Breast-Conserving Surgery with or without Irradiation in Early Breast Cancer.

BACKGROUND: Limited level 1 evidence is available on the omission of radiotherapy after breast-conserving surgery in older women with hormone receptor-positive early breast cancer receiving adjuvant endocrine therapy. METHODS: We performed a phase 3 randomized trial of the omission of irradiation; the trial population included women 65 years of age or older who had hormone receptor-positive, node-negative, T1 or T2 primary breast cancer (with tumors ≤3 cm in the largest dimension) treated with breast-conserving surgery with clear excision margins and adjuvant endocrine therapy. Patients were randomly assigned to receive whole-breast irradiation (40 to 50 Gy) or no irradiation. The primary end point was local breast cancer recurrence. Regional recurrence, breast cancer-specific survival, distant recurrence as the first event, and overall survival were also assessed. RESULTS: A total of 1326 women were enrolled; 658 were randomly assigned to receive whole-breast irradiation and 668 to receive no irradiation. The median follow-up was 9.1 years. The cumulative incidence of local breast cancer recurrence within 10 years was 9.5% (95% confidence interval [CI], 6.8 to 12.3) in the no-radiotherapy group and 0.9% (95% CI, 0.1 to 1.7) in the radiotherapy group (hazard ratio, 10.4; 95% CI, 4.1 to 26.1; P<0.001). Although local recurrence was more common in the group that did not receive radiotherapy, the 10-year incidence of distant recurrence as the first event was not higher in the no-radiotherapy group than in the radiotherapy group, at 1.6% (95% CI, 0.4 to 2.8) and 3.0% (95% CI, 1.4 to 4.5), respectively. Overall survival at 10 years was almost identical in the two groups, at 80.8% (95% CI, 77.2 to 84.3) with no radiotherapy and 80.7% (95% CI, 76.9 to 84.3) with radiotherapy. The incidence of regional recurrence and breast cancer-specific survival also did not differ substantially between the two groups. CONCLUSIONS: Omission of radiotherapy was associated with an increased incidence of local recurrence but had no detrimental effect on distant recurrence as the first event or overall survival among women 65 years of age or older with low-risk, hormone receptor-positive early breast cancer. (Funded by the Chief Scientist Office of the Scottish Government and the Breast Cancer Institute, Western General Hospital, Edinburgh; ISRCTN number, ISRCTN95889329.).

Diagnostic accuracy of core biopsy in patients presenting with axillary lymphadenopathy and suspected non-breast malignancy.

INTRODUCTION: Excision biopsy has been the investigation of choice for patients presenting with pathological axillary lymphadenopathy without a breast abnormality. Core biopsy of nodes can provide sufficient tissue for diagnosis and has advantages in terms of morbidity and speed of diagnosis. This study evaluates the diagnostic accuracy of core biopsy in patients presenting with axillary lymphadenopathy. METHODS: Between 2009 and 2019, 165 patients referred to the Edinburgh Breast Unit had a total of 179 axillary lymph node core biopsies. RESULTS: 152 (92%) of the 165 initial core biopsies were deemed to contain adequate nodal tissue. Core biopsy correctly established malignancy in 75 of the 78 patients with haematological malignancy (96%) and in all 28 patients with metastatic carcinoma (100%) and correctly diagnosed benign changes in 49 of 57 (86%) patients with benign conditions. There were no false positives and no false negatives. In 67 (85.9%) of the 78 patients with haematological malignancy there was sufficient material in the first core biopsy to allow the pathologist to make an actionable diagnosis and not ask for more tissue sampling prior to treatment. There were no complications of core biopsy. On follow up, none of the patients with benign cores has been shown to have malignancy in the axilla and none with lymphoma had their initial disease incorrectly classified. CONCLUSIONS: This study shows that core biopsy is now the investigation of choice for patients presenting with axillary lymphadenopathy even in those suspected as having lymphoma.

Nottingham Prognostic Index Plus: Validation of a clinical decision making tool in breast cancer in an independent series.

The Nottingham Prognostic Index Plus (NPI+) is a clinical decision making tool in breast cancer (BC) that aims to provide improved patient outcome stratification superior to the traditional NPI. This study aimed to validate the NPI+ in an independent series of BC. Eight hundred and eighty five primary early stage BC cases from Edinburgh were semi-quantitatively assessed for 10 biomarkers [Estrogen Receptor (ER), Progesterone Receptor (PgR), cytokeratin (CK) 5/6, CK7/8, epidermal growth factor receptor (EGFR), HER2, HER3, HER4, p53, and Mucin 1] using immunohistochemistry and classified into biological classes by fuzzy logic-derived algorithms previously developed in the Nottingham series. Subsequently, NPI+ Prognostic Groups (PGs) were assigned for each class using bespoke NPI-like formulae, previously developed in each NPI+ biological class of the Nottingham series, utilising clinicopathological parameters: number of positive nodes, pathological tumour size, stage, tubule formation, nuclear pleomorphism and mitotic counts. Biological classes and PGs were compared between the Edinburgh and Nottingham series using Cramer's V and their role in patient outcome prediction using Kaplan-Meier curves and tested using Log Rank. The NPI+ biomarker panel classified the Edinburgh series into seven biological classes similar to the Nottingham series (p > 0.01). The biological classes were significantly associated with patient outcome (p < 0.001). PGs were comparable in predicting patient outcome between series in Luminal A, Basal p53 altered, HER2+/ER+ tumours (p > 0.01). The good PGs were similarly validated in Luminal B, Basal p53 normal, HER2+/ER- tumours and the poor PG in the Luminal N class (p > 0.01). Due to small patient numbers assigned to the remaining PGs, Luminal N, Luminal B, Basal p53 normal and HER2+/ER- classes could not be validated. This study demonstrates the reproducibility of NPI+ and confirmed its prognostic value in an independent cohort of primary BC. Further validation in large randomised controlled trial material is warranted.

FKBPL: a marker of good prognosis in breast cancer.

FK506-binding protein-like (FKBPL) has established roles as an anti-tumor protein, with a therapeutic peptide based on this protein, ALM201, shortly entering phase I/II clinical trials. Here, we evaluated FKBPL's prognostic ability in primary breast cancer tissue, represented on tissue microarrays (TMA) from 3277 women recruited into five independent retrospective studies, using immunohistochemistry (IHC). In a meta-analysis, FKBPL levels were a significant predictor of BCSS; low FKBPL levels indicated poorer breast cancer specific survival (BCSS) (hazard ratio (HR) = 1.30, 95% confidence interval (CI) 1.14-1.49, p < 0.001). The prognostic impact of FKBPL remained significant after adjusting for other known prognostic factors (HR = 1.25, 95% CI 1.07-1.45, p = 0.004). For the sub-groups of 2365 estrogen receptor (ER) positive patients and 1649 tamoxifen treated patients, FKBPL was significantly associated with BCSS (HR = 1.34, 95% CI 1.13-1.58, p < 0.001, and HR = 1.25, 95% CI 1.04-1.49, p = 0.02, respectively). A univariate analysis revealed that FKBPL was also a significant predictor of relapse free interval (RFI) within the ER positive patient group, but it was only borderline significant within the smaller tamoxifen treated patient group (HR = 1.32 95% CI 1.05-1.65, p = 0.02 and HR = 1.23 95% CI 0.99-1.54, p = 0.06, respectively). The data suggests a role for FKBPL as a prognostic factor for BCSS, with the potential to be routinely evaluated within the clinic.

Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial.

BACKGROUND: For most older women with early breast cancer, standard treatment after breast-conserving surgery is adjuvant whole-breast radiotherapy and adjuvant endocrine treatment. We aimed to assess the effect omission of whole-breast radiotherapy would have on local control in older women at low risk of local recurrence at 5 years. METHODS: Between April 16, 2003, and Dec 22, 2009, 1326 women aged 65 years or older with early breast cancer judged low-risk (ie, hormone receptor-positive, axillary node-negative, T1-T2 up to 3 cm at the longest dimension, and clear margins; grade 3 tumour histology or lymphovascular invasion, but not both, were permitted), who had had breast-conserving surgery and were receiving adjuvant endocrine treatment, were recruited into a phase 3 randomised controlled trial at 76 centres in four countries. Eligible patients were randomly assigned to either whole-breast radiotherapy (40-50 Gy in 15-25 fractions) or no radiotherapy by computer-generated permuted block randomisation, stratified by centre, with a block size of four. The primary endpoint was ipsilateral breast tumour recurrence. Follow-up continues and will end at the 10-year anniversary of the last randomised patient. Analyses were done by intention to treat. The trial is registered on ISRCTN.com, number ISRCTN95889329. FINDINGS: 658 women who had undergone breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and 668 were allocated to no further treatment. After median follow-up of 5 years (IQR 3·84-6·05), ipsilateral breast tumour recurrence was 1·3% (95% CI 0·2-2·3; n=5) in women assigned to whole-breast radiotherapy and 4·1% (2·4-5·7; n=26) in those assigned no radiotherapy (p=0·0002). Compared with women allocated to whole-breast radiotherapy, the univariate hazard ratio for ipsilateral breast tumour recurrence in women assigned to no radiotherapy was 5·19 (95% CI 1·99-13·52; p=0·0007). No differences in regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between groups. 5-year overall survival was 93·9% (95% CI 91·8-96·0) in both groups (p=0·34). 89 women died; eight of 49 patients allocated to no radiotherapy and four of 40 assigned to radiotherapy died from breast cancer. INTERPRETATION: Postoperative whole-breast radiotherapy after breast-conserving surgery and adjuvant endocrine treatment resulted in a significant but modest reduction in local recurrence for women aged 65 years or older with early breast cancer 5 years after randomisation. However, the 5-year rate of ipsilateral breast tumour recurrence is probably low enough for omission of radiotherapy to be considered for some patients. FUNDING: Chief Scientist Office (Scottish Government), Breast Cancer Institute (Western General Hospital, Edinburgh).

A Morbidity Screening Tool for identifying fatigue, pain, upper limb dysfunction and lymphedema after breast cancer treatment: a validity study.

PURPOSE: This study aimed to investigate validity of a newly developed Morbidity Screening Tool (MST) to screen for fatigue, pain, swelling (lymphedema) and arm function after breast cancer treatment. METHODS: A cross-sectional study included women attending reviews after completing treatment (surgery, chemotherapy and radiotherapy), without recurrence, who could read English. They completed the MST and comparator questionnaires: Disability of the Arm, Shoulder and Hand questionnaire (DASH), Chronic Pain Grade Questionnaire (CPGQ), Lymphedema and Breast Cancer Questionnaire (LBCQ) and Functional Assessment of Cancer Therapy questionnaire with subscales for fatigue (FACT F) and breast cancer (FACT B + 4). Bilateral combined shoulder ranges of motion were compared (upward reach; hand behind back) and percentage upper limb volume difference (%LVD =/>10% diagnosed as lymphedema) measured with the vertical perometer (400T). RESULTS: 613 of 617 participants completed questionnaires (mean age 62.3 years, SD 10.0; mean time since treatment 63.0 months, SD 46.6) and 417 completed objective testing. Morbidity prevalence was estimated as 35.8%, 21.9%, 19.8% and 34.4% for fatigue, impaired upper limb function, lymphedema and pain respectively. Comparing those self-reporting the presence or absence of each type of morbidity, statistically significant differences in comparator variables supported validity of the MST. Statistically significant correlations resulted between MST scores focussing on impact of morbidity, and comparator variables that reflect function and quality of life. CONCLUSION: Analysis supports the validity of all four short-forms of the MST as providing indications of both presence of morbidity and impacts on participants' lives. This may facilitate early and appropriate referral for intervention.

Comparison of breast cancer-related lymphedema (upper limb swelling) prevalence estimated using objective and subjective criteria and relationship with quality of life.

This study aimed to investigate lymphedema prevalence using three different measurement/diagnostic criterion combinations and explore the relationship between lymphedema and quality of life for each, to provide evaluation of rehabilitation. Cross-sectional data from 617 women attending review appointments after completing surgery, chemotherapy, and radiotherapy included the Morbidity Screening Tool (MST; criterion: yes to lymphedema); Lymphedema and Breast Cancer Questionnaire (LBCQ; criterion: yes to heaviness and/or swelling); percentage limb volume difference (perometer: %LVD; criterion: 10%+ difference); and the Functional Assessment of Cancer Therapy breast cancer-specific quality of life tool (FACT B+4). Perometry measurements were conducted in a clinic room. Between 341 and 577 participants provided sufficient data for each analysis, with mean age varying from 60 to 62 (SD 9.95-10.03) and median months after treatment from 49 to 51. Lymphedema prevalence varied from 26.2% for perometry %LVD to 20.5% for the MST and 23.9% for the LBCQ; differences were not significant. Limits of agreement analysis between %LVD and the subjective measures showed little consistency, while moderate consistency resulted between the subjective measures. Quality of life differed significantly for women with and without lymphedema only when subjective measurements were used. Results suggest that subjective and objective tools investigate different aspects of lymphedema.

GSK3ß and cyclin D1 expression predicts outcome in early breast cancer patients.

Glycogen synthase kinase 3ß (GSK3ß) is phosphorylated and inactivated by the phosphoinositide 3 kinase PI3K/Akt pathway. Activation of Akt phosphorylates GSK3ß preventing phosphorylation of cyclin D1 which leads to accumulation and nuclear localisation of cyclin D1, activation of CDK4/6 and cell cycle progression. The CCND1 gene found at chromosome 11q13 has been shown to be amplified in approximately 15 % of breast cancers. Cyclin D1, the product of the CCND1 gene, is one of the most commonly overexpressed proteins in breast cancer. Protein expression for GSK3ß, phosphorylated-GSK3ß (p-GSK3ß), cyclin D1 and gene expression of CCND1 were examined in tissue microarrays of 1,686 patients from the Edinburgh Breast Conservation Series. High GSK3ß expression was associated with reduced distant relapse-free survival (DRFS), while no association between p-GSK3ß and breast cancer-specific survival was seen. CCND1 amplification is also associated with poor DRFS. On the contrary, cyclin D1 overexpression is associated with an increase in DRFS. Multivariate analysis was performed. We suggest that analysis of both GSK3ß and cyclin D1 expressions can be considered as a marker of good prognosis in early breast cancer.

Expression of activated type I receptor tyrosine kinases in early breast cancer.

Overexpression of EGFR, HER2 and HER3 are known to be associated with poor outcome in breast cancer. Few studies have examined the clinical impact of activation of these proteins. In the present study, we evaluated EGFR, HER2 and HER3 and the activated (phosphorylated) forms of these proteins in patients with early breast cancer. EGFR, HER2, HER3, pEGFR, pHER2 and pHER3 expression was determined by immunohistochemical analysis of tissue microarrays constructed from tumours within the Edinburgh Breast Conservation Series (BCS). The BCS represents a fully-documented consecutive cohort of 1,812 patients treated by breast conservation surgery in a single institution. Our results demonstrate overexpression of HER2 and pHER2 to be associated with a significant reduction in overall survival (OS) (HR: 1.66, 95 % CI 1.22-2.26, p = 0.001 and HR: 1.57, 95 % CI 1.22-2.03, p = 0.001, respectively) and distant relapse-free survival (DRFS) (HR: 1.63, 95 % CI 1.23-2.18, p = 0.001 and HR: 1.55, 95 % CI 1.23-1.97, p = 0.0002, respectively). Paradoxically, expression of pEGFR was associated with a significantly improved OS (HR: 0.67 95 % CI 0.50-0.91, p = 0.01) and DRFS (HR: 0.73, 95 % CI 0.56-0.96, p = 0.025). Expression of activated EGFR/HER2 provides additional information on ER positive breast cancer patients and suggests alternative treatment for those in this subgroup.

Proximity ligation assays for isoform-specific Akt activation in breast cancer identify activated Akt1 as a driver of progression.

The PI3K/Akt signal transduction pathway plays an important role in cancer progression and cell survival. Akt activation is associated with poor outcome in endocrine-treated breast cancer, whereas high levels of cytoplasmic Akt2 are associated with an improved overall survival. Proximity ligation assays (PLAs) were used to determine quantitative expression levels of isoform-specific activation (phosphorylation) of Akt1 and Akt2 in formalin-fixed, paraffin-embedded cell lines and breast cancer tumour tissues in situ. PLAs demonstrated a range of expression in breast cancer samples for total pAkt1 and pAkt2. High levels of pAkt1 were associated with reduced DRFS (HR: 1.45, 95% CI 1.14-1.83, p = 0.002) and OS (HR: 1.42, 95% CI 1.10-1.83, p = 0.007). When PLA results were combined, patients that had high levels of pAkt1 only had a significantly decreased DRFS (HR: 1.92, 95% CI 1.34-2.76, p = 0.005) and OS (HR: 1.94, 95% CI 1.32-2.86, p = 0.008) compared to other patients. Using PLAs to discriminate activation of Akt1 versus Akt2 suggests that Akt1 drives progression in early breast cancers. In cases where both Akt1/Akt2 are activated, Akt2 may act to reverse this effect. Using PLAs, we have measured activation of Akt1 and Akt2 proteins separately in situ in FFPE breast cancer samples.

Impact of screening and risk factors for local recurrence and survival after conservative surgery and radiotherapy for early breast cancer: results from a large series with long-term follow-up.

PURPOSE: To investigate conventional prognostic factors for ipsilateral breast tumor recurrence (IBTR), distant metastasis (DM), and survival after breast-conserving therapy (BCT) in screen-detected and symptomatic cases on surveillance up to 25 years. PATIENTS AND METHODS: A total of 1812 consecutive patients in three cohorts (1981-1989, 1990-1992, and 1993-1998) with T12N01M0 invasive breast cancer were treated with BCT (median follow-up, 14 years). Tumor type and grade were reviewed by a single pathologist. Hormone receptor status was measured by immunohistochemistry on tissue microarrays. A Cox proportional hazards model was used to assess independent prognostic variables for relapse and survival. RESULTS: A total of 205 IBTR occurred, with 5-, 10-, 15-, and 20-year actuarial relapse rates of 4.5% (95% confidence interval [CI] 3.35-5.5%), 8.4% (95% CI 7.1-9.8%), 14.1% (95% CI 12.0-16%), and 17.4% (95% CI 14.5-20.2%). Number of nodes, young age, pathologic tumor size, and multifocality were significant factors for IBTR. Three hundred seventy-eight patients developed DM. The actuarial metastatic rate was 12% at 5 years and 17.9% at 10 years. Young age, number of positive nodes, pathologic tumor size, and tumor grade were significant factors for DM relapse. When conventional prognostic indices were taken into account screen-detected cancers showed no improvement in overall relapse or survival rate compared with symptomatic cases but did show a reduced risk of DM after IBTR. After 10 years IBTR relapse continued at a constant rate of 0.87% per annum. CONCLUSIONS: The Edinburgh BCT series has shown that screen-detected invasive breast cancers do not have significantly different clinical outcomes compared with symptomatic cases when pathologic risk factors are taken into account. This suggests that these patients be managed in a similar way.

The p160 ER co-regulators predict outcome in ER negative breast cancer.

The SRC family of ER co-regulators are frequently overexpressed in breast cancer. Overexpression of AIB1 appears to be linked to hormone resistance in HER2 positive breast cancer. However, the role of these co-regulators in ER negative disease is poorly understood. SRC1, SRC2 and AIB1 expression was determined by immunohistochemical analysis of tissue microarrays constructed from tumours within the Edinburgh Breast Conservation Series (BCS). The BCS represents a fully documented consecutive cohort of 1,812 patients treated by breast conservation surgery in a single institution. Our results demonstrate tumours that overexpress both HER2 and AIB1 were associated with markedly reduced relapse free, distant relapse free and overall survival compared to HER2 and AIB1 only overexpressing tumours irrespective of ER status. In ER negative disease both SRC1 and AIB1 were linked to early relapse and death. The SRC family of ER co-regulators is involved in early relapse and resistance in both ER negative and ER positive breast cancer challenging the conventional concept that this effect is mediated solely via the ER.

Mammostrat as a tool to stratify breast cancer patients at risk of recurrence during endocrine therapy.

INTRODUCTION: Patients with early-stage breast cancer, treated with endocrine therapy, have approximately 90% 5-year disease-free survival. However, for patients at higher risk of relapse despite endocrine therapy, additional adjuvant therapy, such as chemotherapy, may be indicated. The challenge is to prospectively identify such patients. The Mammostrat® test uses five immunohistochemical markers to stratify patients on tamoxifen therapy into risk groups to inform treatment decisions. We tested the efficacy of this panel in a mixed population of cases treated in a single center with breast-conserving surgery and long-term follow-up. METHODS: Tissue microarrays from a consecutive series (1981 to 1998) of 1,812 women managed by wide local excision and postoperative radiotherapy were collected following appropriate ethical review. Of 1,390 cases stained, 197 received no adjuvant hormonal or chemotherapy, 1,044 received tamoxifen only, and 149 received a combination of hormonal therapy and chemotherapy. Median age at diagnosis was 57, 71% were postmenopausal, 23.9% were node-positive and median tumor size was 1.5 cm. Samples were stained using triplicate 0.6 mm2 tissue microarray cores, and positivity for p53, HTF9C, CEACAM5, NDRG1 and SLC7A5 was assessed. Each case was assigned a Mammostrat risk score, and distant recurrence-free survival (DRFS), relapse-free survival (RFS) and overall survival (OS) were analyzed by marker positivity and risk score. RESULTS: Increased Mammostrat scores were significantly associated with reduced DRFS, RFS and OS in estrogen receptor (ER)-positive breast cancer (P < 0.00001). In multivariate analyses the risk score was independent of conventional risk factors for DRFS, RFS and OS (P < 0.05). In node-negative, tamoxifen-treated patients, 10-year recurrence rates were 7.6 ± 1.5% in the low-risk group versus 20.0 ± 4.4% in the high-risk group. Further, exploratory analyses revealed associations with outcome in both ER-negative and untreated patients. CONCLUSIONS: This is the fifth independent study providing evidence that Mammostrat can act as an independent prognostic tool for ER-positive, tamoxifen-treated breast cancer. In addition, this study revealed for the first time a possible association with outcome regardless of node status and ER-negative tumors. When viewed in the context of previous results, these data provide further support for this antibody panel as an aid to patient management in early-stage breast cancer.

Histological grading of invasive breast carcinoma--a simplification of existing methods in a large conservation series with long-term follow-up.

AIMS: To assess the validity of grading in the Edinburgh Breast Conservation Series; a consecutive cohort of 1812 early breast cancer patients treated by breast conservation and radiotherapy between 1981 and 1998 in a single specialist centre with > or =9 years' follow-up and full staging data. METHODS AND RESULTS: A single pathologist (J.St.J.T) graded 1650 cases using the Elston and Ellis method (EE) with particular reference to the component data: acinar differentiation, nuclear pleomorphism and mitotic counts. The original method was then compared with binary scoring of the same components and the relationship to prognosis reassessed. EE grades and individual grade components were prognostic (P < 0.0001) with 10-year cause-specific survival of 95.6%, 86.4% and 74.7% for EE grades 1, 2 and 3, respectively. A binary scoring of grade components produces four groups, splitting EE grade 2 tumours into two groups with different outcomes--10-year survival rates for the four revised grades were 96.0%, 89.0%, 79.7% and 75.4%, respectively. CONCLUSIONS: Existing grading methodology is fully applicable in the narrower context of a conservation series but can be simplified. Subdivision of EE grade 2 into a true intermediate prognosis group and a second group with a worse prognosis also adds benefit.