RR) adjusted for minimisation factors 0.95 (95% confidence interval [CI] 0.86, 1.04). Pre-specified subgroup analyses did not show statistically significant interactions for gestation at birth (completed weeks') or type of enteral milk received (human, formula, or both). Interpretation: Enteral supplementation with bovine lactoferrin does not reduce the incidence of late-onset infection in very preterm infants. Funding: UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

Enteral lactoferrin supplementation for very preterm infants : a randomised placebo-controlled trial

Background: Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. Methods: In this randomised, placebo-controlled trial, very preterm infants (born before 32 weeks' gestation) in 37 UK hospitals were allocated randomly (1:1) within 72 hours after birth to receive enteral bovine lactoferrin (150 mg/kg/day; maximum 300 mg/day) versus sucrose (same dose) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers and outcomes assessors were unaware of group assignment. The primary outcome was microbiologically-confirmed or clinically-suspected lateonset infection (occurring >72 hours after birth). The trial was registered with the International Standard Randomised Controlled Trial Number 88261002. Findings: We recruited 2203 participants between May 2014 and September 2017. Four infants had consent withdrawn or unconfirmed leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants were available for inclusion in the intention-to-treat analyses. In the intervention group, 316/1093 (28.9%) infants acquired a late-onset infection versus 334/1089 (30.7%) in the control group: risk ratio (RR) adjusted for minimisation factors 0.95 (95% confidence interval [CI] 0.86, 1.04). Pre-specified subgroup analyses did not show statistically significant interactions for gestation at birth (completed weeks') or type of enteral milk received (human, formula, or both). Interpretation: Enteral supplementation with bovine lactoferrin does not reduce the incidence of late-onset infection in very preterm infants. Funding: UK National Institute for Health Research Health Technology Assessment programme (10/57/49)

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients