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Toral Gathani and colleagues argue that risk stratification by age and sex should be used to help manage demand on breast clinics efficiently to minimise delays in diagnosis

Supplementary Data from Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results

Supplementary Figure from Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results

Purpose:The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation.Patients and Methods:STAKT was a two-stage, double-blind, randomized, placebo-controlled, “window-of-opportunity” study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring.Results:After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n = 17) produced significant decreases from baseline versus placebo (n = 11) in pGSK3β (H-score absolute change: −55.3, P = 0.006) and pPRAS40 (−83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: −9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (−42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. (n = 5) and 240 mg b.i.d. (n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident.Conclusions:Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.

Purpose:EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer.Patients and Methods:This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects.Results:Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002).Conclusions:Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

Purpose: Tamoxifen remains therapy of choice for premenopausal estrogen receptor α–positive breast cancer. However, resistance and recurrence are serious problems. Our previous work indicated that carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) was significantly up-regulated in tamoxifen-resistant (TAMr) MCF-7 derivatives. The aim of this study was to determine the functional role of CEACAM6 in endocrine-resistant breast cancer and to retrospectively test whether it was predictive of resistance in a large cohort of breast cancers with long-term follow-up.Experimental Design: siRNA silencing of CEACAM6 was done in TAMr cells and effects on clonogenicity and endocrine sensitivity were determined. CEACAM6 immunohistochemistry was done on a tissue microarray comprising 108 relapsed primary human breast cancers and 243 tamoxifen-sensitive controls.Results: siRNA-mediated silencing of CEACAM6 reduced both clonogenicity and anchorage-dependent and anchorage-independent growth of TAMr cells. Importantly, CEACAM6 silencing restored sensitivity of TAMr cells to 4-hydroxytamoxifen and proliferative response to 17β-estradiol. Immunohistochemistry showed significantly more CEACAM expression in the relapsed group compared with nonrelapsed controls [35 of 108 (33.3%) and 32 of 243 (13.2%), respectively; odds ratio, 3.16 (95% confidence interval, 1.83-5.47); P < 0.0001]. Additionally, we derived an outcome predictor model based on CEACAM expression that restratified patients in the Nottingham prognostic index intermediate-risk group into either higher-risk or lower-risk group.Conclusions: Our data support an important role for CEACAM6 in endocrine resistance, which can serve as a powerful predictor of future recurrence.

Supplementary Table S1 from Carcinoembryonic Antigen Cell Adhesion Molecule 6 Predicts Breast Cancer Recurrence following Adjuvant Tamoxifen

Supplementary Data from Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)

Background: EPHOS-B is a multi-centre randomized trial designed to investigate whether anti-HER2 therapy given 11 days pre-surgery inhibited proliferation and/or increased apoptosis in HER2-positive early breast cancer. Significant differences in Ki67 response (≥30% change between baseline and surgery) were observed between treatment groups and control, although no significant increases in apoptosis were seen [1]. We report here 5-year outcomes and their association with peri-operative response, including post-hoc exploratory analyses on stromal tumour infiltrating lymphocytes (TILs). Methods: Patients were randomized (1:2:2) to no treatment (control), trastuzumab or lapatinib (Part-1), and (1:1:2) to control, trastuzumab, or lapatinib and trastuzumab combination (Part-2). Relapse free survival (RFS) is defined as the time from randomisation to local, regional, or distant tumour recurrence or death from any cause, with second primary cancers censored. Five-year RFS rates were estimated by Kaplan-Meier across treatment and peri-operative response groups, and compared by Log-Rank tests. Central scoring of stromal tumour infiltrating lymphocytes (TILs) on scanned H&E baseline and surgery slides was conducted post-hoc according to the International TILs Working Group. Baseline TILs (bTILS) were explored across treatment groups, and associated with trial outcomes. Changes in TILS in patients without pathological regression were correlated with Ki67 changes and RFS. Results: Overall, 257 patients were randomized (Part-1: control 22, trastuzumab 57, lapatinib 51; Part-2: control 29, trastuzumab 32, trastuzumab+lapatinib 66). Central pathology review identified six patients achieving complete pathological response (pCR), and 13 RCB1 (as per the Residual Cancer Burden score), all but two in the combination group. After 6 years median follow-up, 28 women (11%) had recurrence, and 19 (7%) died; no differences between groups were found (Table). No recurrences were observed amongst pCR patients; only 1 local recurrence observed amongst RCB1. Patients with Ki67 falls ≥50% had better RFS than those with modest falls or no falls (Table). In patients with no evidence of disease regression at surgery, those with higher TILs (≥20%) at surgery had better RFS than those with lower TILs. Conclusions: Early response (pCR/RCB1 or Ki67 reductions >50%) after 11 days pre-operative anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway and provides a strategy for individualising treatment, including de-escalation of therapy. [1] Bundred N, Cameron D, Amstrong A et al (2016) Effects of perioperative lapatinib and trastuzumab, alone and in combination, in early HER2+ breast cancer − the UK EPHOS-B trial (CRUK/08/002) European Journal of Cancer;57:S1-S8. Table - Relapse-free survival by treatment and by peri-operative responseN randomisedNRFS event5-year RFS95%CILog-rank p-valueRandomised treatmentTrastuzumab (P1)577 (12.3%)88%76-94%T vs L p=0.75Lapatinib (P1)515 (9.8%)90%77-96%L vs C p=0.41Control (P1)221 (4.6%)95%92-99%Trastuzumab (P2)327 (21.9%)87%69-95%T vs T+L p=0.048Combination (P2)665 (7.6%)92%83-97%T+L vs C p=0.64Control (P2)293 (10.3%)90%71-97%%Ki67 change:>50% decrease722 (2.8%)99%90-100%0.002>10% decrease7717 (22.1%)80%69-88%20%502 (4%)96%85-99Surgery TILS (only RCB2/3)20%653 (4.6%)95%86-98Change in TILS (only RCB2/3)No significant increase15221 (13.8%)88%81-920.16Increase >20%352 (5.7%)94%79-99 Citation Format: Nigel Bundred, Nuria Porta, Adrian Murray Brunt, Angela Cramer, Andrew Hanby, Abeer Shaaban, Emad Rakha, Anne Armstrong, Ramsey Cutress, David Dodwell, Marie Emson, Abigail Evans, Sue Hartup, Kieran Horgan, Stuart McIntosh, Jay Naik, Samkaran Narayanan, Jane Oii, Anthony Skene, David Cameron, Judith Bliss. Combined peri-operative lapatinib and trastuzumab in early HER2-positive breast cancer - Long term results of the randomized UK EPHOS-B trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-08.

Cancer services were seriously disrupted during the COVID-19 pandemic. Using publicly available data for England, we show that breast cancer diagnoses decreased substantially in the first year of the pandemic, but have recovered to at least pre-pandemic levels. Long term follow-up is needed to assess the impact on outcomes.

The role of locoregional treatment (LRT) in the setting of metastatic breast cancer (MBC) is widely debated due to conflicting results on the impact on outcomes. This review provides a brief overview and evaluation of current evidence. The majority of retrospective studies suggest LRT provides some survival benefit, but it is not known exactly which subgroup of patients would benefit the most. The significant concerns about inherent biases associated with these studies make interpretation of results challenging. Recent data from prospective clinical trials are conflicting and suggest that adding LRT to treatment regimens makes no difference to health-related quality of life. Based on the limited high-quality evidence, there is uncertainty that LRT improves outcomes in patients with MBC, and it should not become standard clinical practice. Further prospective research focused on whether subsets of patients benefit from LRT is required.

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.

Background Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy. Methods This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage. Results The study recruited 3416 women (median age 77 (range 69–102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains. Conclusion Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects.

Background Studies reporting lower rates of surgery for older women with early invasive breast cancer have focused on women with oestrogen receptor (ER)-positive tumours. This study examined the factors that influence receipt of breast surgery in older women with ER-positive and ER-negative early invasive breast cancer . Methods Women aged 50 years or above with unilateral stage 1–3A early invasive breast cancer diagnosed in 2014–2017 were identified from linked English and Welsh cancer registration and routine hospital data sets. Logistic regression analysis was used to evaluate the influence of tumour and patient factors on receipt of surgery. Results Among 83 188 women, 86.8 per cent had ER-positive and 13.2 per cent had ER-negative early invasive breast cancer. These proportions were unaffected by age at diagnosis. Compared with women with ER-negative breast cancer, a higher proportion of women with ER-positive breast cancer presented with low risk tumour characteristics: G1 (20.0 versus 1.5 per cent), T1 (60.8 versus 44.2 per cent) and N0 (73.9 versus 68.8 per cent). The proportions of women with any recorded co-morbidity (13.7 versus 14.3 per cent) or degree of frailty (25 versus 25.8 per cent) were similar among women with ER-positive and ER-negative disease respectively. In women with ER-positive early invasive breast cancer aged 70–74, 75–79 and 80 years or above, the rate of no surgery was 5.6, 11.0 and 41.9 per cent respectively. Among women with ER-negative early invasive breast cancer, the corresponding rates were 3.8, 3.7 and 12.3 per cent. The relatively lower rate of surgery for ER-positive breast cancer persisted in women with good fitness. Conclusion The reasons for the observer differences should be further explored to ensure consistency in treatment decisions.

Background: In the UK there is variation in the treatment of older women with breast cancer, with up to\ud 40% receiving primary endocrine therapy (PET), which is associated with inferior survival. Case mix and\ud patient choice may explain some variation in practice but clinician preference may also be important.\ud Methods: A multicentre prospective cohort study of women aged >70 with operable breast cancer. Patient characteristics (health status, age, tumour characteristics, treatment allocation and decision-making\ud preference) were analysed to identify whether treatment variation persisted following case-mix\ud adjustment. Expected case-mix adjusted surgery rates were derived by logistic regression using the\ud variables age, co-morbidity, tumour stage and grade. Concordance between patients’ preferred and\ud actual decision-making style was assessed and associations between age, treatment and decision-making\ud style calculated.\ud Results: Women (median age 77, range 70e102) were recruited from 56 UK breast units between 2013\ud and 2018. Of 2854/3369 eligible women with oestrogen receptor positive breast cancer, 2354 were\ud treated with surgery and 500 with PET. Unadjusted surgery rates varied between hospitals, with 23/56\ud units falling outside the 95% confidence intervals on funnel plots. Adjusting for case mix reduced, but did\ud not eliminate, this variation between hospitals (10/56 units had practice outside the 95% confidence\ud intervals). Patients treated with PET had more patient-centred decisions compared to surgical patients\ud (42.2% vs 28.4%, p < 0.001).\ud Conclusions: This study demonstrates variation in treatment selection thresholds for older women with\ud breast cancer. Health stratified guidelines on thresholds for PET would help reduce variation, although\ud patient preference should still be respected.

Introduction Older patients with early breast cancer (EBC) derive modest survival benefit from chemotherapy but have increased toxicity risk. Data on the impact of chemotherapy for EBC on quality of life in older patients are limited, but this is a key determinant of treatment acceptance. We aimed to investigate its effect on quality of life in older patients enrolled in the Bridging the Age Gap study. Materials and methods A prospective, multicentre, observational study of EBC patients ≥70 years old was conducted in 2013–2018 at 56 UK hospitals. Demographics, patient, tumour characteristics, treatments and adverse events were recorded. Quality of life was assessed using the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaires (EORTC-QLQ) C30, BR23 and ELD 15 plus the Euroqol-5D (eq-5d) over 24 months and analysed at each time point using baseline adjusted linear regression analysis and propensity score-matching. Results Three thousand and four hundred sixteen patients were enrolled in the study; 1520 patients undergoing surgery and who had high-risk EBC were included in this analysis. 376/1520 (24.7%) received chemotherapy. At 6 months, chemotherapy had a significant negative impact in several EORTC-QLQ-C30 domains, including global health score, physical, role, social functioning, cognition, fatigue, nausea/vomiting, dyspnoea, appetite loss, diarrhoea and constipation. Similar trends were documented on other scales (EORTC-QLQ-BR23, EORTC-QLQ-ELD15 and EQ-5D-5L). Its impact was no longer significant at 18–24 months in unmatched and matched cohorts. Conclusions The negative impact of chemotherapy on quality-of-life is clinically and statistically significant at 6 months but resolves by 18 months, which is crucial to inform decision-making for older patients contemplating chemotherapy. Trial registration number ISRCTN 46099296., Highlights • This is a multicentre, cohort study of 3416 women (aged >70 years) with breast cancer. • In older women with high-risk, early breast cancer, chemotherapy reduces quality of life. • The relevant affected domains include cognition, fatigue, physical, role and social functioning. • Chemotherapy QoL impacts are transient and largely resolve completely by 18–24 months.

AIMS: Adjuvant radiotherapy is recommended for most patients with early breast cancer (EBC) receiving breast-conserving surgery and those at moderate/high risk of recurrence treated by mastectomy. During the first wave of COVID-19 in England and Wales, there was rapid dissemination of randomised controlled trial-based evidence showing non-inferiority for five-fraction ultra-hypofractionated radiotherapy (HFRT) regimens compared with standard moderate-HFRT, with guidance recommending the use of five-fraction HFRT for eligible patients. We evaluated the uptake of this recommendation in clinical practice as part of the National Audit of Breast Cancer in Older Patients (NABCOP). MATERIALS AND METHODS: Women aged ≥50 years who underwent surgery for EBC from January 2019 to July 2020 were identified from the Rapid Cancer Registration Dataset for England and from Wales Cancer Network data. Radiotherapy details were from linked national Radiotherapy Datasets. Multivariate mixed-effects logistic regression models were used to assess characteristics influential in the use of ultra-HFRT. RESULTS: Among 35 561 women having surgery for EBC, 71% received postoperative radiotherapy. Receipt of 26 Gy in five fractions (26Gy5F) increased from

Introduction\ud \ud Evidence based guidelines for the optimal management of breast cancer locoregional recurrence (LRR) are limited, with potential for variation in clinical practice. This national practice questionnaire (NPQ) was designed to establish the current practice of UK breast multidisciplinary teams (MDTs) regarding LRR management.\ud \ud \ud \ud Methods\ud \ud UK breast units were invited to take part in the MARECA study MDT NPQ. Scenario-based questions were used to elicit preference in pre-operative staging investigations, surgical management, and adjuvant therapy.\ud \ud \ud \ud Results\ud \ud 822 MDT members across 42 breast units (out of 144; 29%) participated in the NPQ (February–August 2021). Most units (95%) routinely performed staging CT scan, but bone scan was selectively performed (31%).\ud \ud \ud \ud For patients previously treated with breast conserving surgery (BCS) and radiotherapy, few units (7%) always/usually offered repeat BCS. However, in the absence of radiotherapy, most units (90%) always/usually offered repeat BCS. For patients presenting with isolated local recurrence following previous BCS and SLNB (sentinel lymph node biopsy), most units (95%) advocated repeat SLNB. Where SLNs could not be identified, 86% proceeded to a four-node axillary sampling procedure.\ud \ud \ud \ud For ER positive, HER2 negative, node negative local recurrence, 10% of units always/usually offered chemotherapy. For ER positive, HER2 negative, node positive local recurrence, this recommendation increased to 64%. For triple negative breast cancer local recurrence, 90% of units always/usually offered chemotherapy.\ud \ud \ud \ud Conclusion\ud \ud This survey has highlighted where consistencies and variations exist in the multidisciplinary management of breast cancer LRR. However, further research is required to determine how these management patterns influence patient outcomes, which will further refine optimal treatment pathways.

Introduction: Approximately 55,000 women in the United Kingdom are diagnosed with new breast cancer annually. Since emerging in December 2019, SARS-CoV-2 (coronavirus disease 2019, COVID-19) has become a global pandemic, affecting healthcare delivery worldwide. In response to the pandemic, multiple guidelines were issued to assist with rationalising breast cancer care. The primary aim of the B-MaP-C study is to audit and describe breast cancer management of patients newly diagnosed with breast cancer during the COVID-19 pandemic against pre-COVID-19 management practice in the UK. The implications of changes to management will be determined and the impact of a COVID-19 diagnosis on the patient's breast cancer management will be determined. Methods and analysis: This is a multi-centre collaborative audit of consecutive breast cancer patients undergoing treatment decisions during the acute and recovery phases of the COVID-19 pandemic. All patients with newly diagnosed primary breast cancer, whose treatment was decided in a multidisciplinary meeting from the 16th March 2020, are eligible for inclusion. Ethics and dissemination: As this is an audit ethical approval is not required. Each participating centre is required to register the study locally and obtain local governance approvals prior to commencement of data collection. Local audit data will be available to individual participating units for governance purposes. The results of the data analysis will be submitted for publication, as well as disseminated via the ABS newsletter and a webinar. All data will be presented at national and international conferences, circumstances permitting. Registration details: Each participating centre received local governance audit registration.

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 (Ki67 2wk). 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 Ki67 2wk (p2wk. 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. Funding: Cancer Research UK (CRUK/07/015).

INTRODUCTION: Conformity with treatment guidelines should benefit patients. Studies have reported variation in adherence to breast cancer (BC) guidelines, particularly among older women. This study investigated (i) whether adherence to treatment guideline recommendations for women with non-metastatic BC improves overall survival (OS), (ii) whether that relationship varies by age. METHODOLOGY: MEDLINE and EMBASE were systematically searched for studies on guideline adherence and OS in women with non-metastatic BC, published after January 2000, which examined recommendations on breast surgery, chemotherapy, radiotherapy or endocrine therapy. Study results were summarised using narrative synthesis. RESULTS: Sixteen studies met the inclusion criteria. The recommendations for each treatment covered were similar, but studies differed in their definitions of adherence. 5-year OS rates among patients having compliant treatment ranged from 91.3% to 93.2%, while rates among patients having non-compliant treatment ranged from 75.9% to 83.4%. Six studies reported an adjusted hazard ratio (aHR) for non-compliant treatment compared with compliant treatment; all concluded OS was worse among patients whose overall treatment was non-compliant (aHR range: 1.52 [1.30-1.82] to 2.57 [1.96-3.37]), but adjustment for potential confounders was limited. Worse adherence among older women was reported in 12/16 studies, but they did not provide consistent evidence on whether OS was associated with treatment adherence and age. CONCLUSIONS: Individual studies reported that better adherence to guidelines improved OS among women with non-metastatic BC, but the evidence base has weaknesses including inconsistent definitions of adherence. More precise and consistent research designs, including the evaluation of barriers to adherence across the spectrum of healthcare practice, are required to fully understand guideline compliance, as well as the relationship between compliance and OS following a BC diagnosis.

Breast cancer is the commonest cancer to affect women in developed countries and is increasing in frequency in the Western world. Approximately 50,000 women and 400 men are diagnosed with breast cancer in the United Kingdom each year. Eighty per cent of these individuals will survive for at least 5 years after diagnosis. In 2012, 11,762 women died of breast cancer in the United Kingdom. Age-standardized rates of new invasive breast cancer diagnosis have increased from 75 to 126 per 100,000 population in the United Kingdom between 1977 and 2010.

Background\ud \ud Radiotherapy reduces in-breast recurrence risk in early breast cancer (EBC) in older women. This benefit may be small and should be balanced against treatment effect and holistic patient assessment. This study described treatment patterns according to fitness and impact on health-related quality-of-life (HRQoL).\ud \ud \ud \ud Methods\ud \ud A multicentre, observational study of EBC patients aged ≥ 70 years, undergoing breast-conserving surgery (BCS) or mastectomy, was undertaken. Associations between radiotherapy use, surgery, clinico-pathological parameters, fitness based on geriatric parameters and treatment centre were determined. HRQoL was measured using the European Organisation for the Research and Treatment of Cancer (EORTC) questionnaires.\ud \ud \ud \ud Results\ud \ud In 2013–2018 2811 women in 56 UK study centres underwent surgery with a median follow-up of 52 months. On multivariable analysis, age and tumour risk predicted radiotherapy use. Among healthier patients (based on geriatric assessments) with high-risk tumours, 534/613 (87.1%) having BCS and 185/341 (54.2%) having mastectomy received radiotherapy. In less fit individuals with low-risk tumours undergoing BCS, 149/207 (72.0%) received radiotherapy. Radiotherapy effects on HRQoL domains, including breast symptoms and fatigue were seen, resolving by 18 months.\ud \ud \ud \ud Conclusion\ud \ud Radiotherapy use in EBC patients ≥ 70 years is affected by age and recurrence risk, whereas geriatric parameters have limited impact regardless of type of surgery. There was geographical variation in treatment, with some fit older women with high-risk tumours not receiving radiotherapy, and some older, low-risk, EBC patients receiving radiotherapy after BCS despite evidence of limited benefit. The impact on HRQoL is transient.

Highlights • Prescribing was as expected from clinical practice. • 90% received ET prescriptions during the second year after diagnosis. • Prescribing dropped more than five years after diagnosis. • The majority of younger women (under 55) received tamoxifen. • The majority of older women (55+) received AIs., Introduction National cancer registration data were linked to the Primary Care Prescription Database (PCPD) in England. The level of endocrine therapy (ET) prescribed in women after a diagnosis of breast cancer was studied. Materials and methods Cancer registrations for women diagnosed with breast cancer during 1995–2015, who survived to 31st March 2015, were linked to ET prescriptions issued during April–July 2015. Results Among 369 277 survivors of breast cancer diagnosed during 1995–2015, 37% were prescribed ET during April–July 2015. Among women whose breast cancer diagnosis was after 31st July 2010, 81% of those recorded with oestrogen receptor positive (ER+ve) disease were prescribed ET compared with only 6% of those with ER-ve disease. Younger women usually received tamoxifen and older women usually received aromatase inhibitors. Discussion The pattern of ET use observed in these data corresponds to that expected. This provides confidence in the potential of the PCPD for epidemiological research.

Introduction: There is evidence of variation in the patterns of treatment of older women with breast cancer (BC). As women age, there are less similarities in terms of their functional ability, physiology and social wellbeing. This multifaceted relationship between disease and ageing makes the interpretation of age-related differences in BC management and outcomes at a population level complex. Measuring frailty is as an emerging concept and offers a way to standardise how characteristics of ageing are used in BC. Objective: We compared the primary treatment patterns of women aged ≥70yrs compared to those aged 50–69yrs, with early invasive BC (EIBC; stage 1-3A); using a novel measure of frailty in addition to commonly used patient fitness measures. Methods: Women aged ≥50yrs, diagnosed with unilateral EIBC in England and Wales between 01/01/2014 and 31/12/2016; were identified by linkage of several national datasets. Patient fitness was measured by the reported WHO performance status (WHO PS), a calculated Charlson comorbidity score (CCS) and a developed frailty measure based on the electronic Frailty Index (eFI). Multilevel logistic regression was used to account for clustering in the data. Results: Among 126,111 women aged ≥50yrs with BC, 88,028 had EIBC: 88% in women aged 50-69yrs and 75% in women aged ≥70yrs. Table 1 describes the proportion of women who received surgery by age and measures of fitness. Overall, older women were less likely to undergo primary surgery, regardless of fitness. For each measure of fitness, fewer women in both age groups underwent surgery as their levels of fitness decreased; the magnitude of this change was greater for women aged ≥70yrs. Older women were also less likely to receive BCS for tumours Receipt of surgery in women aged ≥50years with EIBC according to CCS, eFi and WHO PS status, by age at diagnosisMeasure of fitness50-69 years70+years No. of patients% having surgeryNo. of patients% having surgeryNumber of women5481796%2343687%Charlson comorbidity score04861697%2343687%1345495%439067%1+106389%309645%Unknown168462%228914%eFIFit5250697%570789%Mild frailty56489%236947%Moderate to severe frailty6362%66921%Unknown168462%228914%WHO performance status01507397%570788%1137293%226474%219885%91146%3-411652%79517%Unknown3805896%2353476% The association between independent factors of ageing and fitness, and 'no surgery' remained after accounting for case-mix differences and clustering within geographical region. Compared to women aged 50–69yrs, there was strong regional variation in the adjusted rate of surgical treatment for EIBC in women aged ≥70yrs. Discussion: Older women are less likely to undergo surgery for EIBC. Even a minor decrease in fitness levels significantly impacts the likelihood of receiving surgery in women ≥70yrs; such a pattern is not observed in women aged 50–69yrs. Long-term follow up of these women will enable further understanding of the implications of this variability in practice on outcomes. We also acknowledge poor data completion for the WHO PS, and propose that eFI is suitable replacement measure of fitness in older patients with BC. Citation Format: Jauhari Y, Gannon M, Medina J, Horgan K, Dodwell D, Cromwell D. The influence of patient fitness on the likelihood of receiving primary surgery in older women with breast cancer: A population based cohort study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-16.

Background: Capivasertib (AZD5363), an AKT1,2,3 inhibitor, significantly improved progression-free and overall survival when added to paclitaxel in triple negative breast cancer (BC) patients (Schmid et al. ASCO 2018). We have previously reported in STAKT, robust target inhibition at 480mg BD versus placebo, including significant decreases in the primary biomarkers (PBs) - Ki67, pPRAS40 & pGSK3β - in primary BCs (Robertson et al. SABCS 2017). We now report the dose- and exposure-response relationship of capivasertib and the correlation between primary and secondary (pAKT, pS6, nuclear FOXO3a) tumor biomarkers. Design: STAKT was a two-stage, double blind, randomized, placebo controlled 'window-of-opportunity' trial in newly diagnosed ER+ BC patients. Stage 1 assessed capivasertib at a dose of 480mg BD p.o. versus placebo. Stage 2 assessed capivasertib at two lower doses 360mg and 240mg BD. Tumor biopsies were taken prior to 1st dose and after 4.5 days of dosing. Evaluable patients (who required pre-defined minimum baseline PD values for PBs) included placebo (n=11), capivasertib at 480mg (n=17), 360mg (n=5) and 240mg (n=6). Blood samples for pharmacokinetic (PK) studies were scheduled at pre-dose; 2, 4, optional 6 & 8 hrs post first dose on Day 1; ˜2-4 h post last dose on Day 5 (before biopsy). The % change from baseline for PBs were evaluated against the following exposure variables (placebo=0): i) Dose, ii) Observed Cmax Day 1 (˜2h post-dose), iii) Observed plasma concentration on Day 5, iv) Model-predicted plasma concentration Day 5 at time of biopsy, and v) Model-predicted AUC on Day 5. Spearman correlation coefficient measured the strength and direction of association between biomarkers. Results: · Significant mean reductions in % change from baseline were observed for the PBs pGSK3β (-39%; p · Dose-response relationships for individual % change from baseline could be described by an Emax model for all PBs. Overall, the correlation to PK exposure (observed or predicted) was similar to the correlation to dose. · Correlation coefficient analyses between biomarkers at capivasertib 480mg BD identified- i) Positive correlations for pGSK3β with Ki67 (ρ = 0.52, p-value < 0.05) & with pS6 (ρ = 0.54, p-value Conclusions · Capivasertib caused dose- and concentration- dependent effects on biomarkers after only 4.5 days. · Significant changes in the PBs were demonstrated at 480 mg BD. Biomarker changes was observed at 360mg and 240mg BD, but statistical analysis was limited by the small sample size at lower doses. · Correlation between a number of tumor biomarkers (relative changes) were identified for capivasertib 480mg BD. Citation Format: Gee J, Coleman RE, Cheung KL, Evans A, Holcombe C, Skene A, Rea D, Ahmed S, Jahan A, Horgan K, Rauchhaus P, Littleford R, Finlay P, Cheung A, Cullberg M, de Bruin E, Foxley A, Koulai L, Pass M, Schiavon G, Rugman P, Deb R, Robertson JFR. Dose- and exposure-response relationship and biomarker correlation analysis in breast tumors from patients treated with capivasertib, an AKT inhibitor, in the STAKT randomized, placebo controlled pre-surgical study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-12-01.

Background Surgery and chemotherapy use were studied among older women with early stage triple negative breast cancer (TNBC) in a population-based cohort. Methods Women aged ≥50 years with unilateral early (stage 1-3a) TNBC diagnosed in 2014–2017 were identified from English cancer registration data. Information on surgery and chemotherapy was from linked Hospital Episode Statistics and Systemic Anti-Cancer Therapy datasets, respectively. Logistic regression was used to investigate the influences of patient age, comorbidity and frailty on uptake of surgery and chemotherapy. Results There were 7094 women with early stage TNBC. Overall rate of surgery was 94%, which only decreased among women aged ≥85 years (74%) and among the most frail. Among the 6681 women receiving surgery, 16% had neoadjuvant and 42% had adjuvant chemotherapy; the use of both decreased with age. More comorbidities and greater frailty were associated with lower rates of chemotherapy. There were differences in the uptake of chemotherapy across geographical regions and in the neoadjuvant and adjuvant chemotherapy regimens between age groups. Conclusion Majority of older women with early TNBC had surgery, although some physically fit older women did not. Chemotherapy use varied by age and fitness.

We report three cases where the connector/sleeve, which helps fix the flexible catheter section to a port injection chamber, was inadvertently left in scar tissue during port removal. Concerned patients presented months later with a palpable subcutaneous nodule, near the port site. The nodules were variably imaged with plain X-rays, mammography or ultrasound with the diagnosis correctly made by a surgeon familiar with devices. Two connectors were removed, and one was left in place following discussions with the patient. Prevention, recognition and management of this problem are discussed.

Background Age-related breast cancer treatment variance is widespread with many older women having primary endocrine therapy (PET), which may contribute to inferior survival and local control. This propensity-matched study determined if a subgroup of older women may safely be offered PET. Methods Multicentre, prospective, UK, observational cohort study with propensity-matched analysis to determine optimal allocation of surgery plus ET (S+ET) or PET in women aged ≥70 with breast cancer. Data on fitness, frailty, cancer stage, grade, biotype, treatment and quality of life were collected. Propensity-matching (based on age, health status and cancer stage) adjusted for allocation bias when comparing S+ET with PET. Findings A total of 3416 women (median age 77, range 69–102) were recruited from 56 breast units—2854 (88%) had ER+ breast cancer: 2354 had S+ET and 500 PET. Median follow-up was 52 months. Patients treated with PET were older and frailer than patients treated with S+ET. Unmatched overall survival was inferior in the PET group (hazard ratio, (HR) 0.27, 95% confidence interval (CI) 0.23–0.33, P 90 years or >85 with comorbidities or frailty) individualised decision making regarding PET versus S+ET may be appropriate and safe to offer. The Age Gap online decision tool may support this decision-making process (https://agegap.shef.ac.uk/). Trial registration number ISRCTN: 46099296., Highlights • Propensity matched study of women >70 with breast cancer comparing surgery or PET • Unmatched analysis found surgery improves overall & disease-specific survival. • Matched analysis (stage, age, health, frailty) found similar disease-specific survival • Surgery led to adverse events in 19% & negative impacts on QoL and physical function • Less fit women >85 may be offered PET to reduce morbidity, without survival detriment

Background: \ud Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses.\ud \ud Methods: \ud POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0–1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing.\ud \ud Findings: \ud Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1–74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75–1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9–92·0) for patients in the POAI group and 90·4% (88·7–91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low–low) was 4·3% (95% CI 2·9–6·3), 8·4% (6·8–10·5) with high Ki67B and low Ki672W (high–low) and 21·5% (17·1–27·0) with high Ki67B and Ki672W (high–high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low–low group was 10·1% (95% CI 3·2–31·3), 7·7% (3·4–17·5) in the high–low group, and 15·7% (10·1–24·4) in the high–high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [

BACKGROUND: Surgery to the primary tumour in women with metastatic breast cancer (MBC) has traditionally been reserved for palliative purposes, and European guidelines suggest it should be performed on an individualised basis1. A lack of consensus on the effectiveness of a procedure can lead to treatment variation in clinical practice. We examined what proportion of women with MBC aged 50+yrs received surgery to the primary tumour, and explored what patient and clinical characteristics influence receipt of surgery, as part of the National Audit of Breast Cancer in Older Patients (NABCOP). METHODS: Details of the NABCOP are available at www.nabcop.org.uk. Data on women aged 50+yrs newly diagnosed with MBC at diagnosis between January 2014 and December 2018 in England and Wales were obtained from national cancer registry datasets linked to routine hospital episodes. Receipt of surgery up to 3 years from diagnosis was examined using Kaplan Meier estimates, both nationally and between Cancer Alliances. The relationship between patient/tumour factors and time to surgery was analysed using log rank tests and a flexible parametric regression model (FPM). RESULTS: Between 2014 and 2018, 7316 women aged 50+yrs with MBC at diagnosis were identified. Overall, 18.7% women had surgery to the primary tumour within 1 year from diagnosis. Having surgery at 1 year was more common among younger women (50–59 yrs vs 80+yrs: 29.8% vs 8.6%, adjusted HR 1.79), those with T1/T2 tumours (T1/T2 vs T3/T4: 33.1% vs 20.8%, adjusted HR 1.72), and positive nodal stage (N0 vs N+: 19.3% vs 29.1%, adjusted HR 1.54). Rates of surgery within 1 year from diagnosis reduced over time, from 23.7% in 2014 to 15.7% in 2018, but to a greater degree among women aged 50–69 yrs (34.8% in 2014 to 21.1% in 2018) compared with women aged 70+yrs: 15.6% to 11.5%. Overall rates of surgery varied from 11.6% to 32.2% between the 20 Cancer Alliance/regions across England and Wales. CONCLUSIONS: Almost 20% of women aged 50+yrs with MBC at diagnosis received breast surgery within 1 year from diagnosis, but this varied between regions in England and Wales, and the use of surgery has decreased in recent years. Research is required to understand why treatment variation exists as well as to generate better evidence on the value of surgery in patients with MBC.

Introduction The COVID-19 pandemic caused widespread changes in delivery of breast cancer care, aiming to protect vulnerable patients whilst minimising compromise to oncological outcomes. This multicentre observational study aimed to establish early surgical outcomes from breast cancer surgery performed during the peak of the COVID-19 pandemic. Materials and methods Data were collected on consecutive patients that underwent breast surgery in four units between 16 March and 24 April 2020. Outcome data at 30 days post-operation were collected, including documented COVID-19 cases in patients and reported cases in healthcare workers directly involved in their care. Recommended modifications to practice to reduce COVID-19 transmission risk, both to patients and healthcare workers in each centre, are described. Results A total of 202 patients underwent surgery in four hospitals delivering breast services in the West Yorkshire region over the six-week period at the peak of the pandemic. The age ranged from 28 to 91 years (median 57, interquartile range, 48-65) with 22% having co-morbidities linked to COVID-19, e.g. diabetes or respiratory disease. No patients presented post-operatively with COVID-19 symptoms and at 30 days there had not been any identified COVID-19 cases. There were no unexpected critical care admissions or deaths. One healthcare worker involved in the delivery of breast surgery was diagnosed with COVID-19 during this time and made an uneventful recovery. Conclusion Breast cancer surgery, in selected groups and with meticulous adherence to measures designed to reduce COVID-19 transmission, does not appear to be associated with elevated risk to patients or healthcare workers.

Delays in cancer diagnosis and treatment due to the COVID-19 pandemic is a widespread source of concern, but the scale of the challenge for different tumour sites is not known. Routinely collected NHS England Cancer Waiting Time data were analysed to compare activity for breast cancer in the first 6 months of 2020 compared to the same time period in 2019. The number of referrals for suspected breast cancer was 28% lower (N = 231,765 versus N = 322,994), and the number of patients who received their first treatment for a breast cancer diagnosis was 16% lower (N = 19,965 versus N = 23,881). These data suggest that the number of breast cancers diagnosed during the first half of 2020 is not as low as initially feared, and a substantial proportion of the shortfall can be explained by the suspension of routine screening in March 2020. Further work is needed to examine in detail the impact of measures to manage the COVID-19 pandemic on breast cancer outcomes.

Background Breast angiosarcomas are rare tumours of vascular origin. Secondary angiosarcoma occurs following radiotherapy for breast cancer. Angiosarcomas have high recurrence and poor survival rates. This is concerning owing to the increasing use of adjuvant radiotherapy for the treatment of invasive breast cancer and ductal cancer in situ (DCIS), which could explain the rising incidence of angiosarcoma. Outcome data are limited and provide a poor evidence base for treatment. This paper presents a national, trainee-led, retrospective, multicentre study of a large angiosarcoma cohort. Methods Data for patients with a diagnosis of breast/chest wall angiosarcoma between 2000 and 2015 were collected retrospectively from 15 centres. Results The cohort included 183 patients with 34 primary and 149 secondary angiosarcomas. Median latency from breast cancer to secondary angiosarcoma was 6 years. Only 78.9 per cent of patients were discussed at a sarcoma multidisciplinary team meeting. Rates of recurrence were high with 14 of 28 (50 per cent ) recurrences in patients with primary and 80 of 124 (64.5 per cent ) in those with secondary angiosarcoma at 5 years. Many patients had multiple recurrences: total of 94 recurrences in 162 patients (58.0 per cent). Median survival was 5 (range 0–16) years for patients with primary and 5 (0–15) years for those with secondary angiosarcoma. Development of secondary angiosarcoma had a negative impact on predicted breast cancer survival, with a median 10-year PREDICT prognostic rate of 69.6 per cent, compared with 54.0 per cent in the observed cohort. Conclusion A detrimental impact of secondary angiosarcoma on breast cancer survival has been demonstrated. Although not statistically significant, almost all excess deaths were attributable to angiosarcoma. The increased use of adjuvant radiotherapy to treat low-risk breast cancer and DCIS is a cause for concern and warrants further study.

Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. Patients and Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, “window-of-opportunity” study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring. Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. (n = 17) produced significant decreases from baseline versus placebo (n = 11) in pGSK3β (H-score absolute change: −55.3, P = 0.006) and pPRAS40 (−83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: −9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (−42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. (n = 5) and 240 mg b.i.d. (n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident. Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.

Background Clinical guidance on recommended treatment for older patients with breast cancer is often ambiguous, particularly in the context of comorbidities and poor functional status. Older patients, aged 70 years and over, account for a substantial proportion of women with breast cancer yet are underrepresented in randomized controlled trials. This paper investigates the initiation of adjuvant chemotherapy and trastuzumab in older patients in routine care. Materials and methods Women, aged 50 years and over, newly diagnosed with human epidermal growth receptor 2 (HER2)-positive early invasive breast cancer from January 2014 to December 2017 were identified from the England Cancer Registry. Chemotherapy and trastuzumab use was obtained from the Systemic Anti-Cancer Therapy (SACT) dataset. Patient and tumor characteristics influential in treatment decision-making were included in multilevel mixed-effects logistic regression models. Results 10% of women had HER2-positive tumors. Initiation of adjuvant chemotherapy and trastuzumab decreased with age from ≥70% among women aged 50–64 years to Conclusions In women with operable HER2-positive early invasive breast cancer, adjuvant chemotherapy plus trastuzumab was started less frequently as age increased, regardless of tumor characteristics or comorbidity burden. There was substantial variation in the proportion of women who started these treatments across the country.