The BIG 2.04 MRC/EORTC SUPREMO Trial: pathology quality assurance of a large phase 3 randomised international clinical trial of postmastectomy radiotherapy in intermediate-risk breast cancer

Introduction SUPREMO is a phase 3 randomised trial evaluating radiotherapy post-mastectomy for intermediate-risk breast cancer. 1688 patients were enrolled from 16 countries between 2006 and 2013. We report the results of central pathology review carried out for quality assurance. Patients and methods A single recut haematoxylin and eosin (H&E) tumour section was assessed by one of two reviewing pathologists, blinded to the originally reported pathology and patient data. Tumour type, grade and lymphovascular invasion were reviewed to assess if they met the inclusion criteria. Slides from potentially ineligible patients on central review were scanned and reviewed online together by the two pathologists and a consensus reached. A subset of 25 of these cases was double-reported independently by the pathologists prior to the online assessment. Results The major contributors to the trial were the UK (75%) and the Netherlands (10%). There is a striking difference in lymphovascular invasion (LVi) rates (41.6 vs. 15.1% (UK); p = <0.0001) and proportions of grade 3 carcinomas (54.0 vs. 42.0% (UK); p = <0.0001) on comparing local reporting with central review. There was no difference in the locally reported frequency of LVi rates in node-positive (N+) and node-negative (N−) subgroups (40.3 vs. 38.0%; p = 0.40) but a significant difference in the reviewed frequency (16.9 vs. 9.9%; p = 0.004). Of the N− cases, 104 (25.1%) would have been ineligible by initial central review by virtue of grade and/or lymphovascular invasion status. Following online consensus review, this fell to 70 cases (16.3% of N− cases, 4.1% of all cases). Conclusions These data have important implications for the design, powering and interpretation of outcomes from this and future clinical trials. If critical pathology criteria are determinants for trial entry, serious consideration should be given to up-front central pathology review

Stage and treatment variation with age in postmenopausal women with breast cancer: compliance with guidelines

Breast cancer-specific mortality is static in older women despite having fallen in younger age groups, possibly due to lack of screening and differences in treatment. This study compared stage and treatment between two cohorts of postmenopausal women (55–69 vs 470 years) in a single cancer network over 6 months. A total of 378 patients were studied (470: N ¼ 167, 55–69 years: N ¼ 210). Older women presented with more advanced disease (470: metastatic/locally advanced 12%, 55–69 years: 3%, Po0.01). Those with operable cancer had a worse prognosis (Nottingham Prognostic Index (NPI) 470: median NPI 4.4, 55–69 years: 4.25, Po0.03). These stage differences were partially explained by higher screening rates in the younger cohort. Primary endocrine therapy was used in 42% of older patients compared with 3% in the younger group (Po0.001). Older women with cancers suitable for breast conservation were more likely to choose mastectomy (470: 57.5% mastectomy rate vs 55–69 years: 20.6%, Po0.01). Nodal surgery was less frequent in older patients (470: 6.7% no nodal surgery, 55–69 years: 0.5%, Po0.01) and was more likely to be inadequate (470: 10.7% o4 nodes excised, 55–69 years: 3.4%, Po0.02). In summary, older women presented with more advanced breast cancer, than younger postmenopausal women and were treated less comprehensively

Minimum follow-up time required for the estimation of statistical cure of cancer patients: verification using data from 42 cancer sites in the SEER database

BACKGROUND: The present commonly used five-year survival rates are not adequate to represent the statistical cure. In the present study, we established the minimum number of years required for follow-up to estimate statistical cure rate, by using a lognormal distribution of the survival time of those who died of their cancer. We introduced the term, threshold year, the follow-up time for patients dying from the specific cancer covers most of the survival data, leaving less than 2.25% uncovered. This is close enough to cure from that specific cancer. METHODS: Data from the Surveillance, Epidemiology and End Results (SEER) database were tested if the survival times of cancer patients who died of their disease followed the lognormal distribution using a minimum chi-square method. Patients diagnosed from 1973–1992 in the registries of Connecticut and Detroit were chosen so that a maximum of 27 years was allowed for follow-up to 1999. A total of 49 specific organ sites were tested. The parameters of those lognormal distributions were found for each cancer site. The cancer-specific survival rates at the threshold years were compared with the longest available Kaplan-Meier survival estimates. RESULTS: The characteristics of the cancer-specific survival times of cancer patients who died of their disease from 42 cancer sites out of 49 sites were verified to follow different lognormal distributions. The threshold years validated for statistical cure varied for different cancer sites, from 2.6 years for pancreas cancer to 25.2 years for cancer of salivary gland. At the threshold year, the statistical cure rates estimated for 40 cancer sites were found to match the actuarial long-term survival rates estimated by the Kaplan-Meier method within six percentage points. For two cancer sites: breast and thyroid, the threshold years were so long that the cancer-specific survival rates could yet not be obtained because the SEER data do not provide sufficiently long follow-up. CONCLUSION: The present study suggests a certain threshold year is required to wait before the statistical cure rate can be estimated for each cancer site. For some cancers, such as breast and thyroid, the 5- or 10-year survival rates inadequately reflect statistical cure rates, and highlight the need for long-term follow-up of these patients

Younger age as a prognostic indicator in breast cancer: A cohort study

<p>Abstract</p> <p>Background</p> <p>The debate continues as to whether younger women who present with breast cancer have a more aggressive form of disease and a worse prognosis. The objectives of this study were to determine the incidence of breast cancer in women under 40 years old and to analyse the clinicopathological characteristics and outcome compared to an older patient cohort.</p> <p>Methods</p> <p>Data was acquired from a review of charts and the prospectively reviewed GUH Department of Surgery database. Included in the study were 276 women diagnosed with breast cancer under the age of forty and 2869 women over forty. For survival analysis each women less than 40 was matched with two women over forty for both disease stage and grade.</p> <p>Results</p> <p>The proportion of women diagnosed with breast cancer under the age of forty in our cohort was 8.8%. In comparison to their older counterparts, those under forty had a higher tumour grade (p = 0.044) and stage (p = 0.046), a lower incidence of lobular tumours (p < 0.001), higher estrogen receptor negativity (p < 0.001) and higher <it>HER2 </it>over-expression (p = 0.002); there was no statistical difference as regards tumour size (p = 0.477). There was no significant difference in overall survival (OS) for both groups; and factors like tumour size (p = 0.026), invasion (p = 0.026) and histological type (p = 0.027), PR (p = 0.031) and <it>HER2 </it>(p = 0.002) status and treatment received were independent predictors of OS</p> <p>Conclusion</p> <p>Breast cancer in younger women has distinct histopathological characteristics; however, this does not result in a reduced survival in this population.</p

Changing pattern of the detection of locoregional relapse in breast cancer: the Edinburgh experience

The guidelines for follow-up of breast cancer patients concentrate on the first 3–5 years, with either reduced frequency of visits or discharge after this. They also recommend mammography, but no evidence exists to inform frequency. We analyse treatable relapses in our unit from 1312 patients with early stage breast cancer treated by breast conserving surgery (BCS) and postoperative radiotherapy between 1991 and 1998 to assess appropriateness of the guidelines. A total of 110 treatable relapses were analysed. Treatable relapse developed at 1–1.5% per year throughout follow-up. Forty-eight relapses were in ipsilateral breast, 25 ipsilateral axilla, 35 contralateral breast, 2 both breasts simultaneously. Thirty-seven relapses (33.5%) were symptomatic, 56 (51%) mammographically detected, 15 (13.5%) clinically detected, 2 (2%) diagnosed incidentally. Mammography detected 5.37 relapses per 1000 mammograms. Patients with symptomatic or mammographically detected ipsilateral breast relapse had significantly longer survival from original diagnosis (P=0.0002) and from recurrence (P=0.0014) compared with clinically detected. Treatable relapse occurs at a constant rate for at least 10 years. Clinical examination detects a minority (13.5%). Relapse diagnosed clinically is associated with poorer outcome. Long-term follow-up based on regular mammography is warranted for all patients treated by BCS

20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years

The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)-positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment

Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials

Background Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. Methods We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). Findings Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5–14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4–8·6]; rate ratio 1·37 [95% CI 1·17–1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92–1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95–1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94–1·15]; p=0·45). Interpretation Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered—eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy

Comprehensive geriatric assessment in 326 older women with early breast cancer

Background: One-third of new early breast cancer diagnoses occur in women over 70 years old. However, older women are less likely to receive radical curative treatments. This study prospectively evaluated a cohort of older women using a Comprehensive Geriatric Assessment (CGA) to determine whether fitness explained the apparent under-treatment in this patient group. Methods: In this multi-centre prospective study, patients aged >= 70 years with Stages I-III breast cancer underwent a pretreatment baseline CGA consisting of eight assessment tools. Patients were defined as 'fit' if they had normal score in seven out of eight of the assessment tools. 'High risk' patients were defined as those with grade 3, ER negative, HER2 positive, or node positive breast cancer. Results: Data on 326 patients were available for full analysis. The median age was 77 years. In all, 182 (56%) of the total population were defined as high risk, with 49%, 61% and 53% of those in the 70-74, 75-84 and >= 85 years age groups respectively having high risk tumours. A total of 301 patients had sufficient CGA records of whom 131 (44%) were reported as fit, with 34%, 54% and 12% of them in the 70-74, 75-84 and >= 85 years age groups respectively. More fit than unfit patients underwent primary breast surgery (100% vs 91%, P = 0.0002), axillary surgery (92% vs 84%, P = 0.0340), and adjuvant chemotherapy for high-risk disease (51% vs 20%, P = 0.0001). Rates of adjuvant radiotherapy after wide local excision were not significantly different (88% vs 90% respectively, P = 0.8195). Conclusions: In this study, all women >= 70 years deemed fit by CGA underwent primary surgery. Nearly 50% of fit women with high-risk disease did not receive adjuvant chemotherapy suggesting under treatment in this group