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Background: To identify the best operative procedure in human participants with a displaced or non-displaced femoral neck fracture comparing cannulated screw (CS) fixation, dynamic hip screw (DHS) fixation, hemiarthroplasty (HA), and total hip arthroplasty (THA) in terms of surgical and functional outcomes, reoperation and postoperative complications. Methods: We searched the following databases for randomized controlled trials (RCTs) or quasi RCTs until July 31st, 2022: PubMed, The Cochrane Library, Clinical trials, CINAHL, and Embase. A pairwise and network meta-analysis was performed to simultaneously assess the comparative effects of the four operative procedures, using fixed-effects and random-effects models estimated with frequentist approach and consistency assumption. Mean differences (MDs) with 95% confidence intervals (CIs) were estimated for continuous variables and odds ratios (ORs) with 95% CIs were estimated for binary variables. Results: A total of 33 RCTs, involving 5,703 patients (92% with a displaced and 8% with a non-displaced femoral neck fracture), were included in our network meta-analysis. Of them, 913 (16%) patients were operated with CS fixation, 372 (6.5%) with DHS fixation, 2,606 (46%) with HA in, and 1,812 (31.5%) with THA. CS fixation was best in operation time (CS: MD=-57.70, 95% CI -72.78;-42.62; DHS: MD=-53.56, 95% CI -76.17;-30.95; HA: MD=-20.90, 95% CI -30.65;-11.15; THA: MD=1.00 Reference) and intraoperative blood loss (CS: MD=-3.67, 95% CI -4.44;-2.90; DHS: MD=-3.20, 95% CI -4.97;-1.43; HA: MD=-1.20, 95% CI -1.73;-0.67; THA: MD=1.00 Reference). In life quality and functional outcome, measured at different time points with EQ-5D and the Harris Hip Score (HHS), THA ranked first and HA second (e.g. EQ-5D 2 years postoperatively: CS: MD=-0.20, 95% CI -0.29; -0.11; HA: MD=-0.09, 95% CI -0.17; -0.02; THA: MD=1.00 Reference; HHS 2 years postoperatively: CS: MD=-5.50, 95% CI -9.98; -1.03; DHS: MD=-8.93, 95% CI -15.08; -2.78; HA: MD=-3.65, 95% CI -6.74; -0.57; THA: MD=1.00 Reference). CS fixation had the highest reoperation risk, followed by DHS fixation, HA, and THA (CS: OR=9.98, 95% CI 4.60; 21.63; DHS: OR=5.07, 95% CI 2.15; 11.96; HA: OR=1.60, 95% CI 0.89; 2.89; THA: OR=1.00 Reference). Distinguishing between displaced and non-displaced fractures showed no relevant differences in our network meta-analysis. Conclusion: In our patient cohort with displaced and non-displaced femoral neck fractures, HHS, EQ-5D, and reoperation risk showed an advantage of THA and HA compared to CS and DHS fixation. Based on these findings, we recommend giving preference to hip arthroplasty, and considering internal fixation of femoral neck fractures only in individual cases.

Contains fulltext : 232050.pdf (Publisher’s version ) (Open Access) BACKGROUND: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer. MATERIAL AND METHODS: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines. RESULTS: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7 vs. 89.8, difference (diff) = -5.80, p=.005), role (83.5 vs. 90, diff = -5.97, p=.02), cognitive (83.7 vs. 91.9, diff = -8.05, p=.001), and social functioning (86.5 vs. 95.1, diff = -8.49, p=

541 Background: The meiotic DNA break regulator HORMAD1 is aberrantly expressed in many cancers and is associated with increased genomic instability. The susceptibility of HORMAD1 expressing tumors to agents targeting DNA damage repair (DDR) pathways is poorly understood since clinical data within the context of a randomized clinical trial (RCT) is lacking. Here, we retrospectively studied HORMAD1 expression as a putative predictive biomarker in an RCT for benefit of adjuvant high-dose platinum-based chemotherapy (HDCT) with autologous stem cell support in patients with high-risk HER2-negative early breast cancer (BC). Methods: Patients with stage III BC participated in an RCT comparing HDCT to conventional chemotherapy (CDCT; Rodenhuis et all, NEJM, 2003; Steenbruggen et all, JAMA Oncol, 2020). We studied the subgroup with HER2-negative BC for whom tumor BRCA1-like classification was previously determined using a validated DNA comparative genomic hybridization algorithm (Vollebergh et all, BCR, 2014). Tumor HORMAD1 expression was determined on FFPE samples using RNAscope, an RNA in situ hybridization method, and classified as negative (no expression) or positive (any expression detected). Results: For 195/246 (79.3%) HER2-negative patients treated according to protocol, HORMAD1 RNAscope status was available; dropout was due to absence or insufficient quality of tumor specimens. HORMAD1 positivity was enriched in triple-negative breast cancer (TNBC) (23/47; 48.9%). Furthermore, in all HER2-negative BCs, HORMAD1 positivity (45/195; 23.1%) was associated with age ≤40 years, histological grade III, 10%. Such association, although not significant, was also observed within TNBC. During a median follow-up of 20.3 years, 124 (63.6%) recurrences and 115 deaths (59.0%) occurred. The prognostic effect of HORMAD1 positivity on overall survival (OS) varied with follow-up time and was borderline significant at 10 years and significant thereafter (10-year: adjusted (adj.) HR 0.47, 95% CI 0.21-1.04; 15-year: adj. HR 0.25, 95% CI 0.07-0.91). Benefit on RFS from HDCT over CDCT was stronger in patients with HORMAD1-positive tumors (adj. HR 0.18, 95% CI 0.06-0.54) than in patients with HORMAD1-negative tumors (adj. HR 0.69, 95% CI 0.46-1.02) (P-interaction = 0.02). Similar results were observed for OS. Conclusions: In this retrospective sub study of 195 patients with high-risk HER2-negative BC participating in an RCT, tumor HORMAD1 expression is predictive for benefit of high-dose platinum-based chemotherapy. Our observations are consistent with the prior observations that HORMAD1 expression is associated with genomic instability and impaired DDR pathways. Further research is warranted to validate our findings. Clinical trial information: NCT03087409.

INTRODUCTION AND OBJECTIVE:The presence of lymphovascular invasion (LVI) and embryonal carcinoma (EC) are important factors that aid clinical decision-making in patients with clinical stage I (CS I...

Background This study is part of the Netherlands Breast Cancer Project, initiated to address research questions that are unlikely answered by future randomized controlled trials (RCT). Here we investigated whether aromatase inhibitors (AI) are superior over tamoxifen (TAM), in the treatment of Estrogen Receptor (ER) positive Human Epidermal growth factor Receptor 2 (HER2) positive breast cancer, using treatment and outcome data from the population based Netherlands Cancer Registry (NCR). RCTs showed superiority of AI over TAM in postmenopausal ER+/HER2+ patients while a (non-significant) suggestion for worse outcome was observed among premenopausal patients treated with AI in the SOFT/TEXT trial. Perimenopausal women were not considered in these trials. Methods Dutch women without a prior malignancy, diagnosed between 2005-2007 with an ER+/HER2+, endocrine treated, non-metastatic, invasive breast cancer, were identified through the NCR and followed until 2013. Since data on menopausal status were lacking, we used age at diagnosis as a proxy to categorize patients as premenopausal (≤45 years), perimenopausal (45-55 years) and postmenopausal (>55 years). A time-dependent variable was calculated indicating whether AI treatment was given for >50% (denoted AI treated) vs. Results We included 1158 patients: 326 pre-, 306 peri- and 526 postmenopausal. Of these, 229 received TAM and 929 AI. During follow-up, 239 RFS and 184 OS events were observed. In the TAM treated group, 56 RFS and 45 OS events were observed, in the AI treated group 183 RFS and 139 RFS events were observed respectively. No differences in RFS were observed comparing AI to TAM treated patients in the premenopausal (HR 1.33; 95% CI 0.71-2.49; P=0.378) and postmenopausal (HR 0.84, 95%CI 0.54-1.32; P=0.456) group. However, perimenopausal patients benefitted significantly from AI compared with TAM (HR 0.50; 95% CI 0.27-0.95). Results were similar for OS: no significant benefit from AI when compared to TAM in pre- (HR 1.41; 95% CI 0.62-3.19; P=0.408) and postmenopausal (HR 0.75; 95% CI 0.47-1.22; P=0.245) patients while perimenopausal patients derived significant benefit from AI treatment (HR 0.42; 95% CI 0.20-0.85; P=0.016). Conclusion In this population based cohort study we observed superiority for AI over TAM in the treatment of ER+/HER2+ perimenopausal patients. Data were suggestive in favor of AI when compared to TAM for postmenopausal patients while an indication of worse outcome with AI was seen in premenopausal patients, consistent with results of the SOFT/TEXT trial. Although we used age as a proxy for menopausal status, our results are consistent with previous RCTs. Population based data may therefore provide a reliable source of information when new RCTs might not be feasible anymore. Citation Format: Dackus GMHE, Jozwiak K, Sonke GS, Van der Wall E, Van Diest PJ, Hauptmann M, Siesling S, Linn SC. How population-based data complement trial data in the adjuvant endocrine treatment of ER+/HER2+ breast cancers [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-16.

This abstract was withdrawn by the authors.

Data on isolated limb perfusion (ILP) in elderly melanoma patients are scarce. We aimed to evaluate the efficacy and safety of ILP in our institutional cohort of melanoma patients. We performed retrospective analysis of stage IIIB/C melanoma patients who underwent ILP for melanoma in-transit metastases (ITMs) in our institution between 2000 and 2016. Normothermic ILP was performed with either melphalan or melphalan and tumor necrosis factor. Baseline and treatment characteristics, locoregional progression-free survival (LPFS) and melanoma-specific survival (MSS) were assessed and prognostic factors for response, recurrence, and survival were analyzed using univariable and multivariable analysis. Overall, 91 patients were included in this study. Based on the median age of 70 years, we split patients into younger and elderly groups. No differences in response rates were observed between age groups, with an overall response rate of 81% and complete response (CR) rate of 47%. LPFS did not differ between age groups, and median LPFS was 16 months for patients with a CR. Median MSS was 38 months and differed between younger (45 months) and elderly patients (18 months). Toxicity was generally mild and did not differ between age groups. Two patients (2.2%) suffered Wieberdink IV toxicity, while no patients required amputation because of severe toxicity. CR was prognostic for improved LPFS and MSS, while patients >70 years of age and patients with stage IIIC disease had a higher risk of melanoma-specific death. Because of its safety profile and high CR rates, ILP is a viable option for patients with bulky or multiple melanoma ITMs, including elderly (>70 years of age) patients.

Diffuse reflectance spectroscopy (DRS) can discriminate different tissue types based on optical characteristics. Since this technology has the ability to detect tumor tissue, several groups have proposed to use DRS for margin assessment during breast-conserving surgery for breast cancer. Nowadays, an increasing number of patients with breast cancer are being treated by neoadjuvant chemotherapy. Limited research has been published on the influence of neoadjuvant chemotherapy on the optical characteristics of the tissue. Hence, it is unclear whether margin assessment based on DRS is feasible in this specific group of patients. We investigate whether there is an effect of neoadjuvant chemotherapy on optical measurements of breast tissue. To this end, DRS measurements were performed on 92 ex-vivo breast specimens from 92 patients, treated with neoadjuvant chemotherapy and without neoadjuvant chemotherapy. Generalized estimating equation (GEE) models were generated, comparing the measurements of patients with and without neoadjuvant chemotherapy in datasets of different tissue types using a significance level of 5%. As input for the GEE models, either the intensity at a specific wavelength or a fit parameter, derived from the spectrum, was used. In the evaluation of the intensity, no influence of neoadjuvant chemotherapy was found, since none of the wavelengths were significantly different between the measurements with and the measurements without neoadjuvant chemotherapy in any of the datasets. These results were confirmed by the analysis of the fit parameters, which showed a significant difference for the amount of collagen in only one dataset. All other fit parameters were not significant for any of the datasets. These findings may indicate that assessment of the resection margin with DRS is also feasible in the growing population of breast cancer patients who receive neoadjuvant chemotherapy. However, it is possible that we did not detect neoadjuvant chemotherapy effect in the some of the datasets due to the small number of measurements in those datasets.

504 Background: In HR+/HER2- N0-1 early BC, postmenopausal patients (pts) with RS™ > 25 and a substantial proportion of premenopausal pts seem to benefit from addition of adjuvant chemotherapy (CT) to endocrine therapy (ET). However, the magnitude of absolute benefit from this treatment intensification seems to depend on clinical-pathological and biological prognostic factors. For the first time, we present outcome from the CT part of the prospective phase III WSG-ADAPT HR+/HER- trial combining both static (RS in baseline core biopsy (CB) and dynamic (Ki67 response) biomarkers to optimize adjuvant therapy in luminal EBC. Methods: Pts with clinically high-risk HR+/HER2- EBC (cT2-4 OR clinically N+ OR G3 OR Ki67>15%) were initially treated by 3 (+/-1) weeks of standard ET (postmenopausal: mostly AI; premenopausal: TAM) before surgery or sequential CB. Pts with cN2-3 or G3/Ki67>40% were randomized directly to the CT trial. pN0-1 pts with RS0-11 OR RS12-25/ET-response (central Ki67postendocrine4 positive LN (n = 390), lower RS was associated with improved iDFS (RS0-11 vs RS > 25: plog-rank= 0.016, 5y-iDFS 90% vs. 64%). In pts with RS > 25 (n = 965), low Ki67postendocrine, N0 status, and c/pT1 status were associated with improved iDFS. In particular, ET-responders had higher 5y-iDFS (84%) than ET-non-responders (77%; plog-rank= 0.040). Younger patients (log-rank= 0.249). Conclusion: First results from the prospective high risk cohort from a large prospective phase III ADAPT trial provide evidence for good prognosis in some pts with >4 positive LN and e.g. low RS. Moreover combination of lower post-endocrine Ki-67 and limited tumor burden may be a promising criterion for CT de-escalation strategies even in patients with high RS. Clinical trial information: NCT01779206.

BackgroundThe association of early changes in the immune infiltrate during neoadjuvant chemotherapy (NACT) with pathological complete response (pCR) in triple-negative breast cancer (TNBC) remains unexplored.MethodsMultiplexed immunohistochemistry was performed in matched tumor biopsies obtained at baseline and after 3 weeks of NACT from 66 patients from the West German Study Group Adjuvant Dynamic Marker-Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer - Triple Negative Breast Cancer (WSG-ADAPT-TN) trial. Association between CD4, CD8, CD73, T cells, PD1-positive CD4 and CD8 cells, and PDL1 levels in stroma and/or tumor at baseline, week 3 and 3-week change with pCR was evaluated with univariable logistic regression.ResultsCompared with no change in immune cell composition and functional markers, transition from ‘cold’ to ‘hot’ (below-median and above-median marker level at baseline, respectively) suggested higher pCR rates for PD1-positive CD4 (tumor: OR=1.55, 95% CI 0.45 to 5.42; stroma: OR=2.65, 95% CI 0.65 to 10.71) and PD1-positive CD8 infiltrates (tumor: OR=1.77, 95% CI 0.60 to 5.20; stroma: OR=1.25, 95% CI 0.41 to 3.84; tumor+stroma: OR=1.62, 95% CI 0.51 to 5.12). No pCR was observed after ‘hot-to-cold’ transition in PD1-positive CD8 cells. pCR rates appeared lower after hot-to-cold transitions in T cells (tumor: OR=0.26, 95% CI 0.03 to 2.34; stroma: OR=0.35, 95% CI 0.04 to 3.25; tumor+stroma: OR=0.00, 95% CI 0.00 to 1.04) and PD1-positive CD4 cells (tumor: OR=0.60, 95% CI 0.11 to 3.35; stroma: OR=0.22, 95% CI 0.03 to 1.92; tumor+stroma: OR=0.32, 95% CI 0.04 to 2.94). Higher pCR rates collated with ‘altered’ distribution (levels below-median and above-median in tumor and stroma, respectively) of T cell (OR=3.50, 95% CI 0.84 to 14.56) and PD1-positive CD4 cells (OR=4.50, 95% CI 1.01 to 20.14).ConclusionOur exploratory findings indicate that comprehensive analysis of early immune infiltrate dynamics complements currently investigated predictive markers for pCR and may have a potential to improve guidance for individualized de-escalation/escalation strategies in TNBC.

10064 Background: Neoadjuvant ipilimumab and nivolumab induces high pathologic response rates of 74-78% (OpACIN and OpACIN-neo trial), thus the role of Therapeutic Lymph Node Dissections (TLND) in patients with major pathologic responses (MPR: pathological (near) complete response) is now unclear. In the PRADO trial, TLND was omitted in patients with MPR in their index lymph node ((ILN), the largest LN marked prior to neoadjuvant therapy). We sought to determine if less extensive surgery is associated with better Health Related Quality of Life (HRQoL). These are the first results of the comparison of HRQoL between patients undergoing a TLND or less extensive ILN excision. Methods: HRQoL was assessed with the European Organisation for Research and Treatment of Cancer QoL questionnaire-C30 (QLQ-C30). A generalized estimation equation was used to assess the difference in HRQoL outcomes between patients who underwent TLND (pathological non- and partial-responders, pNR/pPR) versus those who did not (pathological (near)complete responders, pNCR/pCR). Differences were adjusted for age, gender and follow-up (FU, in weeks), but not for pathological responses (pNR, pPR, pNCR & pCR). Differences in QLQ-C30 scores were classified as clinically important according to published guidelines. Results: A total of 49 patients from the PRADO study had reached at least 24 weeks FU, and were included in the first explorative analysis. The median age of this study population was 58 years (range, 22-84). Questionnaire completion rates were high: 94% at baseline, 100%, 90%, 88% at week 6, 12 and 24, respectively. Sixteen (33%) patients underwent TLND versus 33 (67%) who had ILN excision only. Over a FU period of 24 weeks, patients who underwent TLND scored significantly lower on global (68 vs 78, adjusted difference (diff) = -9.53, p = .005), physical (84 vs 94 diff = -11.1, p = < .001), emotional (69 vs 83, diff = -11.7, p = .001), role (70 vs 85, diff = -13, p = .004), and social functioning (81 vs 91, diff = -8.9, p = .016) and had a higher symptom burden of fatigue (35 vs 23, diff = 11.1, p = .004), insomnia (38 vs 18, diff = 16.6, p = .002) and financial impact (12 vs 4, diff = 7.9, p = .027) than patients undergoing ILN excision only. These differences were indicated as clinically relevant. Conclusions: First results from PRADO suggest that reducing the extent of surgery following neoadjuvant immunotherapy might result in better HRQoL of high-risk stage III melanoma patients. Clinical trial information: NCT02977052.

114 Background: Female survivors of Hodgkin lymphoma (HL) treated with alkylating chemotherapy (CT) and/or pelvic radiotherapy (RT) have an increased risk of primary ovarian insufficiency (POI). Among women with a natural menopause, POI has been associated with increased risk of cardiovascular disease (CVD). We examined whether treatment-induced POI increases long-term CVD risk in HL survivors. Methods: From a large Dutch cohort of 5-year HL survivors, we selected 918 women who were treated before 41 years of age between 1965 and 2000. Data on HL treatment, menopausal status and cardiovascular events (ischemic heart disease (IHD), heart failure (HF) and valvular heart disease (VHD)) were obtained from medical records, general practitioners and patient questionnaires. CVD risks were estimated with Cox regression models using time-dependent covariates and attained age as the time scale. Results: After a median follow-up of 24 years, 299 out of 918 women (33%) had developed POI (median menopausal age, 34 years). We identified 463 cardiovascular events in 300 women, of whom 85 developed CVD after POI. POI was not associated with subsequent CVD risk (HR:0.85, 95% CI 0.62-1.16) compared with a menopausal age of ≥40 years. Compared with women who reached menopause at ages ≥50 years, the HRs for menopausal ages of < 30 years, 30-39 and 40-49 years were 0.90 (95% CI 0.52-1.56), 0.87 (95% CI 0.57-1.33) and 0.96 (95% CI 0.64-1.44), respectively. Furthermore, a short duration of intact ovarian function after HL treatment ( < 5 years) did not increase CVD risk compared to a long duration (≥25 years) (HR:0.72, 95% CI 0.44-1.20). 177 women had used HRT, of whom 115 (65%) with POI (median duration of HRT use, 8.3 years). Women who used HRT for ≥5 years did not have a higher CVD risk than non-HRT users (HR 1.02, 95% CI 0.64-1.62). Similar results were found in analyses with IHD, HF and VHD as separate outcomes. Conclusions: POI and duration of post-treatment intact ovarian function did not affect CVD risk in HL survivors, suggesting that an early artificial menopause does not increase CVD risk.

Background Since the introduction of immune-checkpoint blockade, the overall survival has significantly improved for patients with advanced melanoma. However, to date, there is limited data on patients’ functioning and health-related quality of life (HRQoL), years after active treatment. Therefore, we evaluated these outcomes in advanced melanoma survivors (AMS) and compared these with matched controls. Methods Ipilimumab-treated AMS without systemic treatment for at least 2 years were recruited from 15 hospitals. The primary outcome was HRQoL assessed with the European Organization for Research and Treatment of Cancer quality of life questionnaire-C30 (QLQ-C30). Secondary outcomes were fatigue, anxiety, depression and disease specific HRQoL. Up to 5 controls per AMS were individually matched on age, gender and educational status. Survivors and controls were compared on QLQ-C30 scores using generalized estimating equations. Differences in QLQ-C30 scores were classified as clinically important according to published guidelines. Results A total of 89 AMS were evaluated in this study. After last administration of ipilimumab, the mean follow-up (FU) was 45.5 (SD 20.8) months. Comparison with matched controls showed that AMS scored significantly lower on physical (difference (diff) = -5.80, p=.005), role (diff =-5.97, p=.02), cognitive (diff = -8.05, p=.001), and social functioning (diff = -8.49, p = Conclusions Compared to matched controls, AMS showed overall worse functioning scores and more symptoms of fatigue, dyspnea, diarrhea and financial impact. AMS with a longer FU reported better QoL, but more financial issues. These study results may help to develop interventions to the individual healthcare needs of AMS and contribute to the development of appropriate survivorship care. Legal entity responsible for the study Netherlands Cancer Institute. Funding Bristol-Myers Squibb. Disclosure All authors have declared no conflicts of interest.

IntroductionCurrently used tools for breast cancer prognostication and prediction may not adequately reflect a young patient’s prognosis or likely treatment benefit because they were not adequately validated in young patients. Since breast cancers diagnosed at a young age are considered prognostically unfavourable, many treatment guidelines recommend adjuvant systemic treatment for all young patients. Patients cured by locoregional treatment alone are, therefore, overtreated. Lack of prognosticators for young breast cancer patients represents an unmet medical need and has led to the initiation of the PAtients with bReAst cancer DIaGnosed preMenopausally (PARADIGM) initiative. Our aim is to reduce overtreatment of women diagnosed with breast cancer aged≤40 years.Methods and analysisAll young, adjuvant systemic treatment naive breast cancer patients, who had no prior malignancy and were diagnosed between 1989 and 2000, were identified using the population based Netherlands Cancer Registry (n=3525). Archival tumour tissues were retrieved through linkage with the Dutch nationwide pathology registry. Tissue slides will be digitalised and placed on an online image database platform for clinicopathological revision by an international team of breast pathologists. Immunohistochemical subtype will be assessed using tissue microarrays. Tumour RNA will be isolated and subjected to next-generation sequencing. Differences in gene expression found between patients with a favourable and those with a less favourable prognosis will be used to establish a prognostic classifier, using the triple negative patients as proof of principle.Ethics and disseminationObservational data from the Netherlands Cancer Registry and left over archival patient material are used. Therefore, the Dutch law on Research Involving Human Subjects Act (WMO) is not applicable. The PARADIGM study received a ‘non-WMO’ declaration from the Medical Ethics Committee of the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, waiving individual patient consent. All data and material used are stored in a coded way. Study results will be presented at international (breast cancer) conferences and published in peer-reviewed, open-access journals.

Background In the 1990s, the use of adjuvant systemic therapy was based on nodal involvement but not on tumor size, as was recommended in the Dutch breast cancer guidelines. Tumor size is an important prognostic variable in breast cancer, although this may not hold true for all molecular subtypes or patient ages. Here, we studied the prognostic value of tumor size for young (≤40 years at diagnosis), systemically untreated, node-negative (N0), breast cancer patients, and assessed whether for any given T-stage survival exceeds 90% at 20 years. Methods All female, breast cancer patients, ≤40 years at time of diagnosis (between 1989 and 2000), were selected from the Netherlands Cancer Registry. All lymph node-positive and systemically treated patients were excluded, resulting in a cohort of 2302 women. Clinico-pathological and follow-up data were collected from national databases, patient records, and the original pathology reports. Multivariate cox regression for overall survival was performed using T-stage (TNM 8.0), molecular subtype, and tumor grade (according to Nottingham Histologic Score) as covariates. Results Survival rates at 20-years are shown in Table. Median follow-up was 17 years. Only 1% had a T3 tumor and these patients were excluded from analysis. The 20-yr OS for the 96 (4%) T1a tumors was 81% (not shown). Women with T2 tumors had a significantly lower OS compared to women with T1a (HR 1.9 P = 0.024), T1b (HR 1.7 P = > 0.001) and T1c tumors (HR 1.31 P = 0.002), adjusted for tumor grade and molecular subtype. No OS data is shown for subgroups with less than 35 patients. Table . 179PD Overall survival (OS; %) at 20 years by T-stage, molecular subtype and tumor grade (Gr) T1b T1c T2 All n OS n OS n OS n OS 359 73 1114 69 611 60 2302 68 ER+HER2- Gr 1 + 2 Gr 3 172 82 464 77 165 56 973 73 43 68 130 55 83 49 269 54 All 79 72 55 69 ER-HER2- Gr 1 + 2 Gr 3 6 - 31 - 27 - 70 65 31 - 205 73 158 66 417 68 All 61 71 63 68 HER2+ Gr 1 + 2 Gr 3 31 - 74 54 36 54 159 57 22 - 81 53 54 61 169 56 All 70 54 57 58 Conclusions T-stage is associated with OS in this patient group. At 20 years follow-up, we found no T-stage with OS rates >90% in N0, systemically untreated patients, meaning that patients regardless of T-stage may benefit from some form of systemic treatment. Legal entity responsible for the study The PARADIGM study group. Funding The Netherlands Organization for Health Research and Development (ZonMW); A Sister’s Hope; De Vrienden van UMC Utrecht. Disclosure S.C. Linn: Research grant / Funding (self): Amgen; Research grant / Funding (self), unrestricted research grant SUBITO study (NCT02810743): Eurocept-pharmaceuticals; Research grant / Funding (institution), research grant NCT02810743 & olaparib;fulvestrant NCT00738777;advisory board olaparib breast cancer: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution), unrestricted research grant for NCT02285179 and study drug (taselisib): Genentech; Advisory / Consultancy, Member of the Scientific Advisory Board of Cergentis (unpaid): Cergentis; Advisory / Consultancy, scientific advisory board for Watson for Oncology (paid to institution): IBM; Research grant / Funding (institution), unrestricted research grant and study drug NCT03283384; research support biomarker study NCT02109913: Novartis; Advisory / Consultancy, Research grant / Funding (institution), scientific advisory board palbociclib; TEAM 2b through unrestricted research grant from Pfizer: Pfizer; Research grant / Funding (institution), Unrestricted research grant paid to institution for ABC study and study drug: Tesaro; Honoraria (institution), Fee for teaching paid to institution: Bayer. All other authors have declared no conflicts of interest.

9588 Background: Results from the phase 1b (OpACIN) study comparing neoadjuvant to adjuvant ipilimumab (3mg/kg) plus nivolumab (1mg/kg) demonstrated a high clinical activity of neoadjuvant treatment in high-risk melanoma. However, the toxicity was high, with 90% grade 3 to 4 toxicity. These findings raise questions about long-term quality of life (QoL) in these patients (pts) who were treated with curative intent. Here we present the first analysis of patient-reported outcomes of patients treated with (neo)adjuvant immune checkpoint combination therapy. Methods: Sixteen of 20 pts had completed study treatment and were currently in follow-up (FU). Pts were asked to fill in The European Organisation for Research and Treatment of Cancer QoL questionnaire-C30 (QLQ-C30). The QLQ-C30 was used to assess health-related QoL and is composed of functional, symptomatic dimensions and a dimension of global health/QoL. A reference population (controls without a diagnosis of cancer) was obtained from the ‘Patient Reported Outcomes Following Initial treatment and Long term Evaluation of Survivorship’ registry. Pts were individually matched on age, gender, education and marital status with up to 9 controls. Pts and controls were compared on QLQ-30 scores using univariable linear regression analyses. Results: Thirteen out of 16 invited pts (81% response) returned a completed questionnaire. Median FU was 30 months after randomization. Pts scored significantly lower in emotional (std coeff. = -1.0, p = .007), role (std coeff. = -0.7, p = .08), cognitive (std coeff. = -0.8, p = .018) and social (std coeff. = -1.0, p = .014) functioning and higher in symptom burden of fatigue (std coeff. = .9, p = .024) compared to controls, which were all clinically relevant. The physical functioning and global QoL score did not differ between pts and controls. Conclusions: High risk stage III melanoma pts treated with (neo)adjuvant immune checkpoint combination therapy showed significantly lower emotional, role, cognitive and social functioning scores than controls. Pts reported higher levels of fatigue, however, there was no difference on physical functioning and global QoL between pts and controls.

Previous studies have shown that both exogenous and endogenous estrogens and progestogens increase the risk of breast cancer. it has been suggested that in vitro fertilization (IVF) procedures may increase breast cancer risk. This risk could be could be due to a temporary decrease in estradiol and progesterone levels (during down-regulation of the natural cycle), as well as strongly elevated levels (during stimulation phase). Results of previous studies investigating breast cancer risk after IVF treatment were inconclusive because of limited follow-up. Recent studies have reported no increased risk of this cancer after IVT at a mean follow-up of 8 and 16 years. This historical cohort (OMEGA) study quantified long-term risk of breast cancer after ovarian stimulation for IVF. The aim of the study was to compare the long-term risk of breast cancer among a nationwide cohort of women receiving ovarian stimulation for IVF with that of women receiving other fertility treatments and those in the general population. The study was conducted in 12 IVF clinics in the Netherlands. The cohort was composed of 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women who started other fertility treatments between 1980 and 1995 (non-IVF group) Data were obtained from all 12 IVF clinics. There was complete follow-up through December 2013 for 96% of the cohort. At end of follow-up, the median age was 53.8 years in the IVF group and 55.3 years in the non-IVF group. Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was obtained from medical records and mailed questionnaires. First invasive and in situ breast cancer incidence among women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Risk of breast cancer in the IVF group was compared with risk in the non-IVF group (hazard ratios [HRs]) and the general population (standardized incidence ratios [SIRs]). In the total cohort, the mean age at baseline was 32.8 years, and the mean number of IVF cycles was 3.6. After a median follow-up of 21.1 years, 839 of the cohort had invasive breast cancer, and 109 had in situ breast cancer. Compared with the general population, breast cancer risks were not increased either in the IVF group (SIR, 1.01; 95% confidence interval [CI], 0.93-1.09) or the non-IVF group (SIR, 1.00; 95% CI, 0.88-1.15). At the age of 55 years, cumulative incidence rates of breast cancer were 3.0% in the IVF group and 2.9% in the non-IVF group (P = 0.85). With longer time since treatment (>= 20 years), the SIR did not increase in the IVF group (SIR, 0.92; 95% CI, 0.73-1.15) or in the non-IVF group (SIR, 1.03; 95% CI, 0.82-1.29). Women with 7 or more IVF cycles had a significantly decreased risk of breast cancer than did women who were treated with 1 to 2 IVF cycles; the HR was 0.55, with a 95% CI of 0.39 to 0.77. The risk was also significantly lower (HR, 0.77; 95% CI, 0.61-0.96) after poor response to the first IVF cycle ( = 4 collected oocytes). These data show that IVT treatment did not increase the risk of breast cancer in a cohort of women undergoing fertility treatment in the Netherlands between 1980 and 1995 when compared with women who received non-IVF treatment or those in the general population after a median follow-up of 21 years. These findings are consistent with those from recent reviews showing no significant increase in long-term risk of breast cancer among IVF-treated women.

A mathematical model of chicken processing that quantitatively describes the transmission of Campylobacter on chicken carcasses from slaughter to chicken meat product has been developed in Nauta et al. (2005). This model was quantified with expert judgment. Recent availability of data allows updating parameters of the model to better describe processes observed in slaughterhouses. We propose Bayesian updating as a suitable technique to update expert judgment with microbiological data. Berrang and Dickens's data are used to demonstrate performance of this method in updating parameters of the chicken processing line model.

Background Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. Methods A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)-based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors. Results BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance. Conclusions In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms.

e21549 Background: Data on isolated limb perfusion (ILP) in elderly melanoma patients is scarce. We aimed to evaluate the efficacy and safety of ILP in our institutional cohort of melanoma patients. Methods: Retrospective analysis of AJCC stage IIIB/C melanoma patients who underwent ILP for locally advanced (unresectable) melanoma in-transit metastases of the limb between 2000 and 2016. Normothermic ILP (37-38 °C) was performed with either Melphalan or Melphalan and Tumor Necrosis Factor (TNF). Baseline characteristics, local toxicity (Wieberdink) and systemic toxicity, locoregional progression-free survival (PFS) and melanoma-specific survival (MSS) were assessed and prognostic factors for response to ILP, melanoma recurrence and survival were analyzed using univariable and multivariable analysis. Results: 88 patients were included. The overall response rate to ILP was 81%, with a complete response (CR) rate of 47%. Median overall locoregional PFS was 6 months, while patients with a CR had a median PFS of 16 months. Median overall MSS was 38 months. Two patients (2.3%) suffered Wieberdink IV toxicity (compartment syndrome), while no patients required amputation because of severe toxicity. Based on the median age of 70, we split patients into younger and elderly groups. Toxicity rates, response rates and locoregional PFS did not differ significantly between younger and elderly patients. CR was prognostic for improved locoregional PFS and MSS. Moreover, patients > 70 and patients with stage IIIC disease had a higher risk of melanoma-specific death. Conclusions: ILP has good and potential durable responses, but also less frequent and less severe toxicity than recently developed targeted or immune therapies, which can be reserved for progression to stage IV. This study showed that ILP is an effective and safe procedure for elderly patients ( > 70) with locally advanced melanoma of the limb.

535 Background: Young age at breast cancer diagnosis is considered a poor prognostic factor. As a result, many treatment guidelines advice adjuvant systemic treatment for young patients. Answering prognostic questions on young patients has therefore become a challenge. The PARADIGM (PAtients with bReast cAncer DIaGnosed preMenopausally) project aims to assess the long-term outcome of women diagnosed with breast cancer ≤40 years in the absence of adjuvant systemic therapy, using real world data from the nationwide Netherlands Cancer Registry (NCR) coupled with tissue biobanking. Methods: All women ≤40 years, diagnosed in the Netherlands between 1989-2000 with a primary invasive, histologically proven, TanyN0M0 breast cancer, without adjuvant systemic treatment were identified through the NCR. Back then N0 patients were considered low risk and did not receive adjuvant systemic treatment. Tissue specimens were revised by a team of dedicated breast pathologists. Cox regression was performed to estimate hazard ratios for recurrence-free (RFS) and overall survival (OS) according to immunohistochemical (IHC) subtype. Analyses were adjusted for grade, pathological T-stage, histological subtype and radiotherapy. Results: We included 2310 patients with a mean follow-up of 15.4 years (range 0-25 years). OS for the whole cohort was 68% and RFS 58.4% at 25 years. In total 740 deaths and 1043 recurrences were observed. Hormone receptor (HR)+/HER2+ patients had a significantly worse OS when compared to HR-HER2+ patients (adjusted Hazard Ratio 1.58; 95% confidence interval 1.05-2.38; p=0.029). No difference was observed between HR-HER2+ and the triple negative and HR+/HER2- subgroups at 25-years. RFS was similar for all IHC subtypes. Conclusions: In this large cohort of non-adjuvant systemically treated young breast cancer patients with long-term follow-up HR+/HER2+ patients have a significantly worse survival when compared to triple negative, HR-/HER2+ and HR+/HER2- patients. The latter three subtypes have similar OS at 25 years. Future molecular studies have been planned to distinguish the favorable from the unfavorable prognostic patients.

551Background: Aromatase inhibitors (AI) are superior to tamoxifen (TAM) in postmenopausal estrogen receptor positive (ER+) breast cancer patients. TAM is standard of care for premenopausal ER+ patients. The SOFT/TEXT trials showed, however, that ovarian function suppression combined with the AI exemestane significantly improves disease-free survival compared to TAM in premenopausal patients. Evidence on perimenopausal women at breast cancer diagnosis is scarce as they are usually excluded from studies. We therefore aim to provide evidence for the optimal treatment of ER+ breast cancer patients 45-50 years of age, using data from the population-based Netherlands Cancer Registry (NCR). Methods: All pre-menopausal Dutch women, without prior history of malignancy, diagnosed between 2004-2007 at age 45-50 years with an ER+, non-metastatic, primary invasive breast cancer for which they received chemotherapy and endocrine treatment, were identified through the NCR. Cox proportional hazards regression was used t...

A mathematical model of chicken processing that quantitatively describes the transmission of Campylobacter on chicken carcasses from slaughter to chicken meat product has been developed in Nauta et al. (2005). This model was quantified with expert judgment. Recent availability of data allows updating parameters of the model to better describe processes observed in slaughterhouses. We propose Bayesian updating as a suitable technique to update expert judgment with microbiological data. Berrang and Dickens's data are used to demonstrate performance of this method in updating parameters of the chicken processing line model.