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Background The 16th St. Gallen International Breast Cancer Conference 2019 in Vienna, Austria reviewed substantial new evidence on loco-regional and systemic therapies for early breast cancer. Design Treatments were assessed in light of their intensity, duration and side-effects, estimating the magnitude of clinical benefit according to stage and biology of the disease. The Panel acknowledged that for many patients, the impact of adjuvant therapy or the adherence to specific guidelines may have modest impact on the risk of breast cancer recurrence or overall survival. For that reason, the Panel explicitly encouraged clinicians and patients to routinely discuss the magnitude of benefit for interventions as part of the development of the treatment plan. Results The guidelines focus on common ductal and lobular breast cancer histologies arising in generally healthy women. Special breast cancer histologies may need different considerations, as do individual patients with other substantial health considerations. The panelists' opinions reflect different interpretation of available data and expert opinion where is lack of evidence and sociocultural factors in their environment such as availability of and access to medical service, economic resources and reimbursement issues. Panelists encourage patient participation in well-designed clinical studies whenever available. Conclusions With these caveats in mind, the St. Gallen Consensus Conference seeks to provide guidance to clinicians on appropriate treatments for early-stage breast cancer and guidance for weighing the realistic tradeoffs between treatment and toxicity so that patients and clinical teams can make well-informed decisions on the basis of an honest reckoning of the magnitude of clinical benefit.

Background: EndoPredict has been previously validated as a prognostic test in women with ER-positive, HER2-negative disease who received endocrine therapy only as part of the ABCSG6 and -8 trials. Here, we further evaluate the prognostic value of EndoPredict in this cohort with longer-term follow-up and compare 10-year distant recurrence (DR) and 5-15 years late recurrence according to nodal status. Methods: This analysis included 1702 patients with ER-positive, HER2-negative disease who received endocrine therapy only. Prognostic value of EPclin score and EPclin risk category (high, low) on the risk of distant recurrence adjusted for patient and disease characteristics was evaluated using multivariable Cox proportional hazard models. Kaplan-Meier estimators were used to estimate DR according EPclin class and were compared using log rank test. Analyses were performed for the overall cohort, by nodal status, and for patients who were distant recurrence free at year 5 (late recurrence). Results: The median follow-up was 9.6 years (range 0-16.6), an increase of 4.2 years over previous reports. Reanalysis with longer follow-up confirms that EPclin is a significant predictor of DR after adjusting for clinical factors, regardless of nodal status (Table 1). Overall, 62.6% of patients had low risk EPclin scores and 10-year DR was significantly improved relative to those with high risk scores (p Conclusion: This reanalysis of previous EndoPredict data with a longer follow-up confirms that EPclin can identify a large group of patients at low risk of distant recurrence after 10 years who might be sufficiently treated with 5 years adjuvant endocrine therapy only, independent of nodal status. Replication of these results for the late distant recurrence between years 5-15 also shows that EPclin scores may also be informative in selecting patients who may safely forgo extended endocrine therapy. Table 1.Multivariate analysis 0-15 year DR5-15 year DRCohortHR*p-valueHR*p-valueAll patients2.55 Table 2.DR according to EPclin score Low risk EPclinHigh risk EPclin CohortHR*%0-10 year DR (95% CI)%0-10 year DR (95% CI)Log-rank p-valueAll patients N=17024.7762.60.96 (0.94, 0.97)37.40.80 (0.77, 0.84) Citation Format: Filipits M, Dubsky P, Rudas M, Greil R, Balic M, Fitzal F, Bago-Horvath Z, Singer C, Hlauschek D, Kronenwett R, Bernhisel R, Lancaster J, Gnant M. Prediction of distant recurrence using EndoPredict among women with ER-positive, HER2-negative breast cancer with a maximum follow-up of 16 years [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 P4-08-05.

Background: EndoPredict (EPclin) is a validated prognostic test combining expression of 12 cancer-related genes for breast cancer patients with estrogen receptor (ER) positive, HER2-negative disease who received 5 years of endocrine therapy (Buus et al., 2017; Dubsky et al. 2012) and for women who received chemotherapy (Martin et al., 2014). Here, we determine the EPclin and 10-year distant recurrence free interval (DRFI) rates for patients who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET) using data from five large clinical trials. Methods: A total of 3746 women with ER-positive, HER2-negative disease were included in this analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET+C (GEICAM 2003-02/9906). EPclin incorporates tumor size and nodal status and accounts for different EPClin scores between ET+C and ET alone cohorts. The primary objective was to evaluate the 10-year DRFI rates as a continuous function of EPclin separately for patients in ET+C and ET. Secondary objectives included assessing the difference in the prognostic ability of EPclin between ET+C and ET overall (years 0-10) and for specific follow-up periods (years 0-5 and years 5-10). The primary endpoint was DRFI and the secondary endpoint was breast cancer free interval (BCFI). Cox proportional hazard models were used to estimate 10-year DRFI rates and to assess the prognostic information provided by EPclin. Results: All of the women on ET alone and 49% of those on ET+C were postmenopausal. Women who received ET+C had more node positive disease, more poorly differentiated tumours, and higher EPclin scores than those who received ET alone. Women who received ET+C had significantly smaller increases in 10-year DRFI rates with increasing EPclin score than those receiving ET alone (Table). EPclin was highly prognostic for DRFI in all women who received ET alone (HR=2.79 (2.49-3.13), P Conclusion: In our results from a non-randomized analysis, we observed significantly smaller increases in 10-year DRFI rates with increasing EPclin scores for women who received ET+C compared to those who received ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease. 10-year DRFI risks (%) (95% CI) according to EPclin score for patients who received ET+C versus ET alone. ET+CETEPclin10-year DR risk (%)10-year DR risk (%)11.1% (0.5-1.7)1.0% (0.6-1.4)22.5% (1.5-3.5)2.8% (2.1-3.5)35.7% (4.1-7.2)7.6% (6.4-8.8)412.4% (10.1-14.6)19.8% (17.6-22.0)525.8% (22.0-29.5)46.1% (40.2-51.4) Citation Format: Sestak I, Martin M, Dubsky P, Rojo F, Cuzick J, Filipits M, Ruiz A, Buus R, Hlauschek D, Rodriguez-Lescure A, Dowsett M, Gnant M. Prediction of distant recurrence by EndoPredict in patients with estrogen receptor-positive, HER2-negative breast cancer who received adjuvant endocrine therapy plus chemotherapy (ET+C) or endocrine therapy alone (ET) [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 P2-08-04.

Background: Immune-based therapeutic strategies represent a promising approach in early and advanced breast cancer treatment. MUC1 glycoprotein is overexpressed and aberrantly glycosylated in over 90% of malignant breast cancer. It is involved in oncogenesis and confers resistance to anti-cancer therapies, thus representing a particularly promising target. Tecemotide is a MUC1-based therapeutic cancer vaccine. The aim of this trial was to investigate the efficacy and safety of preoperative tecemotide in primary breast cancer patients receiving neoadjuvant Standard-of-Care (SoC) treatment. Patients and Methods: 400 patients with HER2-negative early breast cancer were recruited into this prospective, multicentre randomized 2-arm academic phase-II trial. Patients received preoperative SoC treatment with or without tecemotide therapy. Postmenopausal women with E+++, or E++ and Ki67 Results: We did not observe a significant difference in RCB0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40), and in endocrine and chemotherapy treated subgroups (25.0% vs 13.3%, p = 0.17; 39.6% vs 37.8%, p = 0.75). Similarly, addition of tecemotide did not affect overall pCR rates (22.5% vs 17.4%, p = 0.23). RCB0/I rates were comparable regardless of docetaxel being given before or after epirubicin/cyclophosphamide (37.2% vs 40.1%, p = 0.61). Tecemotide addition was not associated with a worse toxicity profile (178 AEs, 57 SAEs vs 180 AEs, 48 SAEs based on patient incidence). Conclusion: Immune-based targeting of MUC1 by tecemotide is safe but does not improve RCB and pCR rates in early SoC-treated breast cancer. Citation Format: Singer CF, Pfeiler G, Hubalek M, Bartsch R, Stoeger H, Pichler A, Petru E, Greil R, Rudas M, Tea M-KM, Wette V, Petzer AL, Sevelda P, Egle D, Dubsky PC, Balic M, Tinchon C, Bago-Horvath Z, Frantal S, Michael G. Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomized, neoadjuvant phase-II study (ABCSG-34) [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 P6-10-01.

Background Patients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer. Patients and methods Patients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival. Results After a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709–1.30, log rank P = 0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant ( P = 0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79–1.79; log rank P = 0.408). Zoledronate was well tolerated and no new toxicity signal was identified. Conclusion Postneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.

Background We aimed to analyze the impact of BC subtypes on the clinical course with special emphasis on the occurrence of brain metastases (BM) and outcome in an elderly breast cancer population. Patients and Methods 571 patients ≥65 years receiving treatment for BC from 2007-2011 were identified from a BC database. BC subtypes and clinical characteristics including overall survival (OS) were obtained by chart review. Statistical analysis was performed using the Chi Square test, the log rank test and time depended covariate cox regression model as appropriate. Results Three-hundred-eighty/571 (63%) were grouped among the young-old (65-74 years), 182/571 (31.9%) among the old-old (75-84 years), and 29/571 (5,1%) among the oldest-old (≥85 years). 392/571 (68.8%) patients presented with luminal BC, 119/571 (20.8%) with HER2 positive and 59/571 (10.3%) with triple negative BC. After a median follow up of 38 months (range 0-204), 115/571 (20.1%) patients presented with metastatic recurrence. Highest recurrence rate was observed in HER2 positive BC patients (43/119 (36.1%)), followed by triple negative (15/59 (25.4%) and luminal BC (57/392 (14.5%); p Conclusions In contrast to younger BC patients, HER2 positive BC subtype and not triple negative BC subtype was linked to the most aggressive clinical course including the development of metastatic disease and BM in our elderly cohort. Citation Format: Bergen ES, Tichy C, Berghoff AS, Rudas M, Dubsky P, Bago-Horvath Z, Mader RM, Gnant M, Dieckmann K, Zielinski CC, Steger GG, Preusser M, Bartsch R. Prognostic impact of breast cancer subtypes in elderly patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-08-17.

Background: Taselisib is an orally bioavailable, potent, selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the alpha isoform showing enhanced activity against PIK3CA mutant cancer cell lines. Clinical data have demonstrated confirmed partial responses in patients with PIK3CA mutant breast cancer (BC) treated with single-agent taselisib. Enhanced antitumor activity has been noted when taselisib is combined with either letrozole or fulvestrant in preclinical and Phase Ib clinical studies. Methods: LORELEI is a Phase II, two-arm, randomized, double-blind, multicenter, study of neoadjuvant letrozole and taselisib versus letrozole and placebo in postmenopausal women with newly diagnosed ER+/HER2-, untreated, Stage I-III operable BC. Other eligibility criteria include tumor size  2 cm by magnetic resonance imaging (MRI), ECOG PS 0-1, and evaluable tumor tissue for PIK3CA genotyping. Patients treated with anti-diabetic drugs are not eligible. Patients are randomized (1:1) to receive continuous letrozole (2.5 mg) with either taselisib (4 mg on a 5 days on/ 2 days off schedule) or placebo for 16 weeks, followed by surgery. Stratification is based on tumor size and nodal status. The co-primary endpoints are overall objective response rate (ORR) by centrally assessed breast MRI via modified RECIST criteria and pathologic complete response (pCR) rate in breast and axilla at time of surgery in all randomized patients and PIK3CA mutant patients. Secondary endpoints include ORR by centrally-assessed MRI and pCR rate in PIK3CA wild-type patients. The sample size was calculated to detect an absolute percentage increase of 24% in ORR with 80% power and an absolute percentage increase of 18% in pCR rate. An interim safety analysis will be conducted by an Independent Data Monitoring Committee. As of 1st Jun 2015, 54 of the 330 patients have been enrolled, and global enrollment is ongoing (clinicaltrials.gov NCT02273973). Contact information: Reference Study ID Numbers: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38 Phone: 888-662-6728 (US Only) Email Address: global.rochegenentechtrials@roche.com Citation Format: Oliveira M, de Azambuja E, Saura C, Dubsky P, Zardavas D, Fesl C, Bardia A, Soberino J, Ciruelos Gil E, Ng V, Fredrickson J, Stout TJ, Singel SM, Hsu JY, Piccart M, Gnant M, Baselga J. LORELEI: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/ HER2-negative, early-stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-06.

Background: Cell cycle inhibition is a target of interest for novel cancer therapeutics. Palbociclib (P) is an orally active inhibitor of CDK4/6 which arrests the cell cycle at the G1-S transition. P has demonstrated efficacy in phase II and III randomized trials for first-line and pre-treated hormone receptor positive/HER2 negative (HR+/HER2-) metastatic breast cancer (MBC), with hazard ratios 0.42-0.49 (Finn et al, Lancet Oncol 2015, Turner et al, NEJM 2015), and is approved in combination with letrozole as first-line therapy for HR+/HER2- MBC. Given confirmed benefits of P and endocrine therapy for MBC, the PALLAS study was designed to determine if the addition of P to adjuvant endocrine therapy (ET) improves outcomes over ET alone in HR+/HER2- early breast cancer. Trial Design: PALLAS is an international open label phase III trial randomizing patients to 2 years of P (125 mg daily, 21 days on 7 days off in a 28-day cycle) combined with at least 5 years of provider choice ET (AI, tamoxifen, +/- LHRH agonist), versus ET alone. The primary objective of the study is to compare invasive disease-free survival (iDFS) for the combination of P and ET versus ET alone. Secondary objectives include comparing iDFS excluding cancer of non-breast origin, DRFS, LRRFS, OS, as well as safety. The principal translational science objective is to determine the predictive or prognostic utility of defined genomic subgroups with respect to iDFS and OS. Additional translation objectives include evaluation of tissue and blood biomarkers predictive of benefit or resistance, cfDNA, pharmacogenomics, adherence, BMI, and patient-reported QOL. Eligible patients (pts) may be pre- or post-menopausal, have stage II-III breast cancer, HR+/HER2- by ASCO CAP guidelines, and have recovered from prior therapies. Pts may have already initiated ET, but randomization must occur within 12 months of diagnosis and 6 months of initiation of ET. An FFPE block must be received at the central sample repository for eligibility. Total planned accrual to the trial is 4600 pts, providing 85% power to detect a 25% risk reduction in iDFS from ET alone using a stratified logrank test with an overall one-sided alpha = 0.025. Pts will be randomized 1:1 stratified by stage, receipt of prior chemotherapy, age, and geographic location. Interim analyses for safety, futility/efficacy and sample size re-estimation are planned. PALLAS will open in 9/2015; current accrual will be updated at time of presentation. Citation Format: Mayer E, DeMichele A, Dubsky P, Barry W, Metzger O, Symmans WF, Burstein H, Miller K, Wolff A, Rastogi P, Loibl S, von Minckwitz G, Goulioti T, Zardavas D, Fesl C, Koehler M, Huang Bartlett C, Chen L, Piccart M, Winer E, Gnant M. PALLAS: PAlbociclib Collaborative Adjuvant Study: A randomized phase 3 trial of palbociclib with adjuvant endocrine therapy versus endocrine therapy alone for HR+/HER2- early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-21.

PAM50 is a 50-gene test that is designed to identify intrinsic breast cancer subtypes and generate a Risk of Recurrence (ROR) score. It has been developed to be carried out in qualified routine hospital pathology laboratories.One thousand four hundred seventy-eight postmenopausal women with estrogen receptor (ER)+ early breast cancer (EBC) treated with tamoxifen or tamoxifen followed by anastrozole from the prospective randomized ABCSG-8 trial were entered into this study. Patients did not receive adjuvant chemotherapy. RNA was extracted from paraffin blocks and analyzed using the PAM50 test. Both intrinsic subtype (luminal A/B, HER2-enriched, basal-like) and ROR score were calculated. The primary analysis was designed to test whether the continuous ROR score adds prognostic value in predicting distant recurrence (DR) over and above standard clinical variables.In all tested subgroups, ROR score significantly adds prognostic information to the clinical predictor (P0.0001). PAM50 assigns an intrinsic subtype to all cases, and the luminal A cohort had a significantly lower ROR at 10 years compared with Luminal B (P0.0001). Significant and clinically relevant discrimination between low- and high-risk groups occurred also within all tested subgroups.The results of the primary analysis, in combination with recently published results from the ATAC trial, constitute Level 1 evidence for clinical validity of the PAM50 test for predicting the risk of DR in postmenopausal women with ER+ EBC. A 10-year metastasis risk of3.5% in the ROR low category makes it unlikely that additional chemotherapy would improve this outcome-this finding could help to avoid unwarranted overtreatment.ABCSG 8: NCT00291759.

Introduction Triple-negative breast cancer (TNBC) without pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with high risk of disease recurrence. In ABCSG trials 14 and 24, concomitant epirubicin plus docetaxel (+/- capecitabine) was used as NAC regimen; patients (pts) without pCR routinely received another 4-8 cycles of adjuvant CMF. Tumours harbouring BRCA-1 germline mutations are apparently less responsive to taxane-based chemotherapy, while sensitivity to DNA-damaging agents is retained. In sporadic TNBC, BRCA-1 promotor methylation is frequently observed; this may also result in an impaired activity of genetic repair mechanisms. Therefore, we investigated the effect of adjuvant CMF as salvage therapy in pts with or without BRCA-1 promotor methylation who did not achieve pCR to taxane-based (cyclophosphamide-free) NAC. Moreover, the predictive role of TP53 mutations was investigated in these tumours. Methods All pts with TNBC refractory to taxane-based NAC who received adjuvant CMF were included. DNA was extracted from formalin-fixed paraffin-embedded tissue samples with the Qiagen DNA FFPE Tissue Kit® and purified. For determining BRCA1 promoter methylation status, DNA was bisulfite-treated; the TaqMan® assay was used in order to perform a quantitative methylation-specific PCR. DNA quantity was normalized using Actin-b. For the investigation of TP53 mutations in exons 4-9, purified DNA was PCR amplified, sequenced by Sanger sequencing and results were analyzed with SeqScape® software version 2.7. Mutations were validated using the IARC p53 database. Results Twenty-four pts, median age 47 years, were available for this analysis. In 10/24 pts (41.7%), a BRCA-1 promotor methylation was detected; TP53 mutations were observed in 16/24 pts (66.7%). At a median follow-up of 27.5 months, 2/10 pts (20%) with BRCA-1 promotor metyhlation had a disease-free survival (DFS) event, as compared to 9/14 (64.3%) in the non-methylated group (p = 0.0472; Fisher's exact test). Kaplan Meier estimation of disease-free survival (DFS) in the non-methylated group was 16 months (95% CI 0.0-41.73) and was not reached in the methylated group (n.s.). TP53 mutation was neither associated with increased risk of disease recurrence nor with DFS. No correlation was observed between BRCA-1 promotor methylation and TP53 mutation; still, all methylated samples were exclusively affected be missense and nonsense mutations. Conclusions Adjuvant CMF is of limited activity in TNBC refractory to taxane-based NAC. Still, in breast cancer harbouring BRCA-1 promotor methylation, a significant decrease of DFS events was observed. TP53 mutation status on the other hand, was not associated with outcome; while no correlation was found between BRCA-1 promotor methylation and TP53 mutation status, we only observed missense and non-sense mutations in methylated samples. In conclusion, tumours harbouring BRCA-1 promotor methylation are apparently sensitive to DNA damage caused by cyclophosphamide. Further clinical validation of this concept is warranted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-40.

Background: ER þ/HER2 � breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. Methods: A total of 1702 postmenopausal ER þ/HER2 � breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan–Meier method and Cox regression analysis were used in an early (0–5 years) and late time interval (45 years post diagnosis). Results: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. Conclusion: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

The immune system could mediate the antitumor activity of several anticancer treatments. Several chemotherapy compounds, including anthracyclines and oxaliplatin, induce immunogenic cell death that in turn activates antitumor immune response. Trastuzumab induces antibody-dependant cell-mediated cytotoxicity. On the basis of this background, immune markers have recently been the focus of intense translational research to predict and monitor the efficacy of treatments. Gene expression arrays and immunohistochemistry have assessed immune activation and infiltration by macrophages, natural killer, and T and B lymphocytes. Using these approaches, several retrospective analyses of large trials have shown that activation of immune pathway may predict treatment efficacy and outcome in patients with breast cancers. As examples, intratumoral infiltration by lymphocytes and interferon-response in primary tumor predicted the efficacy of neoadjuvant chemotherapy. Intratumoral infiltration by lymphocytes was associated with good prognosis in patients with triple-negative breast cancer treated with adjuvant chemotherapy. More recently, it has been suggested that lymphocyte infiltration could also predict efficacy of trastuzumab. Finally, small retrospective studies have suggested that postchemotherapy lymphocyte infiltrates could be associated with better outcome in patients who did not reach pathologic complete response. This body of evidence suggests that assessing immune infiltration and activation could be useful in the future to stratify breast cancer patients. In addition, they provide evidence for the development of immunotherapies in breast cancer patients. Clin Cancer Res; 19(1); 28–. ©2012 AACR.

Background In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed. Patients and methods We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan–Meier survival analysis. Results After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%–61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years. Conclusion The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

Aims This study investigates how quality of life (QoL) of breast cancer patients is related to breast symmetry. Methods We objectively measured breast symmetry using the breast analyzing tool (BAT) in 101 patients after breast conserving surgery for breast cancer at different time points during follow up. We correlated the results with the quality of life measured at the same time using the breast image scale (BIS), the EORTC QLQ-BR23 scale and a not validated sexual score scale. Age, tumour size, tumour/breast relation and the use of oncoplastic surgery were also correlated with symmetry and quality of life scales. Using multivariate analyses, independent parameters for an improved quality of life were identified. Results Mean age was 56 (±11.6), and 75.2% of patients had T1 or T2 tumours. Patient age ( p = 0.03) and tumour size ( p = 0.01) significantly influenced objectively measured breast symmetry. The cosmetic result was important for 53% of patients while 48% found it not important. Independent from this, neither overall quality of life nor breast self esteem was influenced by breast symmetry in our patients. Conclusions After breast cancer surgery, breast symmetry is not a major factor for patients' quality of life and breast self esteem. Cosmetic result seems to be less important than oncologic outcome in patients with breast cancer.

The number of removed axillary lymph nodes and the ratio of involved to removed lymph nodes are described as independent prognostic factors beside the absolute number of involved lymph nodes in breast cancer patients. The correlation between these factors and prognosis were investigated in trials of the Austrian Breast and Colorectal Cancer Study Group (ABCSG).This retrospective analysis is based on the data of 7052 patients with endocrine-responsive breast cancer who were randomized in four trials of the ABCSG in the years 1990-2006 and underwent axillary lymph node dissection. The prognostic value of number of removed nodes (NRN), number of involved nodes (NIN), and ratio of involved to removed nodes (lymph node ratio, LNR) concerning recurrence-free survival and overall survival was analyzed.A total of 2718 patients had node-positive disease. No correlation was found between NRN and prognosis. Increasing NIN and LNR were significantly associated with worse recurrence-free survival and overall survival in univariate and multivariate analyses (P.001). Only in the subgroup of patients with one to three positive lymph nodes and treated with mastectomy (n = 728) was LNR an additional prognostic factor in univariate and multivariate analyses.For breast cancer patients stringently medicated in the framework of prospective adjuvant clinical trials and requiring a mandatory minimum of removed nodes, NRN does not influence prognosis, and LNR is not superior to NIN as prognostic factor. In patients with one to three positive lymph nodes and mastectomy, LNR could play a role as an additional prognostic factor.

Background: Sentinel lymph node dissection identifies nodal positivity in early breast cancer. Trials like the ACOSOG Z0011 trial tried to show that the waiver of axillary dissection in nodal positive breast cancer (BC) has no effect on the oncologic outome, however real world data are rare and the role of adjuvant regional radiotherapy is still disputed in this respect. Objective: We initiated a multicenter observational registry to investigate omission of axillary lymph node dissection in nodal positive early BC. Design and Setting: The 18 sites participating in Austria and Switzerland included from 2014 to 2017 178 patients in this trail. Patients: Women with unilateral invasive lymph node positive BC with one or two sentinel lymph node makrometastases, who did not undergo axillary lymph node dissection were included. Results: We had a median follow up time of 3.1 years (range between 0.5 and 10.5 years), the median patient age is 63.6 years (range between 33 – 93 years). In 16.9% women had a G1 Grading, 53.1% had G2 tumor and 29.9% had a G3 tumor. Multifocality was seen in 18.1% of the patients. Luminal A tumors were seen in 16 (8.9%) and Luminal B in 82 (46.1%). Fourteen (7.8%) patients in this cohort had HER2 positive BC. In one (0.5%) local recurrence of the axilla occurred. Three (1.7%) of 178 patients died due to BC recurrence. Conclusion: Patients with macro metastasis in the sentinel lymph node, treated with breast conserving surgery and whole breast radiation did not have an increased risk of BC recurrence. Therefore the authors assume that axillary dissection in patients with early stage BC and macro metastasis is not necessary in this patient cohort. Citation Format: Strobl SA, Dubsky P, Exner R, Gnant M, Jakesz R, Tausch C, Wette V, Heck D, Luisser I, Bjelic-Radisic V, Schrenk P, Poyssl C, Mathis J, Fitzal F. ABCSG 33 - A multi center registry to evaluate the affect of macro metastasis in sentinel lymph node on survival [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 P3-03-24.

Purpose: The aim of the present study was to assess the prognostic and predictive value of Ki67 labeling index in postmenopausal hormone receptor-positive early breast cancer patients who were treated with adjuvant tamoxifen or anastrozole after tamoxifen. Patients and Methods: We determined the expression of Ki67 by immunohistochemistry on whole tissue sections of breast carcinoma patients who had been enrolled in Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8 and received tamoxifen for 5 years or tamoxifen for 2 years followed by anastrozole for 3 years. Ki67 labeling index was evaluated as continuous variable or dichotomized at 10%. Distant recurrence and death were analyzed using Cox models adjusted for clinical and pathological factors. Results: High Ki67 labeling index was observed in 394 of 1587 (23%) tumors and was associated with poor outcome. Patients with high Ki67 labeling index had a significantly shorter distant recurrence-free survival (adjusted hazard ratio [HR] for distant recurrence 2.16, 95% confidence interval [CI] 1.43-3.25, P < 0.001) and overall survival (adjusted HR for death 1.77, 95% CI 1.30-2.42, P < 0.001) as compared to patients with low Ki67 labeling index. No interaction between Ki67 labeling index and treatment was observed (P = 0.84). Conclusion: High Ki67 labeling index is an independent poor prognostic factor for distant recurrence and death in postmenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with either tamoxifen or tamoxifen followed by anastrozole. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-09-02.

Background: Molecular tests predicting outcome of breast cancer patients may be useful for treatment decisions in addition to standard clinicopathologic features. Methods: Using human genome HG-U133A array and qRT-PCR datasets, we developed and validated a gene-expression signature predicting the likelihood of distant recurrence in postmenopausal, early-stage breast cancer patients with estrogen receptor-positive, HER2-negative tumors treated with adjuvant endocrine therapy. RNA levels assessed by qRT-PCR in formalin-fixed paraffin-embedded tumor specimens were used to calculate a risk score (T5) and to determine a risk group (low or high) for each patient. The prospectively defined T5 risk score was then validated independently in patients from two large randomized phase III trials. Distant recurrence-free survival and overall survival were analyzed with Cox models adjusted for clinicopathological factors. The primary endpoint was time to distant recurrence. Results: In a training set of 964 tumors, we identified a gene-expression signature consisting of three proliferation-related genes (BIRC5, UBE2C, DHCR7), five estrogen-regulated genes (RBBP8, IL6ST, AZGP1, MGP, STC2), and three reference genes (CALM2, OAZ1, RPL37A). For the validation, RNA analysis was possible in 1702 of 1725 (99%) tumors of both validation sets. Women were classified as having low risk (n=832; 49%) or high risk (n=870; 51%) by the T5 risk score. The T5 risk score provided prognostic information independent from clinicopathologic risk as estimated by Adjuvant!Online or Ki67 labeling index. Patients with a higher T5 risk score had a significantly shorter time to distant recurrence (adjusted hazard ratio, 1.24; 95% confidence interval [CI], 1.15 to 1.33; P Conclusions: Using formalin-fixed paraffin-embedded tumor specimens, the multigene T5 risk score provides prognostic information independent of Adjuvant!Online or Ki67 labeling index. By combining the T5 risk score with clinicopathological risk, we were able to accurately identify breast cancer patients with low risk or high risk for distant recurrence. Using this new easy-to-use multigene tool in clinical practice will assist in optimizing adjuvant therapy by reducing both undertreatment and overtreatment and thus improves outcome and quality of life of patients with early-stage breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-07.

The objective of this study is to analyse local recurrence rates in patients receiving neoadjuvant chemotherapy (nCT) comparing mastecomized (MX) patients with those undergoing breast conserving therapy (BCT). Patients undergoing breast cancer surgery after nCT (3xCMF or 3-6xED) between 1995 and 2007 at our department were retrospectively analysed. The median follow up was 60 months for 308 patients. Patients who were downsized from MX to BCT with partial or complete response (n = 104) had a similar local recurrence free survival (LRFS) compared to patients who did not experience successful downsizing (n = 67) and finally undergoing MX (LRFS MX-BCT 81% vs. MX-MX 91%; P = 0.79). Uni- and multivariate analyses demonstrated that BCT itself was not an independent prognostic factor for a worse LRFS (P = 0.07 and 0.14). After no pathologic change or progressive disease the risk of local recurrence was increased in patients undergoing BCT (MX-BCT; n = 6 LRFS 66%) compared with MX (n = 44; LRFS 90%; P = 0.04). Overall survival in general was better for the BCT group (n = 197) compared with MX group (n = 111) regardless of clinical response (92% vs. 72%; P < 0.0001). Breast conservation, nodal negativity and low or medium grade histology were prognostic factors for an improved OS (P = 0.02, 0.01, 0.004). In conclusion, our study suggests that BCT is oncologically safe after tumour downsizing by nCT in patients primarily scheduled for mastectomy. These patients, however, should not be treated with breast conservation in the absence of any proven response after nCT.

Background: Vascular endothelial growth factor-C (VEGF-C) is the main inducer of lymphangiogenesis. VEGF-C overexpression is associated with lymphovascular tumor cell invasion, an increased rate of lymph node metastasis and adverse prognosis in various human cancers. However, little is known about the upstream inducers of VEGF-C expression. Recent studies have shown that human epidermal growth factor receptor 2 (HER2/neu) overexpression is associated with high VEGF-C levels in human breast cancer cells. In addition to blocking of HER2/neu, tyrosine kinase significantly decreased VEGF-C expression in vitro. Patients and methods: VEGF-C expression, lymphatic microvessel density (LMVD), lymphovascular invasion (LVI) and HER2/neu expression were evaluated with immunohistochemical/FISH methods in a collective of 150 lymph node-positive human breast cancers with long-term follow-up. Results: Cases with 3+ HER2/neu protein expression showed a significantly stronger VEGF-C expression than all others cases (P = 0.006). In addition, we found a significant correlation between VEGF-C expression and LMVD (P = 0.012) and a strong positive association between LMVD and LVI (P Conclusion: Our data provide evidence for a clinically relevant association between HER2/neu and VEGF-C expression in human breast cancer. Inhibiting HER2/neu may reduce tumor progression by blocking VEGF-C-mediated tumor cell proliferation and lymphogenic metastasis.

BACKGROUND: The benefit of preoperative chemotherapy on outcome in breast cancer has been shown to be highest in patients with complete pathological response (pCR). The objective of this analysis was to determine the predictive value of progesterone receptor status on pCR rate in primary breast cancer patients receiving preoperative chemotherapy. METHODS: Preoperative chemotherapy was administered to 213 patients with primary breast cancer. We assessed the predictive impact of estrogen (ER) and progesterone receptor (PR) in biopsy tissue on response to preoperative chemotherapy. The association of steroid receptor status and pCR was tested by Fisher's exact and Chi-square test. RESULTS: pCR was achieved in 23 patients (10.8%). All patients experiencing pCR were PR negative (100%). ER and PR negativity was significantly associated with pCR, p = 0.00028 and p = 0.0003, respectively. CONCLUSIONS: We conclude from our results that ER and PR negativity represent valuable markers predicting pCR after primary chemotherapy. In PR-positive breast cancer patients, no single case of pCR was observed; therefore, we may recommend no preoperative chemotherapy in PR-positive patients.

The objective of this analysis was to determine the accuracy of steroid receptor measurement in large core needle biopsies compared with surgically removed specimens and the influence of preoperative chemotherapy on hormone receptor status. We consecutively performed 722 large core needle biopsies in palpable lesions of the breast. The diagnosis of breast cancer was confirmed upon biopsy in 450 patients; 236 women underwent immediate surgery, and 214 patients received preoperative chemotherapy. We assessed estrogen (ER) and progesterone receptor (PR) in biopsy tissue and surgically removed specimens and calculated accuracy, sensitivity, specificity, the weighted kappa value and Spearman's rank correlation. The modulation of steroid receptor status in preoperatively treated patients was tested by Cochran-Mantel-Haenszel statistics. The accuracy of ER evaluation in the biopsy material of patients without intervening chemotherapy was 91%, sensitivity and specificity were 94% and 80% respectively. Accuracy, sensitivity and specificity were 86% in patients treated preoperatively. In terms of PR assessment, we obtained slightly inferior results: accuracy, sensitivity and specificity were 80%, 73% and 85% respectively in patients without preoperative treatment, and 79%, 48% and 92% respectively in patients undergoing preoperative therapy. Following preoperative chemotherapy, patients showed a significant increase in ER-negative (P=0.02) and PR-negative (P=0.0005) measurements. We have concluded from our results that ER and PR receptor measurement in core needle biopsy is a reliable basis in clinical practice for selecting patients for neoadjuvant endocrine treatment. Preoperative cytotoxic chemotherapy induced a significant extent of variation in the steroid receptor expression of breast cancer cells.

Purpose: Dendritic cell (DC)-based immunotherapy is rapidly emerging as a viable tool in cancer treatment. This approach has been used mostly in patients in the presence of defined tumor antigens such as melanoma. In this study, cancer patients with advanced disease that lacks defined tumor antigens were vaccinated with tumor lysate-pulsed DCs.Patients and Methods: Twenty patients (pancreatic, hepatocellular, cholangiocellular, and medullary thyroid carcinoma) with stage IV disease were enrolled in the study. In 3-week intervals, freshly isolated autologous CD14 magnetic bead-selected monocytes were cultured in granulocyte-macrophage colony-stimulating factor and interleukin-4 to obtain immature DCs. These cells were pulsed with autologous tumor lysate and matured with tumor necrosis factor alpha. Mature DCs were applied into a groin lymph node, under ultrasound guidance. Adjuvant interleukin-2 (20,000 U/kg) was given subcutaneously daily, for 12 days, after each vaccination. Toxicity, tumor marker profile, immune response, and clinical response were determined.Results: Vaccination was well tolerated. No physical signs of autoimmunity were detected. DC vaccination induced delayed-type hypersensitivity reactivity in 18 patients. Tumor marker responses were observed in eight patients. In addition, in three patients the generation of interferon gamma-positive T cells was induced during the vaccination. Objective changes in measurable lesions or tumor markers were evident in seven of 20 assessed patients. None of the patients was found to meet the criteria for partial or complete responses.Conclusion: These data indicate that vaccination with autologous tumor-pulsed DCs generated from peripheral blood is safe and can induce tumor-specific cellular cytotoxicity. Clinical responses are achievable, even in patients with advanced disease.

Background: In the neoadjuvant treatment setting of ER+/HER2- breast cancer (BC) the choice between preoperative endocrine - (NET) or preoperative chemotherapy (NCT) is largely based on the expression of hormone receptors (HR), grading and possibly Ki-67. The EndoPredict 12-gene molecular score (EP) is a validated prognostic score based on the expression of genes involved in cellular processes including proliferation and ER signaling/differentiation. The application of the EP molecular score may thus provide additional insight into neoadjuvant response of tumors. Methods: This prospective translational study was carried out as an exploratory endpoint within the ABCSG 34 protocol (SABCS 2016, Singer et al.) and included only the HR+ subset of women. ABCSG 34 was a randomized 2-arm academic phase-II trial including 400 patients (250 ER+) with HER2 negative early BC. Patients were selected for either NET or NCT according to the study protocol reflecting standard of care: postmenopausal women with ER+++, or ER++ and Ki67 Results: 134 patients (EP low-risk:9; EP high-risk:125) with HR+ tumors received NCT. Stage I: 14.9%, II/III: 84%; G3: 56%; mean Ki-67: 40.4%. No patient with EP low-risk score showed RCB0/I (NPV: 100%) whereas 26.4% of EP high-risk showed full response. In logistic regression EP as a continuous score (EPc) was a significant predictor of RCB0/I, showed an AUC (95% CI) of 0.736 (0.63 - 0.84) and revealed close correlation with Ki-67. 83 patients (EP low-risk:44; EP high-risk:39) received NET. Stage I: 38.6%, II/III: 60.2%; G3: 4.8%; mean Ki-67: 14.9%. 27.3% (n=12/44) with EP low-risk and 7.7% (n=3/39) with EP high-risk showed RCB0/I. EPc was a significant predictor of RCB0/I with an AUC (95% CI) of 0.726 (0.60 - 0.85). In all multivariate analyses low anatomic stage was the most powerful predictor of RCB0/I. Conclusions: Clinical standard of care separated ABCSG 34 patients into two HR+ cohorts with differing clinical features and treated distinctly with either NET or NCT: In women treated with neoadjuvant Letrozole a high molecular score indicated a very low possibility of endocrine response. In women clinically selected for neoadjuvant chemotherapy, a high EP score was associated with a higher probability of chemotherapy response and the low EP risk group outlined a group of women with very poor tumor response to NCT(NPV 100%). In summary, EP low risk is associated with tumor response to endocrine treatment and predicts resistance in the chemotherapy group. NCT, especially to attain breast conservation in ER+/HER2-/EP low risk should be reconsidered. Citation Format: Dubsky PC, Fesl C, Singer CF, Pfeiler G, Kronenwett R, Hubalek M, Bartsch R, Stoeger H, Pichler A, Petru E, Bjelic-Radisic V, Greil R, Rudas M, Tea M-KM, Wette V, Petzner AL, Sevelda P, Egle D, Fitzal F, Exner R, Jakesz R, Balic M, Tinchon C, Bago-Horvath Z, Lax S, Regitnig P, Gnant M, Filipits M. The EndoPredict score predicts residual cancer burden after neoadjuvant chemotherapy and after neoendocrince therapy in HR+/HER2- breast cancer patients from ABCSG 34 [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS6-04.

Background: While extended adjuvant therapy with aromatase inhibitors (AI) after initial tamoxifen has been demonstrated to improve disease-free-survival (DFS) of postmenopausal patients with hormone-receptor positive breast cancer, the optimal duration of extended AI is unknown. Moreover, it remains unclear whether patients after AI in the first 5 years benefit similarly from extended adjuvant AI therapy as patients after Tamoxifen. Methods: From February 2004 to June 2010, 3484 women with postmenopausal stage I-III hormone-receptor positive early breast cancer were randomized in 71 centers in Austria to receive either 2 years or 5 years of additional Anastrozole (1 mg daily) as extended adjuvant therapy, after initial 5 years of adjuvant endocrine treatment. Eligible patients had to be recurrence-free at 60 months of initial adjuvant therapy with Tamoxifen (Tam) or AI or Tam→AI, and younger than 80 years of age. Stratification factors were tumor stage, nodal status, initial endocrine therapy, adjuvant chemotherapy, and quantitative hormone receptors. Patients were followed-up at least annually. Primary end point of ABCSG-16 was DFS, secondary end points included overall survival (OS), fractures, contralateral breast cancer, and toxicity. Results: As of June 30, 2016, the median follow-up of the 3468 patients included in the analysis of ABCSG-16 was 105.9 months (IQR 102.2-110.3 months) after randomization (i.e. approx. 14 years after diagnosis). Median patient age was 64 years, 2507 (72%) patients had tumors smaller than 2 cm, 2301 (66%) patients were node-negative, 674 (19%) patients had high-grade tumors, 2683 (77%) patients had tumors both ER and PR positive. 2764 (80%) patients were treated with breast conserving surgery. Before randomization into ABCSG-16, 1000 (29%) patients had undergone (neo)adjuvant chemotherapy, 1774 (51%) patients had received 5 years of Tamoxifen, whereas 1688 (49%) patients had received other (AI containing) regimens in the first five years. As of June 30, 2016, 757 DFS events have been recorded, 377 (22%) in the 2-year group, and 380 (22%) in the 5-year group. There was no significant difference in DFS (HR 0.997, 95%CI 0.86-1.15, log rank p=0.982), in OS, time to secondary carcinoma and time to contralateral breast cancer. With respect to drug adherence, 81.2% of patients in the 2-year arm were taking the study drug still at 2 years, and 80.1% at 2 years in the 5-year arm. At 5 years, 65.6% of patients in the 5-year arm were still on the assigned medication. Bone fractures were more frequent in the 5-year arm (i.e. years 3 to 5 after randomization: 6% vs 4 %, HR=1.405, 95%CI 1.03-1.91, p=0.029). Conclusion: After 5 years of adjuvant endocrine therapy (Tamoxifen or AI or Sequence), 2 additional years of Anastrozole are sufficient for extended adjuvant therapy – a further extension to 5 additional years did not yield additional outcome benefit but added toxicity. Support: AstraZeneca Citation Format: Gnant M, Steger G, Greil R, Fitzal F, Mlineritsch B, Manfreda D, Tausch C, Balic M, Dubsky P, Moik M, Thaler J, Egle D, Bjelic-Radisic V, Selim U, Exner R, Singer C, Melbinger-Zeinitzer E, Haslbauer F, Stöger H, Helfgott R, Sevelda P, Trapl H, Wette V, Sölkner L, Jakesz R. A prospective randomized multi-center phase-III trial of additional 2 versus additional 5 years of anastrozole after initial 5 years of adjuvant endocrine therapy – results from 3,484 postmenopausal women in the ABCSG-16 trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-01.

Despite intense efforts, the socioeconomic burden of cancer remains unacceptably high and treatment advances for many common cancers have been limited, suggesting a need for a new approach to drug development. One issue central to this lack of progress is the heterogeneity and genetic complexity of many tumours. This results in considerable variability in therapeutic response and requires knowledge of the molecular profile of the tumour to guide appropriate treatment selection for individual patients. While recent advances in the molecular characterisation of different cancer types have the potential to transform cancer treatment through precision medicine, such an approach presents a major economic challenge for drug development, since novel targeted agents may only be suitable for a small cohort of patients. Identifying the patients who would benefit from individual therapies and recruiting sufficient numbers of patients with particular cancer subtypes into clinical trials is challenging, and will require collaborative efforts from research groups and industry in order to accelerate progress. A number of molecular screening platforms have already been initiated across Europe, and it is hoped that these networks, along with future collaborations, will benefit not only patients but also society through cost reductions as a result of more efficient use of resources. This review discusses how current developments in translational oncology may be applied in clinical practice in the future, assesses current programmes for the molecular characterisation of cancer and describes possible collaborative approaches designed to maximise the benefits of translational science for patients with cancer., SCOPUS: re.j, info:eu-repo/semantics/published

Background: Preoperative chemotherapy (PC) and sentinel node biopsy (SNB) are two modern approaches in the treatment for breast cancer, both aiming at a reduction in surgery. While PC is mainly applied to large primary tumours, SNB is indicated for early breast cancer. By gradually expanding the indication for both methods, a group of patients is going to emerge that may benefit from both methods. The Austrian Sentinel Node Biopsy Study Group of the Austrian Breast and Colorectal Cancer Study Group is trying to find out whether adequate safety can be assured when PC and SNB are combined.

Background: The aim of this study was to examine whether EndoPredict (EP), a novel genomic expression test, is effective in predicting local recurrence (LR)-free survival (LRFS) following surgery for breast cancer in postmenopausal women. In addition, we examined whether EP may help tailor local therapy in these patients. Methods: From January 1996 to June 2004, 3714 postmenopausal patients were randomly assigned to either tamoxifen or tamoxifen followed by anastrozole within the prospective ABCSG 8 trial. Using assay scores from EP, we classified breast tumour blocks as either low or high risk for recurrence. Results: Data were gathered from 1324 patients. The median follow-up was 72.3 months and the cumulative incidence of LR was 2.6% (0.4% per year). The risk of LR over a 10-year period among patients with high-risk lesions (n=683) was significantly higher (LRFS=91%) when compared with patients with low-risk lesions (n=641) (10-year LRFS=97.5%) (HR: 1.31 (1.16–1.48) P

Background: A number of prognostic signatures have been developed for the prediction of breast cancer recurrence in the past decade. We have developed two signatures (Clinical Treatment Score (CTS), four immunohistochemical markers (IHC4)) and validated four prognostic signatures (Oncotype Dx Recurrence Score (RS), PAM50-based Prosigna (ROR), Breast Cancer Index (BCI), and EndoPredict (EPclin)) in the TransATAC cohort. Here, we compare the prognostic performance of these six signatures for distant recurrence (DR) in years 0-10, and specifically in years 5-10 after treatment cessation. Methods: 1231 postmenopausal women with hormone receptor positive and HER2-negative breast cancer had at least one test performed. Of these, 818 women had data on all six signatures available. IHC4, RS and BCI (linear) are molecular only signatures whereas CTS, ROR and EPclin include clinicopathological factors. The primary endpoint was DR and the primary objective was to compare the prognostic value of the six signatures in terms of DR for years 0-10, 0-5, and 5-10. Secondary objectives included the comparison of the prognostic performance for node-negative and node-positive patients separately and the additional prognostic performance of each signature to the others. Likelihood ratio statistics (LR-χ2) were used to assess the prognostic information of each signature alone or in combination with other signatures. Results: Median follow-up for this analysis was 9.94 years (IQR 8.01-10.09) and a total of 126 DR were recorded. 818 women with HER2-negative disease for whom data of all six signatures were available were included in this analysis. For all patients, CTS and EPclin were the most prognostic signatures in years 0-10 (CTS: LR-χ2=124.9; EPclin: LR-χ2=116.2) and years 5-10 (CTS: LR-χ2=59.6; EPclin: LR-χ2=56.8) in the univariate analysis. The other four signatures performed similarly well in years 0-5, but of those only BCI and ROR provided substantial prognostic information in years 5-10 (BCI: LR-χ2=25.3; ROR: LR-χ2=43.8). In multivariate analyses comparing the added information of the molecular signatures over CTS, IHC4 and BCI provided the most information (IHC4: ΔLR-χ2=19.0; BCI: ΔLR-χ2=19.8). In node-negative patients (72.3%), the ROR showed the most prognostic value in years 0-10 (LR-χ2=48.6) and years 5-10 (LR-χ2=31.3) whereas the RS was least prognostic in this patient group. For patients with node-positive disease (27.7%), the CTS and EPclin were the most prognostic and the other four signatures provided much less prognostic information for this patient population (data not shown). Conclusion: Overall, the CTS and EPclin were the most prognostic signatures for DR and also added significant prognostic value to the other scores in women with HER2-negative disease, primarily due to the incorporation of nodal status in these signatures. For women with node-negative disease, the ROR, BCI, and EPclin signatures provided most prognostic value whereas for those with positive nodes CTS and EPclin were most prognostic. Our analyses showed that the inclusion of clinic-pathological factors into gene signatures is highly important for deriving an accurate prognostic assessment, particularly in node-positive patients. Citation Format: Sestak I, Buus R, Cuzick J, Dubsky P, Kronenwett R, Ferree S, Sgroi D, Schnabel C, Baehner R, Mallon E, Dowsett M. Comprehensive comparison of prognostic signatures for breast cancer in TransATAC [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 S6-05.

Background: Estimating distant recurrence (DR) risk among women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 (HER2)-negative early breast cancer helps decisions on using adjuvant chemotherapy. The 21-gene Oncotype DX recurrence score (RS) is widely used for this. EndoPredict (EPclin) is an alternative test combining prognostic information from an eight-gene signature (EP score) with tumor size and nodal status. We compared the prognostic information provided by RS and EPclin for 10-year DR risk. Methods: We used likelihood ratio chi(2) and Kaplan-Meier survival analyses to compare prognostic information provided by EP, EPclin, RS, and the clinical treatment score (CTS) of clinicopathologic parameters in 928 patients with ER+ disease treated with five years' anastrozole or tamoxifen. Comparisons were made for early (0-5 years) and late (5-10 years) DR according to nodal status. All statistical tests were two-sided. Results: In the overall population, EP and EPclin provided substantially more prognostic information than RS (LR chi(2): EP = 49.3; LR chi(2): EPclin = 139.3; LRv 2: RS = 29.1), with greater differences in late DR and in node-positive patients. EP and EPclin remained statistically significantly prognostic when adjusted for RS (Delta LR chi(2): EP+RS vs RS = 20.2; Delta LR chi(2): EPclin+RS vs RS = 113.8). Using predefined cut-offs, EPclin and RS identified 58.8% and 61.7% patients as low risk, with hazard ratios for non-low vs low risk of 5.99 (95% confidence interval [CI] = 3.94 to 9.11) and 2.73 (95% CI = 1.91 to 3.89), respectively. Conclusions: EP and EPclin were highly prognostic for DR in endocrine-treated patients with ER+, HER2-negative disease. EPclin provided more prognostic information than RS. This was partly but not entirely because of EPclin integrating molecular data with nodal status and tumor size.

Background: Adjuvant endocrine therapy compromises bone health in pre- and postmenopausal breast cancer (BC) patients. Bisphosphonates have been shown to prevent and counteract these side effects of endocrine therapy, and to improve disease-free and overall survival outcomes in postmenopausal (natural or induced) BC patients (EBCTCG meta-analysis, Lancet 2015). The aim of ABCSG-18 was to investigate the effects of adjuvant anti-RANK-ligand Denosumab on bone health and disease outcomes in postmenopausal patients with early hormone receptor+ (HR+) BC receiving AI treatment. Patients and Methods: 3,425 postmenopausal patients with HR+ BC receiving AI were recruited in 58 trial sites into this prospective, randomized, double-blind, placebo-controlled, phase-III trial. Patients were randomized 1:1 to either Denosumab 60mg or placebo q6mo s.c. Bone end point results showed that adjuvant denosumab significantly reduced clinical fractures (primary endpoint, HR=0.5, p Results: With a median follow-up of 4 years, 370 DFS events were recorded. 203 DFS events occurred in the placebo group, and 167 in the Denosumab group (HR 0.816, p=0.051). Subgroup analyses indicate that the Denosumab benefit (overall absolute 2.1% at 5 years) may be particularly driven by tumors larger than 2cm (HR=0.66, p=0.016), ductal breast cancer histology type (HR=0.79, p=0.048), and tumors with both ER and PR positive (HR=0.75, p=0.013). Summary and conclusion: Adjuvant Denosumab 60mg q6mo s.c. improves disease-free survival of HR+ breast cancer patients receiving aromatase inhibitors. Numerically, this benefit of adjuvant Denosumab is at least comparable to the DFS-benefit of adjuvant bisphosphonates. Bases on these results and the previously reported dramatic reduction of fractures, adjuvant Denosumab should be offered to all postmenopausal HR+ breast cancer patients on AI. Citation Format: Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF, On behalf of the Austrian Breast and Colorectal Cancer Study Group. The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-02.

Background: RS is widely used for estimating 10-yr risk of DR for br ca patients receiving 5yrs adjuvant endocrine treatment alone. EndoPredict is a prognostic test which unlike RS combines its eight-gene expression signature (EP score) with tumor size and nodal status to provide the EPclin score with a single low/high risk cut-off at 10% risk of DR at 10yrs similar to the low/intermediate risk cut-off with RS. Aims: To determine the prognostic value of EP/EPclin over 10yrs, 0-5yrs and 5-10yrs in ER+/HER2- br ca patients and to compare this with the RS (i) alone (primary objective) and (ii) in addition to the clinical treatment score (CTS [developed in TransATAC]: nodes (N); tumour size; grade; age; tam or AI). Methods: mRNA from 928 ER+/HER2- primary br ca from patients treated with anastrozole or tamoxifen in the ATAC trial on which RS was already available were assessed for the EP/EPclin. Primary end point was DR. Kaplan–Meier and Cox regression analyses were used to determine DR risk for 0-10, 0-5 and 5-10yrs follow-up. Likelihood ratio tests (LR-chi sq) were used to assess the prognostic information provided by EP, EPclin, and RS alone and in combination with CTS. Results: Median follow-up was 9.95 yrs. The table shows the LR-chi sq for the prognostic information provided by each marker alone (univariate) and the information on top of CTS for all patients, and N- and N+ subgroups in 0-10, 0-5 and 5-10yrs. EP and EPclin provided substantially more prognostic information than RS across all three time periods and subgroups, except for N- patients in 0-5yrs. EP and EPclin also provided more information in addition to CTS than RS in 0-10yrs due to better performance of EP and EPclin in 5-10yrs where RS added no significant information to CTS. Using predefined cut-offs, EPclin and RS identified 546 (58.8%) and 573 (61.7%) patients as low risk respectively (HR (95%CI) low vs. non-low risk: 5.9 (3.9-9.1) and 2.7 (1.9-3.8), respectively). The EP score significantly added prognostic information to the RS over 0-10yrs and 5-10yrs in the overall, N- and N+ populations. Cases classified discordantly by EPclin and RS followed the EPclin classification more closely than RS classification. Prognostic information from EP, EPClin, RSLR-chi-sqAll patientsNode-negativeNode-positiveUnivariate0-10yrs0-5; 5-10yrs0-10yrs0-5; 5-10yrs0-10yrs0-5; 5-10yrsEP49.325.7; 23.630.811.9; 15.614.57.9; 6.6EPclin139.380.0; 59.340.017.0; 22.748.332.2; 16.1RS29.126.1; 5.621.318.7; 4.88.08.0; 1.0CTS149.885.0; 64.735.619.0;16.961.635.2; 26.3added to CTS EP16.46.9; 9.815.55.2; 6.68.32.3; 3.4EPClin20.310.5; 9.917.03.6; 9.05.46.4; 2.3RS12.811.8; 2.318.78.1; 1.44.13.7; 0.7LR-chi sq >3.8, p Conclusions: EPclin was highly prognostic for DR in all patients, N-, N+, early and late metastasis. EPclin provided more prognostic information than RS in part but not solely because of the integration of the EP score with N and tumour size parameters. The data stress the importance of including clinicopathological factors in deriving an overall estimate of risk. Citation Format: Dowsett M, Sestak I, Buus R, Kronenwett R, Denkert C, Krappmann K, Scheer M, Petry C, Dubsky P, Cuzick J. EndoPredict (EPclin) score for estimating residual distant recurrence (DR) risk in ER+/HER2- breast cancer (br ca) patients treated with 5 years adjuvant endocrine therapy alone: Validation and comparison with the oncotype DX recurrence score (RS). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S3-01.

The assessment of HER2/neu overexpression in tissue provides information about one of the most relevant prognostic and predictive markers in breast cancer: overexpression of HER2/neu is associated with worse prognosis in primary breast cancer. Since core needle biopsy is increasingly used for the diagnosis of breast cancer, the purpose of this study was to assess the reliability of HER2/neu evaluation using this technique in patients with primary breast cancer.We investigated the accuracy of immunohistochemical assessment of HER2/neu in core needle biopsies compared with surgically obtained specimens in 325 patients with primary breast cancer. In patients strongly positive for HER2/neu, additional fluorescence in situ hybridization (FISH) analysis of needle biopsies was performed.Using immunohistochemistry alone, accuracy of HER2/neu assessment in core biopsies in relation to surgically removed specimens was 92% and increased to 96% with additional FISH analysis (weighted Kappa coefficient: 0.86).As proven with this large series of patients, the assessment of HER2/neu status by core needle biopsy in breast cancer is accurate. Notwithstanding, in order to minimize the number of false-positive results, strongly positive core needle biopsies identified using immunohistochemistry should be confirmed by FISH analysis.

Recommendations for adjuvant treatment of DCIS after breast conservation are controversial. We tried to identify further risk factors in a retrospective study of our own practice.Three hundred and thirty-two patients treated by breast conservation between 1978 and 2001 at the Department of General Surgery, University of Vienna were analysed. Tumour size, nuclear grade, hormone receptors, p53, her-2/neu, multifocality, microinvasion and post-operative therapy (irradiation, tamoxifen or combination) were analysed for their influence on breast recurrence.Overall recurrence rate was 6.1% (8/132). For patients with DCIS showing high nuclear grade or negative estrogen receptor the risk for development of ipsilateral breast recurrence is significantly higher. Newer factors like p53 and her-2/neu do not have any prognostic significance. No recurrence was observed in patients treated by post-operative irradiation and tamoxifen.Nuclear grade remains the most significant factor for breast recurrence after DCIS. Hormone receptor status identifies a subset of patients with more favourable prognosis.

Breast cancer in younger patients appears to be more aggressive than disease occurring in older patients. Even though large population-based studies suggest poorer survival of patients younger than 35 years, data demonstrating the relationship of age and prognosis within premenopausal cohorts are much more scarce and conflicting. In this retrospective analysis of 885 premenopausal patients, the relationship between age, typical prognostic factors, treatment, and patient outcome was investigated. Eight hundred four patients (90.8%) > 35 years and 81 patients (9.2%) ≤ 35 years who had been treated for stage I/II breast cancer were evaluated. Median follow-up time was 71 months. The prevalence of adverse prognostic features such as tumor size, tumor type, tumor grading, pathologic lymph node status, and hormone receptor status were evenly distributed between the two age groups. Age ≤ 35 years proved to be a powerful independent prognostic factor in multivariate analyses of recurrence-free (P < 0.0001; relative risk [RR] = 2.5) and overall survival (P < 0.0039, RR = 2.2). Thus, in the face of evenly distributed risk factors in this strictly premenopausal, homogeneous population, young age was seen as the second most powerful risk factor after lymph node status. According to these findings, patients diagnosed with breast cancer at ≤ 35 years of age have a worse prognosis compared to premenopausal women above this age. Future studies should focus on unveiling the young age surrogate in order to improve treatment and prognosis.

Background: We have previously reported significantly improved disease-free survival (DFS) in premenopausal patients with endocrine-responsive early breast cancer receiving adjuvant zoledronic acid (ZOL) in ABCSG-12 (Gnant M, et al. NEJM. 2009;360:679–91). Other trials, such as ZO-FAST and the postmenopausal (>5 yr) subset analysis of AZURE, have demonstrated similar anticancer effects with ZOL. Now with >6 yr of follow-up in ABCSG-12, we report an overall survival (OS) benefit and preplanned subgroup analyses that more precisely define interactions between the ZOL benefit and patient/tumor characteristics. Methods: Premenopausal women with endocrine-receptor-positive early stage breast cancer (N = 1,803) were randomized to ovarian function suppression with goserelin (3.6 mg q28d) and tamoxifen (TAM; 20 mg/d) or anastrozole (ANA; 1 mg/d) ± ZOL (4 mg q6mo) for 3 yr. Endpoints included DFS and OS, both analyzed using logrank test and Cox models. Results: At median follow-up of 76 mo, patients receiving ZOL had a significant 27% reduction in the risk of DFS events (HR = 0.73; Cox P = .022) and a significant 41% reduction in the risk of death (HR = 0.59; Cox P = .027) vs no ZOL. Multivariate analyses showed a strong interaction between ZOL and patient age, but did not show any interactions between ZOL and ANA/TAM or any classic tumor parameter (eg, T, N, grade, ER). Among patients > 40 yr of age (n = 1,390) with presumed complete ovarian blockade, ZOL significantly reduced the risk of DFS events by 34% (HR = 0.66; Cox P = .014) and the risk of death by 49% (HR = 0.51; Cox P = .020); however, there were no significant DFS or OS benefits in patients Conclusions: Long-term follow-up of ABCSG-12 (76 months) confirms and extends previous results seen at 48 mo and 62 mo follow-up, and suggests that anticancer benefits of adjuvant ZOL result in highly significant DFS and OS benefits mainly in patients with a low-estrogen environment (ie, ovarian suppression and age >40 yr). These results are consistent with the significant DFS and OS improvements seen in the postmenopausal (>5 yr) cohort of the AZURE trial, and suggest that both estrogen deprivation and reduction of bone-turnover-derived growth factors in the bone marrow microenvironment are needed for sufficient suppression of dormant micrometastases. Taken together with the previously demonstrated bone-protective effects of ZOL, these DFS and OS benefits strongly suggest that adding ZOL to adjuvant endocrine therapy should be considered for premenopausal women with endocrine-receptor-positive early breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-2.

Background: Extended adjuvant endocrine therapy beyond 5 years is known to be of benefit to some oestrogen receptor (ER+) patients. Given the significant burden extended endocrine therapy presents, individual prediction of late recurrence risk would be highly valuable. We have previously shown that the PAM50 based Risk of Recurrence (ROR) score is significantly correlated with late recurrence in both the transATAC and ABCSG8 cohorts. Here, we assess the value of the ROR score for predicting distant recurrence beyond 5 years in a combined analysis of these two cohorts. Methods: Long-term follow-up data and tissue samples were obtained from 2,485 postmenopausal women with hormone receptor positive (HR+) early breast cancer from the ABCSG-8 and transATAC trials. We used univariate and multivariate models to determine the prognostic value of ROR (with tumour size) for distant recurrence in years 5-10 in the combined dataset. Changes in likelihood ratio tests (DLR-χ2) are presented. Results: A total of 2137 women who did not have a recurrence in years 0-5 were included in the combined analyses of late recurrence risk. In the univariate and multivariate analyses, CTS was the strongest prognostic score in the late follow-up period (ΔLR-χ2 = 95.17, ΔLR-χ2 = 61.65, respectively) in all patients. The ROR score also added significant prognostic information in years 5-10 in the univariate and multivariate analyses, but somewhat less than the CTS (ΔLR-χ2 = 66.09, ΔLR-χ2 = 32.57, respectively) (Table 1). The risk of distant recurrence at 10 years for the low risk group was 5.7% (95% CI 4.5% to 7.2%), for intermediate risk 14.6% (12.0% to 17.6%), and for high risk 29.3% (25.5% to 33.6%). Patients with a luminal A subtype had a 70% lower risk of late distant recurrence than those with a luminal B subtype (HR = 0.30 (0.21-0.43), P Conclusions: The results of this combined analyses showed that the ROR score added prognostic information to CTS in all patients and in all patient subgroups in the late follow-up period. The risk of distant recurrence in years 5-10 was statistically significantly different for the low, intermediate risk and high risk groups. These results suggest that the ROR score may be used to separate patients into risk groups who could be spared or could benefit from extended hormonal therapy beyond 5 years of treatment. Hazard Ratio (HR) and changes in likelihood ratio test (DLR-χ2) for univariate and multivariate analyses according to all groups. Univariate Multivariate* HR (95% CI)ΔLR-χ2 (P-value)HR (95% CI)ΔLR-χ2 (P-value)All patients (N = 2137) CTS2.05 (1.80-2.34)95.17 ( Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-04.

Background: ER+/HER2− negative (ER+) breast cancers have a proclivity for late recurrence. A first step to an improved adjuvant treatment of late metastasis is to identify women at risk and understand the underlying biology. Several prognostic multigene tests have been developed for ER+ breast cancer patients. Some of these tests have been validated to predict early recurrence events. However, few gene expression assays have been shown to predict late metastases. Here, we assess whether the prognostic EndoPredict (EP) score, which incorporates both the expression levels of proliferative - and ESR1-related genes, can be used to identify late relapse events in ER+ breast cancer patients. Methods: Patients included in this study participated in the ABCSG-6 (tamoxifen-only arm) or ABCSG-8 phase III adjuvant trial and received either tamoxifen for 5 years or tamoxifen for 2 years followed by anastrozole for 3 years. All 1702 ER+/HER2− breast cancer patients were retrospectively assigned into risk categories based on the EP and on common clinical parameters. The primary endpoint was distant metastasis. Ongoing collection of follow-up events allowed estimation of metastasis rates using the Kaplan–Meier method in an early and late time cohort: 0–5 years/early recurrence and 5–10 years/late recurrence. Results: 49% of all patients were classified as low-risk according to the EP score. Kaplan Meier analysis demonstrated that the EP low-risk group had a significantly improved clinical outcome in the first (0–5 years; p < 0.0001) and second time interval (5–10 years; p = 0.002). Nodal metastasis was also significantly associated with the clinical outcome in both time intervals, with node-positive tumors showing a considerably higher rate of late recurrence events. In contrast, Ki67 levels and grading were not significantly associated with late metastasis. Multivariate analysis showed that EP was an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size and Ki67 in both the first and second time interval. The EPclin – a combination of the EP and the clinical risk factors nodal status and tumor size – showed the best performance in predicting late relapse events. Exploratory analyses of proliferative - versus ESR-1 related genes as contributors to early and late distant metastases show differential effects. Conclusions: The EndoPredict test identified a subgroup of patients that have a low likelihood of developing late metastases. The eight genes contained in the test provide complimentary prognostic information to clinico-pathologic parameters. Both the expression of proliferative - and ESR1-related genes contributes to the underlying biology of late distant metastases. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S4-3.

Purpose To assess radiological tumor response to neoadjuvant chemotherapy (NAC) with a high temporal and spatial resolution MR breast imaging protocol at 3Tesla and to correlate with pathological response. Materials and methods 35 patients (mean age 50.2 years) with a histopathologically verified breast cancer (BIRADS 6) who underwent NAC were included in this prospective IRB approved study. The MRI protocol consisted of a coronal T2-weighted TIRM and a coronal combined high temporal and spatial resolution T1-weighted sequence before and after application of a standard dose Gd-DOTA (VIBE with a high temporal resolution of SI 1.7mm isotropic; TA 3.45 min for 17 measurements; FLASH with high spatial resolution of SI 1mm isotropic; TA 2 min). Patients were examined before (baseline) and after 6 cycles of NAC. Tumor response to NAC was assessed using the RECIST 1.1 criteria and classified as complete response, partial response, stable disease and progressive disease. Correlation of imaging and pathological response as well as underestimation and overestimation were calculated. The histopathological assessment of tumor response was used as the standard of reference. Results There were 29 invasive ductal cancers (IDC) and 6 invasive lobular cancers (ILC). Average tumor size was 43.4mm. MRI classified 6 as complete response, 24 partial response, 4 stable disease, 1 progressive disease. MRI correctly identified treatment response in 88.6%. MRI overestimated response in 5.7% and underestimated response in 5.7%. All overestimated and underestimated lesions were IDC, no ILC were misclassified. If complete response and partial response were considered as responders and stable disease and progressive disease as non-responders MRI at 3T had a sensitivity of 96.8% (CI 0.84%-0.99%) and a specificity of 100% (CI 0.51%-100%) in determining response to NAC. The PPV was 100% (CI 88.9%-100%) and the NPV was 80% (CI 38%-96%). Conclusion In conclusion, high-resolution MRI of the breast at 3 Tesla using a high resolution imaging protocol allows accurate assessment of response to NAC, especially in ILC. Disclosure All authors have declared no conflicts of interest.

41 Background: Brain metastases (BM) are diagnosed in up to 40% of patients with HER2-positive metastatic breast cancer (MBC). Since the introduction of trastuzumab in 1999, a rising incidence of BM was reported. We aimed to identify factors that prolong BM free survival (BMFS) in all HER2-positive patients (pts) treated for MBC at the Medical University of Vienna from 1999-2009. Methods: BMFS was defined as primary study endpoint and measured as the interval from diagnosis of metastatic disease until diagnosis of brain metastases. 201 pts with HER2-positive MBC were identified from a breast cancer database. 82 pts (40.8%) were diagnosed with BM; 13 pts were excluded from this analysis as brain was the first site of disease progression. Complete data sets of 69 pts with pathologically verified HER2-positive MBC were available. HER2 status was analyzed by immunohistochemistry and reanalyzed by FISH if a score of 2= was gained. BMFS was estimated by using the Kaplan-Meier product-limit method; factors significantly associated with BMFS in the univariate analysis were included into a Cox proportional hazard model. Results: Median BMFS was 25 months (m; 95%CI 13.37-36.63 m). Trastuzumab-based treatment significantly prolonged median BMFS (29 vs. 11 m; p Conclusions: Trastuzumab-based therapy significantly prolongs BMFS in HER2-positive pts with MBC, probably due to improved systemic disease control. In line with known better survival outcome, ER/HER2 co-positive disease appears to be a less aggressive subtype of HER2-positive breast cancer associated with longer BMFS.

514 Background: Aromatase inhibitors (AIs) are effective as adjuvant endocrine treatment in breast cancer (BC) patients. Recently, it has been argued that BMI at BC diagnosis impacts on the efficac...

572 Background: Trastuzumab (T) prolongs OS over chemotherapy alone in pts with HER2+ MBC. Upon disease progression, pts may switch to lapatinib (L) or continue on T. We aimed at assessing the impa...

597 Background: Brain metastases (BM) occur frequently in Her2+ MBC. We have previously reported that trastuzumab (T) after diagnosis of BM may improve OS due to prolonged systemic disease control....