Immediate and delayed autologous abdominal microvascular flap breast reconstruction in patients receiving adjuvant, neoadjuvant or no radiotherapy: a meta-analysis of clinical and quality-of-life outcomes.

BACKGROUND: Effects of postmastectomy radiotherapy (PMRT) on autologous breast reconstruction (BRR) are controversial regarding surgical complications, cosmetic appearance and quality of life (QOL). This systematic review evaluated these outcomes after abdominal free flap reconstruction in patients undergoing postoperative adjuvant radiotherapy (PMRT), preoperative radiotherapy (neoadjuvant radiotherapy) and no radiotherapy, aiming to establish evidence-based optimal timings for radiotherapy and BRR to guide contemporary management. METHODS: The study was registered on PROSPERO (CRD42017077945). Embase, MEDLINE, Google Scholar, CENTRAL, Science Citation Index and ClinicalTrials.gov were searched (January 2000 to August 2018). Study quality and risk of bias were assessed using GRADE and Cochrane's ROBINS-I respectively. RESULTS: Some 12 studies were identified, involving 1756 patients (350 PMRT, 683 no radiotherapy and 723 neoadjuvant radiotherapy), with a mean follow-up of 27·1 (range 12·0-54·0) months for those having PMRT, 16·8 (1·0-50·3) months for neoadjuvant radiotherapy, and 18·3 (1·0-48·7) months for no radiotherapy. Three prospective and nine retrospective cohorts were included. There were no randomized studies. Five comparative radiotherapy studies evaluated PMRT and four assessed neoadjuvant radiotherapy. Studies were of low quality, with moderate to serious risk of bias. Severe complications were similar between the groups: PMRT versus no radiotherapy (92 versus 141 patients respectively; odds ratio (OR) 2·35, 95 per cent c.i. 0·63 to 8·81, P = 0·200); neoadjuvant radiotherapy versus no radiotherapy (180 versus 392 patients; OR 1·24, 0·76 to 2·04, P = 0·390); and combined PMRT plus neoadjuvant radiotherapy versus no radiotherapy (272 versus 453 patients; OR 1·38, 0·83 to 2·32, P = 0·220). QOL and cosmetic studies used inconsistent methodologies. CONCLUSION: Evidence is conflicting and study quality was poor, limiting recommendations for the timing of autologous BRR and radiotherapy. The impact of PMRT and neoadjuvant radiotherapy appeared to be similar.

ANTECEDENTES: En pacientes sometidas a una reconstrucción mamaria (breast reconstruction, BRR) con tejido autólogo se discuten los efectos de la radioterapia post-mastectomía (post-mastectomy radiotherapy, PMRT) en las complicaciones quirúrgicas, el resultado estético y la calidad de vida (quality of life, QOL). Esta revisión sistemática evaluó dichos resultados tras una reconstrucción mamaria con un colgajo libre abdominal en pacientes tratadas con PMRT, radioterapia preoperatoria (Neo RT) y sin radioterapia (RT), a fin de establecer los momentos óptimos de la RT y BRR basados en la evidencia, como guía del tratamiento actual. MÉTODOS: El estudio se registró en la base de datos PROSPERO (CRD42017077945). Se realizaron búsquedas en Embase, MEDLINE, Google Scholar, CENTRAL, Science Citation Index y Clinicaltrials.gov (enero de 2000-agosto de 2018). La calidad de los estudios y el riesgo de sesgo se evaluaron mediante las herramientas GRADE y ROBINS-I de la Cochrane, respectivamente. RESULTADOS: Se identificaron 12 estudios que incluían 1.756 pacientes (350 PMRT, 683 sin RT y 723 Neo RT), con una mediana de seguimiento de 27,1 meses (rango 12,0-54,0) para PMRT, 16,8 meses (1,0-50,3) para Neo RT y 18,3 meses (1,0-48,7) para sin RT. Se incluyeron tres cohortes prospectivas y nueve retrospectivas. No hubo estudios aleatorizados. Los estudios comparativos de RT evaluaron la PMRT (n = 5) y la Neo RT (n = 4). Todos los estudios fueron de baja calidad, con riesgos de sesgo de moderados a graves. Las complicaciones graves fueron similares entre los grupos: PMRT (n = 92) versus sin RT (n = 141), razón de oportunidades (odds ratio, OR) 2,35, i.c. del 95% 0,63-8,81), P = 0,200; Neo RT (n = 180) versus no RT (n = 392) (OR 1,24, i.c. del 95% 0,76-2,04), P = 0,390; o RT combinada (PMRT y neoadyuvante) (n = 272) versus no RT (n = 453) (OR 1,38, i.c. del 95% 0,83-2,32), P = 0,220. Los estudios de calidad de vida y de resultados estéticos utilizaron metodologías poco consistentes. CONCLUSIÓN: La evidencia es contradictoria y la calidad de los estudios muy pobre, hechos que limitan las posibles recomendaciones para el momento de la BRR con tejido autólogo y la RT. El impacto de la PMRT o la Neo RT parecen ser similares.

International multidisciplinary expert panel consensus on breast reconstruction and radiotherapy.

BACKGROUND: Conflicting evidence challenges clinical decision-making when breast reconstruction is considered in the context of radiotherapy. Current literature was evaluated and key statements on topical issues were generated and discussed by an expert panel at the International Oncoplastic Breast Surgery Meeting in Milan 2017. METHODS: Studies on radiotherapy and breast reconstruction (1985 to September 2017) were screened using MEDLINE, Embase and CENTRAL. The literature review yielded 30 controversial key questions. A set of key statements was derived and the highest levels of clinical evidence (LoE) for each of these were summarized. Nineteen panellists convened for dedicated discussions at the International Oncoplastic Breast Surgery Meeting to express agreement, disagreement or abstention for the generated key statements. RESULTS: The literature review identified 1522 peer-reviewed publications. A list of 22 key statements was produced, with the highest LoE recorded for each statement. These ranged from II to IV, with most statements (11 of 22, 50 per cent) supported by LoE III. There was full consensus for nine (41 per cent) of the 22 key statements, and more than 75 per cent agreement was reached for half (11 of 22). CONCLUSION: Poor evidence exists on which to base patient-informed consent. Low-quality studies are conflicting with wide-ranging treatment options, precluding expert consensus regarding optimal type and timing of breast reconstruction in the context of radiotherapy. There is a need for high-quality evidence from prospective registries and randomized trials in this field.

ANTECEDENTES: El hecho de que la evidencia disponible sea conflictiva supone un reto para la toma de decisiones a la hora de considerar la reconstrucción mamaria en el contexto de radioterapia (radiotherapy, RT). En el seno de un panel de expertos reunidos durante el International Oncoplastic Breast Surgery Meeting celebrado en Milán en 2017, se revisó la literatura disponible y se generaron y discutieron los aspectos más relevantes. MÉTODOS: Se hizo una búsqueda bibliográfica de los estudios de RT y reconstrucción mamaria (1985-septiembre de 2017) en las bases MEDLINE, EMBASE y CENTRAL. La revisión de la literatura permitió identificar 30 cuestiones clave controvertidas. A partir de ellas, se construyeron una serie de afirmaciones, para las que se obtuvo el mayor nivel de evidencia (levels of clinical evidence, LoE) posible. El acuerdo, desacuerdo o abstención respecto a las cuestiones propuestas fueron el resultado de las discusiones de 19 expertos reunidos durante el International Oncoplastic Breast Surgery Meeting. RESULTADOS: Se identificaron 1.522 artículos publicados en revistas con peer review. Se elaboró una lista de 22 afirmaciones clave y se anotó el LoE más alto obtenido para cada una de ellas. El grado de variabilidad fue de II a IV, pero la mayoría de las afirmaciones (54,5%) obtuvieron un LoE III. Hubo un consenso total en el 41% (9/22) de las afirmaciones, mientras que se obtuvo más de un 75% de acuerdo en la mitad de las afirmaciones (11/22). CONCLUSIÓN: La evidencia en la que basar el consentimiento informado en estos pacientes es escasa. Se trata de estudios de baja calidad con gran variedad de opciones terapéuticas, que dificultan el consenso de los expertos acerca del tipo y momento óptimo para la reconstrucción mamaria en el contexto de RT. Para obtener datos de mayor calidad se precisan estudios prospectivos y ensayos clínicos en este campo.

Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BACKGROUND: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). METHODS: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. RESULTS: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. CONCLUSION: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

International validation of the European Organisation for Research and Treatment of Cancer QLQ-BRECON23 quality-of-life questionnaire for women undergoing breast reconstruction.

BACKGROUND: The aim was to carry out phase 4 international field-testing of the European Organisation for Research and Treatment of Cancer (EORTC) breast reconstruction (BRECON) module. The primary objective was finalization of its scale structure. Secondary objectives were evaluation of its reliability, validity, responsiveness, acceptability and interpretability in patients with breast cancer undergoing mastectomy and reconstruction. METHODS: The EORTC module development guidelines were followed. Patients were recruited from 28 centres in seven countries. A prospective cohort completed the QLQ-BRECON15 before mastectomy and the QLQ-BRECON24 at 4-8 months after reconstruction. The cross-sectional cohort completed the QLQ-BRECON24 at 1-5 years after reconstruction, and repeated this 2-8 weeks later (test-retest reliability). All participants completed debriefing questionnaires. RESULTS: A total of 438 patients were recruited, 234 in the prospective cohort and 204 in the cross-sectional cohort. A total of 414 reconstructions were immediate, with a comparable number of implants (176) and donor-site flaps (166). Control groups comprised patients who underwent two-stage implant procedures (72, 75 per cent) or delayed reconstruction (24, 25 per cent). Psychometric scale validity was supported by moderate to high item-own scale and item-total correlations (over 0·5). Questionnaire validity was confirmed by good scale-to-sample targeting, and computable scale scores exceeding 50 per cent, except nipple cosmesis (over 40 per cent). In known-group comparisons, QLQ-BRECON24 scales and items differentiated between patient groups defined by clinical criteria, such as type and timing of reconstruction, postmastectomy radiotherapy and surgical complications, with moderate effect sizes. Prospectively, sexuality and surgical side-effects scales showed significant responsiveness over time (P < 0·001). Scale reliability was supported by high Cronbach's α coefficients (over 0·7) and test-retest (intraclass correlation more than 0·8). One item (finding a well fitting bra) was excluded based on high floor/ceiling effects, poor test-retest and weak correlations in factor analysis (below 0·3), thus generating the QLQ-BRECON23 questionnaire. CONCLUSION: The QLQ-BRECON23 is an internationally validated tool to be used alongside the EORTC QLQ-C30 (cancer) and QLQ-BR23 (breast cancer) questionnaires for evaluating quality of life and satisfaction after breast reconstruction.

Patient-reported outcomes and their predictors at 2- and 3-year follow-up after immediate latissimus dorsi breast reconstruction and adjuvant treatment.

BACKGROUND: The aim of this study was to estimate the impact 2 and 3 years after surgery of implant-assisted latissimus dorsi (LDI) and autologous latissimus dorsi (ALD) flap breast reconstructions on patient-reported outcomes (PROs), and, secondarily, to determine whether baseline characteristics can predict PROs. METHODS: This was a multicentre prospective cohort study. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (QLQ-C30) and breast cancer module (QLQ-BR23), Functional Assessment of Cancer Therapy - Breast (FACT-B), and Hospital Anxiety and Depression Scale (HADS) PROs were completed before surgery and at 2 and 3 years after breast reconstruction. The effects of LDI and ALD, adjusted for baseline clinicodemographic characteristics, were estimated with multiple linear regressions. Effect sizes above 0·5 were considered clinically important. RESULTS: Some 206 patients (LDI 93, ALD 113) were recruited in 2007-2013; 66·5 per cent were node-negative and 34·6 per cent received radiotherapy. Women with adverse clinicopathological factors were more likely to have received radiotherapy and to undergo ALD. Patients in both surgical groups showed clinically important effects at 2 and 3 years, including improvements in emotional scales, but worse physical functioning, social well-being, body image and anxiety. Radiotherapy adversely affected social functioning at 2 years (P = 0·002). Women undergoing ALD reconstruction had significantly improved sexual functioning at 3 years (P = 0·003) relative to those who had LDI procedures, even after adjusting for case mix (P = 0·007). At 3 years, younger women experienced worse physical well-being than older women (P = 0·006), and chemotherapy was associated with worse arm symptoms (P = 0·005). CONCLUSION: Clinically important changes occurred in physical functioning, breast symptoms, body image and psychological distress. These results will guide selections of key PRO domains and sample-size calculation of future studies.

Learning from the QUEST multicentre feasibility randomization trials in breast reconstruction after mastectomy.

BACKGROUND: Breast reconstruction aims to improve health-related quality of life after mastectomy. However, evidence guiding patients and surgeons in shared decision-making concerning the optimal type or timing of surgery is lacking. METHODS: QUEST comprised two parallel feasibility phase III randomized multicentre trials to assess the impact of the type and timing of latissimus dorsi breast reconstruction on health-related quality of life when postmastectomy radiotherapy is unlikely (QUEST A) or highly probable (QUEST B). The primary endpoint for the feasibility phase was the proportion of women who accepted randomization, and it would be considered feasible if patient acceptability rates exceeded 25 per cent of women approached. A companion QUEST Perspectives Study (QPS) of patients (both accepting and declining trial participation) and healthcare professionals assessed trial acceptability. RESULTS: The QUEST trials opened in 15 UK centres. After 18 months of recruitment, 17 patients were randomized to QUEST A and eight to QUEST B, with overall acceptance rates of 19 per cent (17 of 88) and 22 per cent (8 of 36) respectively. The QPS recruited 56 patients and 51 healthcare professionals. Patient preference was the predominant reason for declining trial entry, given by 47 (53 per cent) of the 88 patients approached for QUEST A and 22 (61 per cent) of the 36 approached for QUEST B. Both trials closed to recruitment in December 2012, acknowledging the challenges of achieving satisfactory patient accrual. CONCLUSION: Despite extensive efforts to overcome recruitment barriers, it was not feasible to reach timely recruitment targets within a feasibility study. Patient preferences for breast reconstruction types and timings were common, rendering patients unwilling to enter the trial.

Phase III development of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire module for women undergoing breast reconstruction.

BACKGROUND: Comprehensive outcome assessments after breast reconstruction (BRR) require surgery-specific patient-reported outcome measures. The aims of this study were to assess the relevance, acceptability and redundancy of questions/items (phase III pretesting) of a new BRR questionnaire evaluating patients' health-related quality of life before and after BRR. Phase III occurred in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) following earlier development phases that identified 31 items. METHODS: The EORTC BRR subgroup applied decision-making rules to each question according to eight EORTC criteria. A total of 197 patients (from the UK, Austria, Belgium, Italy and Sweden) were recruited. Forty-seven patients completed pre- and post-BRR questionnaires prospectively, and 150 reported post-BRR questionnaires only retrospectively. Qualitative debriefing interviews were undertaken in 189 patients. Preliminary psychometric analyses were performed. RESULTS: Thirty-one items fulfilled 'relevance', with none producing 'difficulties'. Ten items were not a priority for 10 per cent of respondents. Of these, two questions concerning muscle twitching in the affected breast and problem with donor-site swelling were deleted. Three redundant items were deleted: weakness in arm, which correlated significantly to the Quality of Life Questionnaire (QLQ) BR23 breast questionnaire, and shape and colour of the affected nipple. Descriptive statistics reduced the module to 26 items conceptualized into three provisional scales (disease treatment/surgery-related symptoms, sexuality and cosmetic outcome) within the newly completed questionnaire, EORTC QLQ-BRR26. CONCLUSION: The QLQ-BRR26 is available for psychometric validation in a large-field international sample. The intended use for QLQ-BRR26 is alongside EORTC QLQ-C30 and QLQ-BR23, in women treated by mastectomy for breast cancer and undergoing all types of BRR.

The real-time intra-operative evaluation of sentinel lymph nodes in breast cancer patients using One Step Nucleic Acid Amplification (OSNA) and implications for clinical decision-making.

INTRODUCTION: One Step Nucleic Acid Amplification (OSNA) method for the intraoperative analysis of sentinel lymph nodes (SLNs) in breast cancer, obviates a second operation to the axilla and thereby expedites progression to adjuvant therapy. Recent NICE guidelines have approved OSNA as a method of sentinel node diagnosis to support the above case.(1) METHOD: This is a single centre prospective cohort analysis of all patients undergoing breast cancer surgery including sentinel node biopsy from February 2010 to June 2012. Patients with negative SLN(s) on OSNA had no further axillary surgery. A validation phase was performed prior to using OSNA routinely. Those with micrometastases underwent a level 1 clearance, and >one SLN with macrometastases, underwent treatment by level 2 axillary dissection. The length of time from sentinel node retrieval to OSNA result was recorded. RESULTS: Four hundred and forty nodes were analysed in 212 patients with a mean age of 55 years (range 24-98). The sensitivity and specificity of OSNA was 93% and 94% respectively in cases of macrometastases. The process required additional median anaesthesia time of 20 min (range -48 to +65 min). Non-sentinel node positivity was 5% and 48% for micrometastasis and macrometastasis respectively. CONCLUSION: OSNA identified 62 of 212 patients with at least one positive sentinel node, thereby sparing 29% from a second procedure to clear the axilla subsequently. The median waiting time of 20 min for node results from completion of breast procedure is acceptable and allows for an efficient operating list. OSNA can be incorporated into routine practice and with improved methods of imaging preoperatively, can be an excellent adjunct to the breast cancer patient pathway of care.

The early development phases of a European Organisation for Research and Treatment of Cancer (EORTC) module to assess patient reported outcomes (PROs) in women undergoing breast reconstruction.

INTRODUCTION: A comprehensive evaluation of breast reconstruction (BRR) surgery includes measurement of patient reported outcomes (PROs). There is, however, a lack of validated BRR-specific PRO measures (PROMs) that adequately assess relevant issues. This study is developing a European Organisation for Research and Treatment of Cancer (EORTC) questionnaire/module specific for PROs in BRR to supplement the cancer-core and breast cancer EORTC questionnaires, respectively: the QLQ-C30 and QLQ-BR23. METHODS: Phases I and II of questionnaire development followed EORTC guidelines including a systematic literature review to identify all potential 'issues' (concepts relevant to PROs) and semi-structured interviews with 89 patients and 9 European multi-disciplinary health care professionals (HCPs) (Sweden, Italy and the United Kingdom [UK]). Interviewers asked participants the 'relevance' of outcomes identified in the literature and captured additional 'issues' of importance. RESULTS: The literature search and interviews of patients and HCPs yielded 69 issues relating to BRR operationalised into 31 provisional items (single questions) for the module, which was conceptualised to contain five scales: treatment/surgery related symptoms (affecting the shoulder, arm and reconstructed breast), body image, sexuality, cosmetic outcomes (pertaining to three areas: breast, donor site and nipple) and overall satisfaction. DISCUSSION: The provisional development of the EORTC BRR module has 31 items addressing issues of importance to patients as well as HCPs. Further international testing is underway as a UK National Cancer Research Network trial to ensure that this PROM will be psychometrically and clinically robust and applicable for use in clinical trials, cohort studies, national audit and clinical practice.

Integration of patient-reported outcome measures with key clinical outcomes after immediate latissimus dorsi breast reconstruction and adjuvant treatment.

BACKGROUND: Clinical evidence on patient-reported outcome measures (PROMS) in breast reconstruction is lacking. The aim of this study was to evaluate PROMs in implant-assisted latissimus dorsi (LDI) or tissue-only autologous latissimus dorsi (ALD) flap reconstruction in relation to complications and adjuvant treatments. METHODS: This was a prospective cohort study involving six UK centres. Eligible patients had primary early-stage breast cancer. The European Organization for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 and QLQ-BR23, Functional Assessment of Cancer Therapy-Breast Cancer scale (FACT-B), Body Image Scale, and Hospital Anxiety and Depression Scale were completed before operation and at 3, 6 and 12 months after surgery. RESULTS: A total of 182 patients (82 LDI and 100 ALD) were recruited between 2007 and 2010 with symptomatic (59·9 per cent) or screen-detected (39·6 per cent) cancers. Some 64·3 per cent had lymph node-negative disease; 30 per cent of the LDI group had radiotherapy, compared with 53·0 per cent in the ALD group (P = 0·004). Early complications up to 3 months after surgery were reported in 66 and 51·0 per cent of patients in the LDI and ALD groups respectively (P = 0·062) and long-term complications (4-12 months) in 48 and 45·0 per cent (P = 0·845). Role functioning and pain (P = 0·002 for both) were adversely affected in the ALD group compared with results in the LDI group, with no significant effects of radiotherapy on any health-related quality of life (HRQL). Chemotherapy and early complications adversely affected HRQL, which improved between 3 and 12 months after surgery (P < 0·010 for all). CONCLUSION: There is evidence of similar HRQL between types of latissimus dorsi breast reconstruction for up to a year after surgery. There appear to be no overarching effects for radiotherapy after mastectomy on the specific HRQL domains studied in the short term. The identification of variables that affect HRQL is important, including their integration into the analysis of PROMs.

Randomized clinical trial on the effect of fibrin sealant on latissimus dorsi donor-site seroma formation after breast reconstruction.

BACKGROUND: Latissimus dorsi (LD) flap procedures comprise 50 per cent of breast reconstructions in the UK. They are frequently complicated by seroma formation. Fibrin sealants may reduce seroma volumes at the donor site. The aim was to investigate the effect of fibrin sealant (Tisseel(®)) on total seroma volumes from the breast, axilla and back (donor site) after LD breast reconstruction. Secondary outcomes were specific back seroma volumes together with incidence and severity of wound complications. METHODS: Consecutive women undergoing implant-assisted or extended autologous LD flap reconstruction were randomized to either standard care or application of fibrin sealant to the donor-site chest wall. All participants were blinded for the study duration but assessors were only partially blinded. Non-parametric methods were used for analysis. RESULTS: A total of 107 women were included (sealant 54, control 53). Overall back seroma volumes were high, with no significant differences between control and sealant groups over 3 months. Fibrin sealant failed to reduce in situ back drainage volumes in the 10 days after surgery, and did not affect the rate or volume of seromas following drain removal. CONCLUSION: This randomized study, which was powered for size effect, failed to show any benefit from fibrin sealant in minimizing back seromas after LD procedures.

Hyperglycaemia confers resistance to chemotherapy on breast cancer cells: the role of fatty acid synthase.

The prognosis for women with breast cancer is adversely affected by the comorbidities of obesity and diabetes mellitus (DM), which are conditions associated with elevated levels of circulating fatty acids, hyperglycaemia and hyperinsulinaemia. We investigated the effects of exposure of non-malignant and malignant human breast epithelial cells to elevated levels of fatty acids and glucose on their growth, survival and response to chemotherapeutic agents. We found that palmitate induced cell death in the non-malignant cells but not in the malignant cells, which was abrogated through the inhibition of ceramide production and by oleate but not by IGF1. Fatty acid synthase (FAS) is responsible for the de novo synthesis of fatty acids from sugars, and is over-expressed in many epithelial cancers. Abundance of FAS was higher in malignant cells than in non-malignant cells, and was up-regulated by IGF1 in both cell types. IGF-induced growth of non-malignant cells was unaffected by suppression of FAS expression, whereas that of malignant cells was blocked as was their resistance to palmitate-induced cell death. Palmitate did not affect cell proliferation, whereas oleate promoted the growth of non-malignant cells but had the opposite effect, that is, inhibition of IGF1-induced growth of malignant cells. However, when the phosphatidylinositol 3-kinase pathway was inhibited, oleate enhanced IGF1-induced growth in both cell types. Hyperglycaemia conferred resistance on malignant cells, but not on non-malignant cells, to chemotherapy-induced cell death. This resistance was overcome by inhibiting FAS or ceramide production. Understanding the mechanisms involved in the associations between obesity, DM and breast cancer may lead to more effective treatment regimens and new therapeutic targets.