The impact of the SARS-COV-2 pandemic on the quality of breast cancer care in EUSOMA-certified breast centres.

AIMS: We analysed the impact of the SARS-CoV-2 pandemic (COVID-19) on the quality of breast cancer care in certified EUSOMA (European Society of Breast Cancer Specialists) breast centres. MATERIALS AND METHODS: The results of the EUSOMA quality indicators were compared, based on pseudonymised individual records, for the periods 1 March 2020 till 30 June 2020 (first COVID-19 peak in most countries in Europe) and 1 March 2019 till 30 June 2019. In addition, a questionnaire was sent to the participating Centres for investigating the impact of the COVID-19 pandemic on the organisation and the quality of breast cancer care. RESULTS: Forty-five centres provided data and 31 (67%) responded to the questionnaire. The total number of new cases dropped by 19% and there was a small significant higher tumour (p = 0.003) and lymph node (p = 0.011) stage at presentation. Comparing quality indicators (12,736 patients) by multivariable analysis showed mostly non-significant differences. Surgery could be performed in a COVID-free zone in 94% of the centres, COVID testing was performed before surgery in 96% of the centres, and surgical case load was reduced in 55% of the centres. Modifications of the indications for neoadjuvant endocrine therapy, chemotherapy, and targeted therapy were necessary in 23%, 23%, and 10% of the centres; changes in indications for adjuvant endocrine, chemo-, targeted, immune, and radiotherapy in 3%, 19%, 3%, 6%, and 10%, respectively. CONCLUSION: Quality of breast cancer care was well maintained in EUSOMA breast centres during the first wave of the COVID-19 pandemic. A small but significantly higher tumour and lymph node stage at presentation was observed.

Bridging the Age Gap in breast cancer: Impact of chemotherapy on quality of life in older women with early breast cancer.

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.

Bridging the age gap in breast cancer. Impacts of omission of breast cancer surgery in older women with oestrogen receptor positive early breast cancer. A risk stratified analysis of survival outcomes and quality of life.

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 < 0.001). Unmatched breast cancer-specific survival (BCSS) was also inferior in patients treated with PET (HR: 0.41, CI: 0.29-0.58, P < 0.001 for BCSS). In the matched analysis, PET was still associated with an inferior overall survival (HR = 0.72, 95% CI: 0.53-0.98, P = 0.04) but not BCSS (HR = 0.74, 95% CI: 0.40-1.37, P = 0.34) although at 4-5 years subtle divergence of the curves commenced in favor of surgery. Global health status diverged at certain time points between groups but over 24 months was similar when adjusted for baseline variance. INTERPRETATION: For the majority of older women with early ER+ breast cancer, surgery is oncologically superior to PET. In less fit, older women, with characteristics similar to the matched cohort of this study (median age 81 with higher comorbidity and functional impairment burdens, the BCSS survival differential disappears at least out to 4-5 year follow-up, suggesting that for those with less than 5-year predicted life-expectancy (>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.

Biological effects of fulvestrant on estrogen receptor positive human breast cancer: short, medium and long-term effects based on sequential biopsies.

We report the first study of the biological effect of fulvestrant on ER positive clinical breast cancer using sequential biopsies through to progression. Thirty-two locally/systemically advanced breast cancers treated with first-line fulvestrant (250 mg/month) were biopsied at therapy initiation, 6 weeks, 6 months and progression and immunohistochemically-analyzed for Ki67, ER, EGFR and HER2 expression/signaling activity. This series showed good fulvestrant responses (duration of response [DoR] = 25.8 months; clinical benefit = 81%). Ki67 fell (p < 0.001) in 79% of tumours by 6 months and lower Ki67 at all preprogression time-points predicted for longer DoR. ER and PR significantly decreased in all tumours by 6 months (p < 0.001), with some declines in ER (serine 118) phosphorylation and Bcl-2 (p = 0.007). There were modest HER2 increases (p = 0.034, 29% tumours) and loss of any detectable EGFR phosphorylation (p = 0.024, 50% tumours) and MAP kinase (ERK1/2) phosphorylation (p = 0.019, 65% tumours) by 6 months. While ER remained low, there was some recovery of Ki67, Bcl-2 and (weakly) EGFR/MAPK activity in 45-67% patients at progression. Fulvestrant's anti-proliferative impact is related to DoR, but while commonly downregulating ER and indicators of its signaling and depleting EGFR/MAPK signaling in some patients, additional elements must determine response duration. Residual ER at fulvestrant relapse explains reported sensitivity to further endocrine therapies. Occasional modest treatment-induced HER2 and weakly detectable EGFR/HER2/MAPK signaling at relapse suggests targeting of such activity might have value alongside fulvestrant in some patients. However, unknown pathways must drive relapse in most. Ki67 has biomarker potential to predict fulvestrant outcome and as a quantitative measure of response.

The use of fulvestrant, a parenteral endocrine agent, in intestinal obstruction due to metastatic lobular breast carcinoma.

BACKGROUND: The role of fulvestrant in the management of intestinal obstruction associated with lobular carcinoma has not been specifically described. CASE PRESENTATION: Herein we present two cases where fulvestrant, as the only available parenteral endocrine agent for postmenopausal advanced breast cancer has the opportunity to provide a means to initiate treatment in those patients who present with varying degrees of intestinal obstruction. CONCLUSION: Fulvestrant may obviate the use of chemotherapy while achieving sustained clinical benefit with less toxicity, in appropriately selected patients.

Arzoxifene: the evidence for its development in the management of breast cancer.

INTRODUCTION: Endocrine therapy is an important and integral part of breast cancer management. Selective estrogen receptor modulators (SERMs), such as tamoxifen, remain a vital component in the endocrine therapy armamentarium. However the "ideal SERM", which has antagonist effects on the breast and endometrium but beneficial agonistic effects on bone and lipid profile, remains to be found. AIM: The aim of this review is to examine the evidence for arzoxifene as the "ideal SERM." EVIDENCE REVIEW: Arzoxifene showed initial promise as the "ideal SERM" in preclinical, phase I, and phase II clinical studies. It appeared to have powerful antiestrogenic effects on breast cancer and endometrium, with equally strong favorable estrogenic effects on bone and lipid profile, minimal side effects, and good oral bioavailability. However, phase III trial data found it to be inferior to tamoxifen, bringing an apparent end to its investigation as a breast cancer treatment. CLINICAL POTENTIAL: Despite early promise as the "ideal SERM", results from a phase III trial have relegated arzoxifene to research in breast cancer prevention and osteoporosis treatment.

Serum epidermal growth factor receptor and HER2 expression in primary and metastatic breast cancer patients.

BACKGROUND: Breast tissue expression of the ERBB proto-oncogene family has been extensively studied. It was recently shown that expression of epidermal growth factor receptor (EGFR; c-erbB-1) and epidermal growth factor receptor (HER)2 (c-erbB-2) can be detected in the serum of breast cancer patients. The clinical relevance of this has not been fully established. METHODS: EGFR and HER2 immunoassays were conducted in blood from 57 patients in whom paired serum samples were available (from the times of primary and metastatic diagnoses), from 96 primary breast cancer patients and from 49 normal individuals. Of the 57 patients with paired serum samples, paired tissue samples for HER2 expression were available for eight. RESULTS: Serum levels of EGFR serum levels were significantly higher in normal individuals (median 75.3 ng/ml, range 43.2 to 114.2 ng/ml) than in patients with primary breast cancer (median 59.3 ng/ml, range 21.3 to 94.1 ng/ml; P < 0.001). In the paired serum samples, EGFR levels decreased significantly between the time of primary diagnosis (median 56.3 ng/ml, range 29.1 to 142.7 ng/ml) and metastatic diagnosis (median 30.9 ng/ml, range 10.9 to 106.4 ng/ml; P < 0.001). In six (11%) a change occurred from over-expression (>78 ng/ml) to normal expression. In contrast, no significant difference was seen in HER2 serum levels in normal individuals (median 12.2 ng/ml, range 7.8 to 20.9 ng/ml) and primary breast cancer patients (median 12.5 ng/ml, range 6.9 to 122.2 ng/ml; P = 0.511). However, in the paired serum samples, HER2 levels increased significantly between the time of primary (median 12.2 ng/ml, range 5.7 to 85.0 ng/ml) and metastasis (median 17.7 ng/ml, range 6.3 to 3,337.4 ng/ml; P < 0.001). HER2 over-expression (>15 ng/ml) was observed in 16 out of 57 patients (28%) at primary breast cancer diagnosis and in 31 out of 57 (54%) at metastasis. In 18 patients (32%) HER2 expression changed from normal to over-expression. CONCLUSION: Decisions regarding the use of targeted therapies in the metastatic setting are often based on the oncogene expression of the primary tumour. Our results suggest that serum oncogene assessments may be complementary to this and could potentially widen the indications for these beneficial therapies.