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

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

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Gamma linolenic acid and other fatty acids in the treatment of pancreatic carcinoma

Most patients with carcinoma of the pancreas present late with advanced disease for whom there is no effective chemotherapy. Essential fatty acids (EFA) such as gamma linolenic acid (GLA) and eicosapentaenoic acid (EPA) have shown promise as antitumour agents in previous in vitro, animal and also in some clinical studies. The main advantage is virtual absence of side effects, thus the quality of life is not impaired. Here the aim was mainly to evaluate GLA as an anticancer agent in pancreatic carcinoma. EPA was also studied to a limited extent.The effect of lithium salt of GLA (LiGLA) and 1-γlinolenyl-3-eicosapentaenoyl propane diol against human pancreatic carcinoma cell lines in vitro was tested by incubating these cells with these compounds for 7 days. The influence of iron and albumin on the effect of LiGLA was also studied. In vivo evaluation was carried out in nude mice injected with a human pancreatic cancer cell line and treated with various preparations of GLA and EPA. In the clinical study 278 patients with advanced irresectable pancreatic carcinoma were treated with LiGLA.LiGLA had a dose and time dependent growth inhibitory effect on human pancreatic cancer in vitro. Albumin reduced while free iron but not transferrin-bound iron promoted this effect. Similarly 1-γ-linolenyl-3-eicosapentaenoyl propane diol was also growth inhibitory in vitro. No antitumour effect or a change in tumour lipid fatty acid composition was seen in nude mice with human pancreatic tumours produced with the same cell line which was sensitive in vitro, and treated with the maximum tolerated doses of LiGLA ip or iv or lithium salt of EPA ip. Intra-tumour injection of LiGLA was, however, effective. 1-γ-linolenyl-3-eicosapentaenoyl propane diol was also not growth inhibitory in nude mice, and tumour fatty acid composition was unchanged. Concurrent administration of parenteral iron with this compound did not significantly improve the skills. IV LiGLA in pancreatic cancer patients had no severe side effects and inhibited the acute phase response but was ineffective in prolonging survival.It is difficult to achieve tumour growth inhibition and prolongation of survival in pancreatic carcinoma with EFA's using conventional means of administration. Locoregional therapy may be more effective in this regard.</p

Gamma linolenic acid and other fatty acids in the treatment of pancreatic carcinoma

Most patients with carcinoma of the pancreas present late with advanced disease for whom there is no effective chemotherapy. Essential fatty acids (EFA) such as gamma linolenic acid (GLA) and eicosapentaenoic acid (EPA) have shown promise as antitumour agents in previous in vitro, animal and also in some clinical studies. The main advantage is virtual absence of side effects, thus the quality of life is not impaired. Here the aim was mainly to evaluate GLA as an anticancer agent in pancreatic carcinoma. EPA was also studied to a limited extent.The effect of lithium salt of GLA (LiGLA) and 1-γlinolenyl-3-eicosapentaenoyl propane diol against human pancreatic carcinoma cell lines in vitro was tested by incubating these cells with these compounds for 7 days. The influence of iron and albumin on the effect of LiGLA was also studied. In vivo evaluation was carried out in nude mice injected with a human pancreatic cancer cell line and treated with various preparations of GLA and EPA. In the clinical study 278 patients with advanced irresectable pancreatic carcinoma were treated with LiGLA.LiGLA had a dose and time dependent growth inhibitory effect on human pancreatic cancer in vitro. Albumin reduced while free iron but not transferrin-bound iron promoted this effect. Similarly 1-γ-linolenyl-3-eicosapentaenoyl propane diol was also growth inhibitory in vitro. No antitumour effect or a change in tumour lipid fatty acid composition was seen in nude mice with human pancreatic tumours produced with the same cell line which was sensitive in vitro, and treated with the maximum tolerated doses of LiGLA ip or iv or lithium salt of EPA ip. Intra-tumour injection of LiGLA was, however, effective. 1-γ-linolenyl-3-eicosapentaenoyl propane diol was also not growth inhibitory in nude mice, and tumour fatty acid composition was unchanged. Concurrent administration of parenteral iron with this compound did not significantly improve the skills. IV LiGLA in pancreatic cancer patients had no severe side effects and inhibited the acute phase response but was ineffective in prolonging survival.It is difficult to achieve tumour growth inhibition and prolongation of survival in pancreatic carcinoma with EFA's using conventional means of administration. Locoregional therapy may be more effective in this regard.</p