Gordon Wishart

Randomized Controlled Trial of Intensity-Modulated Radiotherapy for Early Breast Cancer: 5-Year Results Confirm Superior Overall Cosmesis

PURPOSE There are few randomized controlled trial data to confirm that improved homogeneity with simple intensity-modulated radiotherapy (IMRT) decreases late breast tissue toxicity. The Cambridge Breast IMRT trial investigated this hypothesis, and the 5-year results are reported. PATIENTS AND METHODS Standard tangential plans of 1,145 trial patients were analyzed; 815 patients had inhomogeneous plans (≥ 2 cm(3) receiving 107% of prescribed dose: 40 Gy in 15 fractions over 3 weeks) and were randomly assigned to standard radiotherapy (RT) or replanned with simple IMRT; 330 patients with satisfactory dose homogeneity were treated with standard RT and underwent the same follow-up as the randomly assigned patients. Breast tissue toxicities were assessed at 5 years using validated methods: photographic assessment (overall cosmesis and breast shrinkage compared with baseline pre-RT photographs) and clinical assessment (telangiectasia, induration, edema, and pigmentation). Comparisons between different groups were analyzed using polychotomous logistic regression. RESULTS On univariate analysis, compared with standard RT, fewer patients in the simple IMRT group developed suboptimal overall cosmesis (odds ratio [OR], 0.68; 95% CI, 0.48 to 0.96; P = .027) and skin telangiectasia (OR, 0.58; 95% CI, 0.36 to 0.92; P = .021). No evidence of difference was seen for breast shrinkage, breast edema, tumor bed induration, or pigmentation. The benefit of IMRT was maintained on multivariate analysis for both overall cosmesis (P = .038) and skin telangiectasia (P = .031). CONCLUSION Improved dose homogeneity with simple IMRT translates into superior overall cosmesis and reduces the risk of skin telangiectasia. These results are practice changing and should encourage centers still using two-dimensional RT to implement simple breast IMRT.

Can breast MRI help in the management of women with breast cancer treated by neoadjuvant chemotherapy

Contrast-enhanced (CE) MRI was used to monitor breast cancer response to neoadjuvant chemotherapy. Patients underwent CE MRI before and after therapy, together with conventional assessment methods (CAM). CE MRI was carried out at 1.5 T in the coronal plain with 3D sequences before and after bolus injection. An expert panel determined chemotherapy response using both CE MRI and CAM. Histopathological response in the surgical specimen was then used to determine the sensitivity and specificity of CE MRI and CAM. In total, 67 patients with 69 breast cancers were studied (mean age of 46 years). Tumour characteristics showed a high-risk tumour population: median size 49 mm: histopathological grade 3 (55%): oestrogen receptor (ER) negative (48%). Histopathological response was as follows: – complete pathological response (pCR) 17%; partial response (pPR) 68%; no response (NR) 15%. Sensitivity of CAM for pCR or pPR was 98% (CI 91–100%) and specificity was 50% (CI 19–81%). CE MRI sensitivity was 100% (CI 94–100%), and specificity was 80% (CI 44–97%). The absolute agreement between assessment methods and histopathology was marginally higher for CE MRI than CAM (81 vs 68%; P=0.09). In 71%, CE MRI increased diagnostic knowledge, although in 20% it was judged confusing or incorrect. The 2nd MRI study significantly increased diagnostic confidence, and in 19% could have changed the treatment plan. CE MRI persistently underestimated minimal residual disease. In conclusion, CE MRI of breast cancer proved more reliable for predicting histopathological response to neoadjuvant chemotherapy than conventional assessment methods.

PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer

IntroductionThe aim of this study was to develop and validate a prognostication model to predict overall and breast cancer specific survival for women treated for early breast cancer in the UK.MethodsUsing the Eastern Cancer Registration and Information Centre (ECRIC) dataset, information was collated for 5,694 women who had surgery for invasive breast cancer in East Anglia from 1999 to 2003. Breast cancer mortality models for oestrogen receptor (ER) positive and ER negative tumours were derived from these data using Cox proportional hazards, adjusting for prognostic factors and mode of cancer detection (symptomatic versus screen-detected). An external dataset of 5,468 patients from the West Midlands Cancer Intelligence Unit (WMCIU) was used for validation.ResultsDifferences in overall actual and predicted mortality were <1% at eight years for ECRIC (18.9% vs. 19.0%) and WMCIU (17.5% vs. 18.3%) with area under receiver-operator-characteristic curves (AUC) of 0.81 and 0.79 respectively. Differences in breast cancer specific actual and predicted mortality were <1% at eight years for ECRIC (12.9% vs. 13.5%) and <1.5% at eight years for WMCIU (12.2% vs. 13.6%) with AUC of 0.84 and 0.82 respectively. Model calibration was good for both ER positive and negative models although the ER positive model provided better discrimination (AUC 0.82) than ER negative (AUC 0.75).ConclusionsWe have developed a prognostication model for early breast cancer based on UK cancer registry data that predicts breast cancer survival following surgery for invasive breast cancer and includes mode of detection for the first time. The model is well calibrated, provides a high degree of discrimination and has been validated in a second UK patient cohort.

Randomized controlled trial of forward-planned intensity modulated radiotherapy for early breast cancer: interim results at 2 years.

PURPOSE This single-center randomized trial was designed to investigate whether intensity-modulated radiotherapy (IMRT) reduces late toxicity in patients with early-stage breast cancer. METHODS AND MATERIALS The standard tangential plans of 1,145 nonselected patients were analyzed. The patients with inhomogeneous plans were randomized to a simple method of forward-planned IMRT or standard radiotherapy (RT). The primary endpoint was serial photographic assessment of breast shrinkage. RESULTS At 2 years, no significant difference was found in the development of any photographically assessed breast shrinkage between the patients randomized to the interventional or control group (odds ratio, 1.51; 95% confidence interval, 0.83-1.58; p = .41). The patients in the control group were more likely to develop telangiectasia than those in the IMRT group (odds ratio, 1.68; 95% confidence interval 1.13-2.40; p = .009). Poor baseline surgical cosmesis resulted in poor overall cosmesis at 2 years after RT. In patients who had good surgical cosmesis, those randomized to IMRT were less likely to deteriorate to a moderate or poor overall cosmesis than those in the control group (odds ratio, 0.63; 95% confidence interval, 0.39-1.03, p = .061). CONCLUSIONS IMRT can lead to a significant reduction in telangiectasia at comparatively early follow-up of only 2 years after RT completion. An important component of breast induration and shrinkage will actually result from the surgery and not from the RT. Surgical cosmesis is an important determinant of overall cosmesis and could partially mask the longer term benefits of IMRT at this early stage.

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2

Background:Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!.Methods:The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes.Results:All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS.Conclusion:Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

The accuracy of digital infrared imaging for breast cancer detection in women undergoing breast biopsy

BACKGROUND Mammography has a lower sensitivity for breast cancer detection in younger women and those with dense breasts. Recent improvements in digital infrared breast imaging suggest there may be a role for this technology and we have studied its performance in 100 women prior to breast needle core biopsy (CB). METHODS All patients were imaged using a digital infrared breast (DIB) scan (Sentinel BreastScan) prior to breast biopsy. Analysis of the infrared scans was performed, blinded to biopsy results, in four different ways: Sentinel screening report, Sentinel artificial intelligence (neural network), expert manual review and NoTouch BreastScan a novel artificial intelligence programme. RESULTS Of 106 biopsies performed in 100 women, 65 were malignant and 41 were benign. Sensitivity of Sentinel screening (53%) and Sentinel neural network (48%) was low but analysis with NoTouch software (70%) was much closer to expert manual review (78%). Sensitivity (78%) and specificity (75%) using NoTouch BreastScan were higher in women under 50 and the combination of mammography and DIB, with NoTouch interpretation, in this age group resulted in a sensitivity of 89%. CONCLUSION DIB using NoTouch is an effective adjunctive test for breast cancer detection in women under 70 and appears to be particularly effective in women under 50 where maximal sensitivity (78%) and specificity (75%) were observed. The combined sensitivity of NoTouch BreastScan and mammography in women under 50 was encouraging at 89%, suggesting a potential way forward for a dual imaging approach in this younger age group.

A feasibility study (ICG-10) of indocyanine green (ICG) fluorescence mapping for sentinel lymph node detection in early breast cancer

BACKGROUND There is now increasing evidence to support the use of indocyanine green (ICG) for sentinel lymph node (SLN) detection in early breast cancer. The primary objective of this feasibility study (ICG-10) was to determine the sensitivity and safety of ICG fluorescence imaging in sentinel lymph node identification when combined with blue dye and radiocolloid. METHODS One hundred women with clinically node negative breast cancer (95 unilateral; 5 bilateral) had sentinel lymph node (SLN) biopsy using blue dye, radioisotope and ICG. One patient was excluded from analysis and sensitivity, or detection rate, of ICG alone, and in combination with blue dye and/or radioisotope, was calculated for the remaining 104 procedures in 99 patients. RESULTS Transcutaneous fluorescent lymphography was visible in all 104 procedures. All 202 true SLNs, defined as blue and/or radioactive, were also fluorescent with ICG. Detection rates were: ICG alone 100%, ICG & blue dye 95.0%, ICG & radioisotope 77.2%, ICG & blue dye & radioisotope 73.1%. Metastases were found in 25 of 201 SLNs (12.4%) and all positive nodes were fluorescent, blue and radioactive. The procedural node positivity rate was 17.3%. CONCLUSION The results of this study confirm the high sensitivity of ICG fluorescence for SLN detection in early breast cancer. The combination of ICG and blue dye had the highest nodal sensitivity at 95.0% defining a dual approach to SLN biopsy that avoids the need for radioisotope.

Predictors of recurrence for ductal carcinoma in situ after breast-conserving surgery

Ductal carcinoma in situ (DCIS) constitutes a major public health problem, with up to half of screen-detected cancers representing pure forms of DCIS without evidence of invasion. A proportion of cases detected with routine screening would not have progressed to a life-threatening form of breast cancer during the patients lifetime, and overdiagnosis of breast cancer is a cause for concern. Once DCIS has been detected, treatment is obligatory and present technologies do not allow accurate risk stratification such that intensity of treatment can be tailored to risk of recurrence and progression to invasive disease. Present management strategies are based on prognostic and predictive information derived from conventional histopathological and host factors. With increasing molecular characterisation of these preinvasive lesions, data will be available for how factors such as oestrogen receptor, progesterone receptor, HER2, and indicators of proliferative activity can provide additional information about both prognosis and benefit from adjuvant treatments such as radiotherapy and hormonal therapy. Low-risk patients are especially poorly defined in terms of need for adjuvant therapies, which can be associated with both short-term adverse sequelae and long-term effects (eg, cardiotoxicity) that can affect all-cause mortality. Optimum risk prediction in the future is likely to be achieved by integration of both conventional and molecular factors, which should be incorporated into a validated predictive model to help with clinical decision making.

A population-based validation of the prognostic model PREDICT for early breast cancer

INTRODUCTION Predict (www.predict.nhs.uk) is a prognostication and treatment benefit tool developed using UK cancer registry data. The aim of this study was to compare the 10-year survival estimates from Predict with observed 10-year outcome from a British Columbia dataset and to compare the estimates with those generated by Adjuvant! (www.adjuvantonline.com). METHOD The analysis was based on data from 3140 patients with early invasive breast cancer diagnosed in British Columbia, Canada, from 1989-1993. Demographic, pathologic, staging and treatment data were used to predict 10-year overall survival (OS) and breast cancer specific survival (BCSS) using Adjuvant! and Predict models. Predicted outcomes from both models were then compared with observed outcomes. RESULTS Calibration of both models was excellent. The difference in total number of deaths estimated by Predict was 4.1 percent of observed compared to 0.7 percent for Adjuvant!. The total number of breast cancer specific deaths estimated by Predict was 3.4 percent of observed compared to 6.7 percent for Adjuvant! Both models also discriminate well with similar AUC for Predict and Adjuvant! respectively for both OS (0.709 vs 0.712) and BCSS (0.723 vs 0.727). Neither model performed well in women aged 20-35. CONCLUSION In summary Predict provided accurate overall and breast cancer specific survival estimates in the British Columbia dataset that are comparable with outcome estimates from Adjuvant! Both models appear well calibrated with similar model discrimination. This study provides further validation of Predict as an effective predictive tool following surgery for invasive breast cancer.

Ultrasound guided percutaneous axillary lymph node core biopsy: how often is the sentinel lymph node being biopsied?

Patients with breast cancer now frequently undergo axillary ultrasound and core biopsy (CB) in an attempt to reduce the number of unnecessary sentinel lymph node (SLN) biopsies. This study aimed to establish the frequency of successful targeting of the SLN by ultrasound guided biopsy. A total of 137 patients had axillary ultrasound of which 121 underwent CB. 73 (60%) patients proceeded to SLN after negative CB. All SLNs were examined for evidence of metastases and previous CB. Of the 73 patients, 51 had no evidence of malignancy in the SLN (true negative=70%). However nodal deposits were found in the remaining 22 patients, representing a false negative rate for CB of 30%. Overall histopathological evidence of previous CB was identified in 47 (64%) of 73 patients undergoing SLN biopsy. The reason for false negative findings in the 22 (30%) patients was failure to sample the sentinel lymph node in 10 (45%) and failure to sample the metastatic disease in the sentinel node in 11 (55%). This study suggests that both better methods of identifying the sentinel lymph node and more adequate sampling are required.