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For older patients with clinically lymph node-negative breast cancer who have estrogen receptor-positive tumors and are treated with tamoxifen, randomized trials comparing axillary lymph node dissection (ALND) versus no ALND show that the omission of ALND improves patient quality of life and has no adverse effects on mortality. These results have served to justify sentinel node biopsy (SNB) omission in selected older patients with breast cancer. More recently, clinical trials were launched to assess SNB omission in younger patients, with recurrence and survival as the primary outcomes of interest. Three important considerations serve as the basis for these ongoing trials. First, it is assumed that SNB omission will improve patient quality of life, although, to date, there is no level I evidence to support this assumption. Second, axillary surgery has never been shown to reduce breast cancer mortality, but it does reduce the risk of axillary recurrences, although adjuvant systemic therapy and radiotherapy also reduce these recurrence risks. Finally, nodal status is losing importance as a guide for adjuvant systemic therapy decision making because these decisions are now increasingly predicated on tumor biomarkers and gene profiling, but it is gaining importance for adjuvant radiotherapy decision making. Because quality-of-life considerations are the primary motivation for abandoning SNB, there is a need for randomized trials comparing SNB versus no SNB/no axillary surgery, with quality of life as the primary end point (level I evidence). Moreover, suitable alternatives to guide adjuvant radiotherapy decision making will require validation before SNB omission can be justified for patients of all ages who have clinically node-negative breast cancer. LAY SUMMARY: In this review article, the authors provide a brief historical overview of the role of axillary surgery in breast cancer management and discuss additional studies and ramifications that should be considered before abandoning the sentinel node biopsy (SNB) procedure. Specifically, there is a need for level I evidence demonstrating that omission of the SNB procedure will improve patient quality of life and a need to validate suitable alternatives to SNB as a guide for adjuvant radiotherapy decision making.

AIMS: Adjuvant radiotherapy is recommended for most patients with early breast cancer (EBC) receiving breast-conserving surgery and those at moderate/high risk of recurrence treated by mastectomy. During the first wave of COVID-19 in England and Wales, there was rapid dissemination of randomised controlled trial-based evidence showing non-inferiority for five-fraction ultra-hypofractionated radiotherapy (HFRT) regimens compared with standard moderate-HFRT, with guidance recommending the use of five-fraction HFRT for eligible patients. We evaluated the uptake of this recommendation in clinical practice as part of the National Audit of Breast Cancer in Older Patients (NABCOP). MATERIALS AND METHODS: Women aged ≥50 years who underwent surgery for EBC from January 2019 to July 2020 were identified from the Rapid Cancer Registration Dataset for England and from Wales Cancer Network data. Radiotherapy details were from linked national Radiotherapy Datasets. Multivariate mixed-effects logistic regression models were used to assess characteristics influential in the use of ultra-HFRT. RESULTS: Among 35 561 women having surgery for EBC, 71% received postoperative radiotherapy. Receipt of 26 Gy in five fractions (26Gy5F) increased from

Background: Adjuvant whole breast radiotherapy (RT) is provided to almost all women with early-stage invasive breast cancer after breast conserving surgery and appropriate systemic therapy. While there is increasing interest to personalize the use of RT based on molecular profiling, to date, there is no molecular signature available to reliably assess the benefit of radiotherapy after surgical resection. Here we assess the ability of a 16-gene signature named Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) to identify who may be suitable candidates for radiotherapy omission in patients of the Scottish Conservation Trial. Methods: The POLAR signature was applied to archival tissue from the Scottish Conservation Trial, which randomized 585 patients with stage I-II breast cancer, tumor size < 4 cm, and age ≤70 years old to receive RT or not. The archival tissue was measured for ER (ER+ >10%), PgR (PgR+ ≥20%), Ki67 (Ki67 high ≥14%), and HER2 (HER2+ defined as HER2 over-expressed or amplified). 26% received adjuvant chemotherapy, the remainder received tamoxifen 20 mg/daily for 5 years. Cox models for the locoregional recurrence (LRR) endpoint tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered competing events. Results: 224 patients had tissue available and complete clinical data for analysis, 40 (18%) were node-positive. The distribution of clinicopathologic variables between the RT and no RT arms remained balanced. 43% were ER+/PgR+/Ki67 low/HER2-, 31% were ER+/HER2-/Ki67 high or PgR-, 5% were HER2+, and 13% were triple negative. The continuous standardized POLAR score was prognostic for LRR in the no RT arm after adjusting for relevant covariates (HR=1.78 [1.20-2.64], p=0.003). For patients with a POLAR-high score, the 10-year LRR rate was 31% [21%-42%] for patients not receiving RT and 8% [3%-15%] for patients receiving RT (HR 0.36 [0.19-0.69], p=0.0022). For patients with a POLAR low score, the 10-year LRR rates were 20% [10%-33%] for patients not receiving RT and 6% [1%-18%] for patients receiving RT; HR=0.28 [0.08-0.98], p=0.046). In the subgroup of node-negative patients with ER+/HER2-negative tumors (N=137), there was a statistically significant RT benefit for patients with a POLAR high score (HR=0.31 [0.11-0.88], p=0.028) but not for patients with a POLAR low score (HR=0.5 [0.1-2.4], p=0.39). Conclusions: For patients with early-stage invasive breast cancer treated with breast-conserving surgery without RT, POLAR is prognostic for LRR and may refine the selection of “low risk” for omission of RT. Citation Format: Karen J. Taylor, John MS Bartlett, John Bennett, S. Laura Chang, Bradley Arrick, Frederick Baehner, Joseph F. Loane, Tammy Piper, Elizabeth Mallon, Joanna Dunlop, Wilma J. Jack, Jacqueline Caldwell, Ian Kunkler, Linda J. Williams, Corey W. Speers, Felix Y. Feng, Lori Pierce, David A. Cameron. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in early-stage invasive breast cancer patients of the Scottish Conservation Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-12.

Background: There are currently no commercially available tests to identify early stage breast cancer patients treated with breast conserving surgery (BCS) and systemic therapy at low risk of locoregional recurrence (LRR) for whom postoperative radiotherapy (RT) may be safely omitted. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify invasive breast cancer patients who may be candidates for RT omission after BCS. In this work, we seek to validate POLAR in a meta-analysis of three RCTs of BCS +/- RT: SweBCG91RT, Scottish Conservation Trial (SCT) and Princess Margaret Hospital (PMH). Methods: A patient-level meta-analysis was performed in 623 node-negative breast cancer patients with ER+/HER2-negative tumors who were enrolled in the three RCTs and for whom primary tumor material was available for analysis. Contributions from each cohort were as follows: SweBCG91RT N=354 (57%), SCT N=137 (22%), and PMH N=132 (21%). Numbers of LRR events in each cohort were as follows: SweBCG91RT N=72 (20%), SCT N=28 (20%), and PMH N=16 (12%). There was a mix of systemic therapy used (no systemic therapy for SweBCG91RT, chemotherapy or adjuvant endocrine therapy, but not both, in SCT, and tamoxifen but no chemotherapy for PMH). Median follow-up time for the patients who did not have LRR was 13.3 years for SweBCG91RT, 21.1 years for SCT, and 8.6 years for PMH. A multivariable Cox proportional hazards model on time to LRR, including the continuous standardized POLAR score, RT, and interaction, stratified by cohort, was used to test the interaction between the continuous POLAR score and RT. Additional Cox models tested the association between treatment arms separately for patients with a low and high POLAR score using a pre-specified cut point. Cumulative incidences were computed, with distant metastasis and death without recurrence considered as competing events. Results: The test for interaction between RT treatment and POLAR was statistically significant (p = 0.022). Patients with a high POLAR score (N=429 [69%]) had a large benefit from RT (10-year cumulative incidence of LRR: 20% [15%-26%] for those not treated with RT vs 7% [4%-11%] for those treated with RT; hazard ratio for RT vs no RT: 0.37 [0.23-0.60], p < 0.001), whereas there was no evidence of benefit from RT for patients with a low POLAR score (N=194 [31%], 10-year cumulative incidence of LRR: 5% [2%-11%] for those not treated with RT vs 7% [3%-14%] for those treated with RT; hazard ratio for RT vs no RT: 0.92 [0.42-2.02], p = 0.832). Conclusions: To our knowledge, POLAR is the first genomic classifier that is not only prognostic for LRR but also predictive, showing a significant interaction between RT and the classifier. Patients with a high POLAR score should be recommended radiotherapy while patients with a low score may be candidates for omission of radiotherapy after breast conserving surgery. Citation Format: Per Karlsson, Anthony Fyles, S. Laura Chang, Bradley Arrick, Frederick Baehner, Per Malmström, Mårten Fernö, Erik Holmberg, Martin Sjöström, Fei-Fei Liu, David A. Cameron, Linda J. Williams, John MS Bartlett, Joanna Dunlop, Jacqueline Caldwell, Joseph F. Loane, Elizabeth Mallon, Tammy Piper, Wilma J. Jack, Ian Kunkler, Felix Y. Feng, Corey W. Speers, Lori Pierce, John Bennett, Karen J. Taylor. Validation of Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) in a meta-analysis of three randomized controlled trials of breast conserving surgery +/- radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-03.

Summary Background BIG 3-07/TROG 07.01 is an international, multicentre, randomised, controlled, phase 3 trial evaluating tumour bed boost and hypofractionation in patients with non-low-risk ductal carcinoma in situ following breast-conserving surgery and whole breast radiotherapy. Here, we report the effects of diagnosis and treatment on health-related quality of life (HRQOL) at 2 years. Methods The BIG 3-07/TROG 07.01 trial is ongoing at 118 hospitals in 11 countries. Women aged 18 years or older with completely excised non-low-risk ductal carcinoma in situ were randomly assigned, by use of a minimisation algorithm, to tumour bed boost or no tumour bed boost, following conventional whole breast radiotherapy or hypofractionated whole breast radiotherapy using one of three randomisation categories. Category A was a 4-arm randomisation of tumour bed boost versus no boost following conventional whole breast radiotherapy (50 Gy in 25 fractions over 5 weeks) versus hypofractionated whole breast radiotherapy (42·5 Gy in 16 fractions over 3·5 weeks). Category B was a 2-arm randomisation between tumour bed boost versus no boost following conventional whole breast radiotherapy, and category C was a 2-arm randomisation between tumour bed boost versus no boost following hypofractionated whole breast radiotherapy. Stratification factors were age at diagnosis, planned endocrine therapy, and treating centre. The primary endpoint, time to local recurrence, will be reported when participants have completed 5 years of follow-up. The HRQOL statistical analysis plan prespecified eight aspects of HRQOL, assessed by four questionnaires at baseline, end of treatment, and at 6, 12, and 24 months after radiotherapy: fatigue and physical functioning (EORTC QLQ-C30); cosmetic status, breast-specific symptoms, arm and shoulder functional status (Breast Cancer Treatment Outcome Scale); body image and sexuality (Body Image Scale); and perceived risk of invasive breast cancer (Cancer Worry Scale and a study-specific question). For each of these measures, tumour bed boost was compared with no boost, and conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy, by use of generalised estimating equation models. Analyses were by intention to treat, with Hochberg adjustment for multiple testing. This trial is registered with ClinicalTrials.gov , NCT00470236 . Findings Between June 1, 2007, and Aug 14, 2013, 1208 women were enrolled and randomly assigned to receive no tumour bed boost (n=605) or tumour bed boost (n=603). 396 of 1208 women were assigned to category A: conventional whole breast radiotherapy with tumour bed boost (n=100) or no boost (n=98), or to hypofractionated whole breast radiotherapy with tumour bed boost (n=98) or no boost (n=100). 447 were assigned to category B: conventional whole breast radiotherapy with tumour bed boost (n=223) or no boost (n=224). 365 were assigned to category C: hypofractionated whole breast radiotherapy with tumour bed boost (n=182) or no boost (n=183). All patients were followed up at 2 years for the HRQOL analysis. 1098 (91%) of 1208 patients received their allocated treatment, and most completed their scheduled HRQOL assessments (1147 [95%] of 1208 at baseline; 988 [87%] of 1141 at 2 years). Cosmetic status was worse with tumour bed boost than with no boost across all timepoints (difference 0·10 [95% CI 0·05–0·15], global p=0·00014, Hochberg-adjusted p=0·0016); at the end of treatment, the estimated difference between tumour bed boost and no boost was 0·13 (95% CI 0·06–0·20; p=0·00021), persisting at 24 months (0·13 [0·06–0·20]; p=0·00021). Arm and shoulder function was also adversely affected by tumour bed boost across all timepoints (0·08 [95% CI 0·03–0·13], global p=0·0033, Hochberg adjusted p=0·045); the difference between tumour bed boost and no boost at the end of treatment was 0·08 (0·01 to 0·15, p=0·021), and did not persist at 24 months (0·04 [–0·03 to 0·11], p=0·29). None of the other six prespecified aspects of HRQOL differed significantly after adjustment for multiple testing. Conventional whole breast radiotherapy was associated with worse body image than hypofractionated whole breast radiotherapy at the end of treatment (difference –1·10 [95% CI –1·79 to –0·42], p=0·0016). No significant differences were reported in the other PROs between conventional whole breast radiotherapy compared with hypofractionated whole breast radiotherapy. Interpretation Tumour bed boost was associated with persistent adverse effects on cosmetic status and arm and shoulder functional status, which might inform shared decision making while local recurrence analysis is pending. Funding National Health and Medical Research Council, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society.

Background: Radiotherapy (RT) plays an important role in the multimodal treatment of breast cancer (BC). Despite improvements in the accuracy of delivering radiation to specific biological target volumes, the clinical response of BC to RT is still affected by intrinsic/acquired radioresistance. These resistant cancer cells can contribute to the development of recurrent disease and poor patient outcomes. Clinical signs of RT response are often not apparent for several weeks post-treatment; patients who fail to respond will therefore initially go undetected. There are currently no clinically validated biomarkers that can predict which patients will respond to RT or assess response during treatment. Our study aims to address this major clinical need through the identification and validation of biomarkers of radiation responsiveness. Methods: The effects of different radiation doses (2 - 10Gy) at a range of time points (1 - 24h) were investigated by analysing the protein secretion profiles from 3 BC cell lines: MCF-7 (ER+), ZR-751 (ER+) and MDA-MB-231 (ER-). Conditioned media was collected from each dose/time point and proteins isolated for mass spec analysis. For comparison, radioresistant models were derived from each of the 3 cell lines and were characterized by proliferation and colony formation assays, invasion and migration assays, whole-genome transcriptomic sequencing (WGTS) analysis and western blotting. To assess intrinsic response to RT a panel of 16 BC cell lines were evaluated by colony formation assays following a 2Gy dose of radiation. WGTS of a patient cohort of 230 (138 ER+ve, 92 ER-ve) post-menopausal women with BC, treated with breast conserving surgery and adjuvant RT but no systemic adjuvant therapy, with a median follow-up of 14 years, is currently underway. Results: 9 biomarkers emerged whose secretion was significantly increased with radiation. These were evaluated by western blotting of conditioned media 24h after a 2Gy dose of RT in matched radio-sensitive and resistant cell lines; this confirmed significantly higher levels of radiation induced secretion from sensitive cells compared to resistant. Radioresistant cell lines were characterised by epithelial-to-mesenchymal-transition, enhanced invasion/migration, loss of ER and PgR and increased EGFR and PI3K signaling activity. Initial mechanistic investigations suggest that biomarker release in response to radiation occurs via microvesicles. A blood-based assay to test the level of these secreted biomarkers is currently under development. Pre-treatment levels of the 9 biomarkers were also found to be associated with prediction of intrinsic response to RT at both gene and protein level. A gene expression signature comprising the 9 candidates is strongly associated with the intrinsic response to RT across the 16 BC cell lines studied, with higher expression found in those more sensitive to RT compared with those less sensitive or resistant. Validation of the predictive power of these biomarkers in terms of recurrence-free and overall BC specific survival is currently being assessed at gene and protein level in the patient cohort. Conclusions: We have identified 9 biomarkers which are released from BC cells sensitive to radiation 24h after a 2Gy dose (in line with current clinical standards) but not from radio-resistant derivatives.A blood based assay is currently under development which has the potential to monitor response to RT in the neoadjuvant and palliative settings.Intracellular levels of the 9 biomarkers are strongly associated with intrinsic response to RT and may hold predictive potential.These biomarkers may have the potential to improve patient care by identifying patients less likely to benefit from RT, paving the way for personalization of treatment, including altered dosing schedules and the future use of emerging radio-sensitizers. Citation Format: James Meehan, Mark Gray, Carlos Martinez-Perez, Charlene Kay, J Michael Dixon, Jimi Wills, Carol Ward, Alex von Kriegsheim, Niall Quinn, Olga Oikonomidou, David Cameron, Simon P Langdon, David Argyle, Ian H Kunkler, Arran K Turnbull. Development and validation of novel biomarkers of response to radiotherapy in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-18.

Purpose of review We review the role of postmastectomy radiotherapy (PMRT) in the management of patients with early breast cancer.Recent findings PMRT in patients with 4 or more involved axillary lymph nodes is the current standard of care but the indications for PMRT in patients with 1–3 involved nodes remain controversial. The Early Breast Cancer Trialists’ Collaborative Group meta-analysis of randomised trials of PMRT provides the most comprehensive level 1 evidence base. However, its applicability in contemporary practice in the context of recent multidisciplinary advances in surgery, radiation therapy and systemic therapy remains challenging.Summary The lack of consensus on the indications for PMRT in patients with 1–3 positive nodes underpins the variations in the national and international guidelines on PMRT. We emphasise the need for contemporary randomised trial data, and the potential to refine patient selection for PMRT using novel biomarkers of recurrence and radiosensitivity.

Background: Wholebreast irradiation (WBI) after breast conserving surgery for DCIS reduces therisk of local recurrence including invasive recurrence. The objective of BIG3-07/TROG 07.01 is to test radiation dose escalation to the tumor bed (tumorbed boost) and fractionation sensitivity of whole breast irradiation (WBI) inpatients with non-low risk DCIS treated with breast conserving therapy. Methods: BIG3-07/TROG 07.01 is an international, multicenter, randomized, controlled, phase 3 trial. Eligible women were ≥18 years ofage with completely resected non-low risk DCIS defined as age Results: BetweenJune 2007 and June 2014, 1608 patients were randomized to have no boost (805patients) or boost (803 patients) after WBI. Conventional WBI was given in 831 patients(no boost in 416 patients; boost in 415 patients). Hypofractionated WBI wasgiven in 777 patients (no boost in 389 patients; boost in 388 patients). Adjuvantendocrine therapy was planned in 106 patients (13%) in the no boost group and105 patients (13%) in the boost group. Median follow-up was 6.6 years. The 5-yearfree-from- local recurrence rates were 93% in the no boost group and 97% in theboost group (hazard ratio, 0.47; 95% confidence interval [CI], 0.31 to 0.72;P Conclusions: Inwomen with non-low risk DCIS treatedwith breast conserving surgery, the addition of tumor bed boost followingconventional or hypofractionated WBI reduced local recurrence rates. There wasno difference in local recurrence rates between conventional WBI andhypofractionated WBI. (Registered with ClinicalTrials.gov, NCT00470236.) Citation Format: Boon Hui Chua, Emma Link, Ian Kunkler, Ivo Olivotto, Antonia Helen Westenberg, Timothy Whelan, Guenther Gruber, Breast International Group (BIG)-aisbl, Trans Tasman Radiation Oncology Group, Scottish Cancer Trials Breast Group, Canadian Cancer Trials Group, European Organization for Research and Treatment of Cancer, International Breast Cancer Study Group, Cancer Trials Ireland. A randomized phase III study of radiation doses and fractionation schedules in non-low risk ductal carcinoma in situ (DCIS) of the breast (BIG 3-07/TROG 07.01) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-04.

Breast cancer is increasingly prevalent in older adults and is a substantial part of routine oncology practice. However, management of breast cancer in this population is challenging because the disease is highly heterogeneous and there is insufficient evidence specific to older adults. Decision making should not be driven by age alone but should involve geriatric assessments plus careful consideration of life expectancy, competing risks of mortality, and patient preferences. A multidisciplinary taskforce, including members of the European Society of Breast Cancer Specialists and International Society of Geriatric Oncology, gathered to expand and update the previous 2012 evidence-based recommendations for the management of breast cancer in older individuals with the endorsement of the European Cancer Organisation. These guidelines were expanded to include chemotherapy toxicity prediction calculators, cultural and social considerations, surveillance imaging, genetic screening, gene expression profiles, neoadjuvant systemic treatment options, bone-modifying drugs, targeted therapies, and supportive care. Recommendations on geriatric assessment, ductal carcinoma in situ, screening, primary endocrine therapy, surgery, radiotherapy, adjuvant systemic therapy, and secondary breast cancer were updated.

Background:In breast cancer (BC), radiotherapy (RT) is used adjuvantly to prevent recurrence and also in the palliative setting. Clinical signs of RT response are often not apparent for several weeks post-treatment and we currently lack tools to predict or monitor tumor response to RT early during treatment. The aim was to identify tumor-secreted biomarkers whose release reflects response to RT, which could be monitored during treatment in the blood or intratumorally by an implantable biosensor, currently under development within the Implantable Microsystems for Personalised Anti-Cancer Therapy (IMPACT) program. Methods: A series of experiments assessed the effect of different radiation doses (2-10Gy) on 3 human BC cell lines – MDA-MB-231 (ER-), MCF-7 (ER+) and HBL-100 (ER-) –, 1 canine breast cancer and 2 sheep lung cancer lines. Culture media was collected from each dose experiment at a range of post-radiation time-points (1-24 hours). Proteins were isolated from collected media for secretome mass spectrometry (MS) analysis. A subset of treatment/time conditions were repeated in the same BC cell lines and radioresistant (RR) derivatives from which RNA was extracted and analysed using Lexogen QuantSeq for whole-genome transcriptomics.In-lab candidate biomarker validation was carried out using immuhistochemistry (IHC), immunofluorescence (IF) and western blotting (WB) using validated antibodies. Levels of candidate biomarkers were also assessed in normal and untreated BC tissues using IHC. ELISA-based methods are currently under investigation for detection of the lead candidate biomarkers in the blood of large animal cancer models treated with RT. Results: Biomarker discovery using the MS data revealed 4 promising candidates: EIF3G, SEC24C, YBX3 and TK1. These are released from BC and animal cancer cells sensitive to radiation in a dose-dependent manner 24 hours after treatment. Analysis of the transcriptomic data showed an 8-fold higher expression of the genes encoding the 4 candidates in the radio-sensitive parental cell lines compared to the RR cell lines. IF and WB confirmed lower intracellular expression of the 4 proteins in RR cells compared to the parental lines. WB of collected culture media confirmed release of each of the 4 candidates 24 hours after a 2Gy dose of radiation in only the parental lines. GAPDH was not found in these media samples, demonstrating that protein release was not due to cell lysis. Conclusions: · We have identified 4 promising biomarkers which are released from cancer cells sensitive to RT and not released from RR derivatives. · All 4 candidates are released 24 hours after a 2Gy radiation dose, which fits with the current clinical dosing schedule where radiation is administered at 24 hour intervals. Ongoing work will elucidate if these biomarkers can be reliably detected in blood or intratumorally using implantable biosensors. · There are currently no validated predictive tools to monitor RT response during treatment. If successfully validated, these biomarkers could have a clinical role in personalising RT dosing schedules and durations for solid tumors in the neoadjuvant and palliative setting, thus optimising treatment and preventing the administration of ineffective RT and its associated side effects. Citation Format: Meehan J, Gray M, Turnbull AK, Martinez-Perez C, Bonello M, Ward C, Langdon SP, McLaughlin S, MacLennan M, Dixon JM, Wills J, Quinn N, Finich AJ, von Kriegsheim A, Cameron D, Kunkler IH, Murray A, Argyle D. Tumor-secreted predictive biomarkers of response to radiotherapy in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-24.

Purpose of the review: More than 50% of all gynaecological cancers can be classified as rare tumours (defined as an annual incidence of

Background: There is limited level 1 evidence on the long term outcomes after loco-regional radiotherapy after breast conserving surgery (BCS) in older patients when they are also receiving appropriate systemic therapy. Practice and guidelines vary. PRIME 2 is an international phase 3 RCT designed to address this specific question. Methods: From April 2003 to December 2009, 1326 patients were randomised to receive (n=658) or not receive (n=668) whole breast radiotherapy (RT). Eligible patients were aged ≥ 65 years, T1-2 (up to 3cm) NO, MO, hormone receptor positive, clear excision margins (minimum 1mm), axillary node negative (pNO) receiving adjuvant hormonal therapy. Patients were eligible if they had grade 3 tumours or lymphovascular invasion but not both. The target accrual was 1300 patients based on detecting a difference in local recurrence rates between 5% in the no RT arm and 2% in the RT arm at 5 years, with 80% power and 5% significance. Ipsilateral breast tumour recurrence (IBTR) was the primary endpoint. Secondary endpoints were regional recurrence, contralateral breast cancer, distant metastases and overall survival. Results: Median follow up is 7.3 years. At 10 years IBTR was 9.8% (95% CI 6.5, 13.2%) in the no RT arm and 0.9% (95% CI 0.1, 1.6%) in the RT arm. The hazard ratio for IBTR for those receiving RT was 0.12 (95% CI 0.05, 0.31)(p Conclusions: 10 year follow data from the PRIME 2 trial shows that the omission of RT after BCS in women aged ≥ 65 years with T1-2, pN0 hormone receptor positive breast cancer results in only 9.8% IBTR. While this rate is significantly reduced by RT (to 0.9%), the absolute reduction is modest, and there were no differences in the secondary endpoints of distant metastases, contralateral breast cancer or overall survival and a small but significant difference in regional recurrence. These data suggest that postoperative radiotherapy in this patient group who are receiving adjuvant hormonal therapy does not impact on overall survival in the context of modern approaches to local and systemic adjuvant therapy, with most patients in both arms dying of causes unrelated to breast cancer or its treatment. Cause of deathNo RTRTTotalCancer25 (28%)29 (37%)54Of which breast cancer8 (9%)3 (4%)11Cardio-vascular9 (10%)14 (18%)23Other/unknown54 (61%)36 (45%)90Total8879167 Citation Format: Ian H Kunkler, Linda J Williams, Wilma Jack, David A Cameron, Michael Dixon. Prime 2 randomised trial (postoperative radiotherapy in minimum-risk elderly): Wide local excision and adjuvant hormonal therapy +/- whole breast irradiation in women =/> 65 years with early invasive breast cancer: 10 year results [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS2-03.

Radiotherapy (RT) is an important treatment modality for the local control of breast cancer (BC). Unfortunately, not all patients that receive RT will obtain a therapeutic benefit, as cancer cells that either possess intrinsic radioresistance or develop resistance during treatment can reduce its efficacy. For RT treatment regimens to become personalised, there is a need to identify biomarkers that can predict and/or monitor a tumour’s response to radiation. Here we describe a novel method to identify such biomarkers. Liquid chromatography-mass spectrometry (LC-MS) was used on conditioned media (CM) samples from a radiosensitive oestrogen receptor positive (ER+) BC cell line (MCF-7) to identify cancer-secreted biomarkers which reflected a response to radiation. A total of 33 radiation-induced secreted proteins that had higher (up to 12-fold) secretion levels at 24 h post-2 Gy radiation were identified. Secretomic results were combined with whole-transcriptome gene expression experiments, using both radiosensitive and radioresistant cells, to identify a signature related to intrinsic radiosensitivity. Gene expression analysis assessing the levels of the 33 proteins showed that 5 (YBX3, EIF4EBP2, DKK1, GNPNAT1 and TK1) had higher expression levels in the radiosensitive cells compared to their radioresistant derivatives, 3 of these proteins (DKK1, GNPNAT1 and TK1) underwent in-lab and initial clinical validation. Western blot analysis using CM samples from cell lines confirmed a significant increase in the release of each candidate biomarker from radiosensitive cells 24 h after treatment with a 2 Gy dose of radiation, no significant increase in secretion was observed in the radioresistant cells after radiation. Immunohistochemistry showed that higher intracellular protein levels of the biomarkers were associated with greater radiosensitivity. Intracellular levels were further assessed in pre-treatment biopsy tissues from patients diagnosed with ER+ BC that were subsequently treated with breast-conserving surgery and RT. High DKK1 and GNPNAT1 intracellular levels were associated with significantly increased recurrence-free survival times, indicating that these two candidate biomarkers have the potential to predict sensitivity to RT. We suggest that the methods highlighted in this study could be utilised for the identification of biomarkers that may have a potential clinical role in personalising and optimising RT dosing regimens, whilst limiting the administration of RT to patients who are unlikely to benefit.

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 =

Rare cancers epidemiology is better known compared to the other rare diseases. Thanks to the long history of the European population-based cancer registries and to the EUROCARE huge database, the burden of rare cancers has been estimated the European (EU28) population. A considerable fraction of all cancers is represented by rare cancers (24%). They are a heterogeneous group of diseases, but they share similar problems: uncertainty of diagnosis, lack of therapies, poor research opportunities, difficulties in clinical trials, lack of expertise and of centres of reference. This paper analyses the major epidemiological indicators of frequency (incidence and prevalence) and outcome (5-year survival) of all rare cancers combined and of selected rare cancers that will be in depth treated in this monographic issue. Source of the results is the RARECAREnet search tool, a database publicly available. Disparities both in incidence and survival, and consequently in prevalence of rare cancers were reported across European countries. Major differences were shown in outcome: 5-year relative survival for all rare cancers together, adjusted by age and case-mix, varied from 55% or more (Italy, Germany, Belgium and Iceland) and less than 40% (Bulgaria, Lithuania and Slovakia). Similarly, for all the analyzed rare cancers, a large survival gap was observed between the Eastern and the Nordic and Central European regions. Dramatic geographical variations were assessed for curable cancers like testicular and non epithelial ovarian cancers. Geographical difference in the annual age-adjusted incidence rates for all rare cancers together varied between >140 per 100,000 (Italy, Scotland, France, Germany, and Switzerland) and

Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network.

Patients with soft tissue sarcoma (STS) experienced better outcomes when treated according to existing clinical practice guidelines either at reference institution or dedicated treatment networks. Despite increasing evidence supporting referral to sarcoma specialised units, up to half of patients are not managed according to guidelines, particularly those in the early stage of their disease requiring surgery. Also, criteria to certify expertise of institutions, such as the treatment volume, are debated and health authorities have only recently started identification of these centres and creation of treatment networks in Europe as well as in several countries. This process have important implications for both patient outcomes and innovation of existing treatment strategies through clinical research, making improvement of clinical pathways a priority for health care authorities. This article will discuss issues with management of patients with STS, such as pathological diagnosis and adherence to guidelines, and the definition of referral centres and networks will be illustrated along with existing experiences and population-based data.

Purpose Debate continues on what is an adequate margin width to define a clear margin and whether there is a need to excise pectoral fascia or remove skin in breast conserving surgery. This study set out to provide answers to these questions. Patients and methods 1411 patients with invasive breast cancer were treated by breast conserving surgery and post-operative whole breast radiotherapy from January 2000 to December 2005. Distance from each margin to any in situ or invasive cancer was measured and recorded. If full thickness of breast tissue was removed no re excision of anterior and posterior margins was performed even if disease was

Germ-cell tumours (GCT) of the testis and penile squamous cell carcinoma (PeSCC) are a rare and a very rare uro-genital cancers, respectively. Both tumours are well defined entities in terms of management, where specific recommendations - in the form of continuously up-to-dated guide lines- are provided. Impact of these tumour is relevant. Testicular GCT affects young, healthy men at the beginning of their adult life. PeSCC affects older men, but a proportion of these patients are young and the personal consequences of the disease may be devastating. Deviation from recommended management may be a reason of a significant prognostic worsening, as proper treatment favourably impacts on these tumours, dramatically on GCT and significantly on PeSCC. RARECAREnet data may permit to analyse how survivals may vary according to geographical areas, histology and age, leading to assume that non-homogeneous health-care resources may impact the cure and definitive outcomes. In support of this hypothesis, some epidemiologic datasets and clinical findings would indicate that survival may improve when appropriate treatments are delivered, linked to a different accessibility to the best health institutions, as a consequence of geographical, cultural and economic barriers. Finally, strong clues based on epidemiological and clinical data support the hypothesis that treatment delivered at reference centres or under the aegis of a qualified multi-institutional network is associated with a better prognosis of patients with these malignancies. The ERN EURACAN represents the best current European effort to answer this clinical need.

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18–20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18–20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.

Objective: Predicting the outcome of breast cancer (BC) patients based on sentinel lymph node (SLN) status without axillary lymph node dissection (ALND) is a matter of debate, especially when it comes to the definition of regional nodal irradiation (RNI). This is even unclear in the framework of primary systemic therapy (PST). The aim of the NORA (NOdal RAdiotherapy) Survey was to examine the patterns of RNI practiced by European Radiation Oncology centers. Methods: A web questionnaire was distributed to EORTC centers, and responses were received during the period between July 2013-January 2014. Results: A total of 81 European and 3 non-European answers were analyzed. While 3D planning is performed in 81 (96%) of the centers for breast irradiation, nodal areas are delineated in only 51 (61%) of the centers. After breast conserving surgery (BCS), only 14 (17%) centers declared to treat systematically the internal mammary chain (IMC), when supraclavicular node RT (SCN-RT) is indicated. Extra-capsular extension (ECE) is the main factor impacting decision-making regarding IMC and axillary nodal RT (ALN-RT). Only half of the centers advocate SCN-RT for intermediate risk patients (1-3N+). For macro-metastatic SLN involvement, there was a significant impact of ECE on decision-making independently from the number of positive LNs. In the PST setting, only 49 (58%) centers take into account the histologic fibrotic changes of the axillary LNs in post-PST ypN0 patients with unknown pre-PST status. In ypN0 patients with inner and central BC, 32 (39%) and 23 (27%) centers centers indicate SCN-RT and IMC-RT, respectively. SCN-RT is delivered by 30, 44, 58, 67 centers in patients with ypN(i+), ypN(mi), 1-2N+ and > 3-4N+ disease, respectively. ALN-RT is indicated by in 25% of the centers in patients with ypN(mi) or 1-2N+. Older age > 70y was not considered as a limited factor for RNI. Discussion: The term of RNI is not uniformly defined in the literature. In the historic studies, RNI was dedicated to wide RT including whole lymphatic pathways of the breast. ALN and IMC RT indications have declined with the time during the last decades because of the risk of morbidity. However this practice is challenged by the recent RT trials that reported and increase of overall and distant metastatic survival with RNI and IMC delivery in high-risk N0 and inner-central tumors. In addition, AMAROS trial showed equivalence between axillary RT and ALND in SLN (mi+) patients. Taking these data altogether in the context of increased avoidance of ALND, future challenges should concern the multidisciplinary patients’ selection for RNI and better personalization of the lymphatic pathways RT according to the risk of locoregional and distant recurrences. Conclusions: The NORA Survey is unique by evaluating the impact of SLN status and PST on RNI decision-making. IMC RT is not frequently coupled to SCN-RT. ECE is the main factor impacting decision-making for RNI. Only 58% of the centers take fibrotic changes in the LNs into consideration in decision-making for RNI indications. Age is not considered as a limiting factor for prescribing RNI in Europe. Citation Format: Yazid Belkacemi, Orit Kaidar-Person, Philippe Poortmans, Mahmut Ozsahin, Maria-Clara Valli, Nicola Russell, Ian Kunkler, Julie Hermans, Abraham Kuten, Geertjan van Tienhoven, Helen Westenberg. Patterns of practice of regional node irradiation in the sentinel node biopsy era: Results of the nodal radiotherapy (NORA) survey. On behalf of the EORTC Breast Working Party of the Radiation Oncology Group (ROG) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-09.

The management of patients with mesothelioma and thymic malignancy requires continuous multidisciplinary expertise at any step of the disease. A dramatic improvement in our knowledge has occurred in the last few years, through the development of databases, translational research programs, and clinical trials. Access to innovative strategies represents a major challenge, as there is a lack of funding for clinical research in rare cancers and their rarity precludes the design of robust clinical trials that could lead to specific approval of drugs. In this context, patient-centered initiatives, such as the establishment of dedicated networks, are warranted. International societies, such as IMIG (International Mesothelioma Interest Group) and ITMIG (International Thymic Malignancy Interest Group) provide infrastructure for global collaboration, and there are many advantages to having strong regional groups working on the same issues. There may be regional differences in risk factors, susceptibility, management and outcomes. The ability to address questions both regionally as well as globally is ideal to develop a full understanding of mesothelioma and thymic malignancies. In Europe, through the integration of national networks with EURACAN, the collaboration with academic societies and international groups, the development of networks in thoracic oncology provides multiplex integration of clinical care and research, ultimately ensuring equal access to high quality care to all patients, with the opportunity of conducting high level clinical and translational research projects.

Head and neck cancer (HNC) is a rare disease that can affect different sites and is characterized by variable incidence and 5-year survival rates across Europe. Multiple factors need to be considered when choosing the most appropriate treatment for HNC patients, such as age, comorbidities, social issues, and especially whether to prefer surgery or radiation-based protocols. Given the complexity of this scenario, the creation of a highly specialized multidisciplinary team is recommended to guarantee the best oncological outcome and prevent or adequately treat any adverse effect. Data from literature suggest that the multidisciplinary team-based approach is beneficial for HNC patients and lead to improved survival rates. This result is likely due to improved diagnostic and staging accuracy, a more efficacious therapeutic approach and enhanced communication across disciplines. Despite the benefit of MTD, it must be noted that this approach requires considerable time, effort and financial resources and is usually more frequent in highly organized and high-volume centers. Literature data on clinical research suggest that patients treated in high-accrual centers report better treatment outcomes compared to patients treated in low-volume centers, where a lower radiotherapy-compliance and worst overall survival have been reported. There is general agreement that treatment of rare cancers such as HNC should be concentrated in high volume, specialized and multidisciplinary centers. In order to achieve this goal, the creation of international collaboration network is fundamental. The European Reference Networks for example aim to create an international virtual advisory board, whose objectives are the exchange of expertise, training, clinical collaboration and the reduction of disparities and enhancement of rationalize migration across Europe. The purpose of our work is to review all aspects and challenges in and outside this network setting planned for the management of HNC patients.

// James Meehan 1 , Carol Ward 1 , Arran Turnbull 1 , Jimi Bukowski-Wills 2 , Andrew J. Finch 2 , Edward J. Jarman 1 , Chrysi Xintaropoulou 1 , Carlos Martinez-Perez 1 , Mark Gray 1 , Matthew Pearson 3 , Peter Mullen 4 , Claudiu T. Supuran 5 , Fabrizio Carta 5 , David J. Harrison 4 , Ian H. Kunkler 1 and Simon P. Langdon 1 1 Cancer Research UK Edinburgh Centre and Division of Pathology Laboratory, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom 2 Cancer Research UK Edinburgh Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom 3 IGMM Advanced Imaging Resource, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, United Kingdom 4 School of Medicine, University of St Andrews, Fife KY16 9TF, United Kingdom 5 Department of Neurofarba, Sez. Chimica Farmaceutica e Nutraceutica, University of Florence, Sesto Fiorentino 50019, Italy Correspondence to: James Meehan, email: J.Meehan@sms.ed.ac.uk Keywords: carbonic anhydrase IX, NHE1, V-ATPase, breast cancer, hypoxia Received: April 14, 2016 Accepted: March 15, 2017 Published: April 17, 2017 ABSTRACT Hypoxic cancer cells exhibit resistance to many therapies. This study compared the therapeutic effect of targeting the pH regulatory proteins (CAIX, NHE1 and V-ATPase) that permit cancer cells to adapt to hypoxic conditions, using both 2D and 3D culture models. Drugs targeting CAIX, NHE1 and V-ATPase exhibited anti-proliferative effects in MCF-7, MDA-MB-231 and HBL-100 breast cancer cell lines in 2D. Protein and gene expression analysis in 2D showed that CAIX was the most hypoxia-inducible protein of the 3 targets. However, the expression of CAIX differed between the 3 cell lines. This difference in CAIX expression in hypoxia was consistent with a varying activity of FIH-1 between the cell lines. 3D expression analysis demonstrated that both CAIX and NHE1 were up-regulated in the hypoxic areas of multicellular tumor spheroids. However, the induction of CAIX expression in hypoxia was again cell line dependent. 3D invasion assays conducted with spheroids showed that CAIX inhibition significantly reduced the invasion of cells. Finally, the capability of both NHE1 and CAIX inhibitors to combine effectively with irradiation was exhibited in clonogenic assays. Proteomic-mass-spectrometric analysis indicated that CAIX inhibition might be combining with irradiation through stimulating apoptotic cell death. Of the three proteins, CAIX represents the target with the most promise for the treatment of breast cancer.

At the San Antonio Breast Cancer Symposium 2012, long-term follow-up data from large clinical trials support a change in practice for the use of sentinel node mapping after neoadjuvant therapy and the safety and efficacy of hypofractionated radiation therapy. The duration of adjuvant therapy was further defined, with advantages reported with the extended use of adjuvant tamoxifen for 10 years and for 12 months of adjuvant trastuzumab.

SUMMARY: BACKGROUND: Trastuzumab is used as adjuvant treatment in patients with HER2-positive breast cancers and has been shown to reduce the chance of recurrence by up to 50%. However, experience with it given with radiotherapy is limited and there is in vitro evidence of a radiosensiti-sation effect. We describe the first case of trastuzumab-associated radiation-induced myelitis. CASE REPORT: This patient received a calculated dose of 28 Gy to the spinal cord when receiving adjuvant radiotherapy to the chest wall and supraclavicular and axillary lymph nodes. This is well below the accepted radiation tolerance of the spinal cord (50-60 Gy) but she developed radiation-induced myelitis of her spinal cord with characteristic magnetic resonance imaging changes. We postulate that trastuzu-mab given concurrently with radiation may have acted as a radiosensitiser and that normal repair mechanisms in the acute stage were affected by trastuzumab blockage of epidermal growth factor receptors, resulting in demy-elination at a lower dose of radiation than normally seen. CONCLUSIONS: Concomitant radiotherapy and adjuvant trastuzumab treatment should be given with caution and consideration made of delaying trastuzumab until after radiotherapy has been completed. As longer-term data become available for patients who received trastuzumab and radiation, it will become clearer whether there is a significant interaction on organs such as the heart and spinal cord in the radiation field.

Background Completeness of excision is the most important factor influencing local recurrence after breast-conserving surgery (BCS). The aim of this case–control study was to determine factors influencing incomplete excision in patients undergoing BCS. Methods Women with invasive breast cancer treated by BCS between 1 June 2008 and 31 December 2009 were identified from a prospectively collected database in the Edinburgh Breast Unit. The maximum size of the tumour, measured microscopically, was compared with the size estimated before operation by mammography and ultrasound imaging. A multivariable analysis was performed to investigate factors associated with incomplete excision. Results The cohort comprised 311 women, of whom 193 (62·1 per cent) had a complete (CE group) and 118 (40·7 per cent) an incomplete (IE group) excision. Mammography underestimated tumour size in 75·0 per cent of the IE group compared with 40·7 per cent of the CE group (P < 0·001). Ultrasound imaging underestimated tumour size in 82·5 per cent of the IE group compared with 56·5 per cent of the CE group (P < 0·001). The risk of an incomplete excision was greater when mammography or ultrasonography underestimated pathological size: odds ratio (OR) 4·38 (95 per cent c.i. 2·59 to 7·41; P < 0·001) for mammography, and OR 3·64 (2·03 to 6·54; P < 0·001) for ultrasound imaging. For every 1-mm underestimation of size by mammography and ultrasonography, the relative odds of incomplete excision rose by 10 and 14 per cent respectively. Conclusion Underestimation of tumour size by current imaging techniques is a major factor associated with incomplete excision in women undergoing BCS.

The role of radiotherapy is well established in the multidisciplinary management of breast cancer. However, its use could be customised further with the intent of enhancing tumour cell radiosensitisation and reducing normal cell toxicity. The importance of tumour heterogeneity and the microenvironment in the response to radiotherapy is under intense scrutiny and the value of molecular profiling is being increasingly recognised. Genome Wide Association Studies are likely toplay an important role in elucidating the molecular pathogenesis of radiotoxicity in the emerging area of radiogenomics. Biomarkers of tumour radiosensitivity should help indicate potentially responsive and unresponsive cancers. Further understanding of the tumour microenvironment and better preclinical models will help identify targets to enhance radiosensitivity or reverse radioresistance.

Ductal carcinoma in situ (DCIS) represents a growing health challenge with increasing numbers of cases detected through breast screening programmes. It is unclear exactly what factors contribute to the pathogenesis of DCIS and its progression to invasive cancer. Breaching of the myoepithelial cell layer and basement membrane is a key feature of the progression from DCIS to invasive cancer. It is thought that myoepithelial cells have an active role in tumour suppression by downregulating metalloproteinases. While mammography remains the standard imaging modality for detection of DCIS, MRI has an increasing role in assessing its extent. The absolute mortality of DCIS is extremely low. The primary aim of treatment is to prevent local recurrence, particularly invasive recurrence. However, we lack reliable biomarkers to identify which patients are most likely to recur. Some form of surgery (breast conserving or mastectomy) is recommended virtually for all patients. The role of observation for small low-grade lesions is under investigation. Obtaining clear margins is important to minimising the risk of local recurrence. Adjuvant postoperative radiotherapy roughly halves the rate of DCIS and invasive recurrence. Whether there is a subset of patients from whom radiotherapy can be safely omitted is uncertain but the absolute benefit in small, low-grade lesions is very limited. The role of adjuvant hormonal therapy in DCIS is not well established. The principal benefit of adjuvant tamoxifen is the reduction in the risk of contralateral non-invasive disease. This chapter focuses on level 1 evidence as a guide to treatment.

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.

Although there have been major improvements in the management of breast cancer, with a rapidly falling death rate despite an increasing incidence of the disease, metastatic breast cancer remains common and the cause of death in nearly 12 000 women annually in the UK. Numerous treatment options are available that either target the tumour or reduce the complications of the disease. Clinical decision making depends on knowledge of the extent and biology of the disease and available drug options, an understanding of the functional status, and also the wishes and expectations of the individual patient. In addition, the organisation of services and support of the patient are essential components of high-quality care. The National Institute for Health and Clinical Excellence (NICE) has produced guidelines for the treatment of advanced breast cancer, which in some areas have perhaps failed to appreciate the complexity of patient management. This guidance document aims to provide succinct practical advice on the treatment of metastatic breast cancer, highlight some limitations of the NICE guidelines, and provide suggestions for management where available data are limited.

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.

Background Adjuvant chest wall irradiation after mastectomy remains a core and highly effective element in the loco-regional management of early breast cancer. While the evidence base for postmastectomy radiotherapy (PMRT) in patients with 4 or more involved axillary nodes is robust, its role in ‘intermediate' risk patients with 1–3 involved nodes is unclear and practice varies. Traditionally patients have been selected for PMRT on the basis of clinic-pathological factors such tumour size, nodal status, tumour grade and presence of lymphovascular invasion. However these factors alone may not predict the response of individual patients to radiotherapy. There is recent evidence that biological factors such as oestrogen and progesterone receptor and HER-2 status may also influence survival as well as loco-regional control. Methods A literature review was undertaken, searching Pubmed using the mesh heading of ‘breast cancer' and ‘adjuvant chest wall irradiation/radiotherapy'. Priority was given to reports of meta-analyses and randomised trials of postmastectomy radiotherapy. Observations The 2005 Oxford Overview of randomised trials of postoperative radiotherapy established a clear biological link between loco-regional control and survival. Paradoxically the largest survival benefits do not occur in patients at the highest risk of recurrence. Molecular markers to identify exactly which patients are likely to benefit from PMRT are being actively investigated. Surgeons are encouraged to enter patients with 1–3 involved nodes into a clinical trial of postmastectomy radiotherapy.

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 ≥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

Background: EUROCARE found marked differences in cancer survival across European populations, provoking extensive discussion as to the cause. We investigated the influence of socioeconomic indicators on survival, making use of the indicator population-based age-standardized and cancer site-standardized relative survival for all cancers combined ( all cancer survival ). Methods: Bivariate correlation and multivariate regression analyses investigated relations between 1995 socioeconomic variables and all cancer survival in EUROCARE-3 patients from 19 European countries diagnosed 1990–94 and followed to 1999. Results: Gross domestic product (GDP) and total national expenditure on health (TNEH) correlated highly with all cancer survival . Wealthy northern and western European countries had high survival; eastern European countries had low all cancer survival . GDP, TNEH, and number of computed tomography scanners per million—proxy of technological investment in cancer care—explained most survival differences. Low all cancer survival in the UK and Denmark compared to countries of similar wealth was closely related to fewer computed tomography scanners. Low all cancer survival in Poland compared to countries of similar wealth was also related to low TNEH. Conclusions: All cancer survival appears a useful and important indicator for monitoring countries’ performance in cancer control. The most direct way for poorer European countries to improve all cancer survival would be to get richer; for richer countries more investment in health technology is important. However the sharply increasing costs of cancer care may render this impossible suggesting the need to radically rethink cancer control strategies.

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer mortality in women worldwide. Elderly individuals make up a large part of the breast cancer population, and there are important specific considerations for this population. The International Society of Geriatric Oncology created a task force to assess the available evidence on breast cancer in elderly individuals, and to provide evidence-based recommendations for the diagnosis and treatment of breast cancer in such individuals. A review of the published work was done with the results of a search on Medline for English-language articles published between 1990 and 2007 and of abstracts from key international conferences. Recommendations are given on the topics of screening, surgery, radiotherapy, (neo)adjuvant hormone treatment and chemotherapy, and metastatic disease. Since large randomised trials in elderly patients with breast cancer are scarce, there is little level I evidence for the treatment of such patients. The available evidence was reviewed and synthesised to provide consensus recommendations regarding the care of breast cancer in older adults.

The hypoxic areas of solid cancers represent a negative prognostic factor irrespective of which treatment modality is chosen for the patient. Still, after almost 80 years of focus on the problems created by hypoxia in solid tumours, we still largely lack methods to deal efficiently with these treatment-resistant cells. The consequences of this lack may be serious for many patients: Not only is there a negative correlation between the hypoxic fraction in tumours and the outcome of radiotherapy as well as many types of chemotherapy, a correlation has been shown between the hypoxic fraction in tumours and cancer metastasis. Thus, on a fundamental basis the great variety of problems related to hypoxia in cancer treatment has to do with the broad range of functions oxygen (and lack of oxygen) have in cells and tissues. Therefore, activation-deactivation of oxygen-regulated cascades related to metabolism or external signalling are important areas for the identification of mechanisms as potential targets for hypoxia-specific treatment. Also the chemistry related to reactive oxygen radicals (ROS) and the biological handling of ROS are part of the problem complex. The problem is further complicated by the great variety in oxygen concentrations found in tissues. For tumour hypoxia to be used as a marker for individualisation of treatment there is a need for non-invasive methods to measure oxygen routinely in patient tumours. A large-scale collaborative EU-financed project 2009-2014 denoted METOXIA has studied all the mentioned aspects of hypoxia with the aim of selecting potential targets for new hypoxia-specific therapy and develop the first stage of tests for this therapy. A new non-invasive PET-imaging method based on the 2-nitroimidazole [(18)F]-HX4 was found to be promising in a clinical trial on NSCLC patients. New preclinical models for testing of the metastatic potential of cells were developed, both in vitro (2D as well as 3D models) and in mice (orthotopic grafting). Low density quantitative real-time polymerase chain reaction (qPCR)-based assays were developed measuring multiple hypoxia-responsive markers in parallel to identify tumour hypoxia-related patterns of gene expression. As possible targets for new therapy two main regulatory cascades were prioritised: The hypoxia-inducible-factor (HIF)-regulated cascades operating at moderate to weak hypoxia (

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.

Summary Exemestane is a potent steroidal aromatase inhibitor (AI) with activity in post-menopausal women with metastatic breast cancer, with a reported clinical benefit (CB) rate of 24.3% after prior AI therapy. Data on 114 patients (112 female, 2 male) were obtained retrospectively at two cancer centres. Sixty-five percent of patients were confirmed as oestrogen receptor (ER) positive. All patients had received prior third-generation AI therapy. Responses were seen in 5% and the overall CB rate (CR+PR+SD⩾24 weeks) was 46%. Median PFS and OS were 18 and 61 weeks, respectively. In patients with visceral disease, the CBR was 33%. Patients with known ER-positive disease had a CBR of 47%, and a median TTP of 19 weeks. No benefit was seen in patients with known ER-negative disease. Survival was better in those with CB (median survival not reached in those with CB, 28 weeks in those without CB P 0.0001 ). Efficacy persisted in those patients who had received ⩾3 prior lines of hormonal therapy, including adjuvant treatment. These data confirm exemestane to be an effective therapy after third-generation non-steroidal AI in post-menopausal ER-positive metastatic breast cancer, including visceral disease.

Purpose To report the neurocognitive findings in a phase III randomized trial evaluating survival and neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). Patients and Methods Patients were randomly assigned to receive WBRT 30 Gy in 10 fractions with or without MGd 5 mg/kg/d. Monthly neurocognitive testing for memory, executive function, and fine motor skill was performed. Results Four hundred one patients were enrolled (251 with non–small-cell lung cancer, 75 with breast cancer, and 75 with other cancers); 90.5% patients had impairment of one or more neurocognitive tests at baseline. Neurocognitive test scores of memory, fine motor speed, executive function, and global neurocognitive impairment at baseline were correlated with brain tumor volume and predictive of survival. There was no statistically significant difference between treatment arms in time to neurocognitive progression. Patients with lung cancer (but not other types of cancer) who were treated with MGd tended to have improved memory and executive function (P = .062) and improved neurologic function as assessed by a blinded events review committee (P = .048). Conclusion Neurocognitive tests are a relatively sensitive measure of brain functioning; a combination of tumor prognostic variables and brain function assessments seems to predict survival better than tumor variables alone. Although the addition of MGd to WBRT did not produce a significant overall improvement between treatment arms, MGd may improve memory and executive function and prolong time to neurocognitive and neurologic progression in patients with brain metastases from lung cancer.

Aim: To report details concerning symptoms (especially pain) preceding the development of malignant cord compression (MCC); delays between onset/reporting of symptoms and confirmed diagnosis of MCC; accuracy of investigations carried out. Methods: A prospective observational study examined the diagnosis, management and outcome of 319 patients diagnosed with MCC at three Scottish cancer centres between January 1998–April 1999. The process was considered from the perspectives of the patient, the GP and the hospital doctor. Results: At diagnosis, most patients (82%) were either unable to walk or only able to do so with help. Pain was reported by nearly all patients interviewed (94%) and had been present for approximately 3 months (median=90 days). It was severe in 84% of cases, with the distribution and characteristics of nerve root pain in 79%. The site of pain did not correspond to the site of compression. Where reported, weakness and/or sensory problems had been noticed by the patient for some time before diagnosis (median intervals 20 and 12 days, respectively). Most patients reported early symptoms to their General Practitioner (GP) and diagnosis was established, following referral and investigation, approximately 2 months (median=66 days) later. Conclusion: Patients who develop spinal metastases are at risk of irreversible spinal cord damage. Weakness and sensory abnormalities are reported late and identified even later, despite patients having reported pain for a considerable time. Patients with cancer who describe severe back or spinal nerve root pain need urgent assessment on the basis of their symptoms, as signs may occur too late. Plain films and bone scans requested for patients in this audit predicted accurately the level of compression in only 21% and 19% of cases, respectively. The only accurate investigation to establish the presence and site of a compressive lesion is magnetic resonance imaging (MRI). A referral guideline based on suspicious symptoms in addition to suspicious signs is suggested. Levack

Breast cancer in the elderly is a rising health care challenge. Under-treatment is common. While the proportion of older patients receiving adjuvant radiotherapy (RT) is rising, the proportion undergoing breast-conserving surgery without irradiation has also risen. The evidence base for loco-regional treatment is limited, reflecting the historical exclusion of older patients from randomised trials. The 2011 Oxford overview shows that the risk of first recurrence is halved in all age groups by adjuvant RT after breast-conserving surgery, although the absolute benefit in older 'low-risk' patients is small. There is level 1 evidence that a breast boost after breast-conserving surgery and whole-breast irradiation reduces local recurrence in older as in younger women, although in the former the absolute reduction is modest. Partial breast irradiation (external beam or intraoperative or postoperative brachytherapy) is potentially an attractive option for older patients, but the evidence base is insufficient to recommend it routinely. Similarly, shortened (hypofractionated) dose fraction schedules may be more convenient for older patients and are supported by level 1 evidence. There remains uncertainty about whether there is a subgroup of older low-risk patients in whom postoperative RT can be omitted after breast-conserving surgery. Biomarkers of 'low risk' are needed to refine the selection of patients for the omission of adjuvant RT. The role of postmastectomy irradiation is well established for 'high-risk' patients but uncertain in the intermediate-risk category of patients with 1-3 involved axillary nodes or node-negative patients with other risk factors where its role is investigational.Brustkrebs bei älteren Patientinnen stellt eine wachsende Herausforderung im Gesundheitswesen dar. Nicht ausreichende Behandlung kommt häufig vor. Während der Anteil der älteren Patientinnen, die eine adjuvante Radiotherapie (RT) erhalten, steigt, ist der Anteil derjenigen, die sich einer brusterhaltenden Operation ohne Bestrahlung unterziehen, ebenfalls gestiegen. Die Evidenzlage für eine lokoregionale Behandlung ist begrenzt, was den in der Vergangenheit praktizierten Ausschluss von älteren Patientinnen von randomisierten Studien widerspiegelt. Der Oxford Overview 2011 zeigt, dass sich das Risiko eines ersten Rückfalls in allen Altersgruppen durch die adjuvante RT nach einer brusterhaltenden Operation halbiert hat; der absolute Nutzen der älteren «Niedrigrisiko»-Patientinnen ist jedoch klein. Es liegt Level-1-Evidenz vor, dass eine Boost-Bestrahlung nach einer brusterhaltenden Operation mit anschließender Ganzbrustbestrahlung lokale Rezidive bei älteren genauso wie bei jüngeren Frauen reduziert; bei Ersteren ist die absolute Reduktion jedoch nur mäßig. Eine partielle Bestrahlung der Brust (durch externe Bestrahlung oder intraoperative oder postoperative Brachytherapie) ist möglicherweise eine attraktive Option für ältere Patientinnen. Die Evidenzlage ist für eine routinemäßige Empfehlung jedoch unzureichend. Außerdem können verkürzte (hypofraktio-nierte) Dosisfraktionsprogramme für ältere Patientinnen angenehmer sein und werden durch Level-1-Evidenz unterstützt. Es bleibt unklar, ob es eine Untergruppe von Niedrigrisiko-Patientinnen gibt, bei denen die postoperative RT nach einer brusterhaltenden Operation unterlassen werden kann. Biomarker, die ein «niedriges Risiko» anzeigen, werden benötigt, um die Selektion von Patientinnen zu verfeinern, denen eine RT erspart werden kann. Die Bedeutung der Bestrahlung nach einer Mastektomie ist bei «Hochrisiko»-Patientinnen erwiesen, sie ist jedoch unklar bei Patientinnen mit mittlerem Risiko, also mit 1–3 involvierten axillären Lymphknoten oder ohne involvierte Lymphknoten, aber mit anderen Risikofaktoren. Hier wird ihre Bedeutung noch erforscht.