Leveraging AI and patient metadata to develop a novel risk score for skin cancer detection.

Melanoma of the skin is the 17th most common cancer worldwide. Early detection of suspicious skin lesions (melanoma) can increase 5-year survival rates by 20%. The 7-point checklist (7PCL) has been extensively used to suggest urgent referrals for patients with a possible melanoma. However, the 7PCL method only considers seven meta-features to calculate a risk score and is only relevant for patients with suspected melanoma. There are limited studies on the extensive use of patient metadata for the detection of all skin cancer subtypes. This study investigates artificial intelligence (AI) models that utilise patient metadata consisting of 23 attributes for suspicious skin lesion detection. We have identified a new set of most important risk factors, namely "C4C risk factors", which is not just for melanoma, but for all types of skin cancer. The performance of the C4C risk factors for suspicious skin lesion detection is compared to that of the 7PCL and the Williams risk factors that predict the lifetime risk of melanoma. Our proposed AI framework ensembles five machine learning models and identifies seven new skin cancer risk factors: lesion pink, lesion size, lesion colour, lesion inflamed, lesion shape, lesion age, and natural hair colour, which achieved a sensitivity of 80.46 ± 2.50 % and a specificity of 62.09 ± 1.90 % in detecting suspicious skin lesions when evaluated using the metadata of 53,601 skin lesions collected from different skin cancer diagnostic clinics across the UK, significantly outperforming the 7PCL-based method (sensitivity 68.09 ± 2.10 % , specificity 61.07 ± 0.90 % ) and the Williams risk factors (sensitivity 66.32 ± 1.90 % , specificity 61.71 ± 0.6 % ). Furthermore, through weighting the seven new risk factors we came up with a new risk score, namely "C4C risk score", which alone achieved a sensitivity of 76.09 ± 1.20 % and a specificity of 61.71 ± 0.50 % , significantly outperforming the 7PCL-based risk score (sensitivity 73.91 ± 1.10 % , specificity 49.49 ± 0.50 % ) and the Williams risk score (sensitivity 60.68 ± 1.30 % , specificity 60.87 ± 0.80 % ). Finally, fusing the C4C risk factors with the 7PCL and Williams risk factors achieved the best performance, with a sensitivity of 85.24 ± 2.20 % and a specificity of 61.12 ± 0.90 % . We believe that fusing these newly found risk factors and new risk score with image data will further boost the AI model performance for suspicious skin lesion detection. Hence, the new set of skin cancer risk factors has the potential to be used to modify current skin cancer referral guidelines for all skin cancer subtypes, including melanoma.

An updated PREDICT breast cancer prognostic model including the benefits and harms of radiotherapy.

PREDICT Breast ( www.breast .predict.nhs.uk ) is a prognostication tool for early invasive breast cancer. The current version was based on cases diagnosed in 1999-2003 and did not incorporate the benefits of radiotherapy or the harms associated with therapy. Since then, there has been a substantial improvement in the outcomes for breast cancer cases. The aim of this study was to update PREDICT Breast to ensure that the underlying model is appropriate for contemporary patients. Data from the England National Cancer Registration and Advisory Service for invasive breast cancer cases diagnosed 2000-17 were used for model development and validation. Model development was based on 35,474 cases diagnosed and registered by the Eastern Cancer Registry. A Cox model was used to estimate the prognostic effects of the year of diagnosis, age at diagnosis, tumour size, tumour grade and number of positive nodes. Separate models were developed for ER-positive and ER-negative disease. Data on 32,408 cases from the West Midlands Cancer Registry and 100,551 cases from other cancer registries were used for validation. The new model was well-calibrated; predicted breast cancer deaths at 5-, 10- and 15-year were within 10 per cent of the observed validation data. Discrimination was also good: The AUC for 15-year breast cancer survival was 0.809 in the West Midlands data set and 0.846 in the data set for the other registries. The new PREDICT Breast model outperformed the current model and will be implemented in the online tool which should lead to more accurate absolute treatment benefit predictions for individual patients.

An updated PREDICT breast cancer prognostication and treatment benefit prediction model with independent validation.

BACKGROUND: PREDICT is a breast cancer prognostic and treatment benefit model implemented online. The overall fit of the model has been good in multiple independent case series, but PREDICT has been shown to underestimate breast cancer specific mortality in women diagnosed under the age of 40. Another limitation is the use of discrete categories for tumour size and node status resulting in 'step' changes in risk estimates on moving between categories. We have refitted the PREDICT prognostic model using the original cohort of cases from East Anglia with updated survival time in order to take into account age at diagnosis and to smooth out the survival function for tumour size and node status. METHODS: Multivariable Cox regression models were used to fit separate models for ER negative and ER positive disease. Continuous variables were fitted using fractional polynomials and a smoothed baseline hazard was obtained by regressing the baseline cumulative hazard for each patients against time using fractional polynomials. The fit of the prognostic models were then tested in three independent data sets that had also been used to validate the original version of PREDICT. RESULTS: In the model fitting data, after adjusting for other prognostic variables, there is an increase in risk of breast cancer specific mortality in younger and older patients with ER positive disease, with a substantial increase in risk for women diagnosed before the age of 35. In ER negative disease the risk increases slightly with age. The association between breast cancer specific mortality and both tumour size and number of positive nodes was non-linear with a more marked increase in risk with increasing size and increasing number of nodes in ER positive disease. The overall calibration and discrimination of the new version of PREDICT (v2) was good and comparable to that of the previous version in both model development and validation data sets. However, the calibration of v2 improved over v1 in patients diagnosed under the age of 40. CONCLUSIONS: The PREDICT v2 is an improved prognostication and treatment benefit model compared with v1. The online version should continue to aid clinical decision making in women with early breast cancer.

Accuracy of the online prognostication tools PREDICT and Adjuvant! for early-stage breast cancer patients younger than 50 years.

IMPORTANCE: Online prognostication tools such as PREDICT and Adjuvant! are increasingly used in clinical practice by oncologists to inform patients and guide treatment decisions about adjuvant systemic therapy. However, their validity for young breast cancer patients is debated. OBJECTIVE: To assess first, the prognostic accuracy of PREDICT's and Adjuvant! 10-year all-cause mortality, and second, its breast cancer-specific mortality estimates, in a large cohort of breast cancer patients diagnosed <50 years. DESIGN: Hospital-based cohort. SETTING: General and cancer hospitals. PARTICIPANTS: A consecutive series of 2710 patients without a prior history of cancer, diagnosed between 1990 and 2000 with unilateral stage I-III breast cancer aged <50 years. MAIN OUTCOME MEASURES: Calibration and discriminatory accuracy, measured with C-statistics, of estimated 10-year all-cause and breast cancer-specific mortality. RESULTS: Overall, PREDICT's calibration for all-cause mortality was good (predicted versus observed) meandifference: -1.1% (95%CI: -3.2%-0.9%; P = 0.28). PREDICT tended to underestimate all-cause mortality in good prognosis subgroups (range meandifference: -2.9% to -4.8%), overestimated all-cause mortality in poor prognosis subgroups (range meandifference: 2.6%-9.4%) and underestimated survival in patients < 35 by -6.6%. Overall, PREDICT overestimated breast cancer-specific mortality by 3.2% (95%CI: 0.8%-5.6%; P = 0.007); and also overestimated it seemingly indiscriminately in numerous subgroups (range meandifference: 3.2%-14.1%). Calibration was poor in the cohort of patients with the lowest and those with the highest mortality probabilities. Discriminatory accuracy was moderate-to-good for all-cause mortality in PREDICT (0.71 [95%CI: 0.68 to 0.73]), and the results were similar for breast cancer-specific mortality. Adjuvant!'s calibration and discriminatory accuracy for both all-cause and breast cancer-specific mortality were in line with PREDICT's findings. CONCLUSIONS: Although imprecise at the extremes, PREDICT's estimates of 10-year all-cause mortality seem reasonably sound for breast cancer patients <50 years; Adjuvant! findings were similar. Prognostication tools should be used with caution due to the intrinsic variability of their estimates, and because the threshold to discuss adjuvant systemic treatment is low. Thus, seemingly insignificant mortality overestimations or underestimations of a few percentages can significantly impact treatment decision-making.

Indocyanine green fluorescence mapping for sentinel lymph node biopsy in early breast cancer.

INTRODUCTION: A recent feasibility study (ICG-10) has confirmed high sensitivity of ICG fluorescence mapping for sentinel SLN detection in early breast cancer with 95% of nodes both blue and fluorescent. This follow-on study has specifically evaluated a combination of ICG and blue dye for SLN localization. METHODS: Fifty consecutive patients (49 female; 1 male) with unilateral clinically node negative invasive (37) and non-invasive (13) breast cancer underwent SLN biopsy with blue dye and ICG. Median patient age was 48 years and median invasive tumour size 19 mm for primary surgical patients. All patients had a normal pre-operative axillary ultrasound. Nodal and procedural detection rates were calculated for ICG alone and in combination with blue dye. RESULTS: A total of 87 nodes were retrieved with an average nodal count of 1.8 per patient (range 1-4). Eighty four nodes were blue and fluorescent and 3 fluorescent only. Nodal detection rates for ICG alone and combined with blue dye were 100% (87/87) and 96% (84/87) respectively. Metastases were present in 18 nodes (all blue and fluorescent) with 10 patients node positive overall (20%). The procedural detection rate for blue dye and ICG was 96% (48/50) and 2 patients had fluorescent only nodes which were deemed sentinel (4%). CONCLUSION: Fluorescent imaging with ICG is a sensitive, valuable and safe method for SLN biopsy. A combination of blue dye and ICG is useful dual approach when radioisotope is unavailable. ICG has the potential to be a sole tracer agent with improved patient convenience and costs.

Inclusion of KI67 significantly improves performance of the PREDICT prognostication and prediction model for early breast cancer.

BACKGROUND: PREDICT (http://www.predict.nhs.uk) is a prognostication and treatment benefit tool for early breast cancer (EBC). The aim of this study was to incorporate the prognostic effect of KI67 status in a new version (v3), and compare performance with the Predict model that includes HER2 status (v2). METHODS: The validation study was based on 1,726 patients with EBC treated in Nottingham between 1989 and 1998. KI67 positivity for PREDICT is defined as >10% of tumour cells staining positive. ROC curves were constructed for Predict models with (v3) and without (v2) KI67 input. Comparison was made using the method of DeLong. RESULTS: In 1274 ER+ patients the predicted number of events at 10 years increased from 196 for v2 to 204 for v3 compared to 221 observed. The area under the ROC curve (AUC) improved from 0.7611 to 0.7676 (p=0.005) in ER+ patients and from 0.7546 to 0.7595 (p=0.0008) in all 1726 patients (ER+ and ER-). CONCLUSION: Addition of KI67 to PREDICT has led to a statistically significant improvement in the model performance for ER+ patients and will aid clinical decision making in these patients. Further studies should determine whether other markers including gene expression profiling provide additional prognostic information to that provided by PREDICT.

Effect of PREDICT on chemotherapy/trastuzumab recommendations in HER2-positive patients with early-stage breast cancer.

PREDICT is an online prognostication tool for early-stage breast cancer, which incorporates human epidermal growth factor 2 (HER2) status and stratifies absolute treatment benefits for hormone therapy, chemotherapy and trastuzumab. The present study compared historical multidisciplinary team (MDT) decisions regarding adjuvant treatment with PREDICT estimates, to determine whether certain patients are being over- or undertreated, particularly when stratified by age and oestrogen-receptor (ER) status. HER2-positive early-stage breast cancer cases over a five-year period at the Cambridge Breast Unit (Addenbrooke's Hospital, Cambridge, UK) were retrospectively reviewed. Patients receiving neo-adjuvant therapy were excluded. Adjuvant chemotherapy/trastuzumab recommendations based on PREDICT (<3%, no benefit; 3-5%, discuss treatment; and >5%, recommend treatment) were compared with actual MDT decisions. In total, 109 eligible patients were identified. The average age at diagnosis was 59.6 years, with 21 patients older than 70 years (19%). Four patients were predicted to gain an absolute benefit of >5% from chemotherapy/ trastuzumab, but were not offered treatment (all >70 years). Amongst the 19 patients aged >70 years predicted to benefit >3%, six were not offered treatment (32%). In the patients aged <69 years, there was evidence of overtreatment with adjuvant chemotherapy/trastuzumab in 8 out of 12 cases with <3% benefit using PREDICT. For all 20 patients with ER-negative tumours, the MDT and PREDICT decisions correlated, whilst for ER-positive cases, more than half (8 out of 14) were offered treatment despite a <3% predicted benefit. PREDICT can aid decision-making in HER2-positive early-stage breast cancer by identifying older patients at risk of undertreatment with chemotherapy/trastuzumab, and by reducing the overtreatment of patients with little predicted benefit, particularly in ER-positive disease.

Patient reported outcome measures (PROMs) following forward planned field-in field IMRT: results from the Cambridge Breast IMRT trial.

BACKGROUND: The use of intensity-modulated radiotherapy (IMRT) in breast cancer reduces clinician-assessed breast tissue toxicity including fibrosis, telangectasia and sub-optimal cosmesis. Patient reported outcome measures (PROMs) are also important as they provide the patient's perspective. This longitudinal study reports on (a) the effect of forward planned field-in-field IMRT (∼simple IMRT) on PROMs compared to standard RT at 5 years after RT, (b) factors affecting PROMs at 5years after RT and (c) the trend of PROMs over 5 years of follow up. METHODS: PROMs were assessed at baseline (pre-RT), 6, 24 and 60 months after completion of RT using global health (EORTC QLQ C30) and 4 breast symptom questions (BR23). Also, 4 breast RT-specific questions were included at 6, 24 and 60 months: change in skin appearance, firmness to touch, reduction in breast size and overall change in breast appearance since RT. The benefits of simple IMRT over standard RT at 5 years after RT were assessed using standard t-test for global health and logistic regression analysis for breast symptom questions and breast RT-specific questions. Clinical factors affecting PROMs at 5 years were investigated using a multivariate analysis. A repeated mixed model was applied to explore the trend over time for each of PROMs. RESULTS: (89%) 727/815, 84%, 81% and 61% patients completed questionnaires at baseline, 6, 24 and 60 months respectively. Patients reported worse toxicity for all four BR23 breast symptoms at 6 months, which then improved over time (p<0.0001). They also reported improvement in skin appearance and breast hardness over time (p<0.0001), with no significant change for breast shrinkage (p=0.47) and overall breast appearance (p=0.13). At 5years, PROMs assessments did not demonstrate a benefit for simple IMRT over standard radiotherapy. Large breast volume, young age, baseline surgical cosmesis and post-operative infection were the most important variables to affect PROMs. CONCLUSIONS: This study was unable to demonstrate the benefits of IMRT on PROMs at 5years. PROMs are influenced by non-radiotherapy factors and surgical factors should be optimised to improve patients' outcome. Only a small proportion of patients report moderate-severe breast changes post radiotherapy, with most PROMs improving over time. The difference in clinician assessment and PROMs outcome requires further investigation.

Alcohol consumption and survival after a breast cancer diagnosis: a literature-based meta-analysis and collaborative analysis of data for 29,239 cases.

BACKGROUND: Evidence for an association of alcohol consumption with prognosis after a diagnosis of breast cancer has been inconsistent. We have reviewed and summarized the published evidence and evaluated the association using individual patient data from multiple case cohorts. METHODS: A MEDLINE search to identify studies published up to January 2013 was performed. We combined published estimates of survival time for "moderate drinkers" versus nondrinkers. An analysis of individual participant data using Cox regression was carried out using data from 11 case cohorts. RESULTS: We identified 11 published studies suitable for inclusion in the meta-analysis. Moderate postdiagnosis alcohol consumption was not associated with overall survival [HR, 0.95; 95% confidence interval (CI), 0.85-1.05], but there was some evidence of better survival associated with prediagnosis consumption (HR, 0.80; 95% CI, 0.73-0.88). Individual data on alcohol consumption for 29,239 cases with 4,839 deaths were available from the 11 case cohorts, all of which had data on estrogen receptor (ER) status. For women with ER-positive disease, there was little evidence that pre- or postdiagnosis alcohol consumption is associated with breast cancer-specific mortality, with some evidence of a negative association with all-cause mortality. On the basis of a single study, moderate postdiagnosis alcohol intake was associated with a small reduction in breast cancer-specific mortality for women with ER-negative disease. There was no association with prediagnosis intake for women with ER-negative disease. CONCLUSION: There was little evidence that pre- or post-diagnosis alcohol consumption is associated with breast cancer-specific mortality for women with ER-positive disease. There was weak evidence that moderate post-diagnosis alcohol intake is associated with a small reduction in breast cancer-specific mortality in ER-negative disease. IMPACT: Considering the totality of the evidence, moderate postdiagnosis alcohol consumption is unlikely to have a major adverse effect on the survival of women with breast cancer.

The Cambridge post-mastectomy radiotherapy (C-PMRT) index: a practical tool for patient selection.

BACKGROUND AND PURPOSE: Post mastectomy radiotherapy (PMRT) reduces loco-regional recurrence (LRR) and has been associated with survival benefit. It is recommended for patients with T3/T4 tumours and/or ⩾ 4 positive lymph nodes (LN). The role of PMRT in 1-3 positive LN and LN negative patients is contentious. The C-PMRT index has been designed for selecting PMRT patients, using independent prognostic factors for LRR. This study reports a 10 year experience using this index. MATERIALS AND METHODS: The C-PMRT index was constructed using the following prognostic factors (a) number of positive LN/lymphovascular invasion, (b) tumour size (c) margin status and (d) tumour grade. Patients were categorised as high (H) risk, intermediate (I) risk and low (L) risk. PMRT was recommended for H and I risk patients. The LRR, distant metastasis and overall survival (OS) rates were measured from the day of mastectomy. RESULTS: From 1999 to 2009, 898 invasive breast cancers in 883 patients were treated by mastectomy (H: 323, I: 231 and L: 344). At a median follow up of 5.2 years, 4.7% (42/898) developed LRR. The 5-year actuarial LRR rates were 6%, 2% and 2% for the H, I and L risk groups, respectively. 1.6% (14/898) developed isolated LRR (H risk n = 4, I risk group n = 0 and L risk n = 10). The 5-year actuarial overall survival rates were 67%, 77% and 90% for H, I and L risk groups, respectively. CONCLUSION: Based on published literature, one would have expected a higher LRR rate in the I risk group without adjuvant RT. We hypothesise that the I risk group LRR rates have been reduced to that of the L risk group by the addition of RT. Apart from LN status and tumour size, other prognostic factors should also be considered in selecting patients for PMRT. This pragmatic tool requires further validation.

Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial.

BACKGROUND: Anthracyclines and taxanes have been the standard neoadjuvant chemotherapies for breast cancer in the past decade. We aimed to assess safety and efficacy of the addition of gemcitabine to accelerated paclitaxel with epirubicin and cyclophosphamide, and also the effect of sequencing the blocks of epirubicin and cyclophosphamide and paclitaxel (with or without gemcitabine). METHODS: In our randomised, open-label, 2×2 factorial phase 3 trial (Neo-tAnGo), we enrolled women (aged >18 years) with newly diagnosed breast cancer (tumour size >20 mm) at 57 centres in the UK. Patients were randomly assigned via a central randomisation procedure to epirubicin and cyclophosphamide then paclitaxel (with or without gemcitabine) or paclitaxel (with or without gemcitabine) then epirubicin and cyclophosphamide. Four cycles of each component were given. The primary endpoint was pathological complete response (pCR), defined as absence of invasive cancer in the breast and axillary lymph nodes. This study is registered with EudraCT (2004-002356-34), ISRCTN (78234870), and ClinicalTrials.gov (NCT00070278). FINDINGS: Between Jan 18, 2005, and Sept 28, 2007, we randomly allocated 831 participants; 207 received epirubicin and cyclophosphamide then paclitaxel; 208 were given paclitaxel then epirubicin and cyclophosphamide; 208 had epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine; and 208 received paclitaxel and gemcitabine then epirubicin and cyclophosphamide. 828 patients were eligible for analysis. Median follow-up was 47 months (IQR 37-51). 207 (25%) patients had inflammatory or locally advanced disease, 169 (20%) patients had tumours larger than 50 mm, 413 (50%) patients had clinical involvement of axillary nodes, 276 (33%) patients had oestrogen receptor (ER)-negative disease, and 191 (27%) patients had HER2-positive disease. Addition of gemcitabine did not increase pCR: 70 (17%, 95% CI 14-21) of 404 patients in the epirubicin and cyclophosphamide then paclitaxel group achieved pCR compared with 71 (17%, 14-21) of 408 patients who received additional gemcitabine (p=0·98). Receipt of a taxane before anthracycline was associated with improved pCR: 82 (20%, 95% CI 16-24) of 406 patients who received paclitaxel with or without gemcitabine followed by epirubicin and cyclophosphamide achieved pCR compared with 59 (15%, 11-18) of 406 patients who received epirubicin and cyclophosphamide first (p=0·03). Grade 3 toxicities were reported at expected levels: 173 (21%) of 812 patients who received treatment and had full treatment details had grade 3 neutropenia, 66 (8%) had infection, 41 (5%) had fatigue, 41 (5%) had muscle and joint pains, 37 (5%) had nausea, 36 (4%) had vomiting, 34 (4%) had neuropathy, 23 (3%) had transaminitis, 16 (2%) had acute hypersensitivity, and 20 (2%) had a rash. 86 (11%) patients had grade 4 neutropenia and 3 (<1%) had grade 4 infection. INTERPRETATION: Although addition of gemcitabine to paclitaxel and epirubicin and cyclophosphamide chemotherapy does not improve pCR, sequencing chemotherapy so that taxanes are received before anthracyclines could improve pCR in standard neoadjuvant chemotherapy for breast cancer. FUNDING: Cancer Research UK, Eli Lilly, Bristol-Myers Squibb.

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.

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 patient's 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.

Reverse abdominoplasty: a practical option for oncological trunk reconstruction.

OBJECTIVES: Following radical oncological resection, full-thickness upper central trunk defects present a significant challenge. Common reconstructive options include pedicled flaps, such as pectoralis major, rectus abdominis, and latissimus dorsi. In complex cases, free tissue transfer may be required. Reverse abdominoplasty, although initially described for cosmetic body contouring, can be used to reconstruct upper central trunk defects following radical tumour ablation. We present 4 such applications in the management of advanced or recurrent malignancies and review the relative indications for this approach. METHODS: Four consecutive cases (2004-2010) were reviewed with respect to indication, operative procedure, and complications. RESULTS: There were no cases of complete flap loss. One patient underwent revision for marginal flap necrosis while another developed local recurrence, requiring re-excision and reconstruction with flap advancement. CONCLUSIONS: Where pedicled flaps are unavailable or insufficient, adjacent abdominal tissue can be recruited into chest wall defects, avoiding microsurgical free tissue transfer. The authors feel that the reverse abdominoplasty is currently underused in this context and offers an excellent alternative in complex cases where other reconstructive options are unavailable, or where comorbidities preclude free-tissue transfer. The technique is versatile, simple to perform and affords an acceptable cosmetic outcome, yet is not widely reported in the literature. It has particular merit in cases with a high chance of disease recurrence, in the management of recurrent breast cancer, and in patients with multiple comorbidities. The reverse abdominoplasty should therefore be considered when evaluating patients for oncological trunk reconstruction.

Central breast excision with immediate autologous reconstruction for recurrent periductal sepsis: an application of oncoplastic surgical techniques.

OBJECTIVE: The aim of this procedure was to definitively treat periductal mastitis and periareolar sepsis which was previously resistant to multiple surgical procedures and nonoperative treatment of chronic nipple sepsis. METHODS: We employed a multidisciplinary approach to the treatment of end-stage periductal mastitis using a combination of central breast excision and immediate autologous latissimus dorsi flap reconstruction. RESULTS: Clearance of periductal mastitis and infection has been achieved with no recurrence at 3 years. Good symmetry of breast shape and volume has been achieved using this technique. CONCLUSIONS: This method of partial breast reconstruction, commonly used for reconstruction of breast cancer ablative defects, may also provide good outcomes in nonmalignant disease.

The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA­RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

How does imaging frequency and soft tissue motion affect the PTV margin size in partial breast and boost radiotherapy?

PURPOSE: This study investigates (i) the effect of verification protocols on treatment accuracy and PTV margins for partial breast and boost breast radiotherapy with short fractionation schema (15 fractions), (ii) the effect of deformation of the excision cavity (EC) on PTV margin size, (iii) the imaging dose required to achieve specific PTV margins. METHODS AND MATERIALS: Verification images using implanted EC markers were studied in 36 patients. Target motion was estimated for a 15 fraction partial breast regimen using imaging protocols based on on-line and off-line motion correction strategies (No Action Level (NAL) and the extended NAL (eNAL) protocols). Target motion was used to estimate a PTV margin for each protocol. To evaluate treatment errors due to deformation of the excision cavity, individual marker positions were obtained from 11 patients. The mean clip displacement and daily variation in clip position during radiotherapy were determined and the contribution of these errors to PTV margin calculated. Published imaging dose data were used to estimate total dose for each protocol. Finally the number of images required to obtain a specific PTV margin was evaluated and hence, the relationship between PTV margins and imaging dose was investigated. RESULTS: The PTV margin required to account for excision cavity motion, varied between 10.2 and 2.4mm depending on the correction strategy used. Average clip movement was 0.8mm and average variation in clip position during treatment was 0.4mm. The contribution to PTV margin from deformation was estimated to be small, less than 0.2mm for both off-line and on-line correction protocols. CONCLUSION: A boost or partial breast PTV margin of ∼10 mm, is possible with zero imaging dose and workload, however, patients receiving boost radiotherapy may benefit from a margin reduction of ∼4 mm with imaging doses from 0.4cGy to 25cGy using an eNAL protocol. PTV margin contributions from deformation errors are likely to be small in comparison to other sources of error, i.e., set up or delineation.

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.