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Introduction: Tumor biological factors of breast cancer (BC) such as hormone receptor (HR) status, HER2 status, and grade can differ in the metastatic cascade from primary to lymph node (LN) metastasis and to distant metastatic tissue. Systematic data regarding therapeutic consequences are yet limited. Methods: We conducted a prospectively planned, retrospective cohort study comparing BC phenotype in tissue from primary tumors (PTs), locoregional LN metastases, and disease recurrence (DR). HR and HER2 as well as tumor grade in PTs and DR were obtained by a database search. No centralized biomarker testing was performed. The impact of changes in tumor biological factors on post-recurrence survival (PRS) and overall survival was analyzed. Results: PriMet comprises 635 patients (LN tissue in 142 patients). Discrepancies for HR or HER2 status between PT and DR were observed in 18.7 and 21.6% of cases, respectively. For HR status, positivity of PT and negativity of DR was seen more often (13.2%) than vice versa (5.5%). For HER2 status, negativity of the primary and positivity of DR was seen more often (14.9%) than vice versa (6.7%). Discordance was more often observed between PT and LN metastasis compared to LN versus DR. However, numbers were small. Compared to concordant non-triple-negative (TN) disease, concordant TN disease showed significantly inferior PRS. Conclusion: We demonstrate receptor discordance to occur relatively frequently between PT, LN metastasis, and DR and to impact patient prognosis. However, clinical consequences of receptor discordance need to be drawn with caution considering clinical aspects as well as tumor biology.

Background: Optimal treatment, particularly use of anthracyclines in aggressive triple-negative breast cancer (TNBC), is still a controversial issue in early BC management. However, TNBC exhibits substantial molecular heterogeneity: for example, the immune phenotype seems to be associated with better outcome. An important clinical issue in early TNBC is to quantify the impact of subtypes as well as individual genes on survival and especially on anthracycline benefit. Methods: In PlanB, patients with ER and PR Results: RNA expression results were available in n=394 (203 TC vs. 191 EC-Doc): PAM-50 subtype: basal-like 82%; HER2-enriched 7%; luminal (A or B) 3.5%; normal-like 7.4%. Median age was 54; 78% were node-negative. In patients with “discordant” tumors (HR positive by local or central assessment), 76% were still basal-like, compared to 86% in “concordant” TNBC. Of 27 patients with HER2-enriched subtype, HER2 status was positive by central assessment in only five cases (18%). Within this TN cohort, 5y DFS was similar in TC (83%) and EC-Doc (79%) arms; positive nodal status and tumor size >2 cm were (unfavorable) clinical-pathological prognostic markers. Prognostic or predictive impacts of molecular subtype, risk of recurrence subgroups, or proliferation indices were not seen. Twelve genes (incl. CD8, EGFR, GPR160, SPINT2) showed potential multivariate prognostic impact by entering the “forwards stepwise” multivariate Cox model for DFS. The upper half of patients according to the resulting “twelve-gene signature” had well over 90% 5y-DFS, whereas the lowest quartile had under 60% 5-y DFS. Several genes (incl. ERBB2, FOXC1) showed potential for a predictive impact regarding TC vs. EC-Doc by interaction analysis. Further details and perspectives for testing the robustness of these potential impacts will be presented at the meeting. Conclusions To our knowledge, these are the first results from a prospective, adjuvant taxane-based trial regarding molecular predictors of anthracycline efficacy and PAM-50-based prognostic factors in early TNBC. ERBB2 expression, but not HER2-enriched subtype, was predictive for A-benefit in HER2-negative BC. Molecular heterogeneity of TNBC beyond basal-like vs. non-basal-like subtype is clinically relevant and should be considered for patient stratification in ongoing trials with combination therapy. The identified prognostic gene signature should be validated in the WSG-ADAPT-TN and other TNBC trials. Citation Format: Gluz O, Liedtke C, Prat A, Christgen M, Gebauer D, Kates R, Pelz E, Clemens M, Warm M, Aktas B, Kuemmel S, Pare L, Krabisch P, Kreipe HH, Wuerstlein R, Nitz U, Harbeck N. Genomic markers but not molecular subtypes provide prognostic impact and predict anthracycline efficacy in early triple-negative breast cancer: Results from the prospective WSG PlanB 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 P2-10-03.

Recently, a new variant of invasive lobular breast cancer (ILBC) with solid-papillary-like growth pattern has been described. We present a case of ILBC with solid-papillary-like growth pattern in the main tumour mass and classical invasive lobular growth pattern in adjacent satellite foci. The two tumour components were subjected to comprehensive molecular analyses. Both components were ER/PR-positive, HER2-negative, and showed a complete loss of E-cadherin and beta-catenin protein expression, as determined by immunohistochemistry. Gene expression profiling classified the main tumour and a satellite focus as luminal-B and luminal-A subtypes, respectively. Whole-genome copy number profiles were highly similar in both tumour components. Shared copy number alterations (CNAs) included gains of chromosome 1q21.1-q43 and losses of chromosome 16q11.2-q24.3, the locus of the CDH1/E-cadherin tumour suppressor gene. CNAs detected only in the main tumour included a gain of chromosome 20q12-q13.33 and a loss of chromosome 1p36.33-p34.3, which has recently been associated with the solid variant of ILBC. Next generation sequencing revealed an identical, truncating CDH1 mutation (p.G169fs*5) in both tumour components confirming a common clonal ancestry. In conclusion, we confirm the recently described variant of ILBC with solid-papillary-like growth pattern and provide evidence that it evolves from classical ILBC by subclonal evolution.

Granulomatous mastitis (GM) is a rare benign inflammatory breast disease that affects mostly women of childbearing age with a history of breastfeeding. The etiopathogenesis is still unknown; however, inflammation as the result of a reaction to trauma, metabolic or hormonal processes, autoimmunity, and an infection with Corynebacterium kroppenstedtii have all been implicated. Clinical findings are pain, mass, hyperemia, and inflammation. Because the clinical presentation can mimic infectious mastitis or inflammatory carcinoma, the disease course is often protracted. The diagnosis is made by histopathology. Biopsies show a granulomatous formation in combination with a localized infiltration of multi-nucleated giant cells, epithelioid histiocytes, and plasma cells. Ultrasound, mammography, and magnetic resonance imaging are not specific; however, ultrasound and mammography should be done to exclude other pathologies. Due to the lack of data including randomized controlled studies, the management of GM is controversial. In Western industrialized countries, most authors use a therapy regimen starting with antibiotics and corticosteroids, followed by continuous steroid therapy and surgery in patients with persisting symptoms. More data are needed to define the best therapy. The role of immunotherapy has not yet been ascertained. The implementation of a registry to collect more information on this rare disease is highly recommended.

503 Background: Optimal use of de-escalated, particularly chemotherapy(CT)-free, neoadjuvant regimens in HER2+ early breast cancer (EBC) is currently unclear as there are limited survival data so far. In ADAPT-HR-/HER2+, we previously showed an excellent pCR rate of 90% after 12-week neoadjuvant paclitaxel (Pac) +pertuzumab (P) +trastuzumab (T) and a substantial and clinically meaningful pCR rate of 34% after P+T alone in HR-/HER2+ EBC. Here, we present first survival data. Methods: The prospective multicenter WSG-ADAPT-HR-/HER2+ phase II-trial is part of the ADAPT-umbrella protocol. Patients with cT1-cT4c, cN0-3 HR-/HER2+ EBC (n = 134) were randomized to 4 cycles of P+T +/- pac d1,8,15 q3w. All tumors were HR-negative (ER and PR < 1%) and HER2-positive (central lab, i.e., 2+ FISH positive or 3+ by immunohistochemistry. Primary endpoint was pCR (ypT0/is/ypN0); omission of further CT was allowed in pts with pCR. Trial objective was to compare pCR in P+T+pac arm vs. early responders in P+T arm (defined as low cellularity and/or Ki67 decrease >30% after 3 weeks). The trial was stopped early due to the observed pCR superiority in the P+T+pac arm. Secondary endpoints included safety, 5-y (distant)-DFS, OS and translational research. Cox-regression analysis was applied. PAM50 subtype was assessed using the BC360 panel. Results: 134 patients were randomized to P+T (n = 92) or P+T+pac (n = 42). 60% of tumors were cT2-4, 42% clinically node-positive. After a median follow-up of 5 years, no significant differences between study arms were observed regarding DFS, dDFS, and OS; only 13 iDFS events (7 dDFS) were observed in the whole ITT population. pCR (vs. non-pCR) after the 12-week study treatment (irrespective of study arm) was strongly associated with improved iDFS (5y DFS 98.5% vs. 82%, HR = 0.14, 95% CI 0.03-0.64). Of the 69 patients with pCR, 39 (56.5%) received no further CT (P+T arm: n = 9, 29% vs. (P+T+pac arm n = 30, 79%); only 1 distant relapse (1.4%) was observed in these patients. In the CT-free P+T arm, no pCR was observed in patients with low HER2 expression (IHC 1+/2+ and FISH positive) and/or basal-like subtype by PAM50 (n = 17, 19%). In the total study population, low HER2 expression and/or no early response was strongly associated with worse dDFS (p =.029) and iDFS (p =.068). No new safety signals were observed. Conclusions: For the first time, we have shown both excellent pCR and survival in patients treated by de-escalated neoadjuvant CT+P+T irrespective of further CT use in a prospective multicenter study. Investigation of CT-free regimens may need to be focussed on selected patients only (e.g. with high HER2 expression/non-basal-like tumors). In ADAPT HR-/HER2+, early pCR after only 12 weeks of neoadjuvant P+T+pac was strongly associated with improved outcome and may thus serve as a predictive clinical marker for further treatment (de)-escalation. Clinical trial information: NCT01779206.

Background: Pathological complete response (pCR) is associated with improved prognosis in TNBC, but optimal chemotherapy remains unclear. Use of weekly nab- paclitaxel (Nab-Pac) vs. conventional paclitaxel and also addition of carboplatinum(Carbo) to anthracycline-taxane(A/T) containing chemotherapy results in significantly higher pCR rates in TNBC with unclear impact on survival and increased toxicity. The ADAPT study seeks to compare Carbo vs. gemcitabine(Gem) added to nab- paclitaxel as a short 12-week A-free regimen. It also assesses efficacy in early responders vs. non-responders by 3-week proliferation and/or imaging response. Methods: ADAPT TN compares 12-week neoadjuvant regimens: Carbo vs. Gem combined with Nab-Pac and aims to identify early-response markers for pCR (yPN0 and ypT0/is). TNBC patients (centrally confirmed ER/PR Results: 336 patients were enrolled from 47 centers between 06/13-02/15 (n=182 ArmA: Nab-Pac/Gem and n=154 ArmB: Nab-Pac/Carbo). 90% and 95% completed therapy according to protocol respectively (n.s.). Median age was 50y. At baseline: A/B: 73% and 74%% had G3 tumors, median Ki-67 of 70% and 75%; 62.6% and 62.9%% had cT2-4c tumors, pN0 status prior to chemotherapy was confirmed in 50.5% and 50%, respectively. pCR (ypT0/is/ypN0) was A: 28.7% and B: 45.9% (p Nab/Gem arm was associated with significantly higher frequency of dose reductions (20.6% vs. 11.9% (p=0.03), treatment related SAE's (13% vs. 5%, p=0.02), grade 3-4 infections (6.1% vs. 1.3%, p=0.04) and ALAT elevations (11.7 vs. 3.3%, p=0.01) compared to the Nab-Carbo arm. Within the planned interim analysis (n=130: A/B: 69/61), baseline Ki-67 (Nab- Pac/Carbo arm), age>50 years, and low cellularity ( Validation of responder definitions for the whole study will be presented at the meeting. Conclusions: This is the first large randomized study comparing two short 12-week anthracycline- free regimens in unselected TNBC. Our results suggest superior efficacy and excellent toxicity of Nab-Pac/Carbo vs. Gem. Longer A/T-Carbo containing regimens render quite comparable pCR rates, thus overtreatment by 4xEC in unselected TNBC may be present in some patients. Early response criteria seem to differ according to regimen; their assessment may be impaired by substantial tumor necrosis already after the first therapy cycle. Citation Format: Gluz O, Nitz U, Liedtke C, Christgen M, Sotlar K, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kuemmel S, Clemens M, Potenberg J, Staib P, Kohls A, Pelz E, Kates RE, Wuerstlein R, Kreipe HH, Harbeck N. Comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II 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 P1-13-01.

In the neoadjuvant WSG-ADAPT-TN trial, 12-week nab-paclitaxel + carboplatin (nab-pac/carbo) was highly effective and superior to nab-paclitaxel + gemcitabine (nab-pac/gem) in triple-negative breast cancer regarding pathological complete response (pCR). Predictive markers for deescalated taxane/carbo use in TNBC need to be identified. Patients received 4 × nab-pac 125 mg/m2 (plus carbo AUC2 or gem 1,000 mg/m2 d1,8 q21). Expression of 119 genes and PAM50 scores by nCounter were available in 306/336 pretherapeutic samples. Interim survival analysis was planned after 36 months median follow-up. Basal-like (83.3%) compared to other subtypes was positively associated with pCR (38% vs. 20%, p = 0.015), as was lower HER2 score (p < 0.001). Proliferation biomarkers were positively associated with pCR, that is, PAM50 proliferation, ROR scores (all p < 0.004), higher Ki-67 (IHC; p < 0.001). For nab-pac/carbo, expression of immunological (CD8, PD1 and PFDL1) genes and proliferation markers (proliferation and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3 and TYMS) were positively associated with pCR (p < 0.05 for all). For nab-pac/gem, angiogenesis genes were negatively associated with pCR (ANGPTL4: p = 0.05; FGFR4: p = 0.02; VEGFA: p = 0.03). pCR after 12 weeks was strongly associated with favorable outcome (3y event-free survival: 92% vs. 71%, p < 0.001). In early TNBC, basal-like subtype, higher Ki-67 (IHC) and lower HER2 score were, associated with chemosensitivity. Chemoresistance pathways differed between the two taxane based combinations. Combination of proliferation/immune markers and PAM50 subtype could allow patient selection for further deescalated chemotherapy and/or immune treatment approaches.

Taxane–anthracycline-based adjuvant chemotherapy is standard of care in patients with node-positive breast cancer (BC) but is also associated with severe side effects and significant costs. It is yet unclear, which biomarkers would predict benefit from taxanes and/or general chemoresistance. In this study, we investigate a large cohort of patients with intermediate-risk BC treated within the WSG EC-DOC Trial for the predictive impact of topoisomerase-II-alpha, HER2/neu, and TIMP-1. Tumor tissue was available in a representative cohort of 772 cases of the WSG EC-DOC Trial collective which compared 4xEC-4xDoc versus 6xCEF/CMF. In addition to hormone receptor status and Ki-67, HER2/neu+ and topoisomerase-II-alpha status using fluorescence in situ hybridisation (FISH) and immunohistochemistry, TIMP-1 using immunohistochemistry, and aneuploidy of chromosome 17 using FISH were evaluated and correlated with outcome and taxane benefit. There was significant superiority of EC-Doc over CEF regarding 5-year DFS (90 vs. 80 %, respectively, p = 0.006) particularly in patient subgroups defined by HR+, HER2/neu+, high proliferation (i.e., Ki-67 ≥ 20 %), patient age >50 years old and normal chromosome 17 status, high TIMP-1 and low topoisomerase-II-alpha protein expression. Significant prognostic factors in multivariate analysis were EC-Doc therapy (HR = 0.61; 95 %CI 0.38–0.986), age

Background: Prosigna is a standardized test measuring expression levels of 50 classifier genes (PAM50) in breast tumor tissue using nCounter® Technology (Nanostring Technologies, Inc.). It provides intrinsic subtype and risk of recurrence (ROR) score predicting 10-year recurrence probability. WSG prospectively evaluated Prosigna's impact on therapy decisions in EBC and the quality assurance at its implementation in clinical routine. Methods: The study recruited 201 consecutive postmenopausal patients in 11 centers with ER+ HER- N0 EBC (10/2013 to 10/2014). Its primary objective was to assess the extent to which the Prosigna (Breast Cancer Intrinsic Subtype Test (BCIST)) affects the oncologists' treatment recommendations regarding adjuvant chemotherapy (CT) and actual treatments received for EBC patients. Changes in treatment recommendations include (1) endocrine therapy alone, (2) endocrine therapy plus CT, and (3) changes in types of CT before/after the test and confidence in this treatment decision from physician and patient at a 6-month follow up. Secondary objectives included information on (1) physicians' confidence in the recommendations before/after the test, and by cancer recurrence risk groups, (2) rate of CT related adverse events stratified by administration of CT, and (3) patients' decisional conflict status, anxiety levels, and functional status before/after Prosigna's results. As a secondary endpoint for quality assurance, we repeated Prosigna in a second decentralized pathology laboratory in Germany for inter-observation control. Results: In the total evaluable cohort (n=198), 114 (57.6%) of tumors were classified by Prosigna as Luminal A, 79 (39.9%) Luminal B, 3 (1.5%) Basal-like and 2 (1%) HER2-E. Median Prosigna ROR score was 45 (0-94). There was a 29.3% discordance in intrinsic subtyping between Prosigna and IHC. Concordance between central pathology and the second lab regarding molecular subtype was 95.5% with only 9 discordant samples, all within the luminal group. Concordance regarding ROR risk group classification was 92.9%; no clinically relevant differences (low-high or vice versa) were seen. Overall, there was a change of treatment choice (change in CT indication and change in regimens) in 18.2% compared to the pre-Prosigna decision. Post-Prosigna, 87.8% of physicians felt more confident with their prognostic assessment and 89.4% with their intended treatment. 94.8% of the patients expected to stick to their decision after discussing the Prosigna results. Six-month follow up (actual CT administered, its morbidity, perceptions by physicians and patients) will be presented at SABC. Conclusion: Overall, there was a change of treatment choice (change in CT indication and change in CT regimens) in 18.2% compared to the pre-Prosigna decision. Substantial discordance between Prosigna (PAM50) and local IHC underlines the importance of molecular subtyping prior adjuvant treatment decisions. High concordance of Prosigna results between central and decentralized lab testing were found. Results of WSG study can be pooled with two similar European studies and may thus help to improve our understanding of treatment decision making and adherence in EBC. Citation Format: Wuerstlein R, Sotlar K, Gluz O, Hofmann D, Otremba B, Von Schumann R, Witzel I, Schindlbeck C, Janni W, Schem C, Bauerfeind I, Hasmueller S, Tesch H, Paulenz A, Morel P, Cowens W, Hornberger J, Kates RE, Pelz E, Harbeck N. Prosigna® results impact on adjuvant decision making in early breast cancer (EBC): Final analysis of the prospective WSG study. [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 P5-07-03.

Purpose: The West German Study Group (WSG) Breast Cancer Intrinsic Subtype (BCIST) study was designed to assess the influence of Prosigna gene signature assay results on physicians’ adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians’ confidence in their therapeutic recommendations and on patients’ decisional conflict status, anxiety levels, and functional status. Methods: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with estrogen-receptor (ER)-positive, HER2-negative, lymph-node-negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in a WSG central pathology laboratory following manufacturer’s guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay result concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. Results: The present study population consisted predominantly of low-to-intermediate risk patients (N = 198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna test results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna test results. Conclusions: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.

Purpose: The WSG BCIST study was designed to assess the influence of Prosigna results, on physicians’ adjuvant treatment recommendations by determining the extent of change in pre-test treatment recommendations following assay results. Secondary objectives were to assess the influence of Prosigna results on physicians’ confidence in their therapeutic recommendations and on patients’ decisional conflict status, anxiety levels, and functional status. Methods: This prospective, observational, decision impact study enrolled consecutive postmenopausal patients with ER-positive, HER2-negative, lymph-node negative early-stage breast cancer in 11 centers in Germany. Physicians based their pre-test adjuvant treatment recommendations on standard clinico-pathological parameters. Tumor specimens were assayed using the Prosigna test in the WSG central pathology laboratory following manufacturer’s guidelines. An independent pathology laboratory performed subsequent Prosigna assays on tumor sections to assess assay results concordance with the central laboratory. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Patients completed standardized questionnaires on decisional conflict, anxiety, and health status both before and after Prosigna testing. Results: The present study population consisted predominantly of low-to-intermediate risk patients (N=198). Prosigna had 29.3% discordance in intrinsic subtyping with local immunohistochemistry test results. After Prosigna test results, a change in the adjuvant therapy recommendation occurred in 36 (18.2%) patients; 22 (11.1%) patients switched from no chemotherapy to chemotherapy. After Prosigna results, physicians expressed increased confidence in their prognostic assessment in 87.9% of patients, and increased confidence in their treatment recommendation in 89.4%. Patients reported improved anxiety and emotional/functional well-being after receiving Prosigna results. Conclusions: Use of the Prosigna assay led to a change in 18.2% of adjuvant treatment decisions. Prosigna testing was associated with increased patient and physician confidence in treatment decisions, and with decreased patient anxiety and improved well-being. Any comparison of the therapeutic decision-making impacts of different genomic assays must account for potential confounding factors.

Background: Despite extensive research, there is still no consensus on optimal predictors for use of taxane-based chemotherapy (cht) in early breast cancer. Some studies have revealed HER2 as a significant predictive marker for efficacy of taxanes and anthracyclines. TIMP-1 and Topo-II are reported to be predictive for anthracycline efficacy. In our previous reports, both Ki-67≥20% and central G3 status emerged as significant predictors for taxane benefit. We have now compared HER2 and Topo-II (as protein expression and gene amplification) and TIMP-1 immunoreactivity as well as factor combinations (HT (HER2/TIMP-1) and 2T (Topo-II/TIMP-1) regarding their predictive value for benefit from taxane-based cht. Methods: The EC-Doc trial randomized 1950 patients with 1–3 positive LN to 6x CEF/CMF vs. 4xEC-4xDoc. Significantly better DFS and OS favoring EC-Doc have been previously reported (Nitz et al., SABCS 2008). Protein expression and gene amplification data as well central histology/grade were available for 772 patients. Survival analysis was performed using Cox proportional hazards and Kaplan-Meier statistics. Analysis of HER2 survival impact status was prospectively planned. Results: The entire and the investigated study populations did not differ regarding baseline characteristics. After median follow up of 64 months, both DFS (5y 90% vs. 80%, p=0.006) and OS (5y 95% vs. 92%, p=0.022) rates significantly favored EC-Doc vs. CEF in this cohort as well. HER2 over-expression (3+ and/or FISH≥2.0) was reported in 158 tumors (20%), Topo-II aberration (deletion or amplification) was reported in 78 (49.4%) HER2+ and in 83 (13.6%) HER2−negative tumors; 496 tumors were classified as TIMP-1 immunoreactive (65.2%). None of these factors were significantly prognostic for EFS in this collective. Regarding DFS, EC-Doc was strongly superior to FEC in HER2+ tumors (HR=0.29, 95%CI: 0.12−0.7, p=0.006) but not in HER2− tumors (p=0.18). In Topo-II aberrated tumors, the benefit of EC-Doc was remarkably strong (HR=0.28, 95% CI: 0.11−0.69, p=0.006), whereas the benefit was not significant in Topo-II normal tumors (p=0.16), which comprise more than ¾ of the total. In contrast, Topo-II protein overexpression (>10%) was not associated with a stronger benefit in either subgroup. The superiority of EC-Doc to FEC was significant in the larger group of TIMP-1 immunoreactive tumors (HR=0.57, p=0.025) but not in TIMP-1 negative tumors (p=0.14), similar behavior was seen in “HT” and “2T” subgroups (significance with HR about 0.5 in the “+” subgroups). In a multivariate model for DFS including age, tumor size, Ki-67, central grade, HR, HER2, TOPO_II aberration, TIMP-1 status, therapy and interactions of all these factors with therapy arm, the only significant therapy interaction was that of (high) Ki-67 (HR=0.76, 95% CI: 0.59−0.98, p=0.03); significant main effects in this model were age, central grade, and Ki-67. Conclusions: These data suggest predictive significance for Topo-II aberration, TIMP immunoreactivity and HER2 over-expression as well as a multivariate predictive significance of high Ki-67 for enhanced benefit of taxane-based cht. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-06-03.

Background: Pathological complete response (pCR) is associated with improved prognosis in TNBC, but optimal chemotherapy remains unclear. Use of weekly nab- paclitaxel (Nab-Pac) vs. conventional paclitaxel and also addition of carboplatinum(Carbo) to anthracycline-taxane(A/T) containing chemotherapy results in significantly higher pCR rates in TNBC with unclear impact on survival and increased toxicity. The ADAPT study seeks to compare Carbo vs. gemcitabine(Gem) added to nab- paclitaxel as a short 12-week A-free regimen. It also assesses efficacy in early responders vs. non-responders by 3-week proliferation and/or imaging response. Methods: ADAPT TN compares 12-week neoadjuvant regimens: Carbo vs. Gem combined with Nab-Pac and aims to identify early-response markers for pCR (yPN0 and ypT0/is). TNBC patients (centrally confirmed ER/PR Results: 336 patients were enrolled from 47 centers between 06/13-02/15 (n=182 ArmA: Nab-Pac/Gem and n=154 ArmB: Nab-Pac/Carbo). 90% and 95% completed therapy according to protocol respectively (n.s.). Median age was 50y. At baseline: A/B: 73% and 74%% had G3 tumors, median Ki-67 of 70% and 75%; 62.6% and 62.9%% had cT2-4c tumors, pN0 status prior to chemotherapy was confirmed in 50.5% and 50%, respectively. pCR (ypT0/is/ypN0) was A: 28.7% and B: 45.9% (p Nab/Gem arm was associated with significantly higher frequency of dose reductions (20.6% vs. 11.9% (p=0.03), treatment related SAE's (13% vs. 5%, p=0.02), grade 3-4 infections (6.1% vs. 1.3%, p=0.04) and ALAT elevations (11.7 vs. 3.3%, p=0.01) compared to the Nab-Carbo arm. Within the planned interim analysis (n=130: A/B: 69/61), baseline Ki-67 (Nab- Pac/Carbo arm), age>50 years, and low cellularity ( Validation of responder definitions for the whole study will be presented at the meeting. Conclusions: This is the first large randomized study comparing two short 12-week anthracycline- free regimens in unselected TNBC. Our results suggest superior efficacy and excellent toxicity of Nab-Pac/Carbo vs. Gem. Longer A/T-Carbo containing regimens render quite comparable pCR rates, thus overtreatment by 4xEC in unselected TNBC may be present in some patients. Early response criteria seem to differ according to regimen; their assessment may be impaired by substantial tumor necrosis already after the first therapy cycle. Citation Format: Gluz O, Nitz U, Liedtke C, Christgen M, Sotlar K, Grischke EM, Forstbauer H, Braun M, Warm M, Hackmann J, Uleer C, Aktas B, Schumacher C, Bangemann N, Lindner C, Kuemmel S, Clemens M, Potenberg J, Staib P, Kohls A, Pelz E, Kates RE, Wuerstlein R, Kreipe HH, Harbeck N. Comparison of 12 weeks neoadjuvant Nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple- negative breast cancer: WSG-ADAPT TN randomized phase II 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 S6-07.

573 Background: In the ADAPT-TN neoadjuvant trial, 12-week nab-paclitaxel (nab- pac)+carboplatin (carbo) was highly effective and superior to nab-pac+gemcitabine (gem). However, within TNBC, reliable predictive markers for carbo use have yet to be identified. Methods: Patients with early TNBC (centrally confirmed) were treated by nab-pac 125 mg/m2 with either carbo AUC2 or gem 1000 mg/m2 d 1,8 q21 given for 4 cycles. Genomic data (80 genes) and Prosigna (PAM-50) scores were available in 306 pre-therapeutic samples of 331 treated patients. Fisher’s exact test was performed for pCR differences; associations of continuous measurements or scores with pCR were analyzed by the Mann-Whitney statistic. Results: pCR was 44.5% to 28.4% (p=.004) in favor of nab-pac - carbo. Specifically within the carbo- containing arm, immunological (CD8, PD1, PFDL1) genes and proliferation markers (proliferation score and ROR scores, MKI67, CDC20, NUF2, KIF2C, CENPF, EMP3, TYMS) were positively associated with pCR (p

Zielsetzung: Patienten mit HR+ Mammakarzinom. und 1-3 positiven Lymphknoten („intermediate-risk„) werden leitlinienkonform mit einer adjuvanten taxanhaltigen chemo-endokrinen Therapie behandelt. Im Rahmen der EC-Doc Studie wurden erstmals molekularen Subtypen mit konventionellen Prognosemarkern wie z.B. zentrales Grading bezuglich deren prognostischer und pradiktiver Bedeutung verglichen. Methoden: 1950 Patienten mit 1-3 positiven Lymphknoten wurden in die EC-Doc Studie (6xFEC/CMF vs. 4xEC-4xDocetaxel) randomisiert. Proteinexpression (ER, PR, HER2(+FISH), Ki-67, Ck5, EGFR) und Grading wurden zentral evaluiert (n=772). Molekulare Subtypen wurden anhand der beiden publizierten Ki-67 cut-offs (13,25% und 20%) analysiert. Ergebnisse: Patientenkollektive von Gesamt- und Substudie wiesen ahnliche Grundcharakteristika auf. Nach einer medianen Nachbeobachtungszeit von 64 Monaten war EC-Doc vs. FEC beim krankheitsfreien (5J-DFS:90% vs. 80%, p=0.006) und beim Gesamtuberleben (5J-OS:95% vs. 92%, p=0.022) uberlegen.5J-DFS war signifikant besser beim luminal A (ER/PR+/HER2-/Ki-67

Two principal pathways exist for the histogenesis of vulvar squamous cell carcinomas (SCC), one of them unrelated to human papillomaviruses (HPV). These HPV-negative vulvar SCC are observed predominantly in older women. We observed vulvar carcinomas in the same location below the clitoris and with similar clinical aspect in the younger woman. All SCC were HPV-negative. Delay in diagnosis and therapy was characteristic. The operative procedure and results were similar to the results of patients with SCC not located near the clitoris.

535 Background: Prosigna is a standardized test measuring expression levels of 50 classifier genes (PAM50) in formalin-fixed, paraffin-embedded (FFPE) breast tumor tissue using nCounter Technology ...

Background: Current diagnostic tools for breast cancer (BC), including screening, diagnostic breast imaging and biopsy, do not provide information about subtype classification. However, the subtype classification is crucial for the assessment of the recurrence risk and for the choice of optimal adjuvant treatment. A vast amount of data from recent research, clinical trials, and peer reviewed publications support the value of intrinsic subtyping based on gene expression analyses to assess prognosis and treatment options for patients with early BC. Trial design: The multicenter (n=8), prospective study examines whether the Prosigna™ test influences physician and patient adjuvant treatment selection over and above currently used prognostic factors. It also examines the impact of the test results on patients’ reported outcomes including their decisional conflict status, anxiety levels, and functional status. Prosigna™ is a standardized test measuring the expression levels of 50 classifier genes in formalin-fixed, paraffin-embedded tissue samples and provides a subtype classification based on the fundamental biology of individual patient’s tumor (intrinsic subtyping), as well as a prognostic score (risk of recurrence (ROR) score) that predicts the probability of cancer recurrence over 10 years. Eligibility criteria: Postmenopausal women with resected N0, estrogen-receptor-positive (ER) (by immunohistochemistry (IHC); >1% of stained tumor cells is considered positive), HER2-negative (IHC and/or in-situ fluorescence hybridization by local laboratory), early-stage invasive BC (T1-T2, pN0 (i+/mol+), M0). Patients must be able to give consent and must be eligible for treatment with adjuvant chemotherapy (Ctx) (ECOG performance status ≤1). Patients with non-invasive (e.g. Paget’s disease, DCIS), ER-negative or HER2-positive BC must not be included. Metastatic disease and contraindications for adjuvant Ctx (age, ECOG >1, significant comorbidities) are exclusion criteria. Patients unable to complete patient reported outcome surveys will be excluded. Specific aims: Primary endpoint is the proportion of patients whose choice of treatment is changed as a result of receiving the Prosigna™ result. Secondary endpoints include the proportion of patients whose choice of treatment is changed stratified by ROR groups (low, intermediate, high) and who have cancer recurrence risk proximal to the cutoff points between risk strata (± 5% from cutoff point). Investigators’ confidence in treatment recommendations before/after Prosigna™ results and change in patients’ decisional conflict status, anxiety levels, and functional status, stratified by cancer recurrence risk strata, will be investigated. Rate and severity of treatment-related adverse events stratified by whether patient received adjuvant Ctx and agreement in molecular subtyping between Prosigna™ and local IHC will be evaluated. Statistical methods: Sample size of 200 produces a one-sided 95% lower-limit CI with a distance from the sample proportion to the lower limit that is equal to 0.05 when the sample proportion is 0.25. Present and target accrual: A total of 200 patients will be included, current accrual is n=111 as of 3rd June 2014. Citation Format: Rachel Wuerstlein, Karl Sotlar, Burkhard Otremba, Oleg Gluz, Enrico Pelz, Daniel Hofmann, Ronald E Kates, Isabelle Witzel, Christian Schindlbeck, Wolfgang Janni, Christian Schem, Hans Tesch, Nadia Harbeck. Prospective observational study of clinical outcomes for the NanoString® technologies Prosigna™ test by the West German Study Group [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-2-03.

11018 Background: DNA copy number profiles identify patients with a defect in BRCA1 associated with a homologous recombination DNA repair defect. We previously showed that patients with a BRCA1-lik...

Background: Changes in tumor biology (e.g., hormone receptor (HR) / HER2 status or grading) between primary tumor (PT) and metastatic tissue (MT) could impact outcome and treatment choice following first recurrence in breast cancer (BC). Methods: PRIMET is a prospectively planned, retrospective multicenter quality assurance study comparing BC phenotype in tissue from PT, involved lymph nodes (LN) of primary disease, and disease recurrence (DR). PRIMET comprises 635 patients from WSG and DETECT trial groups (11 centers), whose BC was diagnosed between 1980 and 2010; follow-up continued until mid-2012. Patients with unilateral primary BC suffering subsequent local-regional and / or distant DR (LDR / DDR) were included. Clinical data including ER, PR, HER2, and grade were obtained from a systematic chart review in PT and DR; in two centers, these factors were also measured in LN by central pathology. Dependence of post-recurrence survival (PRS) on changes in tumor biological factors was analyzed. Results: Data from 635 patients (including 592 cM0, of whom 46% had LDR only) were available for analysis. Median follow-up in patients alive at analysis was 101 months. Considering cM0 patients, median overall survival (OS) was 176 months; median recurrence-free survival (RFS) was 48 months (DDR present: 45 months; LDR only: 50 months). Median PRS was 59 months (DDR present: 45 months; LDR only: 127 months). In patients with first DR within 18 months, median PRS was 29 months, in others 79 months. HR status in PT/MT was: 61.5% (+/+), 13.2% (+/-), 5.5% (-/+) 19.8% (-/-). Of the HR “switches” in either direction with LN biopsy available, about half already occurred in lymph nodes. HER2 status in PT/MT was: 14.6% (+/+), 6.7% (+/-), 14.9% (-/+) 63.8% (-/-). With LN biopsy available, most losses of HER2 overexpression were already observed in LN tissue, whereas acquired HER2 overexpression was observed in about half of LN biopsies. Triple negative (TN: HR-, HER2-) percentages were 74.4% (non-TN/non-TN), 9.0% (non-TN/TN), 6.1% (TN/non-TN), 10.5% (TN/TN). Compared to HR+/+, loss of HR+ status (HR+/-) was significantly associated with poorer PRS (hazard ratio: 1.62; p = 0.01). Significantly better PRS was associated with a switch from G3 to G1/2 (hazard ratio: 0.47; p = 0.02). Tumors that switched to TN or that lost HER2 overexpression showed trends toward poorer PRS. Persistent TN was associated with poorer PRS than other combinations. Among patients with DDR, metastasis in bone only was associated with better PRS than primary or visceral (CNS, lung, liver, etc.) metastasis. Among patients with visceral metastasis, negative HR status in metastasis was associated with poorer survival than in HR+/+ not only for HR-/- (p = 0.02), but also for HR+/- (p = 0.04). Conclusions: Tumor biology of primary and metastatic tissue differed in a substantial fraction of patients (HR: 19%; HER2: 22%, TN: 18%); more than half of all changes occurred already in LN. Status changes particularly loss of HR+ status, had significant prognostic impact. We can expect a switch in HR or HER2 status (or both) in about 38% of metastatic tissue biopsies, with presumably important clinical therapeutic consequences, in particular regarding targeted therapies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-04-02.

1092 Background: Potential markers for adjuvant taxane-based chemotherapy (CTx) in early, intermediate-risk BC include histologic grade (HG), Ki-67, Genomic Grade (GG) or molecular classification. The randomized EC-Doc trial demonstrated improvements in DFS and OS for EC-Doc vs. FEC in patients with 1-3 positive LN. Methods: Centrally assessed protein expression data by IHC, histology/HG (n=772) and GG (n=476) were obtained. Luminal A/B classes were defined as: ER/PR+/KI-6720% and/or HER2+. Correlations/concordance of these factors were estimated; impact on DFS and value for predicting taxane-based CTx benefit was assessed. Results: Low, equivocal and high GG (GG-1/-EQ/-3) categories were observed among 54 (11%); 60 (13%); 358 patients (76%) and associated with decreasing 5-yr-DFS rates of 100%, 92% and 82% (p < 0.001).There is only 60% concordance between local (L)/central(C) HG assessments and 63% between GG and C-HG. 37.7% of GG-3 tumors were L- HG3 vs. 72% C-HG3; 79% of C-HG2 and 83% of L-HG2 tumors were re-classified (56-71% to GGI3). Only 5.6-6% of GG1 were HG1 by L/C-HG respectively.GG was prognostic only in L-HG subgroups.In univariate subgroup analyses, EC-Doc was significantly superior to FEC: C-G3 (HR=0.58, 0.39-0.93), high Ki-67 (HR=0.55, 0.32E0.92) and GG-3 (HR=0.58, 0.34-0.99) subgroups. In multivariate analyses of HR+ disease (including age, therapy, GGI category, tumor size, LN status, central/local HG, Ki-67, HER2), either C-HG3 / high Ki-67 (as dichotomous variables) or C-HG3 / GGI (as continuous variable) were identified as independent prognostic factors.In interaction analysis, only C-HG, luminal A subtype and interaction of luminal-B/therapy were significant. If local HG was included instead of C-HG, only GG was as independent prognostic factor. Conclusions: These data support GGI as independent prognostic factor in early HR+ BC and as predictive marker regarding taxane benefit by univariate analysis. There is heterogeneity between L/C-HG and GGI. C-HG and Ki-67 assessment appear similarly informative. A predictive effect regarding benefit of taxane-containing CTx was seen in the IHC-luminal B subtype.

The phase retardation of light induced by the birefringent parts of the human retina in vivo is measured with an electro-optical ellipsometer using the principle of confocal imaging. A scanning unit allows to examine an area of 25 degrees by 12.5 degrees on the retina with a resolution of 256 by 128 points with both, incident and exit beam transmitting the cornea at a fixed position. Due to this fixed beam position the Muellermatrix of the cornea can be calculated using light which is specularly reflected on blood vessels lying above the nerve fiber layer of the retina. The obtained images show a homogenous radial distribution of the retinal retardation around the fovea without the appearance of the so called Haidinger brushes. The areas with the thickest nerve fiber layers, the arcuate bundles, appear in their typical arc and were measured quantitatively. In addition, an alternative method for the compensation of corneal birefringence is evaluated by focusing the light beam onto the surface of the lens. Hereby, the measured area in the center of the cornea is 3 X 0.75 mm2.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

10625 Background: Patients with hormone receptor positive breast cancer and 1-3 positive lymph nodes (LN) belong to the intermediate risk-group. Among these patients chemo-endocrine therapy may be ...

(1992). A review of “Earth's Nature from Space”. Edited by N. P. KozLov. (Rotterdam: A. A. Balkema, 1991.) [Pp. 275.] Price £47.00. International Journal of Remote Sensing: Vol. 13, No. 17, pp. 3365-3365.

The first-order theory T of two permutations which commute is investigated and its decidability is proved. Moreover, we show that the computational complexity of the decision algorithm for SAT( T )—on NTM's and ATM's—is the same (for upper and lower bounds) as that of the theory of one permutation.

Preference for a 0.1% solution of sodium saccharin was assessed in a two-bottle, saccharin versus water, preference test. Animals were adult mice from four inbred strains (BAlb/cJ; C57BL/6J; Is/Bi; 101BAg/Rl), both reciprocal F1 crosses of BAlb with C57, and a hetergeneous generation formed by crossing F1 with wild trapped mice. Individuals from the 101 strain demonstrated no preference for saccharin or water while the other inbred strains preferred saccharin. No sex or maternal effect was detected. Heritability (h2) and coefficient of genetic determination (CGD) was estimated by alternative methods. The CGD was between 0.81 and 0.94 ± 0.024; h2 = 0.55 to 0.68. This high degree of genetic involvement suggests that genotype is a major determinant of individual differences in saccharin preference.

The State University of New York (SUNY) Learning Network (SLN) is the online instructional program created for the 64 colleges and nearly 400,000 students of SUNY. The foundation of the program is freedom from schedule and location constraints for our faculty and students. The primary goals of the SLN are to bring SUNY's diverse and high-quality instructional programs within the reach of learners everywhere, and to be the best provider of asynchronous instruction for learners in New York State and beyond. We believe that these goals cannot be achieved unless faculty receives appropriate support.This paper will examine factors that have contributed to the high level of faculty satisfaction we have achieved in the SLN. The analysis will be done on several levels. This first section will look at the SLN at a program-wide level and will provide information regarding the systemic implementation of our asynchronous learning environment.The second section examines issues that contribute to on-line teaching satisfaction from a faculty-development and course-design perspective. This section will present the evolution of the four-stage faculty development process and a seven-step course design process that was developed by SLN and comment on lessons learned.The third section presents results from the SLN Faculty Satisfaction Survey conducted in spring 1999. This section examines factors from a quantitative analysis that significantly contributes to faculty satisfaction with online teaching and offers recommendations for course and program design based on these factors.The fourth section examines faculty satisfaction at the level of individual institutions with examples from specific courses. This section will introduce the reader to local implementation of SLN courses at two college programs in the SUNY system: the Department of Educational Theory and Practice at the University at Albany (UA), and the Internet Academy (IA) of Herkimer County Community College (HCCC). These case studies present and examine important evidence of faculty satisfaction from a single-institution and individual-faculty perspective.

This paper is a follow-up study to a preliminary investigation of teaching presence in the State University of New York Learning Network (SLN). In the present studywe review ongoing issues of pedagogy and faculty development, and their relationship to student satisfaction, and reported learning in SLN. We provide an overview of the SLN program,and summarize a conceptual framework for our current research on higher education, online learning environments. This framework integrates research on how people learn, with principles of good practice in higher education and recent research on learning in asynchronous learning networks (ALNs) in higher education. We also present resultsof a follow-up study on one aspect of the model, “Teaching Presence”.The SUNY Learning Network is a proud recipient of two Sloan-C Awards, the 2001 Award for Excellence in ALN Faculty Development and the 2002 Award for Excellence in ALN Programming. We believe that it is no coincidence that SLN was recognized in this order; that is to say, we feel our efforts to create a systematic faculty development program has allowed us to create an outstanding program of online courses and degrees. A clear vision regarding the prerequisites for a high quality online learning environment, especially prerequisites related to faculty development, is essential to building effective ALN programs. As this special edition of JALN is dedicated to such efforts we would like to focus on our model for learning environments design and share results of research on specific aspects of the model. In past studies we have argued that student-faculty and student-student interaction are among the variables most strongly correlated with student satisfaction and reported learning. In the present study, we focus on one aspect of our model for online learning environments and examine interaction more deeply. Building upon the work of Anderson and colleagues we examine the kinds of activities that comprise and sustain productive interaction. These researchers have categorized interactions that occur in asynchronous learning environments that encourage knowledge creation and identify online behaviors and processes that approximate (and may improve upon) those that occur in face-to-face settings. We look at a key element of their work, “teaching presence,” and present results of a follow-upstudy examining students’ perceptions of this constellation of online faculty behaviors. We also identify the components of teaching presence that correlate most highly with student satisfaction and reported learning.